amphotericin-b and Neutropenia

The purpose of this study is to evaluate the efficacy of prophylactic use amphotericin B in patients with hematologic disorders complicated by neutropenia. We searched the PubMed, EMBASE, The Cochrane Library, CBM, CNKI, VIP and WanFang Data database and the China Clinical Trials Registry ( www.chictr.org.cn ) to collect randomized controlled trials (RCTs) of amphotericin B for patients with hematologic disorders complicated by neutropenia from inception to May 2023. The Cochrane risk-of-bias tool for RCTs was used to assess the bias risk of the included studies. The meta-analysis was performed using RevMan 5.3 software. A total of 6 studies with a total of 1019 patients were included. The results of the meta-analysis showed that the treatment group was superior to the control group in terms of the fungal infection rate, and the differences were statistically significant [RR = 0.47, 95% CI (0.32, 0.69), P < 0.0001]. There was no significant difference between the two groups in terms of the mortality [RR = 0.87, 95% CI (0.61, 1.23), P = 0.43] and the incidence of colonization [OR = 0.51, 95% CI (0.25, 1.03), P = 0.06]. The evidence shows that amphotericin B prophylactic use for patients with hematologic disorders complicated by neutropenia can decrease the fungal infection rate. However, there was no significant difference in reducing mortality or the incidence of colonization. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusion.

Topics: Amphotericin B; China; Databases, Factual; Hematologic Diseases; Humans; Neutropenia

Cases of invasive Trichosporon infections have increasingly emerged; it is now the second leading cause of yeast bloodstream infections after Candida spp., particularly in the immunosuppressed population, where it often causes breakthrough fungemia with high mortality.. We present a case report of a breakthrough Trichosporon asahii infection in a patient with acute myeloid leukemia and review all of the cases of breakthrough Trichosporon spp. infections published in the literature to date.. We extracted 68 cases of breakthrough Trichosporon spp. infections, wherein 95.5% patients had hematological malignancy, 61.8% of them occurred in the presence of echinocandins, 22% of triazoles, 13.2% of amphotericin and 3% of other combinations of antifungals. The most prevalent manifestation was fungemia (94%); 82.8% of these were associated with the presence of a central venous catheter. The overall mortality was 68.7%; the patients who survived recovered from the neutropenic event.. Invasive trichosporonosis is an acute fatal condition that occurs in immunosuppressed patients, usually under antifungal selective pressure. Typically, neutropenia and its underlying diseases are associated with adverse outcomes.

Topics: Adult; Amphotericin B; Antifungal Agents; Central Venous Catheters; Echinocandins; Fungemia; Hematologic Neoplasms; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Middle Aged; Mortality; Neutropenia; Triazoles; Trichosporon; Trichosporonosis; Voriconazole

Emergent fungal infections are uncommon conditions which frequently lead to death. To our knowledge, only a few cases of invasive infection by Cystobasidium minutum (previously known as Rhodotorula minuta) have been reported. Moreover, several factors are responsible for deep site infections, such as catheter-related fungemia. This report describes the first case report of Cystobasidium minutum causing fungemia in Brazil. The pathogens fungemia was demonstrated by catheter and blood culture-proven, and both yeasts were identified by sequences of D1/D2 rDNA region. After the end of antifungal therapy and catheter removal, a second blood culture was found to be negative and the clinical signs and symptoms of the patient improved.

Topics: Amphotericin B; Antifungal Agents; Basidiomycota; Brazil; Catheter-Related Infections; Deoxycholic Acid; DNA, Fungal; DNA, Ribosomal; Drug Combinations; Female; Fungemia; Humans; Immunocompromised Host; Microbial Sensitivity Tests; Middle Aged; Neoplasms; Neutropenia

Mucormycosis is a severe infection that affects a variety of patients, including immunocompromised children and neonates. Given improved survival rates from advances in the treatment of malignancies, the population at risk for mucormycosis is increasing. We conducted a systematic review of cases of mucormycosis in children in the English-language literature reported between August 2008 and June 2017 and analyzed the clinical characteristics, diagnosis, management, and outcome of those infections. The most common underlying diagnoses included neutropenia (41%), hematologic malignancy (39%), prematurity (13%), and hematopoietic stem cell transplant (11%). Sinus disease (28%) and disseminated disease (24%) were the most common presentations. Rhizopus spp were the most common organisms isolated (22%). Amphotericin B remains the backbone of treatment and was prescribed in 86% of these cases. The resulting mortality rate remains high (32%). We provide here the results of a literature review of mucormycosis in children, including its epidemiology and clinical manifestations, and describe current advances in its diagnosis and treatment.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Databases, Factual; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Male; Mucormycosis; Neutropenia; Paranasal Sinus Diseases; Rhizopus; Treatment Outcome

Trichosporonosis is an emerging and often fatal opportunistic fungal infection in immunocompromised patients, particularly those with hematologic malignancy, but data in children are lacking.. We report here 3 cases of invasive infection caused by Trichosporon asahii in pediatric patients with acute lymphoblastic leukemia at Texas Children's Hospital in Houston, Texas. We also conducted a literature review and identified 16 additional reports of pediatric patients with invasive T asahii infection and an underlying malignant or nonmalignant hematologic disorder.. Of the 19 cases of invasive T asahii infection, the most commonly reported underlying hematologic disorder was acute lymphoblastic leukenia (47%), followed by acute myelogenous leukemia (21%). Most of the patients (94%) had neutropenia, defined as an absolute neutrophil count of <500 cells/mm3. Antifungal prophylaxis information was available in 6 of the 19 cases, and micafungin use was reported in 5 cases. Treatment regimens frequently included voriconazole monotherapy (47%) or the combination of an azole antifungal with amphotericin B (35%). The mortality rate was 58%.. Recognizing that echinocandins, which are increasingly used for prophylaxis in patients with a hematologic malignancy, are not active against Trichosporon species is of critical importance. The recommended first-line therapy for trichosporonosis is voriconazole, but successful outcome depends largely on the underlying immune status of the host.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Drug Therapy, Combination; Echinocandins; Female; Humans; Immunocompromised Host; Invasive Fungal Infections; Leukemia, Myeloid, Acute; Lipopeptides; Male; Micafungin; Neutropenia; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Trichosporonosis; Voriconazole

Invasive fungal disease is a serious infectious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Exserohilum rostratum is a species causing phaeohyphomycosis, which rarely causes invasive disease in humans. We treated a case of sinusitis caused by E. rostratum after cord blood transplantation (CBT). A 60-year-old man with myelodysplastic syndrome, who had a medical history of an operation to correct deviation of the nasal septum, developed sinusitis caused by E. rostratum under prolonged profound neutropenia after a second CBT because of the graft rejection of the first transplantation. Liposomal amphotericin B improved the sinusitis. A literature review revealed nine reported cases of sinusitis caused by E. rostratum, including our case. Although five cases had severe neutropenia at onset (HSCT recipients, n = 2; aplastic anemia, n = 3), the remaining four had no preexisting immunosuppressive conditions. However, three of the four patients had preexisting nasal diseases with or without a history of surgery, as in our case. Excluding our case, the outcome was fatal in five neutropenic patients, whereas the four patients without neutropenia recovered. Although sinusitis caused by E. rostratum is rare, E. rostratum should be recognized as a possible pathogen causing sinusitis in highly immunosuppressed patients such as HSCT recipients. Preexisting nasal disease and/or nasal surgery could be risks for this infection.

Topics: Adolescent; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Ascomycota; Bone Marrow Transplantation; Child; Child, Preschool; Female; Fetal Blood; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses; Myelodysplastic Syndromes; Neutropenia; Sinusitis; Young Adult

Invasive aspergillosis (IA) is still one of the leading causes of morbidity and mortality in hematological patients, although its outcome has been improving. Prolonged and profound neutropenia in patients receiving intensive chemotherapy for acute leukemia and stem cell transplantation is a major risk factor for IA. Allogeneic stem cell transplant recipients with graft-versus-host disease and corticosteroid use are also at high risk. Management in a protective environment with high efficiency particular air (HEPA) filter is generally recommended to prevent aspergillosis in patients with prolonged and profound neutropenia. Antifungal prophylaxis against Aspergillus species should be considered in patients with past history of aspergillosis or colonization of Aspergillus species, at facilities with high incidence of IA and those without a protective environment. Early diagnosis and prompt antifungal treatment is important to improve outcome. Imaging studies such as computed tomography and biomarkers such as galactomannan antigen and β-D-glucan are useful for early diagnosis. Empirical antifungal treatment based on persistent or recurrent fever during neutropenia despite broad-spectrum antibiotic therapy is generally recommended in high-risk patients. Alternatively, a preemptive treatment strategy has recently been proposed in the context of progress in the early diagnosis of IA based on the results of imaging studies and biomarkers. Voriconazole is recommended for initial therapy for IA. Liposomal amphotericin B is considered as alternative initial therapy. Combination antifungal therapy of echinocandin with voriconazole or liposomal amphotericin B could be a choice for refractory cases.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Biomarkers; Echinocandins; Hematologic Neoplasms; Humans; Neutropenia; Opportunistic Infections; Risk Factors; Stem Cell Transplantation; Tomography, X-Ray Computed; Voriconazole

Invasive fungal sinusitis (IFS) represents an often fatal condition within the pediatric population. In an effort to characterize demographics, treatment modalities, and prognostic factors, we performed a systematic review.. We systematically reviewed EMBASE, Medline, TRIPdatabase, SCOPUS and the Cochrane database for invasive fungal nasal and sinus infections limited to individuals <18 years of age. Case series including 3 or more patients were included. Demographics, treatment and outcomes were analyzed using R Gui statistical software.. Twelve studies met inclusion criteria (103 patients). There was male preponderance of 48.5% with median age of 11 years old. Majority of patients had underlying leukemia (44.6%). Aspergillus was the predominant organism (47%). Isolated nasal findings occurred in 14% of patients and nasal findings occurred in 49% overall. Absolute neutrophil count (ANC) of immunocompromised patients was below 600 in most patients (99%). Average and median length of neutropenia was 2 weeks. All patients were prescribed amphoterocin with 50% as single medicinal therapy. Surgery occurred in 82.8% of cases. The mortality rate was 46%. Univariate analysis identified presenting with facial pain as a negative predictor of overall mortality (OR 0.296, 95% CI: 0.104-0.843, p < 0.05).. Mortality remains high in pediatric patients with IFS. An ANC of <600 occurred in the majority of immunocompromised patients at a duration of 2 weeks. Presenting with facial pain was a negative predictor of mortality. Many studies label this condition as invasive fungal sinusitis; however, approximately one seventh presented with only nasal findings and half overall had nasal involvement.

Topics: Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillosis; Burkitt Lymphoma; Candidiasis, Invasive; Child; Facial Pain; Female; Fusariosis; Humans; Immunocompromised Host; Leukemia; Male; Mucormycosis; Mycoses; Neutropenia; Otorhinolaryngologic Surgical Procedures; Prognosis; Retrospective Studies; Sinusitis

The risk of invasive fungal infections (IFIs) is extremely high in patients with hematological malignancies due to the prolonged and profound neutropenia and immunosuppression after chemotherapy and hematopoietic stem cell transplantation. There has been increasing interest in mucormycosis despite its relatively uncommon occurrence, because occasional breakthrough infections have been observed under anti-aspergillus prophylaxis. The aggressive nature of mucormycosis easily leads to high mortality because of delays in diagnosis and incorrect treatment decisions, which are due in part to lack of adjunctive diagnostic tools and having similar clinical and radiological features with aspergillosis. The only currently available antifungals against Mucorales in Japan are amphotericin B formulations. Thus, comprehensive therapeutic strategies, including surgery, should be considered in order to achieve a successful outcome.

Topics: Amphotericin B; Didanosine; Early Diagnosis; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Lung Diseases, Fungal; Mucormycosis; Neutropenia; Risk; Surgical Procedures, Operative

Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy is used both empirically and therapeutically in these patients.. To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia.. Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 1 2014), MEDLINE (to January 2014). Letters, abstracts and unpublished trials were accepted. Contact was made with trial authors and industry.. Randomised clinical trials comparing voriconazole with amphotericin B or fluconazole.. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted independently by two review authors.. Three trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infection) in neutropenic cancer patients (849 patients, 58 deaths). The second trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). The third trial compared fluconazole to voriconazole for prophylaxis of fungal infections in patients receiving allogeneic stem cell transplantation (600 patients, number of deaths not stated). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the trial authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from the analysis by the trial authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication to counter side effects and replacement of electrolytes or use of salt water. This choice of comparator resulted in a marked difference in the duration of treatment on the trial drugs (77 days with voriconazole versus 10 days with amphotericin B) and precluded meaningful comparisons of the benefits and harms of the two drugs. The third trial failed to find a difference in fungal free survival or invasive fungal infections at 180 days when voriconazole was compared to fluconazole.. Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of fungal infections in neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions. For prophylactic fungal treatment in patients receiving allogeneic stem cell transplantation, there was no difference between voriconazole and fluconazole regarding fungal free survival or invasive fungal infections.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Fluconazole; Humans; Liposomes; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Pyrimidines; Randomized Controlled Trials as Topic; Triazoles; Voriconazole

Patients with cancer who are treated with chemotherapy or receive a bone marrow transplant have an increased risk of acquiring fungal infections. Such infections can be life-threatening. Antifungal drugs are therefore often given prophylactically to such patients, or when they have a fever.. To compare the benefits and harms of lipid soluble formulations of amphotericin B with conventional amphotericin B in cancer patients with neutropenia.. We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles.. Randomised clinical trials comparing lipid soluble formulations of amphotericin B with conventional amphotericin B.. The two review authors independently assessed trial eligibility and risk of bias and abstracted data.. We found 13 trials (1960 patients). Lipid-based amphotericin B was not more effective than conventional amphotericin B on mortality (relative risk (RR) 0.5; 95% confidence interval (CI) 0.64 to 1.14) but decreased invasive fungal infection (RR 0.65; 95% CI 0.44 to 0.97), nephrotoxicity defined as a 100% increase in serum creatinine (RR 0.45; 95% CI 0.37 to 0.54), and number of dropouts (RR 0.78; 95% CI 0.62 to 0.97).For the drug used in most patients, AmBisome (4 trials, 1214 patients), there was no significant difference in mortality (RR 0.77; 95% CI 0.54 to 1.10) whereas it tended to be more effective than conventional amphotericin B on invasive fungal infection (RR 0.63; 95% CI 0.39 to 1.01, P value 0.053).AmBisome, amphotericin B in Intralipid (6 trials, 379 patients), amphotericin B colloidal dispersion (ABCD) (2 trials, 262 patients), and amphotericin B lipid complex (ABLC) (1 trial, 105 patients) all decreased the occurrence of nephrotoxicity, but conventional amphotericin B was rarely administered under optimal circumstances.. It is not clear whether there are any advantages of lipid-based formulations if conventional amphotericin B is administered under optimal circumstances, and their high cost prohibits routine use in most settings. There is a need for large trials comparing lipid-based formulations of amphotericin B with conventional amphotericin B given in the same dose, with routine premedication for prevention of infusion-related toxicity, and with supplementation with fluid, potassium, and magnesium for prevention of nephrotoxicity.

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Humans; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic

Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or empirically to patients with persistent fever.. To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia.. We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles.. Randomised clinical trials comparing fluconazole with amphotericin B.. The two review authors independently assessed trial eligibility and risk of bias, and abstracted data.. Seventeen trials (3798 patients, 381 deaths) were included. In two large three-armed trials, results for amphotericin B were combined with results for nystatin in a 'polyene' group. Because nystatin is an ineffective drug in these circumstances, this approach creates a bias in favour of fluconazole. Furthermore, most patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. There was overlap among the 'polyene' trials but we were unable to obtain any information from the trial authors or from Pfizer, the manufacturer of fluconazole, to clarify these issues. There were no significant differences in effect between fluconazole and amphotericin B, but the confidence intervals were wide. More patients dropped out of the study when they received amphotericin B, but as none of the trials were blinded decisions on premature interruption of therapy could have been biased. Furthermore, amphotericin B was not given under optimal circumstances, with premedication to reduce infusion-related toxicity, slow infusion, and with fluid, potassium and magnesium supplements to prevent nephrotoxicity. The major harms were hepatic impairment and gastrointestinal adverse effects with fluconazole and infusion-related toxicity, renal impairment and gastrointestinal adverse effects with amphotericin B. For the 2011 and 2014 updates no additional trials were identified for inclusion.. Amphotericin B has been disfavoured in several of the trials through their design or analysis, or both. Since intravenous amphotericin B is the only antifungal agent for which an effect on mortality has been shown, and since it is considerably cheaper than fluconazole, it should be the preferred agent.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Confidence Intervals; Fluconazole; Humans; Injections, Intravenous; Mycoses; Neoplasms; Neutropenia; Nystatin; Odds Ratio; Randomized Controlled Trials as Topic

Treatment with Amphotericin B (AmB) deoxycholate, which is still used widely, particularly in low-resource countries, has been challenged due to nephrotoxicity. We sought to study whether continuous infusion of AmB deoxycholate reduces nephrotoxicity retaining, however, the effectiveness of the drug.. PubMed and Scopus databases were systematically searched to identify studies comparing the outcomes of patients receiving 24-h infusion of AmB ("continuous group") and those receiving 2-6-h infusion of AmB ("conventional group"). Nephrotoxicity and all-cause mortality were the primary outcomes of the review, while treatment failure was the secondary outcome.. Five studies met the inclusion criteria; one randomized controlled trial, two prospective cohort studies, and two retrospective cohort studies. The majority of patients were neutropenic with an underlying hematologic malignancy. All 5 studies (392 patients) provided data regarding the development of nephrotoxicity. A non-significant trend towards lower nephrotoxicity was observed for patients receiving continuous infusion of AmB compared with those receiving conventional infusion [RR = 0.61 (95% CI 0.36, 1.02)]. Four studies (365 patients) provided data regarding mortality; no relevant difference was detected between patients receiving continuous and those receiving conventional infusion of AmB [RR = 0.81 (95% CI 0.36, 1.83)]. Data on treatment failure of the two methods of administration was insufficient for meaningful conclusions.. The available evidence from mainly non-randomized studies suggests that continuous infusion of AmB deoxycholate might offer an advantage over the conventional infusion regarding the development of nephrotoxicity, without compromising patient survival. Further randomized studies are needed to investigate this issue.

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Hematologic Neoplasms; Humans; Infusions, Intravenous; Kidney Diseases; Mycoses; Neutropenia; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Treatment Outcome

Candidemia and invasive candidiasis (CIC) is associated with considerable morbidity and mortality, with a paucity of controlled data in neutropenic patients. A systematic review was conducted of available data for the treatment of CIC during neutropenia. A structured OVID search of multiple databases was performed. Data from randomized controlled trials of CIC and of empirical antifungal therapy in febrile neutropenic patients was included. A total of 17 trials randomizing 342 neutropenic patients were included. Eight of the studies compared amphotericin B (AmB) to other non-polyene antifungal agents. Pooling of results favored use of comparator compounds (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.42-1.29). To strengthen our analysis, a pre-planned sensitivity analysis was also conducted. Overall, there was a non-significant benefit in favor of non-polyene compounds. Across studies, echinocandins provided the benefit of favorable outcomes with fewest side effects and toxicity.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Echinocandins; Humans; Neutropenia; Odds Ratio; Randomized Controlled Trials as Topic

In 2009 the Infectious Diseases Society of America reviewed the guidelines on the treatment of candidemia in non-neutropenic patients. In this document the preferred treatment was either fluconazole or an echinocandin. Amphotericin-B formulations were considered an alternative. However, careful assessment of published data showed similar efficacy between these drugs.

Topics: Adult; Amphotericin B; Animals; Antifungal Agents; Candidemia; Echinocandins; Fluconazole; Fungal Proteins; Humans; Kidney Diseases; Neutropenia; Practice Guidelines as Topic; Treatment Outcome

Fusarium species are the second leading cause of disseminated mold infections in immunocompromised patients. The high mortality caused by such infections is attributed to the high resistance of Fusarium species to current antifungal agents. We report the first case of disseminated fusariosis after the use of alemtuzumab, an anti-CD52 monoclonal antibody, in a patient who presented with striking cutaneous and oral cavity lesions. Case reports of combination antifungal therapy for disseminated fusariosis in immunocompromised patients were reviewed. Among 19 published cases in the last 10 years plus this patient, the patients in 14 cases (70%) responded positively to combination antifungal therapy. A clinical response was achieved in seven cases before resolution of neutropenia.

Topics: Adult; Alemtuzumab; Amphotericin B; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antineoplastic Agents; Combined Modality Therapy; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Fever; Fusariosis; Fusarium; Granulocytes; Humans; Immunocompromised Host; Leukocyte Transfusion; Lymphoma, T-Cell, Cutaneous; Male; Microbial Sensitivity Tests; Neutropenia; Pyrimidines; Skin Neoplasms; Triazoles; Voriconazole

The proportion of patients with cancers who develop invasive fungal infections has increased dramatically over the past few decades. Most of these infections are diagnosed in patients with hematological malignancies, mainly in patients with acute myeloid leukemia and those undergoing allogeneic hematopoietic stem cell transplantation. For years deoxycolate amphotericin B has been considered the drug of choice for the treatment of invasive aspergillosis, but it has been outclassed by its lipid formulations and new triazoles (i.e. voriconazole), that produced better response rates; nonetheless recovery from neutropenia remains the most important factor influencing outcome.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Humans; Neutropenia; Pyrimidines; Triazoles; Voriconazole

Invasive fungal infections are associated with significant morbidity and mortality in children. Optimal treatment strategies are yet to be defined.. This review aims to systematically identify and summarise the effects of different antifungal therapies in children with proven, probable or suspected invasive fungal infections.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE (1966 to September 2008), EMBASE (1980 to September 2008) and CINAHL (1988 to September 2008) without language restrictions. We also handsearched reference lists and abstracts of conference proceedings and scientific meetings, and contacted authors of included studies and pharmaceutical manufacturers.. We included randomised clinical trials (RCTs) comparing a systemic antifungal agent with a comparator (including placebo) in children (one month to 16 years) with proven, probable or suspected invasive fungal infection.. Two review authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. We synthesised data using the random-effects model and expressed results as relative risks (RR) with 95% confidence intervals (CIs).. We included seven trials of antifungal agents in children with prolonged fever and neutropenia (suspected fungal infection) and candidaemia or invasive candidiasis (proven fungal infection). Four trials compared a lipid preparation of amphotericin B with conventional amphotericin B (395 participants), one trial compared an echinocandin with a lipid preparation of amphotericin B (82 participants) in suspected infection; one trial compared an echinocandin with a lipid preparation of amphotericin B in children with candidaemia or invasive candidiasis (109 participants) and one trial compared different azole antifungals in children with candidaemia (43 participants). No difference in all-cause mortality and other primary endpoints (mortality related to fungal infection or complete resolution of fungal infections) were observed. No difference in breakthrough fungal infection was observed in children with prolonged fever and neutropenia.When lipid preparations and conventional amphotericin B were compared in children with prolonged fever and neutropenia, nephrotoxicity was less frequently observed with a lipid preparation (RR 0.43, 95% CI 0.21 to 0.90, P = 0.02) however substantial heterogeneity was observed (I(2) = 59%, P = 0.06). Children receiving liposomal amphotericin B were less likely to develop infusion-related reactions compared with conventional amphotericin B (chills: RR 0.37, 95% CI 0.21 to 0.64, P = 0.0005). Children receiving a colloidal dispersion were more likely to develop such reactions than with liposomal amphotericin B (chills: RR 1.76, 95% CI 1.09 to 2.85, P = 0.02). The rate of other clinically significant adverse reactions attributed to the antifungal agent (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy; hypokalaemia and hepatotoxicity) were not significantly different. When echinocandins and lipid preparations were compared, the rate of clinically significant adverse reactions (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy) were not significantly different.. Limited paediatric data are available comparing antifungal agents in children with proven, probable or suspected invasive fungal infection. No differences in mortality or treatment efficacy were observed when antifungal agents were compared. Children are less likely to develop nephrotoxicity with a lipid preparation of amphotericin B compared with conventional amphotericin B. Further comparative paediatric antifungal drug trials and epidemiological and pharmacological studies are required highlighting the differences between neonates, children and adults with invasive fungal infections.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Candidiasis; Child; Child, Preschool; Echinocandins; Fever; Humans; Infant; Mycoses; Neutropenia; Randomized Controlled Trials as Topic

The growing use of antifungal agents in patients with febrile neutropenia points at combination therapy as a strategy to face the increasing incidence of fungal infections in this population. Likewise, the low efficacy of single-drug therapies calls for research on this approach. Combination therapies should focus on extending their activity to a wider range of microorganisms, considering the mechanisms of action of major known antifungal agents, and also on enhancing the individual effect of each drug alone. In vitro and in vivo findings suggest that combination therapy may be better than single-drug therapy with amphotericin B for the treatment of emergent pathogens in immunosuppressed patients. In order to implement combination treatments, knowledge of the sensitivity profile of most prevalent species is required.

Topics: Amphotericin B; Antifungal Agents; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Fever; Humans; Mycoses; Neutropenia

Liposomal amphotericin B (AmBisome) is a lipid-associated formulation of the broad-spectrum polyene antifungal agent amphotericin B. It is active against clinically relevant yeasts and moulds, including Candida spp., Aspergillus spp. and filamentous moulds such as Zygomycetes, and is approved for the treatment of invasive fungal infections in many countries worldwide. It was developed to improve the tolerability profile of amphotericin B deoxycholate, which was for many decades considered the gold standard of antifungal treatment, despite being associated with infusion-related events and nephrotoxicity. In well controlled trials, liposomal amphotericin B had similar efficacy to amphotericin B deoxycholate and amphotericin B lipid complex as empirical therapy in adult and paediatric patients with febrile neutropenia. In addition, caspofungin was noninferior to liposomal amphotericin B as empirical therapy in adult patients with febrile neutropenia. For the treatment of confirmed invasive fungal infections, liposomal amphotericin B was more effective than amphotericin B deoxycholate treatment in patients with disseminated histoplasmosis and AIDS, and was noninferior to amphotericin B deoxycholate in patients with acute cryptococcal meningitis and AIDS. In adults, micafungin was shown to be noninferior to liposomal amphotericin B for the treatment of candidaemia and invasive candidiasis. Data from animal studies suggested that higher dosages of liposomal amphotericin B might improve efficacy; however, in the AmBiLoad trial in patients with invasive mould infection, there was no statistical difference in efficacy between the standard dosage of liposomal amphotericin B 3 mg/kg/day and a higher 10 mg/kg/day dosage, although the standard dosage was better tolerated. Despite being associated with fewer infusion-related adverse events and less nephrotoxicity than amphotericin B deoxycholate and amphotericin B lipid complex, liposomal amphotericin B use is still limited to some extent by these adverse events. Both echinocandins were better tolerated than liposomal amphotericin B. The cost of liposomal amphotericin B therapy may also restrict its use, but further pharmacoeconomic studies are required to fully define its cost effectiveness compared with other antifungal agents. Based on comparative data from well controlled trials, extensive clinical experience and its broad spectrum of activity, liposomal amphotericin B remains a first-line option for empirical ther

Topics: Amphotericin B; Animals; Antifungal Agents; Antineoplastic Agents; Drug Administration Schedule; Drug Resistance, Fungal; Fever; Fever of Unknown Origin; Humans; Infusions, Intravenous; Mycoses; Neutropenia

Despite the systemic toxicity of amphotericin B (AMB), it still has a place in treatment or prophylactic regimes of fungal infections.. A strategy for minimizing the potential of systemic side effects is to bring it in direct contact with the body site most likely to be infected, such as the administration of AMB as an aerosol. Nebulized amphotericin has been used in humans since 1959. However, due to a lack of sufficient data regarding efficacy, its use is still not established. Little is known about the optimal dose, frequency, duration of administration, and the pharmacokinetics of inhaled AMB in humans.. In this review, published data regarding inhaled AMB are summarized, including available descriptions regarding preparation, dose, efficacy, and toxicity, and its place in therapy is discussed. The results from the studies that were reviewed in this article indicate that inhaled AMB may have a place in the prophylactic regimens of patients with prolonged neutropenia and in lung transplant recipients. Furthermore, nebulized (liposomal) AMB may have a place in the treatment of allergic bronchopulmonary aspergillosis (ABPA) in patients with corticosteroid-dependent ABPA.

Topics: Administration, Inhalation; Amphotericin B; Humans; Lung Transplantation; Mycoses; Nebulizers and Vaporizers; Neutropenia

Zygomycosis is an invasive fungal infection with extremely high mortality caused by filamentous fungi which belong to Class Zygomycetes (Rhizopus spp., Mucor spp., Cunninghamella spp., etc). Despite of the similarities of the ecological characteristics and of the patients' backgrounds, zygomycosis is much rarer than invasive aspergillosis. In addition to well known immunosuppressive risk factors (hematological malignancy, hematopoietic stem cell or solid organ transplant, prolonged neutropenia, corticosteroid, etc), diabetic ketoacidosis, iron overload, and administration of deferoxamine are specific factors predisposing zygomycosis. Rhinocerebral, pulmonary and disseminated disease is characteristic forms. The mainstay of the treatment is surgical resection, reversal of immunosuppressive factors, and administration of high-dose amphotericin B or its liposomal formulation. Because of the difficulty of culture detection and the absence of reliable serological diagnostic methods, premortem diagnosis and no delaying of effective treatment remain a challenge to physicians.

Topics: Amphotericin B; Antifungal Agents; Brain Diseases; Central Nervous System Fungal Infections; Diabetes Complications; Drug Delivery Systems; Humans; Immunocompromised Host; Iron Overload; Liposomes; Lung Diseases, Fungal; Neutropenia; Prognosis; Risk Factors; Surgical Procedures, Operative; Zygomycosis

Until relatively recently, the treatment available for invasive fungal infections in hematological patients consisted of amphotericin B and azoles. Each of these groups had limitations and secondary effects. The echinocandins are a new class of antifungal agent that has shown promising results in the treatment of numerous invasive fungal infections. Anidulafungin is a new echinocandin that, in addition to showing potent in vitro activity against Aspergillus spp. and Candida spp. (including fluconazole- and amphotericin B-resistant microorganisms), also provides some advantages over other candins. In humans, these drugs are degraded through biotransformation rather than a metabolic process. No drug interactions have been found. In hematological patients, anidulafungin would play a "potential" role as empirical therapy in febrile neutropenia, as is the case of caspofungin. Given the epidemiology of Candida infection in these patients, anidulafungin could be used as initial therapy in candidemia before starting treatment with oral flucozanole, if indicated by the fungigram. This drug would also be indicated in the treatment of invasive Aspergillus spp. infections in patients with hepatic or renal insufficiency or in those taking concomitant medications. The available in vitro studies also suggest an important role for this drug in combinations of antifungal agents. Given the excellent safety profile and absence of interactions of anidulafungin, this drug will undoubtedly be of great utility in the management of difficult-to-treat mycotic infections in hematological patients.

Topics: Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Azoles; Candidiasis; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Therapy, Combination; Echinocandins; Fungemia; Hematologic Diseases; Hematologic Neoplasms; Humans; Inactivation, Metabolic; Kidney Diseases; Liver Diseases; Mice; Neutropenia; Risk Factors

Topics: Amphotericin B; Antifungal Agents; Azoles; Drug Interactions; Echinocandins; Humans; Mycoses; Neutropenia

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus; Candida; Clinical Trials, Phase II as Topic; Cryptococcus; Drug Resistance, Fungal; Humans; Mycoses; Neutropenia; Randomized Controlled Trials as Topic

Disseminated Fusarium infection can cause significant morbidity and mortality in immunocompromised patients. We present a case of disseminated fusariosis in a patient with neutropenic fever successfully treated using both liposomal amphotericin B and voriconazole. Combination anti-fungal therapy may be considered for such patients, particularly for those failing single-drug therapy.

Topics: Aged; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Female; Fever; Fusarium; Humans; Immunocompromised Host; Liposomes; Male; Mycoses; Neutropenia; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Invasive fungal infections (IFI) are the main cause of infectious death in cancer patients, especially in hematological malignancies and hematopoietic transplant recipients. Current epidemiology is characterized by a predominance of IFI caused by molds, mainly aspergillosis, along with a emergence of hard-to-treat fungi such are Zygomicetes, Fusarium and Scedosporium. Voriconazole is a broad spectrum antifungal agent with oral and intravenous formulations, approved by the EMEA for the treatment of invasive aspergillosis, candidemia in non-neutropenic patients, IFI caused by fluconazole-resistant species of Candida as well as Scedosporium and Fusarium infections. However, its use in clinical practice is broader, as empirical antifungal treatment and as secondary prophylaxis. It should be kept in mind the possibility of breakthrough IFI, particularly zygomycosis, in patients treated with voriconazole for long periods.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Drug Resistance, Fungal; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Multicenter Studies as Topic; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Pyrimidines; Randomized Controlled Trials as Topic; Salvage Therapy; Spain; Triazoles; Voriconazole; Zygomycosis

Empirical antifungal therapy has been shown to decrease the number of documented fungal infections in the setting of persistent fever during neutropenia. For decades, amphotericin B deoxycholate has been considered the agent of choice for first-line therapy in this setting. New antifungal agents associated with less toxicity, including the lipid formulations of amphotericin, voriconazole, and caspofungin, are now available and are considered to be suitable alternative first-line agents. In order to ensure appropriate therapy, however, the clinician must consider not only the differences between these antifungals but also patient-specific factors before initiating treatment.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Clinical Trials as Topic; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Echinocandins; Fever; Humans; Immunocompromised Host; Kidney Diseases; Lipopeptides; Liposomes; Liver Diseases; Mycoses; Neutropenia; Pyrimidines; Triazoles; Voriconazole

Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy are used both empirically and therapeutically in these patients.. To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia.. MEDLINE and the Cochrane Library (May 2005). Letters, abstracts and unpublished trials were accepted. Contact to authors and industry.. Randomised trials comparing voriconazole with amphotericin B or fluconazole.. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by two authors independently.. Two trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infections) in neutropenic cancer patients (849 patients, 58 deaths). The other trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from analysis by the authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication and substitution with electrolytes and salt water to avoid handicapping this drug. This choice of comparator resulted in a marked difference in the duration of treatment on trial drugs (77 days with voriconazole versus 10 days with amphotericin B), and precludes meaningful comparisons of the benefits and harms of the two drugs.. Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Fluconazole; Humans; Liposomes; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Pyrimidines; Randomized Controlled Trials as Topic; Triazoles; Voriconazole

Zygomycoses are rare invasive mould infections which mainly occur in immunocompromised patients, especially during prolonged neutropenia. The high mortality rate is due to a high failure rate of both intravital diagnosis and treatment. Exact diagnosis requires microscopic examination and proof by culture. The treatment consists of amphotericin B and surgical debridement. We report four recent cases of zygomycosis among 89 patients with intensively treated acute leukaemia at our institution. Three cases were breakthrough infections since the patients were under voriconazole treatment prior to diagnosis of zygomycosis. Only one patient had premortal diagnosis (paranasal sinus infection) and showed clinical response with amphotericin B and surgical debridement. A review of the literature of these emerging fungal infections is given and is focused on patients with acute leukaemia. In addition, the importance of autopsy as a tool for quality control and epidemiological studies is pointed out.

Topics: Amphotericin B; Antifungal Agents; Female; Humans; Immunocompromised Host; Leukemia; Male; Middle Aged; Neutropenia; Pyrimidines; Triazoles; Voriconazole; Zygomycosis

Febrile neutropenic patients who receive antibiotics are at risk for fungal infections. This risk increases greatly with the length and severity of neutropenia. Because diagnostic tests for fungal infections lack sensitivity and specificity and because established fungal infections are associated with poor outcomes, empiric antifungal therapy is frequently given to patients with fever that persists despite antibacterial therapy. Early trials of empiric amphotericin B showed reductions in the number of invasive fungal infections and in related morbidity and mortality. However, as a result of infusion-related and renal adverse effects of amphotericin B, newer agents, such as lipid formulations of amphotericin B, extended-spectrum azoles, and echinocandins, have been developed. Although these alternatives have been associated with decreased toxicity, improved efficacy has not been clearly demonstrated. Although empiric antifungal therapy can prevent undetected breakthrough infections and morbidity associated with many fungal infections, its shortcomings include overtreatment, toxicity, and increased costs of unnecessary treatment. Recent studies have highlighted several questions in trial design and data interpretation. For example, what is the appropriate study design? Who should be enrolled in studies of empiric antifungal therapy? How should successful therapy be defined? These issues are reviewed to determine whether new antifungal agents should be evaluated for empiric use in patients with fever and neutropenia.

Topics: Amphotericin B; Antifungal Agents; Azoles; Chemistry, Pharmaceutical; Echinocandins; Fever of Unknown Origin; Fungal Proteins; Fungemia; Humans; Immunocompromised Host; Neutropenia; Peptides, Cyclic; Randomized Controlled Trials as Topic; Research Design

There is still no consensus on the efficacy of antifungal prophylaxis in neutropenic patients after more than 50 clinical trials.. This review evaluates the current evidence from all available meta-analyses of the use of intravenous amphotericin B, fluconazole and itraconazole for this indication.. Four systematic reviews with meta-analysis and one evidence-based review without meta-analysis were evaluated. Efficacy of fluconazole has been shown on short-term follow-up after allogeneic stem cell transplantation but only itraconazole was effective in neutropenic patients with haematological malignancies for prolonged prophylaxis after allogeneic stem cell transplantation. Direct comparison between fluconazole and itraconazole for this indication shows the superiority of itraconazole which was the only drug able to prevent invasive Aspergillus infections in our previously published meta-analysis of 13 trials and 3597 patients. Efficacy of itraconazole correlates closely with its dose; an effect was seen only in clinical trials using at least 400 mg/day oral solution or 200 mg/day intravenous solution. With this dose, invasive fungal infections were reduced by 53% and mortality from invasive fungal infections was reduced by 47% (P<0.05). Toxicity of itraconazole is rare and usually not severe and drug interactions are easily manageable.. Itraconazole is recommended for antifungal prophylaxis in high-risk neutropenic patients with haematological malignancies or for prolonged prophylaxis after allogeneic stem cell transplantation based on unambiguous evidence of efficacy and low toxicity from clinical trials and systematic reviews.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Hematologic Neoplasms; Humans; Itraconazole; Mycoses; Neutropenia; Stem Cell Transplantation

To evaluate the clinical characteristics of patients affected by hematologic malignancies who developed mucormycosis and to ascertain the factors which influenced the outcome following mycotic infection.. This was a retrospective study conducted over a 15-year period (1987-2001). The study included 59 patients with hematologic malignancies with a proven or probable mucormycosis admitted in 18 Hematology Divisions in tertiary care or university hospitals.. The most frequent sites of infection were lung (64%) and orbito-sinus-facial (24%); cerebral involvement observed in 19% of cases was always associated with other sites of infection. Antifungal treatment was empirically administered in 49 patients (83%); 7 patients underwent radical surgical debridement (12%). Therapy was successful for only 18 patients (37%). Forty-seven patients died within 3 months of the diagnosis of fungal infection: the cause of death was mucormycosis in 41 patients (87%) and progression of hematologic disease in 6 patients (13%). At univariate analysis, the factors that correlated with a positive outcome from infection were the following: male sex, amphotericin B treatment, neutrophil recovery from post-chemotherapy aplasia. At multivariate analysis, the only factor that significantly correlated with recovery from infection was the liposomal amphotericin B treatment.. Mucormycosis is a rare filamentous fungal infection that occurs most frequently in neutropenic patients with acute leukemia. It does not seem to have increased in recent years. Although a reduction of mortality has been observed recently, the mortality rate still remains high. Extensive and aggressive diagnostic and therapeutic procedures are essential in order to improve the prognosis in these patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Encephalitis; Female; Fungemia; Hematologic Neoplasms; Humans; Immunocompromised Host; Italy; Lung Diseases, Fungal; Male; Middle Aged; Mucormycosis; Neutropenia; Retrospective Studies; Risk Factors; Sinusitis; Treatment Outcome; Triazoles

We compared the safety and efficacy of liposomal amphotericin B with other formulations of amphotericin B and voriconazol as an empirical treatment of febrile neutropenia.. Several randomized controlled clinical trials, designed to evaluate the safety and/or efficacy of liposomal amphotericin B in the empirical treatment of febrile neutropenia, in comparison with other amphotericin B formulations or voriconazol, were identified by means of a search in MEDLINE, EMBASE and Cochrane Controlled Trials Register's data bases. American Society of Microbiology and American Society of Clinical Oncology abstracts, presented between 1999 and 2002, were also included in the search. Prior to data extraction, concepts like nephrotoxicity, infusion-related adverse events and efficacy (success rate and mortality) were defined.. Two studies comparing liposomal amphotericin B with conventional amphotericin B, one comparing liposomal amphotericin B with amphotericin B lipid complex and one comparing liposomal amphotericin B with voriconazol were included in the analysis. Patients treated with liposomal amphotericin B had lower nephrotoxicity than patients treated with other amphotericin B formulations or with conventional amphotericin B (RR = 0.49); conversely, no statistically significant differences with regard to voriconazol were observed. In terms of efficacy, mortality rate and therapeutic failure, patients treated with limposomal amphotericin B showed a slightly higher efficacy.. Liposomal amphotericin B is a lipidic formulation with a slightly higher efficacy than other amphotericin B formulations and voriconazol. In terms of nephrotoxicity, liposomal amphotericin B showed lower nephrotoxicity than other amphotericines while its safety rates were similar to those of voriconazol.

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Fever; Humans; Liposomes; Mycoses; Neutropenia; Pyrimidines; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Fungemia; Humans; Immunocompromised Host; Mycoses; Neoplasms; Neutropenia; Premedication; Randomized Controlled Trials as Topic; Risk Factors; Triazoles

Persistent or recurrent unexplained fever in neutropenic patients receiving antibiotics can be caused by invasive fungal infections, which are often difficult to diagnose. Early trials of empirical antifungal therapy with amphotericin B deoxycholate (AmB) documented reductions in the frequency of and the morbidity and mortality associated with invasive fungal infections. Because of AmB's infusional and renal toxicities, subsequent trials used newer, less toxic agents, such as the lipid formulations of AmB, the extended-spectrum azoles, and, more recently, the echinocandins. To date, alternatives to AmB have shown less toxicity, but improved efficacy has been less clear. Overall, empirical antifungal therapy can help prevent the morbidity associated with many fungal infections, eliminate concerns about diagnostic pitfalls, and prevent breakthrough undetected infections. However, its potential shortcomings are overtreatment, toxicity, and increased treatment-related costs when treatment is given to persons not needing it. Newer diagnostic tools are needed to target those most in need of antifungal therapy.

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Deoxycholic Acid; Drug Combinations; Fever; Fluconazole; Fungemia; Humans; Immunocompromised Host; Neutropenia; Opportunistic Infections

To determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) used in children with cancer reduce the rate of febrile neutropenia, hospitalization duration, documented infection rate, parenteral antibiotic duration, amphotericin B use, or infection-related mortality.. We included studies in this meta-analysis if their populations consisted of children, if there was randomization between CSFs and placebo or no therapy, if CSFs were administered prophylactically (before neutropenia or febrile neutropenia), and if chemotherapy treatments preceding CSFs and placebo or no therapy were identical. From 971 reviewed study articles, 16 were included.. The mean rate of febrile neutropenia in the control arms was 57% (range, 39% to 100%). Using a random effects model, CSFs were associated with a reduction in febrile neutropenia, with a rate ratio of 0.80 (95% CI, 0.67 to 0.95; P =.01), and a decrease in hospitalization length, with a weighted mean difference of -1.9 days (95% CI, -2.7 to -1.1 days; P <.00001). CSF use was also associated with reduction in documented infections (rate ratio, 0.78; 95% CI, 0.62 to 0.97; P =.02) and reduction in amphotericin B use (rate ratio, 0.50; 95% CI, 0.28 to 0.87; P =.02). There was no difference in duration of parenteral antibiotic therapy (weighted mean difference, -4.3; 95% CI, -10.6 to 2.0 days; P =.2) or infection-related mortality (rate ratio, 1.02; 95% CI, 0.34 to 3.06; P =.97).. CSFs were associated with a 20% reduction in febrile neutropenia and shorter duration of hospitalization; however, CSFs did not reduce infection-related mortality.

Topics: Adolescent; Amphotericin B; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Fever; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Infant; Infant, Newborn; Infections; Length of Stay; Male; Neoplasms; Neutropenia; Placebos; Randomized Controlled Trials as Topic; Treatment Outcome

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in neutropenic patients with leukemia and those undergoing hematopoietic stem cell transplant (HSCT). Two major IFIs are systemic candidiasis (including candidemia, chronic disseminated candidiasis and pneumonia) and invasive pulmonary aspergillosis. Recently, the incidence of the latter has been increasing. Three levels of diagnosis are specified in the Japanese guidelines for the diagnosis and treatment of IFIs. Proven fungal infections are diagnosed by histological/microbiological evidence of fungi at the site of infection or positive blood culture (fungemia). Clinically documented fungal infections are diagnosed by typical radiological findings such as halo sign on chest CT plus positive serological/molecular evidence of fungi such as Aspergillus galactomannan, beta-glucan or fungal DNA. Possible fungal infections are diagnosed by typical radiological findings or positive serological/molecular evidence of fungi. For patients with high risk such as those undergoing HSCT, antifungal prophylaxis using oral antifungal agents is recommended. For possible fungal infections, empiric therapy with fluconazole (FLCZ) or amphotericin B (AMPH) is recommended. For patients with proven fungal infections or clinically documented fungal infections, targeted therapy is warranted. In case of candidemia, the best choice is FLCZ (400 mg/day) or AMPH (0.5-0.7 mg/kg/day), and for invasive pulmonary aspergillosis, a higher dose of AMPH (1.0-1.5 mg/kg/day) is indicated. Micafungin (MCFG), recently licensed in Japan, is an active agent for both Candida and Aspergillus. This drug seems useful for empiric and targeted therapy of IFIs.

Topics: Amphotericin B; Aspergillosis; Candidiasis; Echinocandins; Fluconazole; Humans; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Micafungin; Neutropenia; Peptides, Cyclic; Practice Guidelines as Topic

Candidiasis and aspergillosis are the most common fungal infections in hematopoietic stem cell transplant recipients and other hematology/oncology patients. Strategies for reducing the morbidity and mortality associated with these infections include antifungal prophylaxis, empiric therapy in patients with persistent fever and neutropenia, and preemptive therapy. Antifungal therapies include amphotericin B deoxycholate, lipid formulations of amphotericin B, the triazoles (fluconazole, itraconazole, and voriconazole), and the echinocandins (caspofungin and the investigational agents micafungin and anidulafungin). Fluconazole is a reasonable choice for the treatment of invasive candidiasis if the patient has not previously received a triazole and the institution has a low incidence of triazole resistance. If resistance is a concern, an echinocandin, such as caspofungin, is an appropriate option. Voriconazole may be the initial choice in most patients with invasive aspergillosis. If patients are intolerant of or refractory to conventional therapy, effective alternatives include a lipid formulation of amphotericin B or an echinocandin.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Hematopoietic Stem Cell Transplantation; Humans; Liposomes; Mycoses; Neoplasms; Neutropenia; Peptides, Cyclic; Randomized Controlled Trials as Topic; Survival Analysis; Triazoles

Invasive fungal infection is an increasing source of morbidity and mortality in patients with hematologic malignancies, particularly those with prolonged and severe neutropenia (absolute white blood cell count < 100/microL). Early diagnosis of invasive fungal infection is difficult, suggesting that antifungal prophylaxis could be the best approach for neutropenic patients undergoing intensive myelosuppressive chemotherapy. Consequently, antifungal prophylaxis has been extensively studied for more than 20 years. Nonabsorbable polyenes reduce superficial mycoses but are not effective in preventing or treating invasive fungal infections. Intravenous amphotericin B and the newer azoles were used in numerous clinical trials, but the value of antifungal prophylaxis in defined risk groups with cancer is still open to discussion. Recipients of allogeneic stem cell transplants and patients with a relapsed leukemia are high-risk patient populations. In addition, certain risk factors are well defined, for example, neutropenia more than 10 days, corticosteroid therapy, sustained immunosuppression, and graft-versus-host disease. In contrast to study efforts, evidence-based recommendations on the clinical use of antifungal prophylaxis according to risk groups are rare. The objective of this review of 50 studies accumulating more than 9000 patients is to assess evidence-based criteria with regard to the efficacy of antifungal prophylaxis in neutropenic cancer patients.

Topics: Adrenal Cortex Hormones; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Clinical Trials as Topic; Disease Susceptibility; Drug Carriers; Evidence-Based Medicine; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Liposomes; Mycoses; Neutropenia; Recurrence; Risk Factors; Triazoles

Pulmonary fungal infections in non-neutropenic ICU-patients are not frequent, however, their incidence is increasing with high morbidity and mortality, leading to prolonged stay in ICU wards and to excessive costs dependent on difficult delayed diagnosis. Candida as well as Aspergillus spp. are most important pathogens, but also species of less frequent genera must be taken into account, such as Fusarium, Scedosporium, Cryptococcus and others. Newly evaluated antimycotic agents, such as voriconazole and caspofungin, apart from fluconazole, are not only new options, but must be regarded as agents of choice in non-neutropenic patients.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fluconazole; Fungi; Humans; Intensive Care Units; Lipopeptides; Lung Diseases, Fungal; Neutropenia; Peptides; Peptides, Cyclic; Pyrimidines; Risk Factors; Triazoles; Voriconazole

During the last decade the incidence of invasive aspergillosis has substantially grown due to the increasing use of powerful immunosupressive drugs in more patients. Unfortunately, the associated mortality with this infection is still very high and has not decreased in recent years. Pulmonary aspergillosis is by far the most frequent clinical picture of this infection, followed by sinus, tracheo-bronchial and central nervous system disease. The degree of immunosupression is the main factor influencing the evolution and dissemination of aspergillosis. Conventional amphotericin B has been the first-line therapy of invasive aspergillosis for the last 30 years, and most authors have long considered amphotericin B related toxicity as one of the main causes for the poor results obtained in the outcome of patients who developed this infection. Fortunately, in the last few years new safer and more effective drugs have been developed for the treatment of this entity. However, if we are really trying to substantially decrease invasive aspergillosis associated-mortality we should use these drugs earlier in the development of the infection, using new more sensitive diagnostic tests and/or a riskbase strategy which could identify patients at the highest risk to develop this infection.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Caspofungin; Dermatomycoses; Drug Therapy, Combination; Echinocandins; Humans; Immunocompromised Host; Immunologic Factors; Itraconazole; Lipopeptides; Neuroaspergillosis; Neutropenia; Peptides; Peptides, Cyclic; Pyrimidines; Respiratory Tract Infections; Triazoles; Voriconazole

Liposomal amphotercin B was compared with conventional amphotericin B for empirical antifungal therapy in febrile neutropenic patients in a randomized, double-blind, multicentre trial. Using a composite end-point, the two drugs were equivalent in overall efficacy. However, the liposomal amphotericin B treatment group had fewer proven fungal infections, fewer infusion-related side effects and less nephrotoxicity. Patient data from that study were analysed to compare the pharmacoeconomics of liposomal versus conventional amphotericin B therapy. Itemized billing data from 414 patients were collected and analysed. Hospital costs from first dose were significantly higher for all patients who received liposomal amphotericin B ($48,962 versus $43,183, P = 0.02). However, hospital costs were very sensitive to the cost of the study medication ($39,648 versus $43,048, when acquisition costs are not included, P = 0.4). Using decision analysis models and sensitivity analyses to vary the cost of study medications and risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients, and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients. Therefore, the drug acquisition costs and the risk of nephrotoxicity are important factors in determining the cost-effectiveness of liposomal amphotericin B as empirical therapy in persistently febrile neutropenic patients. In a recent randomized double-blind study comparing liposomal amphotericin B at 3 or 5 mg/kg/day with amphotericin B lipid complex (ABLC) 5 mg/kg/day as empirical antifungal treatment in patients with febrile neutropenia, liposomal amphotericin B was associated with less toxicity than ABLC, both in terms of infusion-related reactions and nephrotoxicity. The incidence of study drug discontinuation due to toxicity was: liposomal amphotericin B 3 mg/kg/day, 14%; liposomal amphotericin B 5 mg/kg/day, 15%; and ABLC, 42% (P < 0.001).

Topics: Amphotericin B; Antifungal Agents; Drug Combinations; Humans; Liposomes; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols

Invasive pulmonary aspergillosis is a major cause of morbidity and mortality in neutropenic patients. Microbiological and serological tests are of limited value. The diagnosis should be considered in neutropenic patients with fever not responding to antibiotics, and typical findings on thoracic computed tomography scan. Whenever possible, diagnosis should be confirmed by tissue examination. Newer techniques, such as polymerase chain reaction may change the current diagnostic approach. Therapeutic strategies consist of prophylaxis in risk groups and the early application of antifungal agents in suspected or probable disease. Amphotericin B as desoxycholate or lipid formulation is the current standard medication in invasive infection, although it has major side effects. Its role is challenged by the new azole derivates, such as itraconazole and voriconazole, and the new echinocandins. Additional therapies with cytokines, such as granulocyte macrophage colony stimulating factor and interferon-gamma, and with granulocyte transfusions are under evaluation. In selected cases lung resection is of proven diagnostic and therapeutic value. This paper analyses the current understanding of the pathogenesis and epidemiology of invasive aspergillosis and reviews the actual diagnostic and therapeutic strategies for invasive pulmonary aspergillosis in neutropenic patients.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Azoles; Bronchoscopy; Cytokines; Diagnostic Imaging; Humans; Lung Diseases, Fungal; Neutropenia; Pneumonectomy; Serologic Tests; Tomography, X-Ray Computed

Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or to patients with persistent fever.. To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia.. MEDLINE and Cochrane Library (November 2001). Letters, abstracts, and unpublished trials. The industry and authors were contacted.. Randomised trials comparing fluconazole with amphotericin B.. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by both authors independently.. Sixteen trials (3760 patients, 341 deaths) were included. In 3 large 3-armed trials, results for amphotericin B were combined with results for nystatin in a "polyene" group. Because nystatin is an ineffective drug in these circumstances, this approach creates a bias in favour of fluconazole. Furthermore, most patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. It was unclear whether there was overlap among the "polyene" trials. We were unable to obtain any information to clarify these issues from the trial authors or from Pfizer, the manufacturer of fluconazole. There were no significant differences in effect between fluconazole and amphotericin B, but the confidence intervals were wide. More patients dropped out of the study when they received amphotericin B, but as none of the trials were blinded, decisions on premature interruption of therapy could have been biased. Furthermore, amphotericin B was rarely given under optimal circumstances, with premedication to reduce infusion-related toxicity, slow infusion, and with potassium and magnesium supplements to prevent nephrotoxicity.. Amphotericin B had been disfavoured in several of the trials through their design or analysis. Since intravenous amphotericin B is the only antifungal agent for which there is good evidence suggesting an effect on mortality and is considerably cheaper than fluconazole, it should be preferred.

Topics: Amphotericin B; Antifungal Agents; Confidence Intervals; Fluconazole; Humans; Mycoses; Neoplasms; Neutropenia; Odds Ratio; Randomized Controlled Trials as Topic

To update the case-fatality rate (CFR) associated with invasive aspergillosis according to underlying conditions, site of infection, and antifungal therapy, data were systematically reviewed and pooled from clinical trials, cohort or case-control studies, and case series of >/=10 patients with definite or probable aspergillosis. Subjects were 1941 patients described in studies published after 1995 that provided sufficient outcome data; cases included were identified by MEDLINE and EMBASE searches. The main outcome measure was the CFR. Fifty of 222 studies met the inclusion criteria. The overall CFR was 58%, and the CFR was highest for bone marrow transplant recipients (86.7%) and for patients with central nervous system or disseminated aspergillosis (88.1%). Amphotericin B deoxycholate and lipid formulations of amphotericin B failed to prevent death in one-half to two-thirds of patients. Mortality is high despite improvements in diagnosis and despite the advent of newer formulations of amphotericin B. Underlying patient conditions and the site of infection remain important prognostic factors.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Case-Control Studies; Central Nervous System Fungal Infections; Child; Child, Preschool; Clinical Trials as Topic; Cohort Studies; Drug Combinations; Female; Humans; Male; MEDLINE; Middle Aged; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Prognosis

Amphotericin B (amB) remains the gold standard for treatment of invasive fungal infections. Lipid formulations of amB have been developed in an attempt to improve both efficacy and tolerability (especially renal toxicity): amB lipid complex (ABLC), liposomal amB (AmBisome), amB colloidal dispersion (ABCD) and amB in lipid emulsion (Intralipid). This review analyzes the data available in the literature.. ABLC, AmBisome and ABCD are effective in various fungal infections, including invasive aspergillosis, systemic candidiasis, cryptococcal meningitis, mucormycosis and fusariosis. These formulations are also effective in persistent febrile neutropenia and in leishmaniosis. The three formulations show little renal toxicity and are safer than conventional amB in this respect. Preliminary data are available on amB in Intralipid: infusion-related adverse effects are reduced, but few data are available on efficacy in documented mycoses.. Large-scale comparative clinical trials may clarify issues of relative efficacy in various forms of fungal infections.

Topics: Amphotericin B; Antifungal Agents; Antiprotozoal Agents; Chemistry, Pharmaceutical; Drug Combinations; Fat Emulsions, Intravenous; Humans; Liposomes; Neutropenia; Patient Selection; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

The last decade has been remarkable for the dramatic increase in the prevalence of serious fungal infections in patients with haematological disorders and neutropenic cancer patients. The mortality rate of deep-seated infection has been in excess of 90% and there is no doubt that this is one of the greatest challenges currently facing haematologists and oncologists. The development of the lipid-based drugs - liposomal amphotericin (AmBisome(R)), amphotericin B lipid complex, ABLC (Abelcet(R)), amphotericin B colloidal dispersion, Amphocil (ABCD(R)), has meant that doses of amphotericin B can be safely escalated for the first time whilst the problems of nephrotoxicity, infusion related reactions (including chills, rigors, fevers and hypoxia) can be reduced. These toxicities are variably reduced with AmBisome more than Abelcet and more than Amphocil and there is little information from randomised trials other than for AmBisome. AmBisome used in the setting of persistent fever and neutropenia not responding after 3-4 days of intravenous antibiotics, is associated with less breakthrough systemic fungal infections. There is also much less need for premedication, including steroids, compared with amphotericin B and Abelcet. The use of intermittent doses of Ambisome given prophylactically is now being explored. A new and exciting era of antifungal therapy is opening up with new compounds, such as itraconazole voriconazole, posaconazole and echinocandins, being investigated and for the first time, we also have options for combination therapy and prophylaxis.

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Costs and Cost Analysis; Hematologic Diseases; Humans; Mycoses; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic

Invasive fungal infections remain a common cause of morbidity and mortality among patients with leukemia who become further compromised by neutropenia. Candida and Aspergillus spp account for the vast majority of these infections, but other, less commonly recognized fungi can cause life-threatening infection in these hosts as well. The earlier, more limited antifungal armamentarium of ketoconazole, flucytosine, and amphotericin B has been substantially augmented by the availability of fluconazole, itraconazole, and the lipid-associated amphotericin formulations. Intense clinical study has focused on the use of these agents in empiric treatment, treatment of suspected or proven infection, and prophylaxis. Recognition of the limitations of antifungal therapy in the neutropenic host has led to evaluation of the adjunctive role of immunotherapy.

Topics: Amphotericin B; Aspergillosis; Azoles; Candidiasis; Fluconazole; Humans; Immunotherapy; Leukemia; Mycoses; Neutropenia

Invasive aspergillosis remains a life-threatening complication in immunocompromised patients. The pulmonary involvement by the aspergillosis is the most common setting. The dissemination of the disease is correlated with the worse prognosis. The overall improvement of the prognosis needs a global diagnostic and therapeutic strategy. In neutropenic patients (mostly at risk of invasive aspergillosis), an early diagnosis can be achieved by systematic use of thoracic CT scan to search halo sign (that seems to be quite specific of the diagnosis in this setting). The early initiation of the antifungal treatment (conventional or liposomal amphotericin or new azole compounds) could be combined with a surgical approach if necessary. This approach could be able to improve the prognosis of aspergillosis. However, the outcome of these patients remains also correlated to the underlying disease.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Bronchoalveolar Lavage Fluid; Diagnosis, Differential; Drug Combinations; Humans; Immunosuppression Therapy; Itraconazole; Neuroaspergillosis; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Postoperative Complications; Prognosis; Radiography, Thoracic; Risk Factors; Tomography, X-Ray Computed

Opportunistic mycoses have emerged as important causes for morbidity and mortality in pediatric cancer patients, particularly in those with intensively treated hematological malignancies, allogeneic hematopoetic stem cell transplantation, and aplastic anemia. The incidence of invasive fungal infections in these settings may range from 10 to 25 % despite empirical antifungal therapy with an overall case fatality rate of up to 50 and 75 % depending on the organism. Preventive interventions are thus warranted, including but not limited to chemoprophylaxis with antifungal agents. Effective chemoprophylaxis of invasive Candida infections with a long-term benefit for overall survival has been demonstrated in patients with allogeneic bone marrow transplantation. However, its benefit in other high-risk populations is less well established, and a clearly effective approach to chemoprophylaxis for invasive Aspergillus infections has not been documented in appropriately designed clinical trials. This article reviews epidemiology and current approaches to chemoprophylaxis of opportunistic invasive fungal infections in children and adolescents with cancer and/or stem cell transplantation, and provides evidence-based guidelines for indications and modalities of antifungal prophylaxis and antifungal infection control measures in this population.

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Child; Child, Preschool; Cohort Studies; Double-Blind Method; Fluconazole; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Infant, Newborn; Itraconazole; Mycoses; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic; Respiratory Therapy; Risk Factors; Time Factors

Efforts at preventing and treating fungal infection in hematopoietic stem cell transplant (HSCT) recipients must take into account the types of infections likely to be encountered during the different risk periods in hosts with different underlying risks. Given the emergence of molds as prevalent pathogens and the long duration of risk in allogeneic HSCT recipients, optimal antifungal prophylaxis would consist of treatment that can be given over a prolonged period and that would provide both anti-Candida and anti-Aspergillus activity. Optimal empiric therapy would consist of a broad-spectrum agent in the absence of more sensitive and specific methods for microbial diagnosis. Fluconazole (Diflucan) is currently the standard prophylactic agent for candidiasis, although mold-active agents and alternative strategies for polyene administration are being investigated. The gold standardfor empiric therapy is currently a polyene antifungal, yet an increased appreciation for amphotericin B-resistant yeasts and molds, and less toxic mold-active alternatives, might lead to the use of other compounds in the future. The recent development of multiple alternatives emphasizes our need to establish treatment algorithms that consider both the likely pathogens and potential toxicities.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Aspergillosis; Candidiasis; Fluconazole; Hematopoietic Stem Cell Transplantation; Humans; Itraconazole; Neutropenia; Opportunistic Infections; Risk Factors

A number of recent developments in the supportive care of hematological malignancies have been selected for critical discussion. The first section focuses on the role of evidence-based guidelines in influencing the use of hematopoietic growth factors in medical practice. The next section updates the current clinical status of amifostine (Ethyol, Alza Corp., Palo Alto CA, USA, and US Bioscience, West Conshohocken, PA, USA) the first broad-spectrum cytoprotective agent available. The management of invasive fungal infections and the use of liposomal antifungal agents are reviewed next. Finally, the current status of transfusion support is presented.

Topics: Adult; Amifostine; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Blood Transfusion; Bone Marrow; Clinical Trials, Phase I as Topic; Hematologic Neoplasms; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Infection Control; Neutropenia; Patient Care; Practice Guidelines as Topic; Radiation-Protective Agents; Societies, Medical; Transfusion Reaction

Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or to patients with persistent fever.. To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia.. MEDLINE and Cochrane Library (March 2000). Letters, abstracts, and unpublished trials. The industry and authors were contacted.. Randomised trials comparing fluconazole with amphotericin B.. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by both authors independently.. Thirteen trials (2977 patients) were included. In 3 large 3-armed trials, which comprised 43% of the patients, results for amphotericin B were combined with results for nystatin in a "polyene" group. Because nystatin is an ineffective drug in theses circumstances, this approach creates a bias in favour of fluconazole. Furthermore, 79% of the patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. It was unclear whether there was overlap among the "polyene" trials. We were unable to obtain any information to clarify these issues from the trial authors or the manufacturer of fluconazole. There was no significant difference in effect between fluconazole and amphotericin B. Apart from the "polyene" trials, more patients dropped out of the study when they received amphotericin B.. Amphotericin B had been disfavoured in most of the trials through their design or analysis. Since intravenous amphotericin B is the only antifungal agent with a documented effect on mortality and is considerably cheaper than fluconazole, it should be preferred.

Topics: Amphotericin B; Antifungal Agents; Confidence Intervals; Fluconazole; Humans; Mycoses; Neoplasms; Neutropenia; Odds Ratio; Randomized Controlled Trials as Topic

Patients with cancer who are treated with chemotherapy or receive a bone marrow transplant have an increased risk of acquiring fungal infections. Such infections can be life-threatening. Antifungal drugs are therefore often given prophylactically to such patients, or when they have a fever.. To compare the effect and adverse effects of AmBisome and other lipid soluble formulations of amphotericin B with conventional amphotericin B in cancer patients with neutropenia.. MEDLINE and Cochrane Library. Unpublished trials from conference proceedings and contact to industry.. Randomised trials comparing lipid soluble formulations of amphotericin B with conventional amphotericin B.. Data on mortality, invasive fungal infection, nephrotoxicity, serum creatinine and dropouts were extracted by both authors independently.. AmBisome vs conventional amphotericin B (3 trials, 1149 patients): AmBisome tended to be more effective than conventional amphotericin B for invasive fungal infection (relative risk 0.63, 95% confidence interval 0.39 to 1.01, P=0.053) whereas there was no significant difference in mortality (relative risk 0.74, 95% CI 0.52 to 1.07). AmBisome decreased significantly the incidence of nephrotoxicity, defined as a 100% increase in serum creatinine (relative risk 0.51, 95% CI 0.40 to 0.64). Fewer patients dropped out on AmBisome but the difference was not significant (relative risk 0.78, 95% CI 0.56 to 1. 08). Amphotericin B in Intralipid vs conventional amphotericin B (4 trials, 145 patients): There were no significant differences in clinical effect whereas the patients treated with the lipid soluble formulation experienced significantly less nephrotoxicity (relative risk 0.34, 95% CI 0.15 to 0.75) and smaller increases in serum creatinine (weighted mean difference 32 micromol/l, 95% CI 21 to 43 micromol/l). Amphotericin B colloidal dispersion (ABCD) vs conventional amphotericin B (1 trial, 213 patients): There was lower nephrotoxicity with ABCD (relative risk 0.38, 95% CI 0.25 to 0.59).. AmBisome is a better drug than conventional amphotericin B but its high cost prohibits routine use in most settings. Furthermore, the advantages of AmBisome may be smaller than indicated in our review if conventional amphotericin B is administered under optimal circumstances. It is not clear whether other lipid formulations of amphotericin B could offer a worthwhile advantage compared to conventional amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Humans; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic

Fungal infections are life-threatening complications in patients with prolonged neutropenia. Amphotericin B, which is fungicidal and has a broad spectrum of antifungal activity, remains the current gold standard agent. However, because of its low therapeutic index, new lipid formulations of amphotericin B have been developed with better tolerance and less toxicity. The use of 5-fluorocytosine is waning because of the medullar toxicity of this agent. Fluconazole and itraconazole are both fungistatic and are more convenient for the treatment of fungal infections in haemodynamically stable patients.

Topics: Amphotericin B; Antifungal Agents; Fever; Flucytosine; Humans; Mycoses; Neutropenia

Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Treatment with amphotericin B is the main therapeutic approach. However, this treatment is limited by the substantial toxicity. We present the data of the first randomized prospective comparative trial in adults (134 patients with fever of unknown origin) with conventional amphotericin B and a liposomal formulation of amphotericin B (AmBisome, published in 1997 by Prentice et al. (Br. J. Haematol. 98, 711-718) and the data of adults with documented fungal infections (59 patients), treated in this trial. Patients received either conventional amphotericin B 1 mg kg-1 per day, liposomal amphotericin B 1 mg kg-1 per day or liposomal amphotericin B 3 mg kg-1 per day. Patients were entered if they had fever of unknown origin (FUO), defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9) l-1). Efficacy of treatment was assessed, with success defined as resolution of fever for three consecutive days (< 38 degrees C) in the group of patients with FUO and the freedom of clinical signs and/or the elimination of fungus in the group of patients with documented fungal infections. The safety of treatment and renal and hepatic toxicity of liposomal and conventional amphotericin B were compared. No statistically significant difference was found in the treatment efficacy in the three study arms. However, there is a tendency of better treatment results in the two groups of patients, who received liposomal amphotericin B. Thirty-five per cent of patients with documented fungal infections and 46% of patients with FUO responded to amphotericin B. In the patients group, that received 1 mg kg-1 liposomal amphotericin B it was 63 and 49%, in the group of patients that received 3 mg kg-1 liposomal amphotericin B it was 47 and 64%. Evidence of toxicity due to amphotericin B was seen in 50 patients (83%), toxicity due to liposomal amphotericin B, 1 mg kg-1, was seen in 35 patients (50%), and due to liposomal amphotericin B 3 mg kg-1 in 34 patients (54%). This was a statistically significant difference (P = 0.001). It was concluded that liposomal amphotericin B was safer than conventional amphotericin B, but both formulations are equivalent in treatment efficacy. The prophylactic use of amphotericin B in these immunocompromised patients is discussed.

Topics: Adult; Amphotericin B; Child; Female; Fever of Unknown Origin; Humans; Liposomes; Male; Middle Aged; Mycoses; Neutropenia

Although amphotericin B has been the gold standard in treating systemic fungal infections, its use is limited by side-effects including nephrotoxicity. In contrast the empiric or therapeutic use of AmBisome is better tolerated, with less nephrotoxicity.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Humans; Neutropenia

During the past decades, the incidence and severity of invasive fungal infections has been increasing. These events have lead to the development of new antifungal agents, and amphotericin B no longer is the standard therapy for a variety of invasive mycoses. Fluconazole has become the drug of choice for treatment of C. albicans infections in non-neutropenic as well as neutropenic patients. For treatment of cryptococcal meningitis, amphotericin B with flucytosine, followed by fluconazole consolidation therapy is used. For therapy of invasive aspergillosis, the lipid formulations of amphotericin B may be associated with reduced toxicity and allow for larger doses, although the efficacy of each of the formulations still has to be established in randomized trials. Finally, treatment modalities aimed at improving host defense mechanisms, including adjunctive therapy with rG-CSF for disseminated candidiasis and rG-CSF-elicited granulocyte transfusions, are under way.

Topics: Amphotericin B; Antifungal Agents; Catheterization, Central Venous; Contraindications; Drug Therapy, Combination; Flucytosine; Fungemia; Granulocyte Colony-Stimulating Factor; Humans; Immunotherapy; Mycoses; Neutropenia; Triazoles

The role of itraconazole in anti-fungal prophylaxis has been limited by the low bioavailability of the capsule formulation but the bioavailability of the oral solution is much improved. Three multi-centre studies using itraconazole solution (5 mg/kg/day) have recently been completed. The UK trial compared itraconazole solution with fluconazole suspension (100 mg/day). No invasive aspergillosis occurred in the itraconazole arm and there were more fungal deaths due to proven/suspected infection in the fluconazole group than in the itraconazole group (0 versus 7, p = 0.024). An Italian study compared itraconazole solution with placebo. Proven, suspected and superficial fungal infections were fewer in the itraconazole arm compared with placebo, with significant differences in proven and suspected systemic fungal infections (itraconazole 24% versus placebo 33%, p = 0.035). The third study compared itraconazole with amphotericin B capsules (2 g/day). There were more invasive fungal infections, Aspergillus infections and fungal deaths in the amphotericin B arm than with itraconazole but none of these differences were statistically significant. Azole prophylaxis in neutropenic patients may reduce the incidence of Candida infections, empirical amphotericin B usage, and the incidence of proven fungal infections. Itraconazole may be more effective than fluconazole in preventing invasive aspergillosis. All of these effects are more pronounced in high risk patients.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Humans; Itraconazole; Mycoses; Neutropenia

Aspergillosis is an infrequent but commonly fatal infection among HIV-infected individuals. We review 342 cases of pulmonary Aspergillus infection that have been reported among HIV-infected patients, with a focus on invasive disease. Invasive pulmonary aspergillosis usually occurs among patients with <50 CD4 cells/mm3. Major predisposing conditions include neutropenia and steroid treatment. Fever, cough, and dyspnea are each present in >60% of the cases. BAL is often suggestive, but biopsy specimens are necessary for definite diagnosis. Amphotericin B is the mainstay of treatment and mortality is > 80%. Avoiding neutropenia and judicious use of steroids may be helpful in prevention. Aggressive diagnostic approach, early initiation of treatment, adequate dosing of antifungals, and close follow-up may improve the currently dismal prognosis.

Topics: Adrenal Cortex Hormones; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Aspergillosis; Biopsy; Bronchoalveolar Lavage Fluid; CD4 Lymphocyte Count; Cough; Dyspnea; Female; Fever; Follow-Up Studies; Humans; Lung Diseases, Fungal; Male; Neutropenia; Prognosis; Risk Factors; Survival Rate

Geotrichum capitatum sepsis are rare, occurring exclusively in immunocompromised patients.. We report the case of a patient with acute leukemia, presenting with chemotherapy-induced neutropenia and hospitalized in an intensive care unit for a severe sepsis. In spite of an antibiotic and antifungal treatment, the patient died of cardiorespiratory failure. Later on, blood cultures proved to be positive for Geotrichum capitatum.. If fungal infections are common in neutropenic patients, Geotrichum capitatum sepsis remain exceptional. The portal of entry is digestive or respiratory, and the invasion is favored by immunodepression and suppression of the normal microbial flora. Induced lesions can be multiorganic. The treatment is not well established, and the association of either amphotericine B and 5-fluorocytosine or amphotericine B and itraconazole would lead to better results. Nevertheless, the prognosis is still unfavorable, with a mortality rate of approximately 75%.

Topics: Acute Disease; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Drug Combinations; Fatal Outcome; Flucytosine; Geotrichosis; Humans; Immunocompromised Host; Itraconazole; Leukemia; Male; Middle Aged; Neutropenia; Opportunistic Infections

Disseminated zygomycosis in persistently neutropenic patients has been almost uniformly fatal despite aggressive surgical and medical management. We describe a neutropenic patient with disseminated zygomycosis that involved the lungs and kidneys and was successfully treated with amphotericin B lipid complex and granulocyte colony-stimulating factor, followed by suppressive therapy with amphotericin B for 1 year. This approach preserved the patient's renal function and restored systemic host defenses. The single pulmonary lesion was resected, but no resection of renal tissue was attempted because of the bilateral extension of the renal lesions. After a 1-year period of follow-up without antifungal therapy, the patient's condition remains stable, and there has been no relapse of the infection.

Topics: Amphotericin B; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Mucormycosis; Neutropenia

To determine whether antifungal agents given prophylactically or empirically decrease morbidity and mortality in patients with cancer complicated by neutropenia.. Meta-analysis of randomised trials of amphotericin B, various lipid soluble formulations of amphotericin B (for example, AmBisome), fluconazole, ketoconazole, miconazole, or itraconazole compared with placebo or no treatment.. Trials conducted anywhere in the world.. Patients with cancer complicated by neutropenia.. Mortality, invasive fungal infection (defined as positive blood culture, oesophageal candidiasis, or lung or deep tissue infection), and colonisation.. 24 trials with 2758 randomised patients were reviewed; the total number of deaths was 434. Prophylactic or empirical treatment with antifungals as a group bad no effect on mortality (odds ratio 0.92; 95% confidence interval 0.74 to 1.14). Amphotericin B decreased mortality significantly (0.58; 0.37 to 0.93) but the studies were small and the difference in number of deaths was only 15. Antifungal treatment decreased the incidence of invasive fungal infection (0.47; 0.35 to 0.64) and fungal colonisation (0.45; 0.30 to 0.69). For every 73 patients treated (95% confidence interval to 48 to 158) one case of fungal invasion was prevented in surviving patients.. There seems to be no survival benefit of antifungal agents given prophylactically or empirically to patients with cancer complicated by neutropenia. These agents should be restricted to patients with proved infection and those in randomised trials. A large, definitive placebo controlled trial of amphotericin B is needed.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Itraconazole; Ketoconazole; Miconazole; Mycoses; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic

Hematogenous candidiasis is associated with substantial mortality and morbidity. Amphotericin B has routinely been used to treat this infection. However, tolerance of therapy with amphotericin B is limited by the drug's toxicity. The results of recently completed prospective randomized clinical studies comparing amphotericin B with fluconazole for the treatment of hematogenous candididiasis suggest that fluconazole is as effective as amphotericin B and that fluconazole is better tolerated by patients. Nevertheless, several questions remain to be answered regarding the optimal choice of antifungal agent for both nonneutropenic and neutropenic patients, the dosing schedule and duration of therapy, the role of combination antifungal therapy, and the efficacy of the lipid formulations of polyenes. Controversial issues with respect to the role of central venous catheters in the pathogenesis of hematogenous candidiasis, as well as the roles of cytokines and white blood cell transfusions in the treatment of neutropenic patients with hematogenous candidiasis, also need to be addressed.

Topics: Algorithms; Amphotericin B; Antifungal Agents; Candidiasis; Catheterization, Central Venous; Colony-Stimulating Factors; Drug Administration Schedule; Drug Therapy, Combination; Fluconazole; Fungemia; Humans; Leukocyte Transfusion; Liposomes; Neutropenia; Randomized Controlled Trials as Topic

Fungal infections have emerged as a major complication of marrow transplantation in children. Most episodes occur within the first 100 days and are often difficult to diagnose. Until recently, a limited number of therapeutic options were available but with new antifungal agents, including azole compounds and less toxic preparations of amphotericin, there is promise for improvements in the prevention of fungal infections as well as the treatment of established infections. This review will summarize the current approach towards therapeutic options available for the supportive care of children undergoing marrow transplantation.

Topics: Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Child; Clinical Trials as Topic; Fluconazole; Flucytosine; Humans; Imidazoles; Immunocompromised Host; Itraconazole; Mycoses; Neutropenia; Transplantation Conditioning; Triazoles

Infectious complications emerge in more than 80% of neutropenic patients after intensive antineoplastic therapy. Empirical antimicrobial intervention is mandatory, and initial administration of an antipseudomonal betalactam in combination with an aminoglycoside represents the most widely applied standard regimen. At least in patients with short-term neutropenia, also an initial betalactam monotherapy is accepted. Symptoms of skin or venous-catheter-related infection should prompt the addition of a glycopeptide, whereas in case of lung infiltrates, amphotericin B should be administered at least after 96 h. of nonresponse to the antibiotic first-line therapy. In nonresponders with persisting fever of unknown origin, carbapenems or fluoroquinolones in combination with a glycopeptide might be considered for second-line treatment. The supplementation of a recombinant hematopoietic growth factor [G-CSF or GM-CSF] shows no significant benefit and should be restricted to controlled clinical studies. In case of good clinical response, the established antimicrobial treatment regimen should be continued for at least seven days in persistently neutropenic patients.

Topics: Amphotericin B; Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Drug Therapy, Combination; Glycopeptides; Hematopoietic Cell Growth Factors; Humans; Lactams; Neutropenia; Opportunistic Infections

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Drug Resistance, Microbial; Fatal Outcome; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Invasive pulmonary aspergilloses occur in patients with antineoplasic chemotherapy, mainly when associated with a prolonged neutropenia, in transplanted patients with continuous corticotherapy and less frequently in immunocompetent surgical patients. The clinical features are those of an acute infective pneumonia, not responding to antibiotherapy. Radiologic signs are often non specific. Diagnosis is obtained with bronchoalveolar lavage in which Aspergillus is found both at direct examination and in culture. Serological tests are of little interest for the diagnosis of invasive aspergillosis. Extrapulmonary locations such as sinusitis, cutaneous or brain abscesses occur in 20% of cases. The gold standard of treatment is intravenous amphotericin B which elicits an acute reaction often followed by a nephrotoxic effect which can be decreased by fluid loading with saline. Oral itraconazole administration can follow the initial treatment with amphotericin B. The mortality rate remains high and an early diagnosis and an appropriate treatment are essential.

Topics: Amphotericin B; Aspergillosis, Allergic Bronchopulmonary; Bronchoalveolar Lavage Fluid; Bronchoscopy; Critical Care; Humans; Immunocompromised Host; Itraconazole; Neutropenia

We report three cases of zygomycosis (mucormycosis) occurring in three individuals infected with the human immunodeficiency virus (HIV) and review 12 other published cases. We present the only two case reports of disseminated zygomycosis in AIDS patients, and the only AIDS patient with renal zygomycosis to survive without nephrectomy, receiving intravenous (i.v.) amphotericin alone. Coinfection with zygomycosis and HIV is rare, occurs primarily in patients with low CD4+ lymphocyte counts, does not always require the usual predisposing conditions for zygomycosis, and may be the presenting opportunistic infection among HIV-infected persons. Transient episodes of neutropenia occurring within 4 months before presentation may be a risk factor for this disease. Zygomycosis may arise in multiple sites including the basal ganglia, cutaneous tissue, kidney, respiratory tract, and may be disseminated. Occurring more commonly in, but not restricted to, injection drug users, it is significantly associated with sites other than basal ganglia in those patients with advanced HIV disease or AIDS. The presenting symptoms are related to the site of involvement, and the illness may develop insidiously or progress rapidly to a fulminant course. Successful therapy usually consists of surgical debridement and intravenous amphotericin B. Overall mortality in this review is 40%, and is significantly associated with sites of disease inaccessible to surgical debridement.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; CD4 Lymphocyte Count; Female; Fungemia; Humans; Intestinal Diseases; Intestine, Small; Kidney; Kidney Diseases; Male; Middle Aged; Mucorales; Mucormycosis; Neutropenia

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Clinical Trials as Topic; Disease Susceptibility; Drug Administration Routes; Hematopoietic Cell Growth Factors; Humans; Immunocompromised Host; Leukocyte Transfusion; Mycoses; Neoplasms; Neutropenia; Triazoles

Topics: Amphotericin B; Antifungal Agents; Azoles; Flucytosine; Humans; Immunocompromised Host; Mycoses; Neoplasms; Neutropenia

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Candidiasis, Chronic Mucocutaneous; Clinical Trials as Topic; Cryptococcosis; Double-Blind Method; Fluconazole; Humans; Itraconazole; Ketoconazole; Mucormycosis; Mycoses; Neutropenia; Nystatin; Primary Prevention; Recurrence; Retrospective Studies

During the last years, the proportion of cancer patients who develop systemic fungal infections has increased steadily. These infections are characterised by high mortality, especially in patients with persistent granulocytopenia and in those receiving allogeneic bone marrow transplants. The most important pathogens in neutropenic patients are Candida and Aspergillus spp. Usually, Candida infections arise from overgrowth in the gastrointestinal tract, while Aspergillus infections are acquired by inhalation of spores. Prophylaxis of systemic fungal infections seems mandatory since optimal strategies for diagnosis and treatment of these infections are lacking. Treatment with the non-absorbable polyenes nystatin and amphotericin B is useful for prophylaxis of superficial fungal infections, provided that compliance of the patients is optimal. The imidazoles ketoconazole and miconazole can reduce the incidence of superficial fungal infections, but there are conflicting data regarding their value for prevention of systemic mycoses. There are several studies indicating that prophylactic use of fluconazole reduces the incidence of mucosal and systemic fungal infections, especially in patients receiving allogeneic bone marrow transplants. Fluconazole shows reduced activity against several Non-albicans spp. and is not active against Aspergillus spp. Itraconazole has in vitro and in vivo activity against several Aspergillus spp. but high serum and tissue levels are necessary. However, bioavailability of itraconazole is reduced in patients with raised gastric pH and no i.v. formulation is available. Although there is some evidence for its prophylactic activity against Aspergillus infections in neutropenic patients, more studies are necessary to confirm these findings. Intravenous amphotericin B cannot be recommended for routine prophylactic use because of its toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Fluconazole; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Itraconazole; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections

Topics: Amphotericin B; Aspergillosis; Aspergillus fumigatus; Drug Interactions; Drug Therapy, Combination; Fluconazole; Humans; Lung Diseases, Fungal; Neutropenia

Neutropenic patients are at high risk of developing invasive fungal diseases. A number of studies, both randomized and historical, have demonstrated that empiric therapy with amphotericin B in neutropenic patients with fever, refractory to antibiotics, results in a decrease in the frequency and mortality of deep fungal infections. Recent years have seen a number of advances in the management of neutropenic patients. Reasonably effective antifungal prophylaxis now exists and in many centres forms part of the routine care of neutropenic patients. Other centres advocate the use of selective decontamination and/or protective isolation. Furthermore the duration of neutropenia can be reduced with the use of haematopoetic growth factors. The impact of empiric amphotericin B in patients already benefiting from such treatments has not been adequately studied. The optimum dose of empiric amphotericin B is not defined. The criteria for commencing amphotericin B therapy in febrile neutropenic patients must therefore be redefined on the basis of further studies carried out in the context of these developments. We offer an approach to the use of empiric amphotericin B based on risk factors and prophylaxis.

Topics: Amphotericin B; Bone Marrow Transplantation; Clinical Trials as Topic; Fever of Unknown Origin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunologic Factors; Leukemia; Multicenter Studies as Topic; Mycoses; Neutropenia; Patient Isolation; Randomized Controlled Trials as Topic; Risk

Fever is associated with malignancy and is a common problem in cancer patients. Fever in the cancer patients is closely linked with infection, especially when the patient is granulocytopenic. When fever appears, a series of diagnostic and therapeutic measures must be taken even if precise knowledge of the cause of the infection is lacking. Fever can be caused by infection or by the cancer itself through tumor-related necrosis, hemorrhage or pyrogens. Infection is the more common cause, however. Bacterial and fungal sepsis can coexist and the bacteremia can overshadow the more difficult to determine fungal infection. For this reason it has become accepted practice to administer amphotericin B to granulocytopenic patients who remain febrile after a few days of broad-spectrum antimicrobial therapy and in whom no bacteria can be documented. Viral infection is rarely diagnosed in neutropenic patients without concomitant immunosuppression.

Topics: Amikacin; Amphotericin B; Bacteremia; Bacterial Infections; Ceftazidime; Clinical Trials as Topic; Drug Therapy, Combination; Fever; Fever of Unknown Origin; Humans; Mycoses; Neoplasms; Neutropenia; Vancomycin; Virus Diseases

The Candida species account for approximately three-fourths of fungal infections in patients with cancer. Although Candida albicans is the most frequent cause, C. tropicalis is increasingly implicated as an important pathogen. Over a 12 year period 19 children treated for leukemia at our institution developed C. tropicalis infections. We describe their clinical presentation, extent of fungal infection, treatment, and outcome. Fungemia without meningitis in 11 children was treated successfully, whereas C. tropicalis meningitis in 7 children was uniformly fatal. An additional patient had unsuspected, widespread infection detected at autopsy. Multiple sites, including the cerebrospinal fluid yielded C. tropicalis. Previously reported risk factors including neutropenia, broad-spectrum antibiotic usage, corticosteroid therapy, and total parenteral nutrition were observed in our cases. A high index of suspicion and the early use of aggressive antifungal therapy are critical to the successful management of C. tropicalis infections in children with leukemia.

Topics: Abscess; Adolescent; Amphotericin B; Candida; Candidiasis; Cerebrospinal Fluid; Child; Child, Preschool; Combined Modality Therapy; Drainage; Female; Fluconazole; Fungemia; Humans; Infant; Leukemia; Male; Meningitis, Fungal; Neutropenia; Parenteral Nutrition, Total; Retrospective Studies; Risk Factors; Superinfection; Tennessee

Invasive fungal sinusitis is becoming increasingly common in patients undergoing BMT. This study was undertaken to evaluate the incidence, presenting symptoms, diagnosis procedures, treatment and outcome of invasive fungal sinusitis. The study population comprised 423 consecutive BMT patients at Hadassah University Hospital from January 1986 to August 1992. Eleven patients (2.6%) developed invasive fungal sinusitis, 8 had underlying hematologic malignancies and 3 severe aplastic anemia (SAA). Median interval between BMT and fungal sinusitis was 22.5 days (range 2-106 days). Eight of 11 patients had protracted neutropenia (median 8 days with median neutrophil count at the time of fungal sinusitis diagnosis of 0.25 x 10(9)/l). Four patients developed GVHD before fungal sinusitis was diagnosed. Presenting symptoms were fever (100%), orbital swelling (63%), facial pain (54%) and nasal congestion (36%). In 8 patients Aspergillus species were isolated (A. flavus in 7, A. quadrilineatus in 1); in 1 patient Candida albicans was isolated and in the other 2 fungal elements were detected histologically (Fusarium and Mucor, respectively). Six of the patients underwent surgical debridement at diagnosis. Three received granulocyte transfusions. All patients received systemic amphotericin B (7 conventional and 4 amphotericin B colloidal dispersion (ABCD)). Only 2 of the 11 patients responded completely to therapy with a follow-up of 15 months. It appears that invasive fungal sinusitis is a potentially fatal complication in immunocompromised patients post-BMT. Current treatment approaches are largely ineffective and new methods of management of this serious problem are needed.

Topics: Adolescent; Adult; Amphotericin B; Anemia, Aplastic; Bone Marrow Purging; Bone Marrow Transplantation; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Debridement; Drainage; Female; Follow-Up Studies; Graft vs Host Disease; Granulocytes; Humans; Immunocompromised Host; Incidence; Infant; Leukemia; Leukocyte Transfusion; Lymphoma; Male; Middle Aged; Mitosporic Fungi; Mycoses; Neutropenia; Sinusitis; Survival Rate; Treatment Outcome

Fusariosis, a rare infectious disease of the immunocompromised host, is relatively resistant to amphotericin B (AmB) or other antifungal agents. We describe a 5-year follow-up of a 40 year old woman with T-type acute lymphoblastic leukemia who following chemotherapy developed prolonged high fever, chills, night sweats, and severe weakness. Liver function tests were impaired and abdominal computerized tomography (CT) showed multiple lesions in the liver and abnormal structure of the spleen. A laparotomy revealed multiple granulomas containing Fusarium sp. in the liver, and the spleen was heavily infiltrated by the same fungus. The patient failed to respond to the conventional AmB dosage form (Fungizone) even after a total dose of 3.0 g was given, and developed significant renal impairment. AmB was complexed (in a mole ratio of 1:16) with a mixture of the phospholipids dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (mixed in 7:3 mole ratio). The resulting drug complex, AmB-PLC, was then administered (1-4 mg/kg/day, total dose 4.2 g) and subsequently the patient was cured of all symptoms of fusariosis. There were only mild side effects and no nephrotoxicity was evident. On the contrary, marked improvement of the renal function tests occurred during AmB-PLC treatment. Eight months later, she developed a spinal lesion with dense consistency in L5 and S1, and after receiving another course of AmB-PLC (3.1 g) she recovered completely. In a 2 year follow-up period the patient had no further relapse of the fungal disease. Subsequent chemotherapy given for relapse of the leukemia was followed by a new fungal infection, which was treated with AmB-cholesteryl sulfate complex (Amphocil).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Daunorubicin; Dimyristoylphosphatidylcholine; Drug Carriers; Female; Follow-Up Studies; Fusarium; Granuloma; Hepatitis; Humans; Immunocompromised Host; Kidney Diseases; Leukemia-Lymphoma, Adult T-Cell; Mycoses; Neutropenia; Phosphatidylglycerols; Prednisone; Recurrence; Splenic Diseases; Vincristine

Systemic Candida infections are a major cause of infectious morbidity and mortality during chemotherapy-induced neutropenia. Because of the unreliability of conventional diagnostic tests to detect systemic infection early in its course, treatment of established disseminated Candida infection has been generally disappointing with mortality rates of 60-80% in leukemia and bone marrow transplant patients and 30-40% in solid tumor patients. The use of empiric amphotericin B in patients with fever not responding to empiric antibacterial agents has been shown to be successful in reducing morbidity and mortality from fungal infections. However, its toxicity has mitigated the success of this approach. Fluconazole given prophylactically at the institution of chemotherapy has been shown to be a safe and effective alternative. It, however, is not active against all fungal species, especially Aspergillus and some of the less virulent Candida species. Some centers have reported break-through infections by these less susceptible organisms. Whether or not these limitations in its spectrum of activity will limit its usefulness in the future remains unanswered at this time and could pose a cloud to an otherwise bright promise.

Topics: Amphotericin B; Bone Marrow Transplantation; Candidiasis; Disease Susceptibility; Double-Blind Method; Fluconazole; Humans; Immunocompromised Host; Neoplasms; Neutropenia; Survival Rate

We report the first know case of disseminated fungal infection due to Fusarium proliferatum in a bone marrow transplant recipient to our knowledge. Fusarium was cultured from the blood, a paranasal sinus, and necrotic skin lesions. The isolate was sensitive to amphotericin B and on further sensitivity testing, synergy was demonstrated using rifampin in combination with amphotericin B. The patient had this infection while she was receiving alternate-day amphotericin, rifampin, and 5-flucytosine (5-FC) therapy. The infection was documented within 48 h of discontinuing daily granulocyte transfusions, which she had received for 3 weeks. The 5-FC was discontinued when sensitivities showed the organism resistant. After 6 weeks of treatment she showed complete remission of the infection, although neutrophil counts remained below 0.25 X 10(9)/L. From this case and from a review of the literature, it appears that synergic antifungal agents combined with leukocyte transfusions may be beneficial in the successful treatment of fusariosis in the compromised host.

Topics: Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Female; Fusarium; Humans; Mycoses; Neutropenia; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rifampin; Skin; Spider Bites; Staphylococcal Infections

Persistent fever that is refractory to broad-spectrum antibacterials is common in neutropenic patients undergoing induction chemotherapy of acute leukemia. Clinical experience suggests that many of these patients are infected with fungi. Until recently, data supporting the role of empiric antifungal therapy in this setting were limited to small groups of patients or postmortem reports. Evolving evidence in larger patient populations supports data from smaller series: febrile neutropenic patients who have failed to respond to a 4- to 7-day course of broad-spectrum antibacterials may benefit from the early initiation of antifungal therapy. Patients with fungal colonization or pulmonary infiltrates and adult patients who have not received previous fungal prophylaxis may especially benefit from the early use of antifungal drugs. Amphotericin B has been the "gold standard" for empiric antifungal therapy, although the newer azoles may be useful in certain situations.

Topics: Acute Disease; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Bacterial Infections; Clinical Trials as Topic; Fever; Humans; Leukemia; Mycoses; Neutropenia; Remission Induction

C tropicalis is a frequent and virulent pathogen in neutropenic patients. Infection control personnel should be familiar with this microorganism and the significance of a positive culture for C tropicalis in a setting of poor host resistance.

Topics: Amphotericin B; Candida; Candidiasis; Humans; Neutropenia; Opportunistic Infections

Patients with severe neutropenia are at increased risk for systemic infection with bacteria or fungi. This risk is in proportion to both the degree and duration of the neutropenic process. Although granulocyte transfusion as a means of augmenting host defenses would appear to be a logical therapeutic intervention in clinical contexts involving severe and prolonged neutropenia, several features of granulocyte physiology and collection complicate such considerations. These include the large numbers of granulocytes normally produced by healthy hosts, the short survival of the granulocyte in the circulation after transfusion, the relatively small number of granulocytes which can be collected using currently available pheresis techniques, problems associated with alloimmunization, and the possibility of transferring disease (CMV, toxoplasmosis, hepatitis) by means of these transfusions. In the mid-1970s, well-designed clinical studies strongly suggested that patients with documented Gram-negative sepsis or tissue infection that failed to respond to appropriate antibiotics were significantly benefited by granulocyte transfusions. With recent advances in potent, broad-spectrum antibiotic availability, some have questioned whether these observations remain valid. Several studies regarding the prophylactic use of granulocyte transfusions in patients undergoing allogeneic bone marrow transplantation and/or induction therapy for leukemia have failed to reveal therapeutic benefits and suggested the possibility of significant side effects. These studies are reviewed.

Topics: Agranulocytosis; Amphotericin B; Anti-Bacterial Agents; Blood Transfusion; Bone Marrow Transplantation; Cell Separation; Clinical Trials as Topic; Cytomegalovirus Infections; Granulocytes; Humans; Infant, Newborn; Infant, Newborn, Diseases; Leukapheresis; Lung Diseases; Neutropenia; Sepsis; Transfusion Reaction

A neutropenic patient with acute myeloid leukemia developed nasal and perinasal infection caused by the fungus Exserohilum rostratum. Early amphotericin B treatment along with marrow recovery resulted in resolution of the infection. A review of other previously reported cases of Exserohilum and Bipolaris infections show a favourable outcome in most patients who receive systemic antifungal treatment with amphotericin B.

Topics: Agranulocytosis; Amphotericin B; Humans; Immune Tolerance; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitosporic Fungi; Mycoses; Nasal Mucosa; Neutropenia; Nose Diseases; Paranasal Sinus Diseases

Infection is the major cause of morbidity and mortality in children receiving anticancer therapy. Children who have severe neutropenia (neutrophil count less than 100/mm3) for longer than 2 weeks should receive oral antibiotic prophylaxis. At present, trimethoprim sulfamethoxazole in combination with either nystatin or amphotericin B is the best regimen for reducing the incidence of serious infections. Trimethoprim sulfamethoxazole is very effective in the prevention of Pneumocystis carinii pneumonitis. Clinicans will have to balance the advantages and disadvantages of prophylaxis in patients who are at risk for P. carinii pneumonitis.

Topics: Adolescent; Adult; Amphotericin B; Anti-Bacterial Agents; Bacterial Infections; Candidiasis; Child; Compliance; Drug Combinations; Humans; Leukemia; Neoplasms; Neutropenia; Nystatin; Pneumonia, Pneumocystis; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Acute Disease; Adrenal Cortex Hormones; Amphotericin B; Aspergillosis; Blood Transfusion; Candidiasis; Cryptococcosis; Drug Therapy, Combination; Flucytosine; Hodgkin Disease; Humans; Iron; Leukemia; Leukemia, Lymphoid; Lymphoma; Mucor; Multiple Myeloma; Mycoses; Neutropenia; Rhizopus

Febrile neutropenia, a serious complication that can occur during the treatment of hematological malignancies, can sometimes be fatal owing to fungal infection. Prospective randomized trials indicated the utility of liposomal amphotericin B or caspofungin as an empirical antifungal therapy. Itraconazole, a broad-spectrum tri azole antifungal agent, is poorly absorbed in the intestines after oral absorption and makes it difficult to achieve a stable serum drug concentration. Therefore, an intravenous formulation might offer a potentially safer and more effective alternative. To compare the efficacy and safety of empirical antifungal therapy, patients will be randomly assigned to either the liposomal amphotericin B 3.0 mg/kg once daily group or the intravenous itraconazole 200 mg dose group with five stratification factors (disease risk, previous antifungal prophylaxis, age, sex, and institute). The primary endpoint will be overall favorable response, comprising five secondary endpoints: successful treatment of baseline infection by the end of the treatment; absence of breakthrough infection; no discontinuation of the antifungal treatment due to drug-related toxicity; fever resolution during neutropenia; and 7-day survival after termination of the antifungal treatment. The target sample size of 850 subjects is sufficient to prove the non inferiority of itraconazole compared with liposomal amphotericin B, with a non-inferiority margin of 10%, one sided significance level of 5%, and power of 90%.

Topics: Amphotericin B; Antifungal Agents; Equivalence Trials as Topic; Fever of Unknown Origin; Hematologic Neoplasms; Humans; Itraconazole; Multicenter Studies as Topic; Neutropenia; Prospective Studies; Randomized Controlled Trials as Topic

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Creatinine; Female; Humans; Immunocompromised Host; Infusions, Intravenous; Male; Neutropenia; Treatment Outcome; Vomiting

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

Topics: Adult; Amphotericin B; Anemia; Antifungal Agents; Blood Cell Count; Coinfection; Creatinine; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Female; Flucytosine; Hemoglobins; HIV; HIV Infections; Humans; Hypokalemia; Induction Chemotherapy; Kidney; Male; Meningitis, Cryptococcal; Neutropenia; Survival Analysis; Treatment Outcome

A multicenter, uncontrolled clinical study has been conducted to evaluate the safety, efficacy, and pharmacokinetics of liposomal amphotericin B (L-AMB) in children. In this article, the safety and efficacy of L-AMB are discussed. Subjects were diagnosed with invasive fungal infection (definitely diagnosed cases), possible fungal infection (clinically diagnosed cases), and febrile neutropenia with suspected fungal infection (febrile neutropenia cases). Of the 39 subjects treated with L-AMB, 18 received a definite (11) or clinical (7) diagnosis of invasive fungal infection. In these subjects, excluding one unevaluable subject, L-AMB was effective in nine out of 17 subjects(52.9%). Of 12 febrile neutropenia cases, improvement in clinical symptoms, etc., was observed for six but these were excluded from the efficacy analysis because they concomitantly used medications that may have affected efficacy. The causative fungus was identified in four out of 39 subjects and confirmed to be eliminated by treatment with L-AMB in one subject. Adverse events possibly related to L-AMB (adverse drug reactions) were reported in 36 out of 39 subjects (92.3%). The most commonad verse drug reaction was decreased potassium in 20 out of 39 subjects (51.3%), but all these subjects recovered with appropriate treatment, for example potassium supplementation.In a Japanese Phase II clinical study of adult patients, the incidence of adverse drug reactions was 95.3%(82/86 subjects) and the efficacy was 63.6% (42/66). Taken together, these data indicate that the safety and efficacy of L-AMB are almost the same in pediatric and adult patients.

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Creatinine; Female; Humans; Hypokalemia; Male; Mycoses; Neutropenia

Given that the rationale for empirical antifungal therapy in neutropenic children is limited and based on adult patient data, we performed a prospective, randomized, controlled trial that evaluated 110 neutropenic children with persistent fever. Those at high risk for invasive fungal infections (IFI) received caspofungin (Arm C) or liposomal amphotericinB (Arm B); those with a lower risk were randomized to receive Arm B, C, or no antifungal treatment (Arm A). Complete response to empirical antifungal therapy was achieved in 90/104 patients (86·5%): 48/56 at high risk (85·7%) [88·0% in Arm B; 83·9% in Arm C (P = 0·72)], and 42/48 at low risk (87·5%) [87·5% in control Arm A, 80·0% Arm B, 94·1% Arm C; (P = 0·41)]. None of the variables tested by multiple logistic regression analysis showed a significant effect on the probability to achieve complete response. IFI was diagnosed in nine patients (8·2%, 95% confidence interval, 3·8-15·0). This randomized controlled study showed that empirical antifungal therapy was of no advantage in terms of survival without fever and IFI in patients aged <18 years and defined with low risk of IFI. Higher risk patients, including those with relapsed cancer, appear to be the target for empirical antifungal therapy during protracted febrile neutropenia.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Caspofungin; Child; Child, Preschool; Echinocandins; Female; Fever of Unknown Origin; Hospitalization; Humans; Infant; Length of Stay; Lipopeptides; Male; Mycoses; Neutropenia; Opportunistic Infections; Patient Selection; Prospective Studies; Treatment Outcome

To evaluate the cost-effectiveness of caspofungin versus liposomal amphotericin B (L-AmB) for empirical antifungal therapy in patients with persistent fever and neutropenia in Sweden.. With a decision-analytic model, the expected direct costs, life-years lost and quality adjusted life-years lost were estimated for an average patient in Sweden. Efficacy/tolerability data were obtained from analysis of a randomized, double-blind multinational trial. Life expectancy, medical resource use and unit costs data were gathered from the literature and expert opinion. Probabilistic sensitivity analysis was used to evaluate the impact of uncertainty in data on outcomes.. The direct cost with caspofungin amounted to 233,851 SEK (95% uncertainty interval 225,091-242,210) and with L-AmB to 271,921 SEK (262,935-281,363), a difference of 38,070 SEK (31,745-44,811) favouring caspofungin. Treatment with caspofungin resulted in 0.25 (0.01-0.55) quality-adjusted life-years (QALYs) saved in comparison to L-AmB. Given the uncertainty in the estimates there is a >95% probability that caspofungin is economically dominant over L-AmB, i.e. cost-saving and QALY-saving.. Given the underlying assumptions and data used, caspofungin is expected to be cost-effective with at least comparable outcomes compared to L-AmB for the empirical treatment of patients with suspected fungal infections in Sweden.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Cost-Benefit Analysis; Double-Blind Method; Echinocandins; Fever of Unknown Origin; Humans; Lipopeptides; Neutropenia; Quality of Life; Survival Analysis; Sweden

Patients with neutropenic fever after 4-7 days of broad-spectrum antibiotics are given antifungals empirically. This strategy may lead to over-treatment.. Patients with hematological malignancies undergoing intensive chemotherapy or hematopoietic stem cell transplantation were randomized to two arms. Patients in the 'preemptive' arm had regular galactomannan (GM) assays, and received caspofungin, amphotericin or voriconazole (CAV) for persistent febrile neutropenia if they had two positive GM results, or a positive GM result and a computed tomography (CT) of the thorax suggestive of invasive pulmonary aspergillosis (IPA). Patients in the 'empirical' arm received CAV in accordance with established guidelines.. Of 27 episodes in the preemptive arm, two cases of IPA were picked up by monitoring. In six episodes, CAV was started despite persistently negative GM readings. One additional patient received CAV for a false-positive GM. Of 25 episodes in the empirical arm, CAV was started empirically in 10, one of whom had CT features of IPA. By intent-to-treat and evaluable-episode analyses, respectively, the preemptive approach saved 11% and 14% of patients from empirical antifungals. Twelve-week survival was 85.2% in the preemptive arm and 84% in the empirical arm.. A preemptive approach may reduce empirical antifungal use without compromising survival in persistently febrile neutropenic patients.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Caspofungin; Drug Therapy, Combination; Echinocandins; Female; Fever; Galactose; Humans; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Lipopeptides; Male; Mannans; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Prospective Studies; Pyrimidines; Radiography, Thoracic; Risk Factors; Singapore; Tomography, X-Ray Computed; Treatment Outcome; Triazoles; Voriconazole

Pulmonary invasive fungal infections (IFI) are well-recognized complications with high morbidity and mortality in patients with hematologic malignancies.. Aerosolized liposomal amphotericin B (lipAmB) was evaluated as an antifungal prophylaxis in patients with an expected neutropenia of more than 10 days due to intensive chemotherapy or stem cell transplantation, in a prospective phase II trial.. 98 treatment episodes were included in the study and compared to 105 historical control patients. Inhalation was performed between 0 and 103 days. No severe side effects of therapy occurred. 40 patients considered inhalations as unpleasant, 2 as very unpleasant, mostly due to bad taste or cough. Few cases of definite or probable IFI were recorded, whereas a large number of patients were treated with systemic antifungal therapy for pneumonia or fever of unknown origin without a significant difference between study patients and controls. In a predefined subgroup analysis of 48 patients with newly diagnosed acute myeloid leukemia (AML), significantly more patients survived for 1 year in the AmB prophylaxis than in the control group (80% vs. 54%, p < 0.01).. Inhalations of lipAmB are feasible and safe. Results in the subgroup of patients with AML together with data from other trials suggest further evaluation of effectiveness.

Topics: Amphotericin B; Antifungal Agents; Female; Humans; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Treatment Outcome

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Caspofungin; Child; Child, Preschool; Drug Therapy, Combination; Echinocandins; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Male; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Pyrimidines; Transplantation Conditioning; Triazoles; Voriconazole; Young Adult

Persistently febrile neutropenic children at risk for invasive fungal infections receive empiric antifungal therapy as a standard of care. However, little is known about the role of echinocandins and liposomal amphotericin B (L-AmB) for empiric antifungal therapy in pediatric patients.. Patients between the ages of 2 to 17 years with persistent fever and neutropenia were randomly assigned to receive caspofungin (70 mg/m loading dose on day 1, then 50 mg/m daily [maximum 70 mg/d]) or L-AmB (3 mg/kg daily) in a 2:1 ratio. Evaluation of safety was the primary objective of the study. Efficacy was also evaluated, with a successful outcome defined as fulfilling all components of a prespecified 5-part composite endpoint. Suspected invasive fungal infections were evaluated by an independent, treatment-blinded adjudication committee.. Eighty-two patients received study therapy (caspofungin 56, L-AmB 26), and 81 were evaluated for efficacy (caspofungin 56; L-AmB 25). Outcomes for safety and efficacy endpoints were similar for both study arms. Adverse drug-related event rates [95% confidence interval] were similar between the caspofungin and L-AmB groups (clinical 48.2% [34.7-62.0] versus 46.2% [26.6-66.6]; laboratory 10.7% [4.0-21.9] versus 19.2% [6.6-39.4]). Serious drug-related adverse events occurred in 1 (1.8%) of caspofungin-treated patients and 3 (11.5%) of L-AmB-treated patients. Overall success rates [95% CI] were 46.4% [33.4-59.5] for caspofungin and 32.0% [13.7-50.3] for L-AmB.. Caspofungin and L-AmB were comparable in tolerability, safety, and efficacy as empiric antifungal therapy for persistently febrile neutropenic pediatric patients.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Caspofungin; Child; Child, Preschool; Double-Blind Method; Echinocandins; Female; Fever of Unknown Origin; Humans; Lipopeptides; Male; Neutropenia; Treatment Outcome

The objective of this study was to assess the costs and effectiveness (avoided invasive fungal infections - IFIs; overall mortality) of prophylaxis with posaconazole 200 mg per os TID and standard azoles (fluconazole 400 mg per os OD, itraconazole 200 mg per os BID) in neutropenic patients with acute myelogenous leukaemia or myelodysplastic syndromes. A 100-day cost-effectiveness model was developed following the Italian hospital perspective. The probability of IFIs, death from IFIs, and death from other causes was obtained from the literature. Health care sector resources (type, volume, unit cost) are given in Euros and refer to 2009. The robustness of the cost-effectiveness model was tested via one-way and probabilistic sensitivity analyses. Total costs for posaconazole (standard azoles) was estimated at Euros 3365.26 (Euros 2339.96). Posaconazole is consistently more effective than standard azoles. The incremental cost-effectiveness ratio for avoided IFI (avoided overall mortality) with posaconazole is Euros 15,850.51 (Euros 18,038.43). Sensitivity analyses confirmed the robustness of such findings. In conclusion, posaconazole as a prophylaxis in neutropenic patients with AML or MDS who are at risk of IFI is good value for money for Italian hospitals.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Deoxycholic Acid; Drug Combinations; Drug Costs; Equipment and Supplies; Fluconazole; Follow-Up Studies; Hospital Costs; Humans; Immunocompromised Host; Infusions, Intravenous; Italy; Itraconazole; Leukemia, Myeloid, Acute; Mycoses; Myelodysplastic Syndromes; Neutropenia; Oncology Nursing; Treatment Outcome; Triazoles

In a non-comparative study, caspofungin was effective salvage therapy for approximately half of the patients refractory to or intolerant of standard antifungal agents for invasive aspergillosis. To establish a frame of reference for these results, we compared the response to caspofungin with responses to other antifungal agents in a historical cohort of similar patients. The efficacy could be evaluated in 83 patients who received caspofungin 50 mg daily after a 70-mg loading dose. The historical control group, identified through a retrospective review of medical records, included 214 evaluable patients possibly refractory to or intolerant of ≥1 week of standard antifungal therapy. All patients had documented invasive aspergillosis. Favorable response was defined as a complete or partial response to therapy. Underlying diseases, baseline neutropenia, corticosteroid use, and sites of infection were similar in both studies. Most patients had received amphotericin B formulations and/or itraconazole, and were refractory to standard therapy. Favorable response rates were 45% with caspofungin and 16% with standard therapy. The unadjusted odds ratio for a favorable response (caspofungin/standard therapy) was 4.1 (95% confidence interval: 2.2, 7.5). After adjusting for potential imbalances in the frequency of disseminated infection, neutropenia, steroid use, and bone marrow transplantation between groups, the odds ratio remained at 4.1 (2.1, 7.9). Although only tentative conclusions about relative efficacy can be drawn from retrospective comparisons, caspofungin appeared to be at least as efficacious as an amphotericin B formulation and/or itraconazole for the treatment of invasive aspergillosis in patients refractory to or intolerant of their initial antifungal therapy.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Humans; Invasive Pulmonary Aspergillosis; Itraconazole; Lipopeptides; Male; Middle Aged; Neutropenia; Prognosis; Salvage Therapy; Treatment Failure; Treatment Outcome; Young Adult

A major randomized clinical trial, evaluating voriconazole versus liposomal amphotericin B (LAMB) as empirical therapy in febrile neutropenia, recommended voriconazole as a suitable alternative to LAMB. The current study sought to investigate the health economic impact of using voriconazole and LAMB for febrile neutropenia in Australia.. A decision analytic model was constructed to capture downstream consequences of empirical antifungal therapy with each agent. The main outcomes were: success, breakthrough fungal infection, persistent baseline fungal infection, persistent fever, premature discontinuation and death. Underlying transition probabilities and treatment patterns were derived directly from trial data. Resource use was estimated using an expert panel. Cost inputs were obtained from the latest Australian representative published sources. The perspective adopted was that of the Australian hospital. Uncertainty and sensitivity analyses were undertaken via the Monte Carlo simulation.. Compared with voriconazole, LAMB was associated with a net cost saving of AU$1422 (2.9%) per patient. A similar trend was observed with the cost per death prevented and successful treatment. LAMB dominated voriconazole as it resulted in higher efficacy and lower costs when compared with voriconazole. The results were most sensitive to the duration of therapy and the alternative therapy used post discontinuations. In uncertainty analysis, LAMB had 99.8% chance of costing less than voriconazole.. In this study, which used the current standard five component endpoint to assess the impact of empirical antifungal therapy, LAMB was associated with cost savings relative to voriconazole.

Topics: Amphotericin B; Australia; Cost-Benefit Analysis; Fever; Humans; Mycoses; Neutropenia; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Empirical antifungal therapy is the standard of care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Recent diagnostic improvements may ensure the early diagnosis of potentially invasive fungal disease. Reserving antifungals for this stage may achieve similar survival rates and reduce treatment toxicity and costs.. In this multicenter, open-label, randomized noninferiority trial, we compared an empirical antifungal strategy with a preemptive one. Empirical treatment was defined as antibacterial treatment of patients who have persistent or recurrent fever. Preemptive treatment was defined as treatment of patients who have clinical, imaging, or galactomannan-antigen-assay evidence suggesting fungal disease. First-line antifungal treatment was amphotericin B deoxycholate (1 mg/kg/day) or liposomal amphotericin (3 mg/kg/day), depending on daily renal function. The primary efficacy outcome was the proportion of patients alive at 14 days after recovery from neutropenia.. The median duration of neutropenia (neutrophil count, <500 cells/mm3) for the 293 patients enrolled was 18 days (range, 5-69 days). By intention-to-treat analysis, survival was 97.3% with empirical treatment and 95.1% with preemptive treatment. The lower 95% confidence limit for the difference in mortality was -5.9%, which was within the noninferiority margin of -8%. Probable or proven invasive fungal infections were more common among patients who received preemptive treatment than among patients who received empirical treatment (13 of 143 vs. 4 of 150; P < .05), and most infections occurred during induction therapy (12 of 73 patients in the preemptive treatment group vs. 3 of 78 patients in the empirical treatment group were infected during induction therapy; P < .01). Preemptive treatment did not decrease nephrotoxicity but decreased costs of antifungal therapy by 35%.. Preemptive treatment increased the incidence of invasive fungal disease, without increasing mortality, and decreased the costs of antifungal drugs. Empirical treatment may provide better survival rates for patients receiving induction chemotherapy.

Topics: Adult; Aged; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Chi-Square Distribution; Deoxycholic Acid; Drug Combinations; Female; Fever; Humans; Male; Middle Aged; Multicenter Studies as Topic; Mycoses; Neutropenia; Opportunistic Infections; Risk Factors; Statistics, Nonparametric

In a major clinical trial, caspofungin was as efficacious as liposomal amphotericin B (LAmB) for empirical therapy in febrile neutropenia. The current study sought to evaluate the economic impact of caspofungin as compared with LAmB for febrile neutropenia in Australia.. A decision analytic model was developed to capture the downstream consequences of the empirical antifungal therapy. The main outcomes were success, breakthrough infection, persistent baseline infection, persistent fever, premature discontinuation and death. Underlying transition probabilities and treatment patterns were derived directly from trial data. Resource use was estimated using an expert panel. Cost inputs were obtained from the latest Australian representative sources. The perspective adopted was that of the Australian hospital system. Uncertainty and sensitivity analyses were undertaken via Monte Carlo simulation.. Caspofungin was associated with a net cost saving of AU$7245 (12.6%) per patient over LAmB (AU$50 267 versus AU$57 512). A similar trend was observed with cost per success and death prevented (AU$24 169 and AU$7270, respectively). Caspofungin dominated LAmB as it resulted in higher efficacy and lower costs when compared with LAmB. Persistent fever was the main contributing clinical outcome to the therapeutic costs of both antifungals. The results were most sensitive to therapy duration. Monte Carlo simulation suggested a 99.8% chance for LAmB to cost more than caspofungin.. This is the first economic study to evaluate the place of caspofungin as empirical therapy in Australia. Caspofungin is more cost-beneficial than LAmB, which contradicts the current Australian guidelines of recommending LAmB as the first choice for empirical therapy.

Topics: Amphotericin B; Antifungal Agents; Australia; Caspofungin; Echinocandins; Fever of Unknown Origin; Humans; Lipopeptides; Models, Statistical; Neutropenia; Treatment Outcome

A high intermittent dose regimen (group A: 10 mg kg(-1) on day 1, 5 mg kg(-1) on days 3 and 6) was compared with standard dosing (group B: 3 mg kg(-1) per day for 14 days) of liposomal amphotericin B (LAB) for empirical treatment of persistent febrile neutropenia. A total cumulative dose of 1275 mg (group A) and 2800 mg (group B) was administered. Infusion-related adverse drug events, mainly rigors/chills, occurred more frequently with group A (11/45, 24 % infusions) than with group B (12/201, 6 % infusions) (P=0.002), which extended the mean infusion time by 20 min (P=0.001). Creatinine levels were similar in the two regimens: the A : B ratio of the area under the curve for creatinine (AUC(CREATININE)) for days 2-7 was 1.09 (P=0.27) and for days 2-14 was 1.05 (P=0.51). Rises in creatinine were mild (clinical toxicity criteria 1) in all patients with elevations. Hypokalaemia tended to be less severe in group A with a lower proportion of hypokalaemic days [57/143 (39 %) vs 80/137 (58 %), P=0.21], a higher AUC(POTASSIUM) (A : B ratio of 1.06, P=0.12), a lower proportion of patients with hypokalaemia at the end of study (10 vs 61 %, P=0.01) and fewer potassium-supplemented days [12/210 (6 %) vs 41/210 (19.5 %), P<0.1]. There were mildly elevated median levels of serum bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, which were similar for the two regimens and were usually associated with other co-existing co-morbid conditions. The AUC for these enzymes was also similar in the two groups. No patient had discontinuation of the study drug due to toxicity. Composite success was identical for each regimen (11/15 patients, 73 %). Three of the fifteen patients in group B and none in group A developed invasive fungal infections (IFIs). Beta-D-Glucan levels were similar in both groups for patients without an IFI [AUC(GLUCAN) of 362 and 683 (P=0.36) for groups A and B, respectively]. The rate of defervescence was similar for each regimen (P=0.75). This feasibility study suggests that a short intermittent high-dose course of 10/5/5 mg LAB kg(-1) on days 1, 3 and 6 may be as safe and effective as a standard 14 day course of 3 mg kg(-1) per day, with drug-acquisition cost savings and reduced drug exposure. A larger study is indicated for confirmation of this.

Topics: Adolescent; Adult; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Drug Administration Schedule; Feasibility Studies; Female; Fever; Humans; Kidney; Liver; Male; Middle Aged; Mycoses; Neutropenia; Treatment Outcome; Young Adult

Invasive pulmonary aspergillosis (IPA) is a leading cause of mortality in immunocompromised patients, with the highest risk observed in patients with acute leukaemia or lung transplantation. IPA-prophylactic strategies include administration of aerosolized amphotericin-B. Liposomal amphotericin-B (L-AmB) is one of the formulations available, although few data exist on safety and tolerability.. Data on tolerability, systemic toxicity and effects of aerosolized L-AmB on pulmonary function were recorded in a subgroup out of 271 haematological patients enrolled in a placebo-controlled trial on the efficacy of aerosolized L-AmB for the prevention of IPA. Using an adaptive aerosol-delivery system, nebulization of L-AmB or placebo was performed during chemotherapy-induced neutropenia for 30 min/day on 2 consecutive days/week with a maximum of 6 weeks.. Thirty-eight patients (41 episodes) received L-AmB, 39 patients (49 episodes) received placebo. Proportions of patients with >20% post-nebulization decline in forced expiratory volume in 1s (FEV(1)) or forced vital capacity (FVC) did not differ between groups. Also 26/38 L-AmB patients (68%) versus 31/39 patients (79%) on placebo had no significant decline during the entire treatment (p=0.20). Coughing was significantly more reported in L-AmB patients (p<0.0001). No differences were observed when baseline and post-nebulization serum levels of renal function and hepatic enzymes were compared.. Short-term prophylactic nebulization of L-AmB was well tolerated and not associated with decline in pulmonary function or systemic adverse effects.

Topics: Adult; Aerosols; Aged; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Aspergillosis; Female; Forced Expiratory Volume; Humans; Kidney Function Tests; Liver Function Tests; Lung; Male; Middle Aged; Neutropenia; Placebos; Vital Capacity

In patients with hematologic malignancy, invasive aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. To investigate novel antifungal agents, we compared 53 patients who received posaconazole salvage therapy to 52 contemporary control patients who received high-dose lipid formulation of amphotericin B (HD-LPD/AMB at > or = 7.5 mg kg(-1) per day) and 38 other control patients who received caspofungin plus HD-LPD/AMB. Patients in the three groups had similar. The overall response rate to salvage therapy was 40% for posaconazole, 8% for HD-LPD/AMB (P < or = 0.001) and 11% for combination therapy (P < 0.002). Aspergillosis contributed to the death of 40% of posaconazole group, 65% of the HD-LPD/AMB group and 68% of the combination group (P < or = 0.008). By multivariate analysis, posaconazole therapy independently improved response (9.5; 95% confidence interval, 2.8-32.5; P < 0.001). HD-LPD/AMB alone or in combination was associated with a significantly higher rate of nephrotoxicity (P < or = 0.02) and hepatotoxicity (P < 0.03). In conclusion, posaconazole salvage therapy demonstrated greater efficacy and safety than HD-LPD/AMB alone or in combination with caspofungin in the salvage therapy of invasive aspergillosis in hematologic malignancy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Caspofungin; Combined Modality Therapy; Drug Combinations; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Itraconazole; Lipopeptides; Male; Middle Aged; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Pyrimidines; Salvage Therapy; Treatment Outcome; Triazoles; Voriconazole

Invasive pulmonary aspergillosis (IPA) is a significant problem in patients with chemotherapy-induced prolonged neutropenia. Because pulmonary deposition of conidia is the first step in developing IPA, we hypothesized that inhalation of liposomal amphotericin B would prevent IPA.. We performed a randomized, placebo-controlled trial of patients with hematologic disease with expected neutropenia for >or=10 days. Patients were randomized to receive liposomal amphotericin B or placebo inhalation twice a week, using an adaptive aerosol delivery system, until neutrophil counts increased to >300 cells/mm3. In subsequent neutropenic episodes, the assigned treatment was restarted. The primary end point was the occurrence of IPA according to European Organization for Research and the Treatment of Cancer-Mycoses Study Group definitions. Kaplan-Meier curves were compared with log-rank tests for intent-to-treat and on-treatment populations.. A total of 271 patients were studied during 407 neutropenic episodes. According to the intent-to-treat analysis, 18 of 132 patients in the placebo group developed IPA versus 6 of 139 patients in the liposomal amphotericin B group (odds ratio, 0.26; 95% confidence interval, 0.09-0.72; P=.005). According to the on-treatment analysis, 13 of 97 patients receiving placebo versus 2 of 91 receiving liposomal amphotericin B developed IPA (odds ratio, 0.14; 95% confidence interval, 0.02-0.66; P=.007). Some adverse effects, but none serious, in the liposomal amphotericin B group were reported, most frequently coughing (16 patients vs. 1 patient; P=.002).. In high-risk patients, prophylactic inhalation of liposomal amphotericin B significantly reduced the incidence of IPA.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Female; Humans; Kaplan-Meier Estimate; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Treatment Outcome

Safety, tolerability and efficacy of itraconazole and amphotericin B (AMB) were compared for empirical antifungal treatment of febrile neutropenic cancer patients.. In an open, randomised study, 162 patients with at least 72 h of antimicrobial treatment received either intravenous followed by oral itraconazole suspension or intravenous AMB for a maximum of 28 days. Permanent discontinuation of study medication due to any adverse event was the primary safety parameter. Efficacy parameters included response and success rate for both treatment groups.. Significantly fewer itraconazole patients discontinued treatment due to any adverse event (22.2 vs. 56.8% AMB; p < 0.0001). The main reason for discontinuation was a rise in serum creatinine (1.2% itraconazole vs. 23.5% AMB). Renal toxicity was significantly higher and more drug-related adverse events occurred in the AMB group. Intention-to-treat (ITT) analysis showed favourable efficacy for itraconazole: response and success rate were both significantly higher than for AMB (61.7 vs. 42% and 70.4 vs. 49.3%, both p < 0.0001). Treatment failure was markedly reduced in itraconazole patients (25.9 vs. 43.2%), largely due to the better tolerability.. Itraconazole was tolerated significantly better than conventional AMB and also showed advantages regarding efficacy. This study confirms the role of itraconazole as a useful and safe agent in empirical antifungal therapy of febrile neutropenic cancer patients.

Topics: Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Cross-Over Studies; Empiricism; Female; Fever of Unknown Origin; Germany; Hematologic Neoplasms; Humans; Infusions, Intravenous; Itraconazole; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Patient Dropouts; Treatment Outcome

Topics: Aged; Amphotericin B; Antifungal Agents; Drug Carriers; Female; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Mycoses; Neutropenia

Invasive mold infections continue to account for significant morbidity and mortality in immunocompromised patients; outcomes are dependent on both underlying host factors and appropriate therapy. The antifungal armamentarium has gradually increased during the past, with liposomal amphotericin B (L-AMB) being an important representative. Still, the question of what dose to use - a maximum tolerated or a minimum effective - has yet to be answered. On this basis, a randomized trial comparing a high-loading dose regimen with a standard dosing of L-AMB (AmBiLoad trial) for primary therapy of mold infections was initiated. No significant differences in response between the treatment groups were detected, although recipients of the 10-mg/kg daily dose experienced higher rates of nephrotoxicity and hypokalemia. Uncontrolled malignancy and allogeneic stem cell transplantation were significantly associated with poor survival. This article analyzes the study, discusses the rationale and the results and concludes that this study supports the routine application of L-AMB.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Dose-Response Relationship, Drug; Double-Blind Method; Hematologic Neoplasms; Humans; Hypokalemia; Nephrotic Syndrome; Neutropenia; Survival Rate; Treatment Outcome

In a recently reported randomized trial, low-dose intravenous liposomal amphotericin B (L-AmB) reduced the incidence of invasive fungal infections (20.2 vs. 4.6%, p < 0.001) in high-risk patients with hematological malignancies and prolonged neutropenia.. In the present study, we performed a retrospective cost-benefit analysis of L-AmB prophylaxis from the hospital perspective.. Ninety-nine patients were eligible; baseline characteristics were balanced for age, sex, underlying disease, and duration of neutropenia. The mean duration of hospitalization was 42.9 days and 52.3 days in the prophylaxis arm and in patients without antifungal prophylaxis, respectively (p = 0.096). The L-AmB prophylaxis was associated with additional costs of approximately EUR 630 per patient. However, total medication costs (including L-AmB prophylaxis) were EUR 1,219 and EUR 2,815 in patients with L-AmB prophylaxis and in patients in the control arm, respectively (p < 0.001). When involving also costs for medical procedures, the L-AmB prophylaxis reaches a positive net benefit of EUR 1,094 per patient.. Our data shows that antifungal prophylaxis, e.g. with L-AmB, can be a safe and effective strategy to reduce the frequency of invasive fungal infections in selected high-risk patients and to obtain significant cost savings for the hospital.

Topics: Amphotericin B; Antifungal Agents; Comorbidity; Cost of Illness; Cost-Benefit Analysis; Female; Germany; Hematologic Neoplasms; Humans; Incidence; Male; Middle Aged; Mycoses; Neutropenia; Risk Assessment; Risk Factors; Treatment Outcome

Sensitivity analyses were incorporated in a Phase III study of caspofungin vs. liposomal amphotericin B as empirical antifungal therapy for febrile neutropenic patients to determine the impact of varying definitions of fever resolution on response rates.. The primary analysis used a 5-part composite endpoint: resolution of any baseline invasive fungal infection, no breakthrough invasive fungal infection, survival, no premature discontinuation of study drug, and fever resolution for 48 h during the period of neutropenia. Pre-specified analyses used 3 other definitions for fever resolution: afebrile for 24 h during the period of neutropenia, afebrile at 7 days post therapy, and eliminating fever resolution altogether from the composite endpoint. Patients were stratified on entry by use of antifungal prophylaxis and risk of infection. Allogeneic hematopoietic stem cell transplants or relapsed acute leukemia defined high-risk patients.. In the primary analysis, 41% of patients in each treatment group met the fever-resolution criteria. Low-risk patients had shorter durations of neutropenia but failed fever-resolution criteria more often than high-risk patients. In each exploratory analysis, response rates increased in both treatment groups compared to the primary analysis, particularly in low-risk patients.. Response rates for the primary composite endpoint for both treatment groups in this study were driven by low rates of fever resolution. Requiring fever resolution during neutropenia in a composite endpoint can mask more clinically relevant outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Caspofungin; Double-Blind Method; Echinocandins; Female; Fever; Hematopoietic Stem Cell Transplantation; Humans; Lipopeptides; Male; Middle Aged; Mycoses; Neutropenia; Peptides, Cyclic; Risk Factors; Time Factors; Transplantation, Homologous; Treatment Outcome

We performed a prospective, randomized, open-label trial to evaluate the efficacy of low-dose liposomal amphotericin B (L-AmB) to reduce the incidence of invasive fungal infections (IFI) in patients with hematological malignancies and prolonged neutropenia (>10 days) following intensive chemotherapy.. In 219 neutropenic episodes (NE) of 132 patients randomization was performed. Patients received either 50 mg L-AmB every other day (arm A) or no systemic antifungal prophylaxis (arm B).. In the first NE of each patient the incidence of proven or probable IFI (primary end point) was five of 75 patients (6.7%) in arm A and 20 of 57 patients (35%) in arm B (P=0.001). Invasive aspergillosis occurred less frequently in patients receiving L-AmB-prophylaxis (P=0.0057), whereas the reduction of invasive candidiasis did not reach statistical significance (P=0.0655). In all NE the incidence of IFI was five of 110 NE (4.6%) in arm A versus 22 of 109 NE (20.2%) in arm B (P<0.01). Adverse events, possibly related to L-AmB, were observed in five NE (4.6%) and L-AmB was discontinued in three NE (2.8%). No grade 3 or 4 toxicities were observed.. Antifungal prophylaxis with low-dose L-AmB proved to be feasible and effective in our trial.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Female; Hematologic Neoplasms; Humans; Injections, Intravenous; Male; Middle Aged; Neutropenia

Amphotericin B dexoycholate is currently the standard empirical antifungal therapy for neutropenic patients with hematologic malignancies and who also have persistent fever that does not respond to antibacterial therapy. The antifungal triazoles offer a potentially safer and effective treatment alternative to Amphotericin B dexoycholate.. We assessed the efficacy and safety of intravenous itraconazole, as compared with the efficacy and safety of amphotericin B deoxycholate, as an empirical antifungal therapeutic agent in a matched case-control clinical trial from June 2004 to August 2005.. Efficacy was evaluated in 96 patients (48 received itraconazole and 48 received amphotericin B deoxycholate) and all the patients who received the study drugs were evaluated for safety. The baseline demographic characteristics were well matched. The overall success rates were 47.9% for itraconazole and 43.8% for amphotericin B deoxycholate (% difference: 4.1% [95% confidence interval for the difference: -15.8 to 24]), which fulfilled the statistical criteria for the non-inferiority of itraconazole. The proportions of patients who survived for at least seven days after discontinuation of therapy or who were prematurely discontinued from the study were not significantly different between the two groups. The rates of breakthrough fungal infections and resolution of fever during neutropenia were similar in both groups. More patients who received amphotericin B deoxycholate developed nephrotoxicity, hypokalemia or infusion-related events than did those patients who received itraconazole (nephrotoxicity: 16.7% vs. 1.8%, hypokalemia: 66.7% vs. 24.6%, and infusion-related events: 41.7% vs. 3.5%, respectively).. Intravenous itraconazole is as effective as amphotericin B deoxycholate and it is generally better tolerated than amphotericin B deoxycholate when it is given as empirical antifungal therapy for Korean patients with persistent neutropenic fever.

Topics: Adult; Amphotericin B; Antifungal Agents; Case-Control Studies; Chronic Disease; Female; Fever; Hematologic Neoplasms; Humans; Infusions, Intravenous; Itraconazole; Male; Neutropenia

The usefulness to diagnose and monitor invasive candidiasis (IC) using beta-glucan (BG) and antibodies against Candida albicans germ tubes (CAGT) was evaluated in a twice-weekly screening of 35 episodes in neutropenic adults at high risk. Three proven IC and three probable IC were assessed. Diagnostic levels of both markers were detected in 100% of proven IC and in 66% of probable IC. Sensitivity, specificity, positive and negative predictive values of BG and anti-CAGT antibodies detection were 83.3%, 89.6%, 62.5% and 96.3%, and 83.3%, 86.2%, 55.5%, 96.1%, respectively. False positive reactions occurred at a rate of 10.3% and 13.8% for the detection of BG and anti-CAGT antibodies, respectively. However, the patients with false positive results were different by each test. Both tests anticipated the clinical and radiological diagnosis, and the initiation of antifungal therapy in most patients. Combination of both tests improved specificity and positive predictive value to 100%.

Topics: Adolescent; Adult; Aged; Amphotericin B; Anemia, Aplastic; Antibodies, Fungal; Antibody Specificity; Antifungal Agents; Antigens, Fungal; beta-Glucans; Candida albicans; Candidiasis; False Positive Reactions; Female; Fluconazole; Fungemia; Hematologic Neoplasms; Hepatitis; Humans; Liposomes; Male; Middle Aged; Neutropenia; Patient Isolation; Predictive Value of Tests; Sensitivity and Specificity

Invasive candidiasis is a common and serious complication of cancer and its therapy.. We retrospectively identified patients with malignancies enrolled in a double-blind randomized trial of caspofungin (50 mg/day after a 70 mg loading dose) vs. conventional amphotericin B (0.6-1.0 mg/kg/day) as treatment of documented invasive candidiasis. A favorable response required complete resolution of signs and symptoms plus eradication of the Candida pathogen(s). The primary efficacy analysis used a modified intention-to-treat (MITT) approach that included all patients with a confirmed diagnosis of invasive candidiasis who received > or =1 dose of study medication.. 74/224 (33%) patients in the MITT population had active malignancies. 25/30 (83%) hematological malignancies were acute or chronic leukaemias. 22/44 (50%) solid tumors were related to the gastrointestinal tract. Patients with hematological malignancies tended to be younger (median [range] age: 49 [19-74] vs. 59 [19-81] years) and have higher baseline acute physiology and chronic health evaluation (APACHE) II scores (mean [range]: 17 [0-28] vs. 15 [5-35]) than patients with solid tumors. Neutropenia [< or =500/microl] was present on entry in 23 (77%) patients with hematological malignancies and in one (3%) patient with a solid tumor. Candidemia was demonstrated in 56 (88%) cancer patients. C. albicans was the single most frequent isolate in cancer patients, although the majority of cases were caused by non-albicans species. Cancer patients in the caspofungin arm had more hematological malignancies (55 vs. 29%), higher baseline APACHE II scores (>20 in 36 vs. 15%), more frequent neutropenia (42 vs. 24%), and less C. albicans infections (27 vs. 49%) than the amphotericin B-treated cancer patients. Favorable response rates were 11/18 (61%) and 6/12 (50%) for patients with hematological malignancies treated with caspofungin or amphotericin B, respectively; the corresponding outcomes in patients with solid tumors were 12/15 (80%) and 17/29 (59%) for the 2 treatment arms. 7/14 (50%) caspofungin- and 4/10 (40%) amphotericin B-treated patients who were neutropenic on entry responded favorably. All-cause mortality rates during the study for caspofungin recipients were 11/18 (61%) with hematological malignancies and 6/15 (40%) with solid tumors, and for amphotericin recipients were 4/12 (33%) with hematological malignancies and 6/29 (21%) with solid tumors.. Underlying cancers, most commonly leukaemias and gastrointestinal tumors, were present in one-third of patients enrolled in this study of invasive candidiasis. Overall, 70% of caspofungin-treated and 56% of amphotericin B-treated cancer patients responded favorably. Response rates were lower for neutropenic leukaemic patients than for non-neutropenic patients with solid tumors in both treatment groups.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Female; Fungemia; Gastrointestinal Neoplasms; Hematologic Neoplasms; Humans; Leukemia; Lipopeptides; Male; Middle Aged; Neoplasms; Neutropenia; Peptides, Cyclic; Retrospective Studies; Species Specificity; United States

The safety and efficacy of early bacterial prophylaxis with piperacillin-tazobactam were prospectively evaluated in 51 autologous peripheral blood stem cell transplantation (PBSCT) recipients. The results were compared with those obtained in 51 control patients receiving oral fluoroquinolones in a retrospective matched-pair control study. Overall, 76% of the study group and 98% of the control group developed at least one febrile episode during neutropenia (P=0.002). Time from neutropenia to the first febrile episode (FFE) was significantly longer in the study group than in the control group (P=0.04). Once a febrile episode appeared, the duration of fever was significantly longer in cases than in controls (median of 5 and 2 days respectively, P<0.001), and led to a more frequent use of empirical amphotericin B (AmB), not statistically significant (P=0.13). However, the total time of antibiotic administration was significantly greater in the control than in the study group (P=0.05). The duration of AmB treatment shows a trend toward a longer duration in the control than in study group (P=0.2). Overall, 86% of the Gram-positive bacteremia and 85% of the Gram-negative bacteria were susceptible to the tested antibiotics. Our study suggests that a subgroup of patients could benefit from prophylaxis with piperacillin-tazobactam without increasing toxicity or bacterial resistance.

Topics: Adolescent; Adult; Aged; Amphotericin B; Bacteremia; Bacterial Infections; Female; Fever; Fluoroquinolones; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Male; Matched-Pair Analysis; Middle Aged; Neutropenia; Penicillanic Acid; Peripheral Blood Stem Cell Transplantation; Piperacillin; Piperacillin, Tazobactam Drug Combination; Premedication; Transplantation, Autologous

Fungal infections are a major cause of morbidity and mortality in patients with hematological malignancies. Candida and Aspergillus species are the most important opportunistic fungal pathogens in this patient population. Amphotericin B is the treatment of choice, but its administration is often hampered by severe side-effects, which may be reduced by continuous infusion of this drug. We describe 17 consecutive patients with hematological malignancies, suffering from fever of unknown origin with possible fungal infections, treated with amphotericin B as continuous infusion compared with a control group of 10 patients treated with conventional rapid infusion of amphotericin B over 2 - 6 h. No acute side-effects or severe nephrotoxicity were observed during continuous infusion of amphotericin B. Target doses were reached faster in patients with continuous infusion of amphotericin B than in patients with rapid infusion. We conclude that continuous infusion of amphotericin B is safe in neutropenic patients with hematological malignancies.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; C-Reactive Protein; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Combinations; Female; Fever; Hematologic Neoplasms; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

Conventional amphotericin B (c-AmB) remains the empirical antifungal treatment of choice for neutropenic patients with persistent fever of unknown origin (FUO). Unfortunately, empirical treatment with c-AmB is hampered by its safety profile, with frequent infusion-related adverse events (IRAEs) and renal toxicity. Amphotericin B lipid complex (ABLC) has been investigated for this indication due to its low toxicity profile. The recommended dose of ABLC is 5 mg/kg/d, which is five to seven times higher than the recommended dose of c-AmB.. This randomized, controlled trial includes 105 adult patients with hematologic malignancies and with FUO after receiving chemotherapy or autologous stem cell transplantation. Patients were randomly allocated to receive ABLC at 1 mg/kg/d or c-AmB at 0.6 mg/kg/d for empirical antifungal therapy.. The incidence of renal toxicity was significantly lower in the ABLC group, compared with c-AmB group: 8% vs. 32%, respectively (P = 0.003). The rates of IRAEs were similar in both groups (73% for ABLC vs. 77% for c-AmB). The overall response rate was 72% for ABLC compared with 48% for c-AmB (P = 0.018). This difference was mainly due to the significantly higher renal toxicity in the c-AmB group. The number of emergent fungal infections and overall mortality were similar in both groups.. This randomized trial suggests that ABLC at 1 mg/kg/d produces less nephrotoxicity than c-AmB, without differences in the incidence of IRAEs and with similar efficacy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Drug Combinations; Female; Fever of Unknown Origin; Hematologic Neoplasms; Humans; Hypokalemia; Immunocompromised Host; Incidence; Kidney Diseases; Male; Middle Aged; Mycoses; Neutropenia; Peripheral Blood Stem Cell Transplantation; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

Patients with persistent fever and neutropenia often receive empirical therapy with conventional or liposomal amphotericin B for the prevention and early treatment of invasive fungal infections. Caspofungin, a member of the new echinocandin class of compounds, may be an effective alternative that is better tolerated than amphotericin B.. In this randomized, double-blind, multinational trial, we assessed the efficacy and safety of caspofungin as compared with liposomal amphotericin B as empirical antifungal therapy. At study entry, patients were stratified according to risk and according to whether they had previously received antifungal prophylaxis. A successful outcome was defined as the fulfillment of all components of a five-part composite end point.. Efficacy was evaluated in 1095 patients (556 receiving caspofungin and 539 receiving liposomal amphotericin B). After adjustment for strata, the overall success rates were 33.9 percent for caspofungin and 33.7 percent for liposomal amphotericin B (95.2 percent confidence interval for the difference, -5.6 to 6.0 percent), fulfilling statistical criteria for the noninferiority of caspofungin. Among patients with baseline fungal infections, a higher proportion of those treated with caspofungin had a successful outcome (51.9 percent vs. 25.9 percent, P=0.04). The proportion of patients who survived at least seven days after therapy was greater in the caspofungin group (92.6 percent vs. 89.2 percent, P=0.05). Premature study discontinuation occurred less often in the caspofungin group than in the amphotericin B group (10.3 percent vs. 14.5 percent, P=0.03). The rates of breakthrough fungal infections and resolution of fever during neutropenia were similar in the two groups. Fewer patients who received caspofungin sustained a nephrotoxic effect (2.6 percent vs. 11.5 percent, P<0.001), an infusion-related event (35.1 percent vs. 51.6 percent, P<0.001), or a drug-related adverse event or discontinued therapy because of drug-related adverse events.. Caspofungin is as effective as and generally better tolerated than liposomal amphotericin B when given as empirical antifungal therapy in patients with persistent fever and neutropenia.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Caspofungin; Double-Blind Method; Echinocandins; Female; Fever; Humans; Kidney Diseases; Lipopeptides; Liposomes; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Peptides; Peptides, Cyclic; Survival Rate; Treatment Outcome

We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Cause of Death; Child; Drug Resistance, Fungal; Female; Follow-Up Studies; Humans; Liposomes; Male; Middle Aged; Neutropenia; Nystatin; Salvage Therapy; Survival; Treatment Outcome

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.

Topics: Adult; Amphotericin B; Antifungal Agents; Candida; Candidiasis; Catheterization; Double-Blind Method; Drug Therapy, Combination; Female; Fluconazole; Fungemia; Humans; Male; Middle Aged; Neutropenia; Treatment Outcome

We assessed the impact of prophylaxis with the oral itraconazole solution and amphotericin B solution on fungal colonization and infection in a randomized study among patients with hematological malignancies and neutropenia. Infecting and colonizing Candida strains of patients suffering from candidiasis were genotyped by random amplification of polymorphic DNA (RAPD) analysis. A total of 106 patients were evaluated in this study: 52 patients in the itraconazole and 54 in the amphotericin B arm. During neutropenia fungal colonization in the oropharynx occurred in 11 (19.6%) and 24 (40.6%) and in the rectum in 11 (19.6%) and 23 (38.9%) courses in the itraconazole and amphotericin B groups ( P<0.05), respectively. Candida albicans was the most prevalent species in both study groups. Mixed fungal colonization with Candida krusei and Candida glabrata was increased in the amphotericin B group, yet without clinical importance since infections were due to C. albicans. The occurrence of invasive candidiasis was significantly increased in multicolonized compared to monocolonized patients. In the amphotericin B group 20 and in the itraconazole group 2 neutropenic patients showed multicolonization with Candida spp. ( P<0.05). Overall fungal infections were 3.8% in the itraconazole and 14.8% in the amphotericin B group ( P<0.05). RAPD typing showed oropharynx strains involved in superficial infections in four of five patients. In all four patients with deep fungal infections, it appears that the colonizing rectum strains were identical to infecting strains of Candida spp. Itraconazole solution significantly reduced Candida colonization and infection compared to amphotericin B solution. Most patients remained infected with the colonized strains for the entire study period, irrespective of antifungal prophylaxis.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Candida; Candidiasis; Genotype; Hematologic Neoplasms; Humans; Itraconazole; Neutropenia; Oropharynx; Random Amplified Polymorphic DNA Technique; Rectum

Caspofungin is an echinocandin agent with fungicidal activity against candida species. We performed a double-blind trial to compare caspofungin with amphotericin B deoxycholate for the primary treatment of invasive candidiasis.. We enrolled patients who had clinical evidence of infection and a positive culture for candida species from blood or another site. Patients were stratified according to the severity of disease, as indicated by the Acute Physiology and Chronic Health Evaluation (APACHE II) score, and the presence or absence of neutropenia and were randomly assigned to receive either caspofungin or amphotericin B. The study was designed to compare the efficacy of caspofungin with that of amphotericin B in patients with invasive candidiasis and in a subgroup with candidemia.. Of the 239 patients enrolled, 224 were included in the modified intention-to-treat analysis. Base-line characteristics, including the percentage of patients with neutropenia and the mean APACHE II score, were similar in the two treatment groups. A modified intention-to-treat analysis showed that the efficacy of caspofungin was similar to that of amphotericin B, with successful outcomes in 73.4 percent of the patients treated with caspofungin and in 61.7 percent of those treated with amphotericin B (difference after adjustment for APACHE II score and neutropenic status, 12.7 percentage points; 95.6 percent confidence interval, -0.7 to 26.0). An analysis of patients who met prespecified criteria for evaluation showed that caspofungin was superior, with a favorable response in 80.7 percent of patients, as compared with 64.9 percent of those who received amphotericin B (difference, 15.4 percentage points; 95.6 percent confidence interval, 1.1 to 29.7). Caspofungin was as effective as amphotericin B in patients who had candidemia, with a favorable response in 71.7 percent and 62.8 percent of patients, respectively (difference, 10.0 percentage points; 95.0 percent confidence interval, -4.5 to 24.5). There were significantly fewer drug-related adverse events in the caspofungin group than in the amphotericin B group.. Caspofungin is at least as effective as amphotericin B for the treatment of invasive candidiasis and, more specifically, candidemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; APACHE; Candida; Candidiasis; Caspofungin; Echinocandins; Female; Fungemia; Humans; Infusions, Intravenous; Lipopeptides; Male; Middle Aged; Neutropenia; Peptides; Peptides, Cyclic; Recurrence

Patients with neutropenia and persistent fever are often treated empirically with amphotericin B or liposomal amphotericin B to prevent invasive fungal infections. Antifungal triazoles offer a potentially safer and effective alternative.. In a randomized, international, multicenter trial, we compared voriconazole, a new second-generation triazole, with liposomal amphotericin B for empirical antifungal therapy.. A total of 837 patients (415 assigned to voriconazole and 422 to liposomal amphotericin B) were evaluated for success of treatment. The overall success rates were 26.0 percent with voriconazole and 30.6 percent with liposomal amphotericin B (95 percent confidence interval for the difference, -10.6 to 1.6 percentage points); these rates were independent of the administration of antifungal prophylaxis or the use of colony-stimulating factors. There were fewer documented breakthrough fungal infections in patients treated with voriconazole than in those treated with liposomal amphotericin B (8 [1.9 percent] vs. 21 [5.0 percent], P=0.02). The voriconazole group had fewer cases of severe infusion-related reactions (P<0.01) and of nephrotoxicity (P<0.001). The incidence of hepatotoxicity was similar in the two groups. Patients receiving voriconazole had more episodes of transient visual changes than those receiving liposomal amphotericin B (22 percent vs. 1 percent, P<0.001) and more hallucinations (4.3 percent vs. 0.5 percent, P<0.001). Parenteral voriconazole was changed to the oral formulation in 22 percent of the voriconazole group, with a reduction in the mean duration of hospitalization by one day in all patients (P=0.17) but by two days in patients at high risk (P=0.03).. Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Chemical and Drug Induced Liver Injury; Child; Chronic Disease; Female; Fever; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Prospective Studies; Pyrimidines; Triazoles; Voriconazole

Nephrotoxicity is the major adverse effect of amphotericin B (AmB), often limiting administration of full dosage. Selective distal tubular epithelial toxicity seems to be responsible for the profound potassium wasting that is a major clinical side effect of treatment with AmB. Potassium depletion also potentiates the tubular toxicity of AmB. This study was designed to assess the ability of spironolactone to reduce potassium requirements and to prevent hypokalemia in neutropenic patients on AmB treatment.. In this study 26 patients with various hematological disorders were randomized to receive either intravenous AmB alone or AmB and oral spironolactone 100 mg twice daily when developing a proven or suspected fungal infection.. Patients receiving concomitant AmB and spironolactone had significantly higher plasma potassium levels than those receiving AmB alone (P = 0.0027). Those patients receiving AmB and spironolactone required significantly less potassium supplementation to maintain their plasma potassium within the normal range (P = 0.022). Moreover, urinary potassium losses were significantly less in patients receiving AmB and spironolactone than those receiving AmB alone (P = 0.040).. This study showed that spironolactone can reduce potassium requirements and prevent hypokalemia by reducing urinary potassium loss in neutropenic patients on AmB treatment.

Topics: Amphotericin B; Antifungal Agents; Humans; Hypokalemia; Kidney Function Tests; Mineralocorticoid Receptor Antagonists; Mycoses; Neoplasms; Neutropenia; Potassium; Spironolactone

This study was conducted to characterise the pharmacokinetics of a liposomal pharmaceutical product of amphotericin B (LAB) in three neutropenic cancer patients complicated by suspected fungal infections. LAB was administered at a constant dose of 50 mg/day over 1--6 h by intravenous infusion, and blood samples were obtained between two infusion intervals without complicating the systemic therapy of the patients. Quantitative analysis of amphotericin B (AB) in plasma was established by a validated reversed-phase high-performance liquid chromatographic (HPLC) assay. Model independent pharmacokinetic parameters were estimated using area and moment analysis. Administration of LAB to the first patient (day 1) diagnosed as malignant melanoma resulted in a mean maximum concentration (C(max)) of 679+/-6 ng/ml and a mean minimum concentration (C(min)) of 139+/-9 ng/ml of AB. Pre-dose, C(max) and C(min) values of AB, after multiple LAB dosing to the other two patients both having acute myeloblastic leukemia were found to be 440+/-6, 1140+/-10, 409+/-11 ng/ml (day 19) and 408+/-3, 1180+/-10, and 283+/-1 ng/ml (day 9), respectively. The area under the plasma concentration-time curve (AUC) and the mean residence time (MRT) calculated between the two infusion intervals were 6180 ngh/ml, 7.79 h (day 1) for the first patient; 13,700 ng.h/ml, 10.5 h (day 19) and 14,000 ng.h/ml, 9.93 h (day 9) for the other two patients, respectively. The pharmacokinetic profiles and non-compartmental parameters calculated were comparable for both patients diagnosed with acute myeloblastic leukemia after multiple dosing at steady state, which also demonstrated a twofold increase in their AUC values compared with the AUC of the first patient. Although C(min) values supported the assumption that there was AB accumulation in plasma and this accumulation could be increased at high doses, LAB was administered safely to these patients and well tolerated at the doses given.

Topics: Adult; Amphotericin B; Antifungal Agents; Area Under Curve; Chromatography, High Pressure Liquid; Drug Carriers; Female; Humans; Infusions, Intravenous; Liposomes; Middle Aged; Neoplasms; Neutropenia; Spectrophotometry, Ultraviolet

To test the hypothesis that amphotericin B deoxycholate is less toxic when given by continuous infusion than by conventional rapid infusion.. Randomised, controlled, non-blinded, single centre study.. University hospital providing tertiary clinical care.. 80 mostly neutropenic patients with refractory fever and suspected or proved invasive fungal infections.. Patients were randomised to receive 0.97 mg/kg amphotericin B by continuous infusion over 24 hours or 0.95 mg/kg by rapid infusion over four hours.. Patients were evaluated for side effects related to infusion, nephrotoxicity, and mortality up to three months after treatment. Analysis was on an intention to treat basis.. Patients in the continuous infusion group had fewer side effects and significantly reduced nephrotoxicity than those in the rapid infusion group. Overall mortality was higher during treatment and after three months' follow up in the rapid infusion than in the continuous infusion group.. Continuous infusions of amphotericin B reduce nephrotoxicity and side effects related to infusion without increasing mortality.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Administration Schedule; Drug Combinations; Female; Follow-Up Studies; Humans; Kidney Diseases; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Prospective Studies; Survival Rate

The efficacy and safety of itraconazole oral solution and a combination of amphotericin B capsules plus nystatin oral suspension were compared in the prophylaxis of fungal infections in neutropenic patients. In an open, randomized, multicentre trial, 144 patients received itraconazole oral solution 100 mg bd, and 133 patients received amphotericin B 500 mg tds plus nystatin 2 MU qds. Overall, 65% of itraconazole-treated patients were considered to have had successful prophylaxis, compared with 53% in the polyene group. Proven deep fungal infections occurred in 5% of patients in each group. Fewer patients receiving itraconazole than amphotericin plus nystatin had superficial infections (3 versus 8%; P = 0.066). This trend in favour of itraconazole was seen in patients with profound neutropenia (neutrophil count <0.1 x 10(9) cells/L at least once) or prolonged neutropenia (neutrophil count <1.0 x 10(9) cells/L for >14 days). The median time to prophylactic failure was longer in the itraconazole group (37 days) than in the polyene group (34 days). The number of patients with fungal colonization (nose, sputum, stool) changed more favourably from baseline to endpoint in the itraconazole group than in the polyene group. Both treatments were safe and well tolerated; however, patients receiving amphotericin plus nystatin had a higher incidence of nausea and rash. In conclusion, itraconazole oral solution at doses of 100 mg bd and oral amphotericin B plus nystatin have similar prophylactic efficacy against fungal infections in neutropenic patients. On the basis of reduced incidence of superficial fungal infections, fungal colonization and specific adverse events, itraconazole may be the preferred treatment.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Female; Humans; Itraconazole; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Nystatin

To determine the usage patterns of the lipid-based amphotericin B formulations at our institution and to compare the observed nephrotoxicity and efficacy of these formulations.. Prospective and retrospective observational study. Urban 350-bed teaching hospital.. Sixty-seven nonhemodialysis patients who were prescribed greater than 3 days of amphotericin B lipid complex (ABLC) or liposomal amphotericin B (L-AmB) from 1996-1999.. Forty-six patients received ABLC and 21 received L-AmB. Oncology patients accounted for most prescriptions of both formulations. Amphotericin B lipid complex most frequently was prescribed for treatment of documented fungal infections (50%), followed by treatment of neutropenic fever (33%). Liposomal amphotericin B most frequently was prescribed for treatment of neutropenic fever (62%), followed by treatment of documented fungal infections (29%). Seventy-eight percent of patients treated with ABLC and 90% of those who received L-AmB were started on the lipid-based formulation due to being refractory or intolerant to prior antifungal therapy. Two (4.4%) patients receiving ABLC and four (19%) patients receiving L-AmB experienced nephrotoxicity at the end of therapy (NS). Of the patients with a documented fungal infection, 20 out of 23 (87%) of those treated with ABLC and 4 out of 5 (80%) of those treated with L-AmB had a complete or partial response to therapy (NS). One patient with febrile neutropenia had a breakthrough fungal infection while receiving L-AmB.. No significant differences in nephrotoxicity or efficacy were found between ABLC and L-AmB. Until further studies indicate clinically significant differences in nephrotoxicity between the two liposomal amphotericin B formulations, it is recommended that economics continue to be the major determinant for product selection.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Candidiasis; Child; Child, Preschool; Drug Carriers; Female; Humans; Kidney Diseases; Lipids; Liposomes; Male; Middle Aged; Neutropenia; Prospective Studies; Retrospective Studies

Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting.. To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy.. An open randomized, controlled, multicenter trial, powered for equivalence.. 60 oncology centers in 10 countries.. 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy.. Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution.. Defervescence, breakthrough fungal infection, drug-related adverse events, and death.. For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, -0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days.. Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.

Topics: Administration, Oral; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Deoxycholic Acid; Drug Combinations; Fever; Humans; Infusions, Intravenous; Itraconazole; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Risk Factors; Treatment Failure

Invasive fungal infections (IFI) are a major cause of morbidity and mortality in patients with cancer. A retrospective analysis of children with cancer at high risk for IFI treated at Münster University Hospital showed that the incidence (7.4% vs. 1.8%) and lethality (28.1% vs. 0) of documented IFI were lower in patients receiving systemic antifungal prophylaxis with liposomal amphotericin B (l-AmB) in comparison to a historical control group. To determine whether this decline in incidence and lethality was due to antifungal prophylaxis or was produced by advances in diagnostic procedures and early empirical antifungal therapy, a prospective study was initiated. Patients in the prophylaxis arm received thrice-weekly 1 mg kg(-1) body weight l-AmB, whilst patients in the early intervention arm received no prophylaxis. Diagnostic procedures and antifungal therapy for suspected or proven IFI were initiated as clinically indicated for all patients. The primary endpoint of the study was the incidence of IFI. Secondary endpoints were the use of therapeutic doses of l-AmB, the safety of prophylactic l-AmB, and the total consumption of l-AmB for antifungal therapy. The interim analysis after 1 year showed no differences between the two approaches with respect to the incidence of IFI and to safety issues.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Humans; Incidence; Infant; Infant, Newborn; Liposomes; Male; Mycoses; Neutropenia; Prospective Studies

To evaluate the efficacy of itraconazole capsules in prophylaxis for fungal infections in neutropenic patients, we conducted a prospective, double-blind, placebo-controlled, randomized trial. Patients with hematologic malignancies or those who received autologous bone marrow transplants were assigned either a regimen of itraconazole (100 mg orally twice daily; n=104) or of placebo (n=106). Overall, fungal infections (superficial or systemic) occurred more frequently in the placebo group (15% vs. 6%; P=.03). There were no differences in the empirical use of amphotericin B or systemic fungal infections. Among patients with neutropenia that was profound (<100 neutrophils/mm3) and prolonged (for at least 7 days), those receiving itraconazole used less empirical amphotericin B (22% vs. 61%; P=.0001) and developed fewer systemic fungal infections (6% vs. 19%; P=.04). For patients with profound and prolonged neutropenia, itraconazole capsules at the dosage of 100 mg every 12 h reduce the frequency of systemic fungal infections and the use of empirical amphotericin B.

Topics: Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Fungemia; Hematologic Neoplasms; Humans; Itraconazole; Male; Middle Aged; Neutropenia; Prospective Studies; Survival Rate; Transplantation, Autologous; Treatment Outcome

Systemic fungal infections are a major problem in bone marrow transplant recipients who have prolonged neutropenia or who receive high-dose corticosteroids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoing allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o. or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to >500/microl. Patients were removed from their study drug for drug-associated toxicity, invasive fungal infection or suspected fungal infection (defined as the presence of fever >38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day). Patients were randomized at each institution and stratified for the type of transplant. The primary end-point of the study was prevention of documented fungal infection; secondary endpoints included fungal colonization, drug toxicity, duration of hospitalization, duration of fever, duration of neutropenia, duration and total dose of high-dose amphotericin B and overall survival to hospital discharge. From July 1992 to October 1994, a total of 355 patients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age, sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was significantly more toxic than Fluconazole especially in related allogeneic transplantation where 19% of patients developed toxicity vs 0% of Fluconazole recipients (p < 0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal infection. Proven fungal infections occurred in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, respectively. Proven fungal infections occurred in 9.1% and 14.3% of related allogeneic marrow recipients receiving Fluconazole or amphotericin B, respectively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconazole or amphotericin B, respectively (P > 0.05). In this prospective trial, low-dose amphotericin B

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Confidence Intervals; Female; Fever; Fluconazole; Humans; Male; Middle Aged; Mycoses; Neutropenia; North America; Prospective Studies; Renal Insufficiency; Survival

We conducted an open label, randomised clinical trial to compare amphotericin B colloidal dispersion (ABCD, Amphocil) 2 mg/kg/day intravenously with fluconazole 200 mg/day orally, for the prevention of fungal disease in neutropenic patients with haematological malignancies. In the event of unresolved fever after 4 days of empirical antibacterial therapy, patients in both treatment groups were to receive ABCD, 4 mg/kg/day. However, the study had to be stopped in an early phase, due to severe side-effects of ABCD. A total of 24 patients were enrolled, 12 patients were randomly assigned to receive prophylactic ABCD, which was administered for a mean of 13.9 days. Fluconazole prophylaxis was given to 12 patients for a mean of 21.2 days. Therapeutic ABCD, 4 mg/kg, was initiated in four patients because of suspected fungal infection, all of whom had initially received fluconazole. A high rate of infusion-related toxicity of ABCD was observed. Chills occurred in 15/16 ABCD recipients (94%), accompanied by a temperature rise of >/=2 degrees C in 4/16 patients and of >/=1 degrees C but <2 degrees C in 10/16 patients. Other ABCD-related adverse events were hypotension (4/16), nausea with vomiting (5/16), tachycardia (7/16), headache (3/16) and dyspnoea (3/16). For premedication patients received: antihistamines (12/16), hydrocortisone (9/16) and/or morphine (6/16). ABCD was discontinued in 8/16 patients (50%) due to side-effects, which ultimately dictated early termination of the study. We conclude that ABCD is not suitable for antifungal prophylaxis in neutropenic patients due to severe infusion-related side-effects. Subject numbers were too low for conclusions on variables of antifungal efficacy.

Topics: Adolescent; Adult; Aged; Amphotericin B; Bilirubin; Consumer Product Safety; Contraindications; Female; Fluconazole; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Male; Middle Aged; Morphine; Mycoses; Neutropenia; Respiratory Tract Diseases; Shivering; Survival; Time Factors; Transaminases

In a randomized, double-blind, comparative, multicenter trial, liposomal amphotericin B was equivalent to conventional amphotericin B for empirical antifungal therapy in febrile neutropenic patients, using a composite end point, but was more effective in reducing proven emergent fungal infections, infusion-related toxicities, and nephrotoxicity. The purpose of this study was to compare the pharmacoeconomics of liposomal versus conventional therapy.. Itemized hospital billing data were collected on 414 patients from 19 of the 32 centers that participated in the trial. Hospital length of stay and costs from the first dose of study medication to the time of hospital discharge were assessed.. Hospital costs from the time of first dose to discharge were significantly higher for all patients who received liposomal amphotericin B ($48,962 v $43,183; P =.022). However, hospital costs were highly sensitive to the cost of study medication ($39,648 v $43,048 when drug costs were not included; P =.416). Using decision analysis models and sensitivity analyses to vary the cost of study medications and the risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients.. The cost of liposomal amphotericin B and patient risk for developing nephrotoxicity play large roles in determining whether liposomal amphotericin B is cost-effective as first-line empirical therapy in persistently febrile neutropenic patients.

Topics: Adult; Amphotericin B; Anti-Bacterial Agents; Antineoplastic Agents; Cost-Benefit Analysis; Double-Blind Method; Drug Carriers; Drug Costs; Economics, Pharmaceutical; Female; Fever; Hospital Costs; Humans; Kidney Diseases; Liposomes; Male; Middle Aged; Neoplasms; Neutropenia

Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 x 10(9) neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%]; P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of p

Topics: Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Double-Blind Method; Female; Hematologic Neoplasms; Humans; Itraconazole; Male; Middle Aged; Neutropenia

To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer.. A total of 317 neutropenic patients (<500 cells/mm3) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death.. A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with fluconazole (20 [13%] of 158 patients, P = 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P = 0.005). Overall mortality (27 [17%] patients treated with fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group.. Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy.

Topics: Amphotericin B; Antifungal Agents; Cause of Death; Female; Fever; Fluconazole; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Treatment Outcome

In this double-blind study to compare safety of 2 lipid formulations of amphotericin B, neutropenic patients with unresolved fever after 3 days of antibacterial therapy were randomized (1:1:1) to receive amphotericin B lipid complex (ABLC) at a dose of 5 mg/kg/d (n=78), liposomal amphotericin B (L Amph) at a dose of 3 mg/kg/d (n=85), or L Amph at a dose of 5 mg/kg/d (n=81). L Amph (3 mg/kg/d and 5 mg/kg/d) had lower rates of fever (23.5% and 19.8% vs. 57.7% on day 1; P<.001), chills/rigors (18.8% and 23.5% vs. 79.5% on day 1; P<.001), nephrotoxicity (14.1% and 14.8% vs. 42.3%; P<.01), and toxicity-related discontinuations of therapy (12.9% and 12.3% vs. 32.1%; P=.004). After day 1, infusional reactions were less frequent with ABLC, but chills/rigors were still higher (21.0% and 24.3% vs. 50.7%; P<.001). Therapeutic success was similar in all 3 groups.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Chills; Double-Blind Method; Drug Carriers; Female; Fever; Humans; Infusions, Intravenous; Liposomes; Male; Middle Aged; Mycoses; Nausea; Neutropenia; Survival Rate; Vomiting

Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Treatment with amphotericin B is the main therapeutic approach. However, this treatment is limited by the substantial toxicity. We present the data of the first randomized prospective comparative trial in adults (134 patients with fever of unknown origin) with conventional amphotericin B and a liposomal formulation of amphotericin B (AmBisome, published in 1997 by Prentice et al. (Br. J. Haematol. 98, 711-718) and the data of adults with documented fungal infections (59 patients), treated in this trial. Patients received either conventional amphotericin B 1 mg kg-1 per day, liposomal amphotericin B 1 mg kg-1 per day or liposomal amphotericin B 3 mg kg-1 per day. Patients were entered if they had fever of unknown origin (FUO), defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9) l-1). Efficacy of treatment was assessed, with success defined as resolution of fever for three consecutive days (< 38 degrees C) in the group of patients with FUO and the freedom of clinical signs and/or the elimination of fungus in the group of patients with documented fungal infections. The safety of treatment and renal and hepatic toxicity of liposomal and conventional amphotericin B were compared. No statistically significant difference was found in the treatment efficacy in the three study arms. However, there is a tendency of better treatment results in the two groups of patients, who received liposomal amphotericin B. Thirty-five per cent of patients with documented fungal infections and 46% of patients with FUO responded to amphotericin B. In the patients group, that received 1 mg kg-1 liposomal amphotericin B it was 63 and 49%, in the group of patients that received 3 mg kg-1 liposomal amphotericin B it was 47 and 64%. Evidence of toxicity due to amphotericin B was seen in 50 patients (83%), toxicity due to liposomal amphotericin B, 1 mg kg-1, was seen in 35 patients (50%), and due to liposomal amphotericin B 3 mg kg-1 in 34 patients (54%). This was a statistically significant difference (P = 0.001). It was concluded that liposomal amphotericin B was safer than conventional amphotericin B, but both formulations are equivalent in treatment efficacy. The prophylactic use of amphotericin B in these immunocompromised patients is discussed.

Topics: Adult; Amphotericin B; Child; Female; Fever of Unknown Origin; Humans; Liposomes; Male; Middle Aged; Mycoses; Neutropenia

In patients with persistent fever and neutropenia, amphotericin B is administered empirically for the early treatment and prevention of clinically occult invasive fungal infections. However, breakthrough fungal infections can develop despite treatment, and amphotericin B has substantial toxicity.. We conducted a randomized, double-blind, multicenter trial comparing liposomal amphotericin B with conventional amphotericin B as empirical antifungal therapy.. The mean duration of therapy was 10.8 days for liposomal amphotericin B (343 patients) and 10.3 days for conventional amphotericin B (344 patients). The composite rates of successful treatment were similar (50 percent for liposomal amphotericin B and 49 percent for conventional amphotericin B) and were independent of the use of antifungal prophylaxis or colony-stimulating factors. The outcomes were similar with liposomal amphotericin B and conventional amphotericin B with respect to survival (93 percent and 90 percent, respectively), resolution of fever (58 percent and 58 percent), and discontinuation of the study drug because of toxic effects or lack of efficacy (14 percent and 19 percent). There were fewer proved breakthrough fungal infections among patients treated with liposomal amphotericin B (11 patients [3.2 percent]) than among those treated with conventional amphotericin B (27 patients [7.8 percent], P=0.009). With the liposomal preparation significantly fewer patients had infusion-related fever (17 percent vs. 44 percent), chills or rigors (18 percent vs. 54 percent), and other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxic effects (defined by a serum creatinine level two times the upper limit of normal) were significantly less frequent among patients treated with liposomal amphotericin B (19 percent) than among those treated with conventional amphotericin B (34 percent, P<0.001).. Liposomal amphotericin B is as effective as conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia, and it is associated with fewer breakthrough fungal infections, less infusion-related toxicity, and less nephrotoxicity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Child; Child, Preschool; Double-Blind Method; Drug Carriers; Female; Fever; Humans; Infusions, Intravenous; Kidney; Liposomes; Male; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

Liposomal amphotericin (AmBisome) 2 mg/kg three times weekly was compared with placebo as prophylaxis against fungal infection in patients undergoing chemotherapy or bone marrow transplantation (BMT) for haematological malignancies. Prophylaxis began on day 1 of chemotherapy and continued until neutrophils regenerated or infection was suspected. Of 161 evaluable patients, 74 received AmBisome and 87 received placebo. Proven fungal infections developed in no patients on AmBisome and in three on placebo (3.4%) (P = NS). Suspected fungal infections requiring intervention with systemic antifungal therapy (usually amphotericin B) occurred in 31 patients on AmBisome (42%) and in 40 on placebo (46%) (P = NS). Suspected deep-seated infections developed in 21 (28.3%) and 31 (35.6%) patients, respectively (P = NS). Time to develop a suspected or proven deep-seated infection showed a trend in favour of AmBisome (P = 0.11). Fifty patients had fungal colonisation (48 with Candida spp, two with Aspergillus spp) of at least one body site during prophylaxis; 15 patients while receiving AmBisome (20%) and 35 while on placebo (40%) (P < 0.01). Time to colonisation was significantly delayed in the group receiving AmBisome (P < 0.05). Treatment-related toxicity was modest and no additional toxicity was observed in patients receiving AmBisome. AmBisome 2 mg/kg three times weekly is safe and reduces fungal colonisation in patients receiving intensive chemotherapy or BMT. However, despite encouraging trends, prophylactic AmBisome did not lead to a significant reduction in fungal infection or in requirement for systemic antifungal therapy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antigens, Fungal; Aspergillus; Candida; Double-Blind Method; Female; Humans; Liposomes; Lung Diseases, Fungal; Male; Middle Aged; Mycoses; Neutropenia; Placebos

Effective prophylaxis against fungal infection is important in neutropenic patients with hematologic malignancies, but the best method remains unclear. We investigated the effectiveness of fungal prophylaxis with amphotericin B or fluconazole. We reviewed the data on fungal isolates, plasma (1-->3)-beta-D glucan (beta-D glucan) levels, febrile periods (the number of days with an axillary temperature > 38 degrees C), and the duration of an axillary temperature > 38 degrees C when the neutrophil count was < 500/microliter. Of the 124 patients studied, 57 had acute myelogenous leukemia, 19 had acute lymphoblastic leukemia, 18 had non-Hodgkin's lymphoma, six had chronic myeloid leukemia, three had adult T-cell leukemia, and five had chronic lymphocytic leukemia. There were no significant differences in clinical characteristics between the 70 patients treated with amphotericin B and the 54 patients given fluconazole. There was a significant decrease of fungal isolates (chi 2-test, p < 0.001), the plasma beta-D glucan level (Wilcoxon test, p = 0.0001), and the febrile period (t-test, p < 0.05) in the patients given fluconazole compared with those given amphotericin B. In neutropenic patients with hematologic malignancies, prophylaxis with fluconazole significantly decreased fungal isolation and other indicators of fungal infection when compared with amphotericin B. Fluconazole may therefore be more effective for fungal prophylaxis in these patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Female; Fluconazole; Hematologic Neoplasms; Humans; Male; Middle Aged; Neutropenia; Opportunistic Infections

Invasive pulmonary aspergillosis (IPA) is a life-threatening infectious complication in neutropenic patients after high-dose chemotherapy or hematopoietic stem cell transplantation. Its diagnosis is mainly based on clinical symptoms, and radiological signs on thoracic CT scan. The value of bronchoscopy is controversial. We analyzed the diagnostic yield of bronchoscopy in 23 consecutive patients with histologically proven invasive pulmonary aspergillosis. In seven patients (30%) bronchoscopically obtained specimens were diagnostic for pulmonary fungal infection. Typical hyphae were detected by cytology in six patients and fungal cultures were positive in four cases. Patients with a positive bronchoscopic result presented more often with multiple changes on thoracic CT scan (71%; 5/7), but had received a lower median cumulative dose of amphotericine B (300 mg; 168-3010 mg) compared to patients with non-diagnostic bronchoscopy (25% multiple lesions (4/16); amphotericine dose 1100 mg, 260-2860 mg). The diagnostic yield of bronchoscopy was not associated with clinical symptoms or duration of neutropenia. Bronchoscopy allows the diagnosis of IPA in about one third of patients. Fungal cultures and cytological examination of intrabronchial specimens obtained during bronchoscopy have a high specificity, but its sensitivity is low. It is advisable to perform diagnostic bronchoscopy before starting antifungal therapy. Better diagnostic tools are urgently needed.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Bronchoscopy; Child; Female; Fever; Hematopoietic Stem Cell Transplantation; Humans; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Radiography, Thoracic; Time Factors; Tomography Scanners, X-Ray Computed

To assess the economic impact of adding granulocyte colony-stimulating factor (G-CSF) to amphotericin B to treat a presumed deep-seated fungal infection in neutropenic patients. This study was conducted from the perspective of the National Health Service (NHS) hospital sector.. We used our previously reported trial as the clinical basis for the analysis (see Participants and interventions). These data were combined with resource utilisation data, enabling us to construct a decision tree model of the treatment paths attributable to managing patients in each arm of the trial. The model was used to calculate the cost effectiveness of using amphotericin B plus G-CSF compared to amphotericin B monotherapy in neutropenic patients with a presumed deep-seated fungal infection.. An adult leukaemia/bone marrow transplant (BMT) unit in a large UK teaching hospital.. Patients with a neutrophil count of < 0.5 x 10(9)/L and having a presumed deep-seated fungal infection after either chemotherapy or stem cell/bone marrow transplantation for haematological malignancy.. 29 patients received intravenous amphotericin B (1 mg/kg daily) plus subcutaneous G-CSF (3 to 5 micrograms/kg daily) and 30 patients received intravenous amphotericin B (1 mg/kg daily) monotherapy. The clinical trial showed that 62% of patients responded to antifungal treatment with amphotericin B plus G-CSF compared to 33% of patients who responded to amphotericin B monotherapy (p = 0.027). Nonresponders went on to receive a lipid formulation of amphotericin B.. The mean cost per patient treated with amphotericin B plus G-CSF was 11,247 Pounds and the corresponding cost for amphotericin B monotherapy was 14,317 Pounds (1996/1997 values)--a cost reduction of 3070 Pounds per patient. Sensitivity analyses demonstrated that the addition of G-CSF to conventional amphotericin B in the treatment of a presumed deep-seated fungal infection offers not only clinical benefits, but cost benefits which are robust to changes in clinical and economic parameters.. From a UK hospital perspective, amphotericin B plus G-CSF is cost effective compared with amphotericin B monotherapy in managing a presumed deep-seated fungal infection in neutropenic patients. This result should provide strong arguments to clinicians and policy-makers for the adoption of this treatment strategy in such patients.

Topics: Adult; Amphotericin B; Antifungal Agents; Cost-Benefit Analysis; Decision Trees; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Mycoses; Neutropenia; United Kingdom

We compared the efficacy and tolerability of fluconazole (FCA) with amphotericin B/flucytosine (ABF) in neutropenic patients with haematological malignancies. Antifungal therapy started on day 4 when fever was unresponsive to antibiotics or on day 1 together with the antibiotics, if there was evidence of mycosis. If patients did not respond to FCA after 7 days they switched to ABF. 98 patients, 51 FCA and 47 ABF were included in the study. Response to fever was achieved in 28/51 FCA patients and in another 16 after switching to ABF. So in overall 44/51 (86.2%) of the FCA and 37/47 (78.8%) of the ABF group defervescence was observed. 46 patients (21 FCA, 25 ABF) developed radiological signs of pneumonia. Resolution of infiltrates was achieved in 5/21 FCA and 20/25 ABF patients, and another 10 of 15 initially not responding patients showed regression when switched to ABF, 5 of these had highly suspected aspergillosis. Adverse events occurred in 19.6% of FCA and 97.9% of ABF patients. In conclusion fluconazole and amphotericin B/flucytosine seem to be equally effective. In view of its lower toxicity fluconazole may be preferred as first line empiric antifungal agent, but in case of nonresponse, pneumonia or aspergillosis it may be replaced by amphotericin B combined with flucytosine.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Female; Fluconazole; Flucytosine; Humans; Male; Middle Aged; Mycoses; Neutropenia

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation; Humans; Hypokalemia; Lung; Lung Diseases, Fungal; Middle Aged; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

The purpose of this study was to test the comparative efficacy and toxicity of empiric gentamicin and ciprofloxacin, in combination with piperacillin, in febrile patients with treatment-induced neutropenia. Fifty patients were prospectively randomized to receive piperacillin plus gentamicin (PG), and 46 were randomized to receive piperacillin plus ciprofloxacin (PC). The groups were similar in age, sex, diagnosis, duration of neutropenia, and incidence of positive cultures. The two antibiotic regimens were associated with comparable rates of defervescence in the patients with gram-positive bacteremia. In the patients with gram-negative bacteremia and those with negative cultures, however, defervescence was more prompt in the PC group. In particular, 27% of the culture-negative patients on PC, compared to only 5% of those on PG, defervesced within 72 hr (P = 0.015). Because of the more prompt defervescence in the PC group, amphotericin B was used less frequently; 78% of the patients on PG compared with only 56% of those on PC were started on amphotericin B (P = 0.025). PC is an effective alternative to the more traditional PG for treatment of febrile neutropenic hosts who have not been given prophylactic quinolones. More important, PC appears to hasten defervescence compared with PG, especially in culture-negative patients and those with gram-negative bacteremia, and may decrease the necessity of additional antimicrobial agents such as amphotericin B.

Topics: Adult; Amphotericin B; Bacterial Infections; Ciprofloxacin; Drug Therapy, Combination; Female; Fever; Gentamicins; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycoses; Neutropenia; Piperacillin; Prospective Studies; Time Factors; Vancomycin

To compare the feasibility of treatment, safety, and toxicity of intravenous amphotericin B deoxycholate prepared in either glucose or intralipid for empirical antimycotic treatment of neutropenic cancer patients.. Single centre stratified, randomised non-blinded phase II study.. University hospital providing tertiary clinical care.. 51 neutropenic patients (leukaemia (35), lymphoma (11), solid tumours (5)) with refractory fever of unknown origin (24) or pneumonia (27).. Amphotericin B 0.75 mg/kg/day in 250 ml glucose 5% solution or mixed with 250 ml intralipid 20%, given on eight consecutive days then alternate days, as a 1-4 hour infusion.. Feasibility of treatment, subjective tolerance (questionnaire), and objective toxicity (common toxicity criteria of the National Cancer Institute).. Study arms were balanced for age, sex, underlying malignancy, renal and liver function, and pre- and concomitant treatment with antibiotics and nephrotoxic agents. No statistically significant or clinically relevant differences were found between the treatment groups for: daily or cumulative dose and duration of treatment with amphotericin B; incidence and time of dose modifications or infusion duration changes related to toxicity; dose or duration of symptomatic support with opiates, antipyretics, or antihistamines; renal function; subjective tolerance; most common toxicity scores; course of infection; and incidence of treatment failures. Patients treated with amphotericin B in intralipid were given fewer diuretics (P<0.05) and therefore had more peripheral oedema (P<0.01) and needed less potassium supplementation (P<0.05) than patients given amphotericin in glucose. Acute respiratory events were more common in the intralipid arm (P<0.05).. Amphotericin B 0.75 mg/kg/day in intralipid given on eight consecutive days then alternate days provides no benefit and is associated with potential pulmonary side effects possibly because of fat overload or an incompatibility of the two drugs.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Drug Carriers; Drug Compounding; Fat Emulsions, Intravenous; Feasibility Studies; Female; Fever of Unknown Origin; Glucose; Humans; Infusions, Intravenous; Male; Middle Aged; Neutropenia; Pneumonia; Prospective Studies

We conducted a prospective, randomized, double-blind study comparing amphotericin B colloidal dispersion (ABCD) with amphotericin B in the empirical treatment of fever and neutropenia. Patients with neutropenia and unresolved fever after > or = 3 days of empirical antibiotic therapy were stratified by age and concomitant use of cyclosporine or tacrolimus. Patients were then randomized to receive therapy with ABCD (4 mg/[kg.d]) or amphotericin B (0.8 mg/[kg.d]) for < or = 14 days. A total of 213 patients were enrolled, of whom 196 were evaluable for efficacy. Fifty percent of ABCD-treated patients and 43.2% of amphotericin B-treated patients had a therapeutic response (P = .31). Renal dysfunction was less likely to develop and occurred later in ABCD recipients than in amphotericin B recipients (P < .001 for both parameters). Infusion-related hypoxia and chills were more common in ABCD recipients than in amphotericin B recipients (P = .013 and P = .018, respectively). ABCD appeared comparable in efficacy with amphotericin B, and renal dysfunction associated with ABCD was significantly less than that associated with amphotericin B. However, infusion-related events were more common with ABCD treatment than with amphotericin B treatment.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Colloids; Cyclosporine; Double-Blind Method; Female; Fever; Humans; Immunosuppressive Agents; Infant; Infusions, Intravenous; Kidney Function Tests; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Pilot Projects; Prospective Studies; Tacrolimus; Treatment Outcome

It has been suggested that a better outcome of neutropenia-associated invasive fungal infections can be achieved when high doses of lipid formulations of amphotericin B are used. We now report a randomized multicentre study comparing liposomal amphotericin B (AmBisome, 5 mg/kg/d) to amphotericin B deoxycholate (AmB, 1 mg/kg/d) in the treatment of these infections. Of 106 possible patients, 66 were enrolled and analysed for efficacy: nine had documented fungaemia, 17 had other invasive mould infections and 40 had suspected pulmonary aspergillosis. After completion of the course medication, in the AmBisome group (n = 32) 14 patients had achieved complete response, seven a partial response and 11 were failures as compared to 6, 13 and 15 patients (n = 34) treated with AmB (P=0.09); P=0.03 for complete responders. A favourable trend for AmBisome was found at day 14, in patients with documented infections and in patients with pulmonary aspergillosis (P=0.05 and P=0.096 respectively). Mortality rates were lower in patients treated with AmBisome (adjusted for malignancy status, P=0.03). More patients on AmB had a >100% increase of their baseline serum creatinine (P<0.001). The results indicate that, in neutropenic patients with documented or suspected invasive fungal infections AmBisome 5 mg/kg/d was superior to AmB 1 mg/kg/d with respect to efficacy and safety.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Humans; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Survival Analysis; Treatment Outcome

Several studies have documented the efficacy of amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia. Amphotericin, however, is a toxic drug. Fluconazole has broad-spectrum antifungal activity with an excellent safety profile. Although prophylactic use of fluconazole is widespread, its efficacy as an empiric antifungal agent has not been extensively investigated.. We randomly assigned 106 patients with absolute neutropenia (< or = 500 cells microL) and persistent fever of undetermined origin (> 38 degrees C) despite 1 week of broad-spectrum antibiotic therapy to receive either fluconazole 400 mg orally daily or amphotericin B 0.5 mg/kg/day. Patients with obvious invasive fungal infections were excluded, as were those with abnormal renal or hepatic function. Success was defined as defervescence with the initially assigned antifungal regimen without development of clinically evident invasive fungal infection.. Six patients were excluded from the analysis, mostly because they did not have severe neutropenia. Forty-eight patients received amphotericin B, and 52 received fluconazole. Baseline clinical characteristics and laboratory parameters as well as duration of neutropenia (7.7 versus 6.9 days), duration of fever (7.8 versus 8.1 days), and duration of hospitalization (10.4 versus 8.3 days) were similar between those receiving amphotericin and fluconazole. Treatment success rates and mortality rates were similar in the two groups: 22 (46%) patients in the amphotericin group and 29 (56%) patients in the fluconazole group responded successfully to therapy (P = 0.3), whereas 16 (33%) patients in the amphotericin group and 14 (27%) patients in the fluconazole group died during hospitalization (P = 0.5). Adverse events such as chills and fever (4 versus 1), bronchospasm (2 versus none), severe hypokalemia (25 versus 12) and nephrotoxicity (9 versus 3) were more frequently observed in patients receiving amphotericin. Adverse prognostic factors included prolonged duration of neutropenia and pneumonia.. These results suggest that fluconazole is an equally effective but less toxic alternative to amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Female; Fever; Fluconazole; Humans; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Treatment Outcome

Bone marrow transplant (BMT) recipients are at increased risk of invasive fungal disease as a result of the profound neutropenia associated with transplantation. Amphotericin B lipid complex injection (ABLC, ABELCET) was developed to preserve the broad spectrum and fungicidal activity of conventional amphotericin B while avoiding its associated nephrotoxicity. ABLC was made available to physicians in an emergency-use program to treat seriously ill patients with advanced fungal infections who had failed to respond to previous systemic antifungal therapy (mostly amphotericin B), had experienced nephrotoxicity or severe acute toxicity due to amphotericin B or other drugs, or had pre-existing renal disease. Of 59 clinically evaluable BMT recipients with presumed or confirmed fungal infections, 31 (53%) responded to treatment: 23 (39%) were cured and eight (14%) improved. For 38 mycologically evaluable patients, pathogens were eradicated in 19 (50%). For 30 patients who began ABLC treatment with a serum creatinine > 221 mumol/l, significant reductions were observed at weeks 1 to 3 (P < 0.01) and 6 (P < 0.001). Trends in serum creatinine during ABLC therapy between autologous and allogeneic transplant recipients were similar. In summary, the results of this evaluation indicate that ABLC appears to be less nephrotoxic than conventional amphotericin B as well as an effective treatment for BMT recipients with presumed or confirmed fungal infections.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Child; Child, Preschool; Creatinine; Drug Combinations; Female; Humans; Male; Middle Aged; Mycoses; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols

To assess the clinical and economic benefit of low-dose (50 microg/m2) filgrastim after peripheral blood stem-cell transplantation (PBSCT) in a randomized, placebo-controlled double-blinded study.. Thirty-eight patients with lymphoproliferative disorders were randomized to receive low-dose filgrastim (19 patients) or placebo (19 patients) beginning on the first day after stem-cell reinfusion and continuing until absolute neutrophil count (ANC) was greater than 0.5 x 10(9)/L. All patients received greater than 2.5 x 10(6) CD34+ cells/kg, which was mobilized with chemotherapy and filgrastim 300 microg from the fifth day. An economic analysis was performed based on the outcome in the two groups.. Neutrophil engraftment was significantly more rapid in patients who received filgrastim with a median number of days until ANC was greater that 0.5 x 10(9)/L of 10 (9 to 13) versus 14 (9 to 19; P < .0001). The time to reach an ANC greater than 1 x 109/L was 12 (9 to 14) versus 16 days (10 to 25; P < .0001). The total number of patients who required intravenous antibiotic therapy was lower in the filgrastim-treated group (68%) compared with the placebo group (89%); also, the median number of days with fever and the duration of antibiotic therapy were shorter, although these differences did not reach statistical significance. However, although only three of 19 (16%) patients who received filgrastim required amphotericin, 11 of 19 (58%) who received placebo did require it, and amphotericin usage was significantly less in the filgrastim group (P = .029). Finally, in-patient stay was significantly shortened in those who received filgrastim from 16 (13 to 23) to 13 days (11 to 18; P = .0003).. Low-dose filgrastim significantly reduces neutrophil engraftment time post-PBSCT and also reduces in-patient stay and costs, which makes it economically viable for patients who are undergoing high-dose chemotherapy.

Topics: Adult; Aged; Amphotericin B; Anti-Bacterial Agents; Cost-Benefit Analysis; Double-Blind Method; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Length of Stay; Lymphoproliferative Disorders; Male; Middle Aged; Neutropenia; Neutrophils; Recombinant Proteins; Transplantation, Autologous; Treatment Outcome

Neutropenia-related fungal infections can be life-threatening despite antifungal therapy. We evaluated the role of recombinant granulocyte colony-stimulating factor (rG-CSF)-elicited white blood cell (WBC) transfusions in patients with neutropenia-related fungal infections. Adult patients with hematologic malignancies, absolute neutrophil counts (ANC) <500/microl and fungal infections refractory to amphotericin B, received daily transfusions of rG-CSF-elicited and irradiated WBC transfusions from related donors. Donors received 5 microg/kg/day of rG-CSF subcutaneously. Donors achieved a mean ANC of 29.4 x 10(3) per microliter. The mean yield of neutrophils per transfusion was 41 x 10(9) (range, 10-116). Fifteen patients received a median of eight transfusions (range, 3-16). Fourteen patients had received rG-CSF for a median of 12 days. The median ANC baseline was 20/microl. Eleven patients had favorable responses and eight of them remained free of infection 3 weeks after therapy. Favorable responses occurred among patients with better Zubrod performance status (median, 3 vs 4) and shorter duration of both profound neutropenia (median, 15 vs 25 days) and active infection (median, 8 vs 17 days). The mean 1- and 24-h post-transfusion ANCs were 594/microl (range, 98-1472/microl) and 396/microl (range, 50-1475/microl), respectively. Adverse reactions were observed in nine of 35 donors and in the recipients of six of 130 transfusions. rG-CSF-elicited WBC transfusions may be a safe and promising approach for treating neutropenia-related fungal infections.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Blood Donors; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Transfusion; Male; Middle Aged; Mycoses; Neutropenia; Pilot Projects; Prospective Studies

One hundred and thirty-four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive either conventional amphotericin B 1 mg/kg/d (c-AMB), liposomal amphotericin B 1 mg/kg/d(L-AMB1) or liposomal amphotericin B 3 mg/ kg/d (L-AMB3). Patients were entered if they had a pyrexia of unknown origin (PUO) defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9)/l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatment was assessed, with success defined as resolution of fever for 3 consecutive days (< 38 degrees C) without the development of any new fungal infection. Clinical and laboratory parameters were collected for safety analysis. In both the paediatric and adult populations, L-AMB treated patients had a 2-6-fold decrease in the incidence (P < or = 0.01) of test-drug-related side-effects, compared to c-AMB. Severe trial-drug-related side-effects were seen in 1% of L-AMB treated patients, in contrast to 12% of patients on c-AMB (P < 0.01). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline serum creatinine level, was not observed in the L-AMB1 arm whereas the incidence was 3% in patients on L-AMB3 and 23% in those on c-AMB (P < 0.01). Moreover, time to develop nephrotoxicity was longer in both L-AMB arms than c-AMB (P < 0.01). Severe hypokalaemia was observed less frequently in both L-AMB arms (P < 0.01). Analysis was by intention-to-treat and included all patients randomized. Success was defined by a minimum of 3 consecutive days with fever (< 38 degrees C) continuing to study end indicated by recovery of neutrophils to 0.5 x 10(9)/l. Addition of systemic antifungal therapy or development of systemic fungal infection were failures as was persistent fever to study end. Efficacy assessments indicated success in 49% of the total group treated with c-AMB, 58% of patients responded to L-AMB1 and 64% to L-AMB3. A statistically significant difference was found between c-AMB and L-AMB3 (P = 0.03) but a Kaplan-Meier analysis of time to differvescence of fever showed there was no significant difference between the arms. It was concluded that liposomal amphotericin at either 1 or 3 mg/kg/d was significantly safer than conventional amphotericin B in children and adults.

Topics: Adult; Amphotericin B; Antifungal Agents; Child; Female; Fever of Unknown Origin; Humans; Male; Mycoses; Neutropenia; Prospective Studies

Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examined in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concentration performed by high-pressure liquid chromatography. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger volume of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and volume of distribution were increased with dose, peak and trough concentrations after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estimated half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concentrations in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Area Under Curve; Chromatography, High Pressure Liquid; Drug Combinations; Drug Interactions; Half-Life; HIV Infections; Humans; Kidney Diseases; Leishmaniasis, Mucocutaneous; Mycoses; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Reference Values

The purpose of this study was to determine if patients with high vancomycin (VAN) serum levels experience more toxicity than underdosed patients with lower (VAN) levels, and whether low VAN serum levels cause therapeutic failures in patients with gram-positive bacteremia. In 198 cancer patients trough and peak serum levels of VAN were measured. Acute toxicity (Red Man syndrome) appeared in 3 patients (1.5%). Patients previously or currently treated with other nephrotoxic compounds (134 patients) presented the same incidence of nephrotoxicity as those receiving VAN for the first time in monotherapy (64 patients). VAN did not increase the toxicity when patients were dosed simultaneously or previously with aminoglycosides or amphotericin B. Our second observation, when studying serum levels in our 198 patients was that high VAN trough serum levels (trough > 15 microg/mL) were associated with significantly more nephrotoxicity (33.3% vs. 11.1%, P < 0.03) than low levels in the subgroups of either pretreated patients or unpretreated with other nephrotoxic drugs. None of 198 patients who had trough levels below 15 microg/mL had peak levels exceeding 40 microg/mL. This suggests that only serum monitoring of trough levels may predict nephrotoxicity. A case control study was conducted to compare a group of 22 VAN failures with 22 successfully treated patients matched in underlying disease and neutropenia who were treated in the same period, under the same antibiotic policy, at the same cancer center, for gram-positive bacteremia. Persisting, enterococcal, or mixed enterococcal plus staphylococcal bacteremia were the only statistically significant risk factors which predicted therapy failure in cancer patients. Neither peak nor trough VAN serum levels predicted failure or cure of gram-positive bacteremia in cancer patients.

Topics: Aminoglycosides; Amphotericin B; Anti-Bacterial Agents; Bacteremia; Case-Control Studies; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Humans; Kidney Diseases; Neoplasms; Neutropenia; Risk Factors; Slovakia; Vancomycin

Topics: Adult; Amphotericin B; Antifungal Agents; Child; Drug Carriers; Fever of Unknown Origin; Humans; Liposomes; Mycoses; Neutropenia; Randomized Controlled Trials as Topic

The pharmacokinetics of amphotericin B administered in a conventional 5% dextrose (glucose) (5% D) solution and in a 20% fat emulsion formulation (Intralipid; 20% IL) were compared in 16 patients (mean age, 42 years [range, 18 to 70 years]) who had been hospitalized for hematological malignancies and with proven or suspected fungal infections. All of the patients received 50 mg (approximately 1 mg/kg of body weight per day) of amphotericin B daily in random order, either as a 50-ml lipid emulsion (20% IL) (group I) or in 500 ml of 5% D (group II). Five serum samples were taken during the 24 h after drug administration, and the levels of amphotericin B were measured by high-pressure liquid chromatography. Serum amphotericin B concentrations declined rapidly during the first 6 h, and subsequent measurements revealed a slow terminal elimination phase in both groups. The maximum serum amphotericin B concentration was significantly lower when the drug was administered in 20% IL (1.46 +/- 0.61 versus 2.83 +/- 1.17 micrograms/ml; P = 0.02). The area under the concentration-time curve from 0 to 24 h was also much lower in group I (17.22 +/- 11.15 versus 28.98 +/- 15.46 micrograms.h/ml). The half-life of the distribution phase was approximately three times longer in group I (2.92 +/- 2.34 h versus 0.64 +/- 0.24 h; P = 0.011). Conversely, the half-lives of the elimination phase were approximately equal in the two groups (11.44 +/- 5.18 versus 15.23 +/- 5.25 h). The mean residence times were also similar in both groups (19.41 +/- 11.13 versus 19.65 +/- 7.86 h). The clearance and the steady-state volume of distribution of amphotericin B in group I were about twice as great as those in group II (62.97 +/- 35.51 versus 33.01 +/- 14.33 ml/kg/h and 1,043.92 +/- 512.10 versus 562.32 +/- 152.05 ml/kg [P = 0.034], respectively). Finally, the volume of distribution in the central compartment was greater in group I than in group II (618.17 +/- 231.80 versus 328.19 +/- 151.71 ml/kg; P = 0.013), but there were no differences in the volume of distribution in the peripheral compartment (425.75 +/- 352.87 versus 234.14 +/- 75.92 ml/kg). These results suggest that amphotericin B has a different pharmacokinetic profile when it is administered in 20% IL than when it is administered in the standard 5% D form and that the main difference is due to a clear-cut difference in the steady-state volume of distribution, especially that in the central compartment.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Fat Emulsions, Intravenous; Female; Half-Life; Humans; Male; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Solutions

Fungal infections are a major problem in patients with hematologic malignancy. Attempts to reduce their frequency with antifungal agents have not been successful. A double-blind, controlled, single-center trial was conducted with 96 consecutive patients undergoing 154 episodes of chemotherapy. Patients received 400 mg of fluconazole or placebo until bone marrow recovery or initiation of intravenous amphotericin B infusions. End points were amphotericin B use, fungal infection, stable neutrophil count > 0.5 x 10(9)/L, toxicity precluding further fluconazole use, and death. By Kaplan-Meier estimation, the time to initiation of amphotericin B therapy was shorter in 76 patients treated with placebo than in 75 treated with fluconazole (P = .003). Also, fluconazole reduced the number of febrile days by 20% (P = .002) and prevented oropharyngeal candidiasis (1/75 vs. 9/76, P = .018). The frequency of deep mycoses (8/76 vs. 8/75) and outcome were unaffected. Fluconazole did not have a favorable effect on infection-related health care costs and was associated with prolonged severe neutropenia (P = .01).

Topics: Adult; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Aspergillosis; Bacteremia; Candidiasis, Oral; Double-Blind Method; Drug Therapy, Combination; Fever; Fluconazole; Humans; Incidence; Infusions, Intravenous; Leukemia; Lymphoma; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

A pilot exploratory study was undertaken to collect preliminary information relating to safety and overall outcome in using intravenous fluconazole (FLUC) for managing antibiotic resistant neutropenic fever (ARNF), with the objective of assessing feasibility of performing a larger prospective controlled study. Patients who were neutropenic from treatment for leukaemia or bone marrow transplantation, received either fluconazole (FLUC) or amphotericin B (AB). Eight of 16 patients (50%) on FLUC and 21 of 25 patients (84%) on AB defervesced; the mean time to defervescence was 11.0 +/- 10.0 days for FLUC compared to 7.7 +/- 6.3 days for AB, and a similar proportion in each treatment group defervesced within 5 days (50% vs. 52%), respectively. Six of 16 patients (37.5%) on FLUC and three of 25 patients (12%) on AB developed overt invasive fungal disease, including pulmonary aspergillosis (FLUC 4 cases, AB 2 cases) and invasive candidiasis (FLUC 2 cases, AB 0 cases). The mean time to these events was 19.5 +/- 13.4 (FLUC) and 9.0 +/- 3.6 (AB) days. The fungal related mortality rates were higher in the FLUC group: five of 16 patients (31%) vs. two of 25 patients (18%) died respectively; the time to fungal death was 43.2 +/- 18.2 (FLUC) and 25.0 +/- 18.4 (AB) days. This tendency towards a more favourable outcome in patients on AB may have been due to absence of prior fluconazole prophylaxis in patients subsequently receiving IV FLUC. Analysis of a small subgroup of patients who had all received prior prophylaxis with clotrimazole only, indicated that a greater number of patients subsequently receiving IV FLUC died from fungal disease (5/16 vs.0/6, P = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amphotericin B; Aspergillosis, Allergic Bronchopulmonary; Bone Marrow Transplantation; Female; Fever; Fluconazole; Humans; Leukemia; Male; Mycoses; Neutropenia; Pilot Projects; Prospective Studies; Treatment Outcome

To determine the value of aerosol amphotericin B inhalations for prevention of invasive pulmonary aspergillosis (IPA), we initiated a prospective randomized multicenter trial. The scheduled intent-to-treat interim analysis included 115 patients (30%) with prolonged neutropenia after chemotherapy for acute myeloid leukemia, acute lymphoblastic leukemia/high-grade non-Hodgkin's lymphoma, or solid tumors undergoing autologous stem cell transplantation. Sixty-five patients had been randomized to receive prophylactic aerosol amphotericin B inhalations at a dose of 10 mg twice daily (group A); for the remaining 50 patients no aerosol amphotericin B prophylaxis was used (group B). No serious side effects from amphotericin B inhalations occurred, but coughing (54%), bad taste (51%), and nausea (37%) caused early cessation of aerosol amphotericin B prophylaxis in 23% (15/65) of courses. In group A, the incidence of proven, probably, or possible IPA was 5% (3/65) as compared with 12% (6/50) in group B (p > 0.05). Microbiologically documented bacterial pneumonias were observed in 5/65 (8%) patients in group A and in 1/50 (2%) patients in group B (p > 0.05). Thus, no reduction in incidence of IPA from use of prophylactic aerosol amphotericin B inhalations was found in this interim analysis. As there were no serious side effects from aerosol amphotericin B prophylaxis, accrual in the study will continue for a total of 380 patients.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Female; Humans; Leukemia; Lung Diseases, Fungal; Lymphoma; Male; Middle Aged; Neutropenia

To evaluate the usefulness of a 20% lipid emulsion as a delivery system for amphotericin B (1 mg/mL) administered over 1 hour to patients with neutropenia with hematologic malignancies compared with amphotericin B (0.1 mg/mL) administered in dextrose 5% solution over the same time.. A prospective, comparative, randomized, labeled study.. Hematology unit, pharmacy service, university general hospital.. Twenty patients with neutropenia with hematologic malignancies and proven or suspected fungal infections, 10 in the fat emulsion group (group 1) and 10 in the dextrose 5% group (group 2).. Clinical tolerance (i.e., fever, shaking chills, nausea, blood pressure, pulse rate) and biologic tolerance (i.e., urea, creatinine, sodium, potassium).. Clinical tolerance was comparable in both groups although amphotericin B in fat emulsion was better tolerated. Medication for symptoms related to the administration of amphotericin B was given in 6 cases in group 1 and in 8 cases in group 2. There was a statistically significant difference in the urea concentrations between the 2 groups (p = 0.023); there was an observed increase between the initial and the final serum urea (56.8 mg/d in group 1, 79.8 mg/dL in group 2). Statistically significant differences in creatinine serum concentrations (84.9 mumol/L in group 1, 123.8 mumol/L in group 2) (p = 0.047) were found. No differences were found in the antifungal efficacy of the treatment. However, as amphotericin B was started in the majority of cases (75%) as empiric treatment for fever unresponsive to antibiotic therapy, it is difficult to compare the efficacy of both preparations.. The clinical tolerance of lipid-emulsion infusions is similar to that of conventionally administered amphotericin B therapy. Renal toxicity appears to be decreased when the drug is administered in a fat emulsion. This type of preparation permits the reduction of the volume and the time of administration for amphotericin B therapy.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Fat Emulsions, Intravenous; Female; Glucose; Hematologic Diseases; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Solutions

Our previous experiences with liposomal amphotericin have suggested that it is an effective antifungal agent in neutropaenic patients with relatively few toxicity problems compared with conventional amphotericin B. This interim report presents early data from a single-centre, prospective randomised study with AmBisome. The study was designed to compare the early initiation of AmBisome in febrile neutropaenic patients (with haematological malignancy) with its later use, and to examine the efficacy and toxicity of different doses of this antifungal agent. Our experiences from the first 137 patients recruited (n = 200) are discussed, in addition to some of the difficulties that have arisen during the study.

Topics: Amphotericin B; Ceftazidime; Fever; Humans; Leukemia; Lymphoma; Neutropenia; Prospective Studies

The efficacy and toxicity of teicoplanin and vancomycin in the initial empirical antibiotic regimen in febrile, neutropenic patients with hematologic malignancies were compared in a prospective, randomized, unblinded, multicenter trial in the setting of 29 hematologic units in tertiary-care or university hospitals. A total of 635 consecutive febrile patients with hematologic malignancies and chemotherapy-induced neutropenia were randomly assigned to receive intravenously amikacin plus ceftazidime plus either teicoplanin at 6 mg/kg of body weight once daily or vancomycin at 1 g twice daily. An efficacy analysis was done for 527 evaluable patients: 275 treated with teicoplanin and 252 treated with vancomycin. Overall, successful outcomes were recorded for 78% of patients who received teicoplanin and 75% of those who were randomized to vancomycin (difference, 3%; 95% confidence interval [CI], -10 to 4%; P = 0.33). A total of 102 patients presented with primary, single-agent, gram-positive bacteremia. Coagulase-negative staphylococci accounted for 42%, Staphylococcus aureus accounted for 27%, and streptococci accounted for 21% of all gram-positive blood isolates. The overall responses to therapy of gram-positive bacteremias were 92 and 87% for teicoplanin and vancomycin, respectively (difference, 5%; CI, -17 to 6%; P = 0.22). Side effects, mainly represented by skin rash, occurred in 3.2 and 8% of teicoplanin- and vancomycin-treated patients, respectively (difference, -4.8%; CI, 0.7 to 8%; P = 0.03); the rate of nephrotoxicity was 1.4 and 0.8% for the teicoplanin and vancomycin groups, respectively (difference, 0.6%; CI, -2 to 1%; P = 0.68). Further infections were caused by gram-positive organisms in two patients (0.7%) treated with teicoplanin and one patient (0.4%) who received vancomycin (difference, 0.3%; CI, -0.9 to 1.0%; P = 0.53). Overall mortalities were 8.5 and 11% for teicoplanin- and vancomycin-treated patients, respectively (difference, -2.5%; CI, - 2 to 7%; P = 0.43); death was caused by primary gram-positive infections in three patients (1%) in each treatment group. When used for initial empirical antibiotic therapy in febrile, neutropenic patients, teicoplanin was at least as efficacious as vancomycin, but it was associated with fewer side effects.

Topics: Adolescent; Adult; Aged; Amikacin; Amphotericin B; Bacteremia; Ceftazidime; Drug Therapy, Combination; Female; Fever; Gram-Positive Bacterial Infections; Hematologic Diseases; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Prospective Studies; Teicoplanin; Vancomycin

The results are presented of two preliminary studies conducted to assess the role of GM-CSF as adjuvant treatment in neutropenic patients with bacterial or fungal infections. In the first study the effect of GM-CSF on the rate of response to antibiotics was assessed. Febrile neutropenic patients (n = 91) were randomized to receive ticarcillin-clavulanate plus netilmicin with or without GM-CSF (60 micrograms/m2). Response rates were significantly higher in patients who received antibiotics plus GM-CSF (p = 0.05). An increase in neutrophil count was seen in 89% of GM-CSF patients with initial low neutrophil counts (< 100/microliters) compared with 67% of control patients (p = 0.04). In the second study the activity of GM-CSF in patients with fungal infections was assessed. Neutropenic patients with documented fungal infections received amphotericin B plus GM-CSF. Of the eight evaluable patients, six responded and four had a complete response to treatment. The neutrophil counts of the two non-responding patients did not increase substantially during GM-CSF treatment and both died of their fungal infection. The prognosis of neutropenic patients with fungal infections is usually poor and the results of this pilot study are therefore very encouraging. The two studies show that GM-CSF is able to stimulate neutrophil recovery in neutropenic patients and may improve the response to antibiotic and antifungal treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Anti-Bacterial Agents; Bacterial Infections; Drug Therapy, Combination; Female; Fungemia; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Middle Aged; Neutropenia; Prospective Studies; Treatment Outcome

The association between colonization with Candida spp., subsequent occurrence of invasive candidiasis and empiric use of amphotericin B was investigated prospectively in 139 neutropenic patients with hematologic malignancies. Treatment with amphotericin B was required in 67% of patients colonized in multiple non-contiguous body sites (multicolonized) versus 31% of patients colonized in single or contiguous sites (monocolonized) and in 21% of non-colonized patients (p = 0.0037 and p = 0.00026, respectively). Invasive candidiasis was documented in 22.2% of multicolonized versus 4.8% of monocolonized patients and in none of the non-colonized patients (p = 0.035 and p = 0.0036, respectively). Analysis of the spectrum of colonizing Candida spp. showed that multicolonized subjects were colonized with increased frequently by Candida albicans compared to monocolonized subjects, and that the association between multicolonization, invasive candidiasis and amphotericin B usage was statistically significant in patients colonized by Candida albicans but not in patients colonized by other Candida species. The association between Candida multicolonization and the occurrence of Candida infection seems to be confirmed by a double-blind placebo-controlled study performed in a small subgroup of the multicolonized patients treated with fluconazole.

Topics: Adolescent; Adult; Aged; Amphotericin B; Candida; Candidiasis; Child; Child, Preschool; Colony Count, Microbial; Double-Blind Method; Female; Fluconazole; Hematologic Diseases; Humans; Male; Middle Aged; Neutropenia; Prospective Studies

Amphotericin B has long been the standard treatment for candidemia, but its use is complicated by its toxicity. More recently, fluconazole, a water-soluble triazole with activity against candida species and little toxicity, has become available. We conducted a multicenter randomized trial that compared amphotericin B with fluconazole as treatment for candidemia.. To be eligible, patients had to have a positive blood culture for candida species, a neutrophil count > or = 500 per cubic millimeter, and no major immunodeficiency. Patients were randomly assigned to receive either amphotericin B (0.5 to 0.6 mg per kilogram of body weight per day) or fluconazole (400 mg per day), each continued for at least 14 days after the last positive blood culture. Outcomes were assessed by a group of investigators blinded to treatment assignment.. Of the 237 patients enrolled, 206 met all entry criteria. The most common diagnoses were renal failure, nonhematologic cancer, and gastrointestinal disease. There was no statistically significant difference in outcome: of the 103 patients treated with amphotericin B, 81 (79 percent) were judged to have been treated successfully, as were 72 of the 103 patients treated with fluconazole (70 percent P = 0.22; 95 percent confidence interval for the difference, -5 to 23 percent). The bloodstream infection failed to clear in 12 patients in the amphotericin group and 15 in the fluconazole group; the species most commonly associated with failure was Candida albicans. There were 41 deaths in the amphotericin group and 34 deaths in the fluconazole group (P = 0.20). Intravascular catheters appeared to be the most frequent source of candidemia. There was less toxicity with fluconazole than with amphotericin B.. In patients without neutropenia and without major immunodeficiency, fluconazole and amphotericin B are not significantly different in their effectiveness in treating candidemia.

Topics: Amphotericin B; Candidiasis; Catheters, Indwelling; Female; Fluconazole; Follow-Up Studies; Fungemia; Humans; Male; Middle Aged; Neutropenia; Treatment Outcome

To compare the efficacy and tolerability of fluconazole and oral amphotericin B in preventing fungal infection in neutropenic patients with acute leukemia.. A randomized, controlled, multicenter trial.. 30 hematologic units in tertiary care or university hospitals.. 820 consecutive, afebrile, adult patients with acute leukemia and chemotherapy-induced neutropenia.. Patients were randomly assigned to receive fluconazole, 150 mg, as a once-daily capsule, or amphotericin B suspension, 500 mg every 6 hours.. An intention-to-treat analysis was done for 820 patients: 420 treated with fluconazole and 400 treated with oral amphotericin B.. Definite systemic fungal infection occurred in 2.6% of fluconazole recipients and 2.5% of amphotericin B recipients; suspected systemic fungal infection requiring the empiric use of intravenous amphotericin B occurred in 16% of fluconazole recipients and 21% of oral amphotericin B recipients, a difference of 5 percentage points (95% CI for difference, -0.02% to 10%; P = 0.07). Superficial fungal infection was documented in 1.7% of fluconazole recipients compared with 2.7% of amphotericin B recipients, a difference of one percentage point (CI of difference, -0.9% to 3%; P > 0.2). The distribution of fungal isolates in systemic and superficial fungal infection was similar in both groups. The overall mortality rate accounted for 10% in both groups. An excellent compliance was documented for 90% of patients treated with fluconazole compared with 72% of those treated with amphotericin B suspension, a difference of 18 percentage points (CI for difference, 13% to 23%). Side effects were documented less frequently in fluconazole than in amphotericin B recipients (1.4% compared with 7%, a difference of 5.6 percentage points; CI for difference, 2% to 8%; P < 0.01).. Fluconazole was at least as effective as oral amphotericin B in preventing systemic and superficial fungal infection and the empiric use of amphotericin B in neutropenic patients with acute leukemia but was better tolerated.

Topics: Acute Disease; Administration, Oral; Administration, Topical; Adolescent; Adult; Aged; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Child; Female; Fluconazole; Humans; Leukemia; Male; Middle Aged; Mycoses; Neutropenia; Patient Compliance; Treatment Outcome

The pharmacokinetics and applicability of aerosol amphotericin B administrations were studied in 40 neutropenic patients and 4 healthy volunteers. Particle size was measured and pulmonary deposition was demonstrated by radioisotope studies. Inhalations were easy to administer and were well tolerated, with minimal systemic absorption of the drug.

Topics: Administration, Inhalation; Administration, Oral; Aerosols; Amphotericin B; Aspergillosis; Humans; Lung Diseases, Fungal; Neutropenia; Particle Size; Tissue Distribution

An open, randomized study was performed at 18 European centres to compare the efficacy, safety and tolerance of oral fluconazole with oral polyenes for the prophylaxis of fungal colonization and infection in adults at high risk of developing neutropenia. Five hundred and thirty-six hospitalized patients with malignant disease, about to receive chemotherapy, radiotherapy, or bone marrow transplantation, and who were already neutropenic or were expected to develop neutropenia were included in the study. Before therapy or transplantation, patients commenced either oral fluconazole therapy (50 mg/day as a single dose) or oral polyenes therapy (amphotericin B 2 g/day and/or nystatin 4 x 10(6) units/day in four or more divided doses), for a mean of 29.3 days and 31.3 days, respectively. After baseline clinical and mycological testing, patients were re-evaluated at least weekly during prophylaxis, at the end of prophylaxis and two to six weeks later to identify proven or suspected fungal infection and to determine rates of colonization with fungi. Fungal infection was diagnosed in 41 of 511 evaluable patients, 10 (3.9%) of 256 in the fluconazole group and 31 (12.2%) of 255 in the polyene group (P = 0.001). This total included four patients (1.6%) in the fluconazole group who developed oropharyngeal candidiasis compared with 22 (8.6%) in the polyene group (P < 0.001). Systemic infections comprised 6 (2.3%) in the fluconazole group and 9 (3.5%) in the polyene group (P = not significant), and included three Candida krusei infections in each group. Parenteral amphotericin B therapy was given empirically for persistent fevers in an additional 62 (24.2%) patients receiving fluconazole and 59 (23.1%) receiving polyenes (P = not significant). Colonization with fungi was generally similar in each treatment group, although an increased proportion of patients receiving fluconazole developed colonization of the faeces (P < 0.01). Adverse reactions, possibly related to treatment, were recorded in 15 (5.6%) of 269 patients in the fluconazole group and 14 (5.2%) of 267 in the polyene group; these necessitated discontinuation of therapy in seven patients in each group. Once-a-day fluconazole was therefore more effective than oral polyenes for the prevention of oropharyngeal fungal infection and as effective for the prevention of infections at other sites in patients with neutropenia.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Child; Female; Fluconazole; Humans; Male; Middle Aged; Mycoses; Neutropenia; Nystatin

Systemic Candida infections are a major cause of infectious morbidity and mortality during chemotherapy-induced neutropenia. Because of the unreliability of conventional diagnostic tests to detect systemic infection early in its course, treatment of established disseminated Candida infection has been generally disappointing with mortality rates of 60-80% in leukemia and bone marrow transplant patients and 30-40% in solid tumor patients. The use of empiric amphotericin B in patients with fever not responding to empiric antibacterial agents has been shown to be successful in reducing morbidity and mortality from fungal infections. However, its toxicity has mitigated the success of this approach. Fluconazole given prophylactically at the institution of chemotherapy has been shown to be a safe and effective alternative. It, however, is not active against all fungal species, especially Aspergillus and some of the less virulent Candida species. Some centers have reported break-through infections by these less susceptible organisms. Whether or not these limitations in its spectrum of activity will limit its usefulness in the future remains unanswered at this time and could pose a cloud to an otherwise bright promise.

Topics: Amphotericin B; Bone Marrow Transplantation; Candidiasis; Disease Susceptibility; Double-Blind Method; Fluconazole; Humans; Immunocompromised Host; Neoplasms; Neutropenia; Survival Rate

Treatment of fungal infections in neutropenic patients continues to be a major problem for the clinician. Treatment of such infections with amphotericin B is difficult, because of its many side-effects. In a neutropenic mouse model, itraconazole appeared to be as effective as amphotericin B against Candida albicans, and was more effective than amphotericin B in treating an Aspergillus infection in a patient with chronic granulomatous disease. In a randomized, comparative trial of itraconazole and amphotericin B as treatment for Candida and Aspergillus infections, 32 neutropenic patients were evaluated. Patients received either oral itraconazole, 200 mg twice daily, intravenous amphotericin B, 0.6 mg/kg/day, or in some cases of Candida infection intravenous amphotericin B, 0.3 mg/kg/day, plus flucytosine, 150 mg/kg/day. The causative organism of fungal infection was Candida spp. in 16 patients and Aspergillus spp. in 13 patients; 27 patients had pneumonia. The median duration of treatment was 13 days with amphotericin B and 20 days with itraconazole. Nine of 16 patients responded to amphotericin B, and 10 of 16 patients responded to itraconazole. Of the patients with Aspergillus infection, 6/8 treated with itraconazole and 2/5 treated with amphotericin B responded. Three patients with Aspergillus infection died in the amphotericin B arm and none in the itraconazole arm; 2 patients treated with itraconazole died from candidal infections. Absorption of itraconazole was unreliable in these seriously ill patients with disturbed gastrointestinal function. These results suggest that itraconazole could be an effective drug against systemic fungal infections in neutropenic patients. One retrospective study also suggest that itraconazole is superior to ketoconazole in prophylaxis for Aspergillus infections. Further studies are needed.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Humans; Itraconazole; Ketoconazole; Mycoses; Neutropenia

Invasive aspergillosis continues to be a significant cause of morbidity and mortality in patients with prolonged neutropenia. We performed a phase I trial of escalating doses of aerosolized amphotericin B given by a face mask nebulizer system with a disposable bacterial exhale filter. Five, 10, 15, and 20 mg of drug were dissolved in sterile water and inhaled over 10 to 15 minutes twice daily. Tolerance was studied in 26 patients (18 transplant recipients, and 8 leukemia patients). No side effects were observed at any dose level. Prophylactic treatment ended for 14 patients (54%) when intravenous (IV) amphotericin B was begun empirically for antifungal coverage following fevers. Eleven patients (43%) continued inhaled amphotericin B until blood counts recovered. One patient was taken off study when she developed cardiogenic pulmonary edema. No patient developed clinically suspicious or pathologically documented infection with invasive aspergillosis. Prophylactic aerosolized amphotericin B is well tolerated at 5, 10, 15, and 20 mg twice daily dosing. In addition, prophylactic aerosolized amphotericin B does not appear to sensitize patients to the subsequent use of IV amphotericin B. Although this study suggests that prophylactic inhaled amphotericin B is well tolerated and effective, a large scale controlled trial is needed.

Topics: Adult; Aerosols; Amphotericin B; Aspergillosis; Bone Marrow Transplantation; Female; Humans; Immunocompromised Host; Incidence; Leukemia; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Opportunistic Infections; Pilot Projects

The clinical use of amphotericin B is sometimes limited by nephrotoxicity. In a randomized prospective study, 32 patients treated for haematological malignancies received either amphotericin B in 5% dextrose (group A, 16 patients, 0.7-1 mg/kg/day), or amphotericin B mixed with Intralipid (group B, 16 patients, 0.7-1 mg/kg/day) during prolonged neutropenia. Renal dysfunction occurred in 9/16 patients in group A and 2/16 patients in group B (P < 0.05). Clinical tolerance was improved with a reduction of fever with chills in 12/16 patients in group A compared with 5/16 in group B (P < 0.05). Preparation of amphotericin B with Intralipid reduces nephrotoxicity, improves clinical tolerance, may allow an increase in the daily dose of amphotericin B, and be an alternative to liposomal-amphotericin B infusion.

Topics: Adult; Aged; Amphotericin B; Creatinine; Drug Therapy, Combination; Drug Tolerance; Fat Emulsions, Intravenous; Female; Humans; Kidney; Male; Middle Aged; Mycoses; Neutropenia

The use of high-dose chemotherapy and the subsequent prolonged neutropenia in patients with haematological diseases has resulted in an increased incidence of fungal infections. The only drug with proven efficacy in the treatment of deep seated fungal infections or invasive aspergillosis is amphotericin B. Unfortunately, this drug has adverse side effects, most importantly dose dependent nephrotoxicity. Furthermore, some patients fail to show a response to amphotericin B. We have treated 40 patients undergoing myeloablative chemotherapy and or bone marrow transplantation for haematological diseases with liposomal amphotericin for proven or suspected fungal infections. All patients had failed treatment with conventional Amphotericin B. Fourteen patients received liposomal amphotericin (AmBisome) due to progression of infection on conventional amphotericin B. Twenty six patients received liposomal amphotericin due to nephrotoxicity caused by conventional Amphotericin B. Nine patients had mycologically proven fungal infection and of these, 7 patients (78%) showed a complete response to liposomal amphotericin. Thirty one patients received liposomal amphotericin due to suspected fungal infection. Eleven of these 31 patients (35%) showed a complete clinical response to liposomal amphotericin. However in the patients with suspected fungal infections 14 patients had no response and 6 patients could not be evaluated for response to liposomal amphotericin. Overall, of the 18 patients showing a response to liposomal amphotericin, 15 patients had either recovered their neutrophil count (> 0.5 x 10(9)/l) or achieved remission from their underlying haematological disease. Recovery from fungal infection in this group of patients occurred when there was complete remission of underlying disease and recovery of neutrophil counts, when concurrently treated by liposomal amphotericin.

Topics: Adolescent; Adult; Aged; Amphotericin B; Child; Female; Humans; Leukocyte Count; Liposomes; Male; Middle Aged; Mycoses; Neutropenia

This study assessed the efficacy, toxicity, and pharmacology of low-dose amphotericin B given prophylactically to patients (serum concentrations of 0.2-0.4 microgram/ml) undergoing bone marrow transplantation. Yeast isolates from patients' oropharyngeal areas had MICs of 0.1-0.2 microgram/ml, and none were amphotericin B resistant. The effect of low-dose amphotericin B on reducing the numbers of yeast colonizing the oropharyngeal area was significant (P less than .01). The average delay in switching to high-dose prophylactic amphotericin B was only 1 day; the decision to do so because of a perceived fungal infection occurred more frequently for the placebo group (P = .06). Fewer patients from the low-dose amphotericin B group (8.8%) than from the placebo group (14.3%) had fungi isolated from normally sterile body sites (P = .35). Infusion-related side effects but not systemic toxicities were significantly greater (P less than .001) in the amphotericin B group. The 6-week survival was greater in those receiving amphotericin B (P less than .03), but the improved survival could not be attributed to the prevention of fungal infections.

Topics: Adult; Amphotericin B; Bone Marrow Transplantation; Candidiasis, Oral; Female; Humans; Infusions, Intravenous; Male; Mycoses; Neutropenia; Oropharynx

In a randomised clinical trial, we compared the efficacy of the new triazole drug itraconazole (200 mg orally twice daily) with that of amphotericin B (0.6 mg/kg daily or 0.3 mg/kg in combination with flucytosine) in neutropenic (less than 500 x 10(6)/l neutrophils) patients with proven or highly suspected systemic fungal infections. Patients with unexplained fever alone were not included in the study. Of the 40 patients enrolled, 32 patients (16 males, 16 females) were evaluable. Sixteen patients (median age 49 years) were treated with itraconazole for a median period of 20 days and 16 patients (median age 32 years) received amphotericin B for a median period of 13 days. The overall clinical response was 10/16 (63%) for patients treated with itraconazole and 9/16 (56%) for patients treated with amphotericin B (P greater than 0.90). Itraconazole seemed to be more effective against Aspergillus infections, whereas amphotericin B seemed to be more effective against candidal infections, although the differences were not statistically significant.

Topics: Amphotericin B; Aspergillosis; Aspergillus fumigatus; Candidiasis; Drug Therapy, Combination; Female; Flucytosine; Humans; Itraconazole; Ketoconazole; Male; Middle Aged; Neutropenia; Prospective Studies

Forty patients with acute leukemia (age 16-71 years, 13 females, 27 males) with induced neutropenia due to chemotherapy received either 50 mg fluconazole or 800 mg amphotericin B per day orally as prophylaxis against fungal infection. Nasal and genital swabs, mouth washings, urine, stool and blood serum were taken for mycological and serological examination before and weekly during one episode of neutropenia (less than 10(9) granulocytes/l) per patient. The quantitative determination of the yeast concentration in stool specimens demonstrated that amphotericin B led to intestinal yeast count reduction in only one third of the patients and could not prevent the increase of the intestinal yeast flora in another third of the patients. Beyond that the quantitative determination of yeast colonization in oropharynx, genital region, blood and stool did not prove to be a reliable tool for evaluating the host-fungus relationship during neutropenia. On the other hand mycoserology reflected episodes of candidosis well. 19 patients treated with fluconazole showed only minor titer increases. In 21 patients treated with amphotericin B, four fungemias were found: two by both hemagglutination (HAT) and immunofluorescence (IFT), one by IFT and one by antigen detection (Ramco Cand-Tec) alone. In only one of these cases yeast cells were released in urine. From these results is concluded that control of serology is essential in studies of that type and that fluconazole seems to provide better protection from candidosis than amphotericin B during induced neutropenia.

Topics: Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Antineoplastic Agents; Female; Fluconazole; Humans; Leukemia; Male; Middle Aged; Mycoses; Neutropenia

Teicoplanin is a glycopeptide antibiotic with a mode of action and spectrum of activity similar to those of vancomycin. Its efficacy and tolerability as empiric therapy and its pharmacokinetic properties in neutropenic patients are being studied in a double-blinded, randomized trial in comparison with those of vancomycin. We report here a modified agar diffusion bioassay which is suitable for monitoring levels of either teicoplanin or vancomycin in serum during combination therapy with beta-lactams, aminoglycosides, and amphotericin B. Serum samples spiked with either teicoplanin or vancomycin gave reproducible results (mean coefficient of variation, 8.8%) regardless of the presence of tobramycin, amikacin, piperacillin, ceftazidime, amphotericin B, or their combinations. Among 25 patients who received teicoplanin at a dosing schedule of 6 mg/kg every 24 h intravenously, steady state was reached after 14.2 +/- 4.0 days, and 1-h peak and trough concentrations of teicoplanin in serum at steady state were 40.8 +/- 15.0 and 12.5 +/- 3.2 mg/liter, respectively. In contrast, among 25 patients who received vancomycin at a dosing schedule of 15 mg/kg every 12 h intravenously, steady state was reached by 24 h, and the 1-h peak and trough concentrations in serum were 37.5 +/- 15.6 and 8.3 +/- 3.8 mg/liter, respectively. The elimination half-lives for teicoplanin estimated by two separate approaches agreed closely with each other: 80.5 +/- 21.5 h by an accumulation model (M. Gilbaldi and D. Perrier, Pharmacokinetics, 2nd ed., p. 121, 1982) and 87.3 +/- 19.3 h as predicted from the degree of renal function (M. Rowland, Clin. Pharmacokinetic 18:184-209, 1990). These values were 14- to 15-fold higher than that for vancomycin (5.6 +/- 1.8 h). Since considerable variability was noted in the pharmacokinetic parameters for both teicoplanin and vancomycin among the individual patients, our data further emphasized the need for frequent monitoring of these drugs during empiric therapy of the febrile neutropenic patient.

Topics: Adult; Aged; Aminoglycosides; Amphotericin B; Anti-Bacterial Agents; Double-Blind Method; Female; Fever; Glycopeptides; Humans; Lactams; Male; Middle Aged; Neutropenia; Reproducibility of Results; Teicoplanin; Vancomycin

Twenty neutropenic patients with various haematological disorders were randomised prospectively to receive either intravenous amphotericin B alone or amphotericin B and oral amiloride 5 mg twice a day for treatment of confirmed or suspected fungal infection. Patients receiving amiloride had a significantly higher plasma potassium (p less than 0.01), a significantly lower urinary potassium loss (p less than 0.01), and required significantly less potassium chloride supplementation to maintain their plasma potassium within the normal range (p less than 0.001). Amiloride was well tolerated, had no clinically important side effects, and provided effective control of plasma potassium in patients treated with amphotericin B.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amiloride; Amphotericin B; Clinical Trials as Topic; Humans; Hypokalemia; Middle Aged; Mycoses; Neutropenia; Potassium; Random Allocation

Patients with severe neutropenia are at increased risk for systemic infection with bacteria or fungi. This risk is in proportion to both the degree and duration of the neutropenic process. Although granulocyte transfusion as a means of augmenting host defenses would appear to be a logical therapeutic intervention in clinical contexts involving severe and prolonged neutropenia, several features of granulocyte physiology and collection complicate such considerations. These include the large numbers of granulocytes normally produced by healthy hosts, the short survival of the granulocyte in the circulation after transfusion, the relatively small number of granulocytes which can be collected using currently available pheresis techniques, problems associated with alloimmunization, and the possibility of transferring disease (CMV, toxoplasmosis, hepatitis) by means of these transfusions. In the mid-1970s, well-designed clinical studies strongly suggested that patients with documented Gram-negative sepsis or tissue infection that failed to respond to appropriate antibiotics were significantly benefited by granulocyte transfusions. With recent advances in potent, broad-spectrum antibiotic availability, some have questioned whether these observations remain valid. Several studies regarding the prophylactic use of granulocyte transfusions in patients undergoing allogeneic bone marrow transplantation and/or induction therapy for leukemia have failed to reveal therapeutic benefits and suggested the possibility of significant side effects. These studies are reviewed.

Topics: Agranulocytosis; Amphotericin B; Anti-Bacterial Agents; Blood Transfusion; Bone Marrow Transplantation; Cell Separation; Clinical Trials as Topic; Cytomegalovirus Infections; Granulocytes; Humans; Infant, Newborn; Infant, Newborn, Diseases; Leukapheresis; Lung Diseases; Neutropenia; Sepsis; Transfusion Reaction

Patients treated with cytotoxic therapy expected to produce neutropenia lasting two or more weeks were randomly assigned in a double-blind study to receive intravenous miconazole or placebo concomitant with empiric antibiotics to test whether miconazole can prevent fungal sepsis. The study drug was initiated at the time of first fever along with antibiotics and was continued until neutropenia resolved, fungal sepsis occurred, or persistent or recurrent unexplained fever after six or more days prompted substitution of the study drug by amphotericin B. Two hundred eight treatment courses in 180 patients were evaluated. Fungal sepsis occurred in only one patient receiving miconazole compared with eight patients receiving placebo (p = 0.03). Fatal fungal sepsis occurred in four patients receiving placebo and in none of the patients receiving miconazole (p = 0.08). There was no evidence for the development of resistance to polyenes or imidazoles in fungal isolates recovered from patients in this randomized trial or an increase in Aspergillus infections in patients who received miconazole in this randomized trial or in 121 subsequently treated patients who received unblinded use of miconazole. Thus, intravenous miconazole was more effective than placebo in preventing fungal sepsis in patients with chemotherapy-induced prolonged neutropenia.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amphotericin B; Bacterial Infections; Bone Marrow Transplantation; Child; Clinical Trials as Topic; Double-Blind Method; Humans; Injections, Intravenous; Miconazole; Middle Aged; Mycoses; Neutropenia; Random Allocation

Fungal infections in neutropenic cancer patients have increased in frequency and constitute an important cause of morbidity and mortality. Empiric antifungal therapy is often administered to those patients who have failed to respond to antibacterial antibiotics. We conducted a prospective, randomized trial of amphotericin B and ketoconazole for 172 neutropenic cancer patients with presumed or proven fungal infections. Overall, amphotericin B and ketoconazole were equally effective. Amphotericin B may have been more effective than ketoconazole for the treatment of pneumonia. Also, five of eight Candida tropicalis infections treated with amphotericin B responded, whereas all eight infections treated with ketoconazole failed to respond (P = 0.03). Response rates for localized fungal infections were similar with both drugs. Ketoconazole should not be used as empiric antifungal therapy at institutions where there is a high frequency of infections caused by Aspergillus spp. or C. tropicalis because this agent lacks activity in vitro against these species.

Topics: Adolescent; Adult; Aged; Amphotericin B; Female; Humans; Ketoconazole; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Prospective Studies; Random Allocation

Forty-eight neutropenic patients with acute leukaemia were randomly allocated to receive, as antifungal prophylaxis, either ketoconazole, 400 mg once daily (K), or amphotericin B tablets and lozenges (A), or both ketoconazole and amphotericin B together (K + A). Antifungal prophylaxis was considered to have failed if (1) there was evidence of increasing colonization of the oropharynx or faeces with Candida spp. or other yeasts, or (2) if systemic antifungal therapy was begun empirically. Prophylaxis failed in nine of 17 patients given K, in four of 19 given A, and in four of 12 given K + A. The differences between the three regimens were not statistically significant, neither was there any significant difference in the mean duration of neutropenia before prophylaxis failed. The absorption of ketoconazole was impaired when patients were neutropenic. We conclude that ketoconazole was neither more nor less effective than amphotericin B in the prevention of yeast colonization in neutropenic patients.

Topics: Adolescent; Adult; Amphotericin B; Antineoplastic Agents; Candidiasis, Oral; Candidiasis, Vulvovaginal; Drug Therapy, Combination; Female; Humans; Ketoconazole; Leukemia, Myeloid; Male; Middle Aged; Neutropenia; Random Allocation

The prevention of fungal infections in granulocytopenic patients seems necessary to improve the final outcome of neoplastic patients. In particular, aspergillosis and candidiasis represent common life-threatening infections among the patients with acute hematological malignancies. Despite extensive investigations during this last decade, the optimal approaches to prevent these complications are still controversial. This situation probably reflects and stresses the numerous factors which predispose to these opportunistic fungal infections. Therefore, the effective prophylaxis of candidiasis and aspergillosis should result from the use of basic and specific approaches. General and simple measures including well trained personnel (physicians, nurses but also individuals in charge of the housekeeping, etc.), careful patient teaching of personal hygiene and control of the food intake (limited to cooked food diet), will reduce the acquisition of potential fungal pathogens. Moreover, the isolation in a laminar air flow room seems to be the optimal specific technique to prevent the colonization as well as the development of pulmonary aspergillosis. The meticulous evaluation of the respiratory sinus status as well as surveillance cultures obtained from the nose have been shown to be helpful to predict patients at high risks. Until now, there is no systemic chemoprophylaxis available to decrease the incidence of invasive aspergillosis. However, the topical application of antifungal agent using nasal spray or aerosols should be further investigated. Exogenous candidiasis such as catheter or TPN products related yeast infections can be avoided by aseptic manipulations. Endogenous candidiasis, resulting from the dissemination of the yeasts from the gastro-intestinal tract (which represents the major reservoir), are still much more difficult to prevent.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Agranulocytosis; Amphotericin B; Aspergillosis; Candidiasis; Clinical Trials as Topic; Humans; Ketoconazole; Neoplasms; Neutropenia; Nystatin; Patient Isolation

72 patients severely immunocompromised by their underlying disease (marrow aplasia, acute leukaemia, or solid tumour) or by the treatment they were receiving, or both, were randomised to receive antifungal prophylaxis with either oral ketoconazole or conventional doses of oral amphotericin B and nystatin. All patients also had gut decontamination with non-absorbable antibiotics, skin antisepsis, sterile food, and oral cotrimoxazole. Protection against fungal infection was significantly superior with ketaconazole. When patients who had received allogeneic bone-marrow transplant were studied separately, there was no significant difference between the two treatments, probably because there was a fall-off in ketoconazole absorption from the end of the third week after the transplant. However, ketoconazole greatly reduced the likelihood of fungal infection in non-transplant patients.

Topics: Amphotericin B; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Imidazoles; Immunosuppressive Agents; Ketoconazole; Leukemia; Mycoses; Neutropenia; Nystatin; Piperazines; Random Allocation

Most invasive fungal infections are opportunistic in nature but the epidemiology is constantly changing, with new risk groups being identified. Neutropenia is a classical risk factor for fungal infections, while critically ill patients in the ICU are now increasingly at risk of yeast and mould infections. Factors to be considered when choosing antifungal treatment include the emergence of rarer fungal pathogens, the risk of resistance to azoles and echinocandins and the possibility of drug-drug interactions. Liposomal amphotericin B has retained its place in the therapeutic armamentarium based on its clinical profile: a broad spectrum of antifungal activity with a low risk of resistance, predictable pharmacokinetics with a rapid accumulation at the infection site (including biofilms), a low potential for drug-drug interactions and a low risk of acute and chronic treatment-limiting toxicities versus other formulations of amphotericin B. It is a suitable choice for the first-line empirical or pre-emptive treatment of suspected fungal infections in neutropenic haematology patients and is an excellent alternative for patients with documented fungal disease who can no longer tolerate or continue their first-line azole or echinocandin therapy, both in the haematology setting and in the ICU. Moreover, it is the first-line drug of choice for the treatment of invasive mucormycosis. Finally, liposomal amphotericin B is one of the few antifungal agents approved for use in children of all ages over 1 month and is included in paediatric-specific guidelines for the management of fungal disease.

Topics: Amphotericin B; Antifungal Agents; Azoles; Echinocandins; Humans; Invasive Fungal Infections; Neutropenia

Invasive fungal diseases are crucial causes of morbidity and mortality among patients with febrile neutropenia (FN). Though liposomal amphotericin B (L-AMB) is one of the agents recommended for first-line empirical antifungal therapy in patients with FN, large-scale clinical studies have not been performed in Japan.. An open-label prospective multi-center study was carried out to evaluate the safety and efficacy of L-AMB in Japanese patients with FN suspected of having fungal infection.. Of the 426 patients registered, safety and efficacy evaluations were conducted for 424 and 399, respectively. By clinical response criteria using 5 composite endpoints, the response rate was 46.6% (186/399). The response rate by age were 54.5% (child: 30/55), 47.5% (adult: 97/204), 42.1% (elderly: 59/140) respectively. Regarding the composite endpoints, resolution of fever was observed in 61.2% (244/399), no breakthrough fungal infection in 99.0% (395/399), survival for 7 days or longer after the completion of treatment in 83.7% (334/399), no discontinuation of treatment due to toxicity or lack of efficacy in 60.9% (243/399), and successful treatment of any baseline fungal infection in 10/18. Adverse drug reactions (ADRs) developed in 61.1% (259/424), and frequent ADRs were hypokalemia, kidney dysfunction, and liver dysfunction, as previously reported.. The safety and efficacy profile of L-AMB in Japanese patients with FN suspected of having fungal infection were elucidated for the first time, through the analysis of a large number of cases including pediatric patients under real-world clinical settings collected in this nationwide study.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Child; Humans; Japan; Neutropenia; Prospective Studies

Here, we describe an invasive infection due to Trichosporon coremiiforme in an HIV positive patient with neutropenia. The strain was first erroneously identified as Trichosporon asahii by conventional methods, but correctly identified by mass spectrometry using matrix-assisted laser desorption/ionization time-of-flight technology (MALDI-TOF MS) and ribosomal DNA sequencing. The infection was successfully resolved after antifungal treatment with amphotericin B and fluconazole. This case report is a contribution to the study of T. coremiiforme infections and reinforces its relevance as a species capable of causing invasive human infection in immunocompromised patients and also contributes to the study of its susceptibility profile against antifungal drugs.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antitubercular Agents; Bacteremia; Catheter-Related Infections; Central Venous Catheters; Drug Therapy, Combination; Female; Fluconazole; HIV; HIV Infections; Humans; Immunocompromised Host; Middle Aged; Neutropenia; Trichosporon; Trichosporonosis; Tuberculosis, Pulmonary

Recent years have seen important advances in the diagnosis of invasive pulmonary aspergillosis (IPA), complemented by the introduction of new therapies. Despite this, IPA remains a major cause of infection-related mortality in patients with haematological diseases. There are two main reasons for this. First, diagnosis of IPA remains a challenge, since risk factors and the clinical, radiological and mycological presentations vary not only by fungal disease stage, but also by patient group (eg neutropenic vs non-neutropenic patients). Diagnosis is particularly challenging in patients receiving mould-active prophylactic or empirical treatment, which reduces the sensitivity of all diagnostic tests for IPA. Second, treatment of IPA is complex due to unpredictable pharmacokinetic profiles of antifungal agents, small therapeutic window in terms of exposure and adverse events, and multiple drug-drug interactions through the CYP450 system. Here we report a case of a 23-year-old male with severe aplastic anaemia and subpleural nodules. Diagnostic tests for IPA obtained during ongoing mould-active empirical treatment were negative. Intravenous voriconazole was stopped after visual disturbances and hallucinations. The patient then had an anaphylactic reaction to liposomal amphotericin B and was switched to intravenous posaconazole, which had to be discontinued due to a significant increase in transaminase levels. He was treated with oral isavuconazole with reduced dosage, triggered by increasing transaminases under the standard dosage. Even under reduced dosage, blood concentrations of isavuconazole were high and treatment was successful. The case illustrates real-world challenges and unmet needs in the diagnosis and treatment of IPA in patients with haematological diseases.

Topics: Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillus; Hematologic Diseases; Humans; Invasive Pulmonary Aspergillosis; Male; Neutropenia; Nitriles; Pyridines; Transaminases; Treatment Outcome; Triazoles; Voriconazole; Young Adult

Continuous administration of amphotericin B deoxycholate over 24 hours (24 h-D-AmB) is better tolerated than rapid infusions. However, toxicity and outcome have not been assessed in a homogenous patient population with acute myeloid leukaemia (AML). We retrospectively analysed renal function and outcome in all adult patients with AML undergoing intensive chemotherapy between 2007 and 2012 at our institution. We compared a patient group with exposure to 24 h-D-AmB to a patient group without exposure to 24 h-D-AmB. One hundred and eighty-one consecutive patients were analysed, 133 (73.5%) received at least 1 dose of 24 h-D-AmB, and 48 (26.5%) did not. Reasons for 24 h-D-AmB initiation were invasive fungal disease (IFD) in 63.5% and empirical treatment for febrile neutropenia in 36.5% of the cases. Most patients with IFD received an oral triazole drug at hospital discharge. Baseline characteristics were well matched. Amphotericin B deoxycholate over 24 hours was given for a median 7 days (interquartile range 3-13). Peak creatinine concentration was higher in the 24 h-D-AmB-group (104.5 vs. 76 μmol/L, P < .001) but normalized within 1 month after therapy (65.5 vs. 65 μmol/L, P = .979). In neither of the 2 groups, end-stage renal disease occurred. There was no difference in 60-day survival (90% vs. 90%) and 2-year survival (58% vs. 58%). Invasive fungal disease partial response or better was observed in 68% of the patients. We conclude that antifungal therapy with continuously infused amphotericin B deoxycholate is safe in patients with AML. An antiinfective strategy based on 24 h-D-AmB in first line followed by an oral triazole compound represents an economically attractive treatment option.

Topics: Acute Disease; Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Deoxycholic Acid; Drug Combinations; Female; Humans; Infusion Pumps; Leukemia, Myeloid; Male; Middle Aged; Mycoses; Neutropenia; Retrospective Studies; Survival Analysis; Treatment Outcome

We report a case of a patient with acute lymphoblastic leukemia (ALL), who developed a disseminated infection by Fusarium verticillioides during chemotherapy-induced neutropenia. He was successfully treated only after combination therapy with voriconazole plus amphotericin B deoxycolate was used, but not when these compounds were used in an isolated form.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Fusariosis; Humans; Male; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Voriconazole

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Echinocandins; Female; Fluconazole; Fungemia; Geotrichosis; Geotrichum; Humans; Immunocompromised Host; Invasive Fungal Infections; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Neutropenia; Registries; Saccharomycetales; Voriconazole; Young Adult

Topics: Adult; Aged; Allografts; Amphotericin B; Hematopoietic Stem Cell Transplantation; Humans; Lebanon; Leukemia; Middle Aged; Neutropenia

Scopulariopsisis an emerging opportunistic fungus characterized by its high resistance to antifungal therapies. We have developed a murine model of disseminated infection in immunosuppressed animals by intravenous inoculation ofScopulariopsis brevicaulisandScopulariopsis brumptii, the most clinically relevant species, in order to evaluate their virulence and their responses to conventional antifungal treatments. Survival and tissue burden studies showed thatS. brumptiiwas more virulent thanS. brevicaulis The three drugs tested, liposomal amphotericin B, posaconazole, and voriconazole, prolonged the survival of mice infected withS. brumptii, but none showed efficacy againstS. brevicaulis The different therapies were only able to modestly reduce the fungal burden of infected tissue; however, in general, despite the high serum levels reached, they showed poor efficacy in the treatment of the infection. Unfortunately, the most effective therapy forScopulariopsisinfections remains unresolved.

Topics: Amphotericin B; Animals; Antifungal Agents; Cyclophosphamide; Disease Models, Animal; Drug Resistance, Fungal; Humans; Immunocompromised Host; Male; Mice; Mycoses; Neutropenia; Scopulariopsis; Species Specificity; Survival Analysis; Triazoles; Virulence; Voriconazole

We describe a case of isolated acute appendicitis due to Aspergillus carneus in a neutropenic child with acute myeloid leukemia (AML) treated according to the AIEOP AML 2002/01 protocol. Despite prophylaxis with acyclovir, ciprofloxacin and fluconazole administered during the neutropenic phase, 16 days after the end of chemotherapy the child developed fever without identified infective foci, which prompted a therapy shift to meropenem and liposomial amphotericin B. After five days of persisting fever he developed ingravescent abdominal lower right quadrant pain. Abdominal ultrasound was consistent with acute appendicitis and he underwent appendectomy with prompt defervescence. PAS+ fungal elements were found at histopathology examination of the resected vermiform appendix, and galactomannan was low positive. A. carneus, a rare species of Aspergillus formerly placed in section Flavipedes and recently considered a member of section Terrei, was identified in the specimen. Treatment with voriconazole was promptly started with success. No other site of Aspergillus localization was detected. Appendicitis is rarely caused by fungal organisms and isolated intestinal aspergillosis without pulmonary infection is unusual. To our knowledge, this is the first report of infection due to A. carneus in a child and in a primary gastrointestinal infection.

Topics: Acute Disease; Acyclovir; Amphotericin B; Antifungal Agents; Appendicitis; Aspergillosis; Aspergillus; Child; Ciprofloxacin; Fluconazole; Humans; Leukemia, Myeloid, Acute; Male; Neutropenia; Pyrimidines; Voriconazole

Mucormycosis has emerged as a rare but frequently fatal invasive fungal disease. Current knowledge on paediatric mucormycosis is based on case reports and small series reported over several decades. Contemporary data on a large cohort of patients is lacking.. Two large international registries (Zygomyco.net and FungiScope™) were searched for mucormycosis cases in ≤19 year-old patients. Cases enrolled between 2005 and 2014 were extracted, and dual entries in the two databases merged. Epidemiology, clinical characteristics, diagnostic procedures, therapeutic management and final outcome were recorded and analysed with SPSS v.12.. Sixty-three unique cases (44 proven and 19 probable) were enrolled from 15 countries (54 in European and 9 in non-European countries). Median age was 13 years [Interquartile Range (IQR) 7.7] with a slight predominance (54.1 %) of females. Underlying conditions were haematological malignancies (46 %), other malignancies (6.3 %), haematopoietic stem cell transplantation (15.9 %), solid organ transplantation, trauma/surgery and diabetes mellitus (4.8 % each) and a variety of other diseases (7.9 %); in 9.5%, no underlying medical condition was found. Neutropenia was recorded in 46 % of the patients. The main sites of infection were lungs (19 %), skin and soft tissues (19 %), paranasal sinus/sino-orbital region (15.8 %) and rhino-cerebral region (7.9 %). Disseminated infection was present in 38.1 %. Mucormycosis diagnosis was based on several combinations of methods; culture combined with histology was performed in 31 cases (49.2 %). Fungal isolates included Rhizopus spp. (39.7 %), Lichtheimia spp. (17.5 %), Mucor spp. (12.7 %), Cunninghamella bertholletiae (6.3 %) and unspecified (23.8 %). Treatment comprised amphotericin B (AmB) monotherapy in 31.7 % or AmB in combination with other antifungals in 47.7 % of the cases, while 14.3 % received no antifungals. Surgery alone was performed in 6.3 %, and combined with antifungal therapy in 47.6 %. Crude mortality at last contact of follow-up was 33.3 %. In regression analysis, disseminated disease and prior haematopoietic stem cell transplantation were associated with increased odds of death, whereas the combination of systemic antifungal therapy with surgery was associated with improved survival.. Paediatric mucormycosis mainly affects children with malignancies, presents as pulmonary, soft tissue, paranasal sinus or disseminated disease and is highly lethal. Outcome is improved when active antifungal therapy and surgery are combined.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Diabetes Mellitus; Europe; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lung Diseases, Fungal; Male; Mucormycosis; Neutropenia; Prospective Studies; Registries; Rhizopus; Treatment Outcome

Topics: Amphotericin B; Antifungal Agents; Azoles; Candida glabrata; Candidemia; Echinocandins; Humans; Male; Microbial Sensitivity Tests; Molecular Sequence Data; Neutropenia; Sequence Analysis, DNA

A 70-year-old man received a course of therapy that consisted of prednisolone, cyclosporine, and etoposide due to hemophagocytic syndrome which had developed during primary myelofibrosis. He also received micafungin (MCFG) as prophylaxis against a potential fungal infection. We diagnosed febrile neutropenia due to the hemophagocytic syndrome therapy and candidemia because Candida species were detected in blood cultures. He received liposomal amphotericin B (L-AMB) for the candidemia but did not respond to this treatment. Oliguria was diagnosed and renal failure progressed rapidly. We suspected that his renal failure had been induced by the antibiotics. We thus changed the antibiotic regimen but he died of progressive renal failure. We performed renal necropsy and diagnosed acute interstitial tubular nephritis, due to a yeast-like fungus that generally invades the renal tubules. The yeast-like fungus was later identified as Trichosporon asahii, rather than candida, by blood cultures. An immunocompromised host receiving MCFG for acute progressive renal failure requires an appropriate antifungal drug considering the possibility of disseminated Trichosporon.

Topics: Acute Disease; Aged; Amphotericin B; Echinocandins; Humans; Kidney Tubules; Lipopeptides; Male; Micafungin; Neutropenia; Primary Myelofibrosis; Trichosporon; Trichosporonosis

Studies that analyze the epidemiology and risk factors for invasive fungal disease (IFD) after engraftment in alloSCT are few in number. This single-center retrospective study included 404 alloSCT adult recipients surviving >40 days who engrafted and were discharged without prior IFD. All patients who received ⩾20 mg/day of prednisone were assigned to primary oral prophylaxis (itraconazole or low-dose voriconazole). The primary end point was the cumulative incidence (CI) of probable/proven IFD using the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. The independent prognostic factors after multivariate analyses were used to construct a post-engraftment IFD risk score. The 1-year CI of IFD was 11%. The non-relapse mortality was 40% in those developing IFD and 16% in those who did not. The intent-to-treat analysis showed that 17% of patients abandoned the assigned prophylaxis. Age >40 years, ⩾1 previous SCT, pre-engraftment neutropenia >15 days, extensive chronic GVHD and CMV reactivation were independent risk factors. The post-engraftment IFD score stratified patients into low risk (0-1 factor, CI 0.7%), intermediate risk (2 factors, CI 9.9%) and high risk (3-5 factors, CI 24.7%) (P<0.0001). The antifungal prophylaxis strategy failed to prevent post-engraftment IFD in 11% of alloSCT. Our risk score could be useful to implement risk-adapted strategies using antifungal prophylaxis after engraftment.

Topics: Administration, Oral; Adult; Aged; Allografts; Amphotericin B; Antifungal Agents; Aspergillosis; Caspofungin; Cause of Death; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Incidence; Lipopeptides; Male; Medication Adherence; Middle Aged; Mycoses; Neutropenia; Patient Compliance; Premedication; Retrospective Studies; Risk Assessment; Risk Factors; Survival Analysis; Transplantation Conditioning; Treatment Failure; Triazoles; Young Adult

Bloodstream infection (BSI) after allogeneic hematopoietic stem cell transplantation (HSCT) is a well-known complication during the pre-engraftment phase. Knowledge of trends in etiology and antibiotic susceptibility of BSI is important as the time to effective antibiotic treatment is closely associated with survival in bacteremic patients with septic shock.. BSI during the pre-engraftment phase was studied retrospectively in 521 patients undergoing HSCT at our center in 2001-2008. Incidence, risk factors, outcome, and microbiology findings were investigated and compared with BSI in a cohort transplanted during 1975-1996.. The incidence of at least 1 episode of BSI was 21%, the total attributable mortality of BSI was 3.3%, and crude mortality at day 120 after transplantation was 21%. The rate of gram-positive and gram-negative BSI was 80% and 13%, respectively. Gram-negative BSI was more frequent both in 2001-2004 and in 2005-2008 compared with 1986-1996 (P = 0.023 for 2001-2004, P = 0.001 for 2005-2008), with fluoroquinolone-resistant Escherichia coli as the predominant finding. BSI with viridans streptococci and E. coli occurred significantly earlier after HSCT than BSI with Enterococcus species, with median time of 4, 8, and 11 days, respectively (P < 0.01 both for viridians streptococci vs. Enterococcus species, and E. coli vs. Enterococcus species). Risk factors for BSI in multivariate analysis were transplantation from unrelated donor and cord blood as stem cell source, whereas peripheral blood as stem cell source was protective.. Despite low attributable mortality of BSI, crude mortality at day 120 after transplantation was 21%, indicating an association between BSI and other risk factors for death. The risk of gram-negative BSI increased over time in parallel with an increased rate of quinolone resistance. However, the incidence and attributable mortality of gram-negative BSI remained low. Thus, prophylaxis with ciprofloxacin is still deemed appropriate, but continued assessments of the risk and benefits of fluoroquinolone prophylaxis must be performed.

Topics: Adolescent; Adult; Aged; Amphotericin B; Anti-Infective Agents; Bacteremia; Candidiasis; Child; Child, Preschool; Ciprofloxacin; Cohort Studies; Enterococcus; Female; Fluconazole; Fungemia; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Infant; Male; Middle Aged; Multivariate Analysis; Neutropenia; Retrospective Studies; Risk Factors; Staphylococcal Infections; Streptococcal Infections; Time Factors; Transplantation, Homologous; Viridans Streptococci; Young Adult

Invasive pulmonary aspergillosis (IPA) is a life-threatening disease of immunocompromised patients that requires aggressive therapy. Detection of the disease and monitoring of the therapeutic response during IPA are complex, and current molecular diagnostics are not suitably robust. Here, we explored proteomic profiles of bronchoalveolar lavage fluid (BALF) specimens from a persistently neutropenic rabbit model of IPA. Three experimental arms, uninfected control animals, infected untreated animals, and animals infected and treated with ravuconazole/amphotericin B, were studied. Total proteins were evaluated by two-dimensional (2D) gel electrophoresis, followed by matrix-assisted laser desorption ionization-time of flight/time of flight (MALDI-TOF/TOF) mass spectrometry (MS) and quantified by enzyme-linked immunosorbent assay (ELISA). Host-derived proteins haptoglobin (Hp), C-reactive protein (CRP), and annexin A1 (Anx A1) were prominently found in BALF during the IPA infection and showed significant changes in response to antifungal therapy (P < 0.0001). In serum, differences in Hp (P = 0.0001) between infected and treated rabbits were observed. Preliminary in vitro studies revealed that Aspergillus fumigatus-secreted proteases may contribute to the cleavage of Anx A1 during IPA. In summary, host protein biomarkers Hp, CRP, and Anx A1 may have value in monitoring therapeutic response to antifungal agents in IPA patients with confirmed disease.

Topics: Amphotericin B; Animals; Annexin A1; Antifungal Agents; Aspergillus fumigatus; Biomarkers; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Invasive Pulmonary Aspergillosis; Neutropenia; Proteomics; Rabbits; Thiazoles; Triazoles

Topics: Amphotericin B; Antifungal Agents; Humans; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Pyrimidines; Triazoles

We used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between the posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral suspension, delayed-release tablet, and intravenous formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice with Aspergillus fumigatus strain 293 (posaconazole MIC, 0.5 mg/liter) or Rhizopus oryzae strain 969 (posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of deferasirox, but not liposomal amphotericin or caspofungin, improved the activity of a suboptimal posaconazole regimen (AUC/MIC, 33) in animals with pulmonary mucormycosis. However, no combination was as effective as the high-dose posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that posaconazole pharmacodynamics are similar for A. fumigatus and R. oryzae when indexed to pathogen MICs.

Topics: Amphotericin B; Animals; Antifungal Agents; Area Under Curve; Aspergillosis; Aspergillus fumigatus; Benzoates; Caspofungin; Deferasirox; Disease Models, Animal; Drug Therapy, Combination; Echinocandins; Female; Invasive Pulmonary Aspergillosis; Lipopeptides; Lung; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mucormycosis; Neutropenia; Rhizopus; Treatment Outcome; Triazoles

We prospectively observed 36 haematological patients with mucormycosis from nine hospitals of St. Petersburg during 2004-2013. The most frequent underlying diseases were acute leukaemia (64%), and main risk factors were prolonged neutropenia (92%) and lymphocytopenia (86%). In 50% of the patients, mucormycosis was diagnosed 1-65 days after invasive aspergillosis. Main clinical form of mucormycosis was pulmonary (64%), while two or more organ involvement was noted in 50% of the cases. The most frequent aetiological agents of mucormycosis were Rhizopus spp. (48%). Twelve-week survival rate was 50%. Combination therapy (echinocandins + amphotericin B forms) and recovery from the underlying disease significantly improved the survival rate.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Drug Combinations; Echinocandins; Female; Humans; Lymphopenia; Male; Middle Aged; Mucormycosis; Neutropenia; Prospective Studies; Rhizopus; Risk Factors; Russia; Young Adult

There is a great need for novel strategies to overcome the high mortality associated with invasive pulmonary aspergillosis (IPA) in immunocompromised patients. To evaluate the antifungal and antihepatotoxic potentials of Sepia ink extract, its effect on liver oxidative stress levels was analyzed against IPA in neutropenic mice using amphotercin B as a reference drug.. Eighty neutropenic infected mice were randomly assigned into four main groups. The 1(st) group was treated with saline, neutropenic infected (NI), the 2(nd) group was treated with ink extract (200 mg/kg) (IE) and the 3(rd) group was treated with amphotericin B (150 mg/kg) (AMB) and 4(th) group was treated with IE plus AMB. Treatment was started at 24 h after fungal inoculation (1×10(9) conidia/ml).. The present study revealed good in vitro and in vivo antifungal activity of IE against A. fumigatus. IE significantly reduced hepatic fungal burden and returns liver function and histology to normal levels. Compared with the untreated infected group, mice in the IE, AMB, and IE+ AMB groups had increased glutathione reduced (GSH) and superoxide dismutase (SOD) and significantly reduced malondialdehyde (MDA) levels at 24 and 72 h after inoculation with A. fumigatus conidia.. It is then concluded that in combination with antifungal therapy (AMB), IE treatment can reduce hepatic fungal burden, alleviate hepatic granulomatous lesions and oxidative stress associated with IPA in neutropenic mice.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Glutathione; Humans; Invasive Pulmonary Aspergillosis; Liver; Male; Malondialdehyde; Mice; Neutropenia; Oxidative Stress; Pigments, Biological; Sepia; Superoxide Dismutase

There are concerns of a reduced effect of liposomal amphotericin B (L-AmB) given sequentially after mold-active azoles due to a possible antagonism in their antifungal mechanism. To investigate this possible effect in the clinic, we retrospectively studied 182 high risk hematologic patients with invasive fungal infections (IFI) who were treated with L-AmB. Overall, 96 patients (52.7%) had possible, 52 (28.6%) probable and 34 (18.7%) proven IFI according to EORTC classification. Most had suspected or proven invasive aspergillosis. We compared patients with prior exposure to mold-active azoles (n=100) to those having not (n=82). The group with prior mold-active azoles included more patients with poor risk features for IFI as acute myeloid leukemia (p<0.05) and prolonged neutropenia (p<0.05). A favorable response in the IFI, defined as a complete or partial response, was achieved in 75% and 74.4% of patients in the whole cohort, and in 66% and 74.4% of patients with probable or proven IFI in the two groups. None of these differences were significant. Multivariate analysis showed that refractory baseline disease and renal dysfunction were adverse factors for response in the IFI (p<0.05). Survival was poorer for patients with prior broad spectrum azoles (p<0.05), and for those who did not recover from neutropenia (p<0.05). In conclusion, the effectiveness of treatment of breakthrough fungal infection with L-AmB is not likely to be affected by prior exposure to mold-active azoles prophylaxis, but survival largely depends on host and disease factors.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Candidiasis, Invasive; Child; Child, Preschool; Combined Modality Therapy; Cross Infection; Drug Evaluation; Female; Fungemia; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Postoperative Complications; Retrospective Studies; Risk; Transplantation, Homologous; Treatment Outcome; Triazoles; Young Adult

The case of a patient who experienced probable infusion-related reactions to amphotericin B lipid complex (ABLC) but tolerated continued amphotericin B therapy after a switch to an alternative lipid-based formulation is reported.. A 28-year-old immunocompromised man with pneumonia, respiratory failure, and neutropenic fever was initiated on ABLC and other antibiotics for suspected invasive aspergillosis. Due to the patient's deteriorating renal function, the use of amphotericin B was deemed preferable to the standard therapy for invasive aspergillosis (voriconazole) even though he had experienced likely infusion-related reactions to ABLC on two prior occasions. During the infusion of ABLC, significant increases in the man's temperature, respiratory rate, systolic blood pressure, and heart rate were observed. Although those symptoms were suspected to be infusion related, it was decided that continuing amphotericin B therapy with an alternative lipid-based form of the drug was the best course of action. After the patient was switched to liposomal amphotericin B one day later, no further infusion-related adverse reactions were noted for the duration of therapy. While this case suggests that adverse reactions to one type of amphotericin B might not occur with the use of an alternative formulation, further research is needed to better define the potential for cross-reactivity among various forms of amphotericin B and related safe-infusion practices.. A patient with invasive aspergillosis who experienced likely infusion- related reactions to ABLC was able to tolerate continued amphotericin B therapy after a switch to the liposomal formulation.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Comorbidity; Cross Reactions; Dosage Forms; Drug Administration Routes; Humans; Immunocompromised Host; Infusions, Intravenous; Male; Neutropenia; Pneumonia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Renal Insufficiency, Chronic; Respiratory Insufficiency

Aerosolized amphotericin B lipid complex (aeABLC) has been successfully used to prevent fungal disease. Experience with aeABLC as treatment of fungal lung disease is limited.. We evaluated the safety and efficacy of aeABLC adjunct therapy for fungal lung disease in a retrospective study of 32 immunosuppressed adults. All values are given as ± standard deviation.. National Cancer Institute-designated Comprehensive Cancer Center.. Acute leukemia (69%) and severe neutropenia (63%) were common. Fifty-six percent of patients had undergone allogeneic hematopoietic stem cell transplantation 185 ± 424 days prior to aeABLC was commenced.. High-dose corticosteroids were administered during aeABLC in 28% of patients. Fungal lung disease was proven or probable in 41% of patients. Most patients (78%) received concurrent systemic antifungal therapy for a median of 14 ± 18 days before aeABLC. The median cumulative aeABLC dose was 1050 ± 2368 mg, and the median duration of aeABLC therapy was 28 ± 130 days. Most patients (78%) received 50 mg aeABLC twice daily. Partial or complete resolution of fungal lung disease was noted in 50% of patients. In three patients (9%) modest cough, mild bronchospasm, and transient chest pain with accompanying nausea and vomiting resolved completely after discontinuation of aeABLC. No patient required hospitalization for drug toxicity or had a serious (grade III or IV) drug-related adverse event.. Treatment with aeABLC was tolerated without serious toxicity and may be considered in the setting of severe immunosuppression, cancer, and/or hematopoietic stem cell transplantation in patients with difficult-to-treat fungal lung disease.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Female; Glucocorticoids; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Lung Diseases, Fungal; Male; Middle Aged; Neoplasms; Neutropenia; Retrospective Studies; Severity of Illness Index; Young Adult

Topics: Adolescent; Amphotericin B; Antifungal Agents; Female; Fungi; Humans; Liposomes; Mucormycosis; Neutropenia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Stem Cell Transplantation; Tomography, X-Ray Computed; Triazoles

Fusarium species are among the leading fungal pathogens to cause invasive mould infections in patients with hematopoietic malignancy. The Fusarium species most frequently involved in human infections are Fusarium solani, Fusarium oxysporum and Fusarium verticillioides. However, identification is a cumbersome and time-consuming task. Fusarium is resistant in vitro to many of the antifungal agents and the management of fusariosis is not well defined.. To emphasise the difficulty of identifying Fusarium spp. by conventional methods and the need of new rapid molecular tests to achieve earlier diagnosis and appropriate therapy.. A disseminated Fusarium infection due to F. verticillioides was documented in a neutropenic refractory patient with acute myeloid leukaemia, relapsed after allogeneic hematopoietic stem cell transplantation.. The patient died despite liposomal amphotericin B and voriconazole combination and "in vitro" susceptibility of agents employed. Morphological and molecular identification of F. verticillioides was obtained only after the death of the patient.. This case highlights the poor outcome of an invasive fungal disease caused by Fusarium in aplastic patients. Identification of members of Fusarium genus remains restricted to selected laboratories and should be introduced into routine mycological diagnostics. In immunocompromised patients, diagnosis of fusariosis is directly related to prompt diagnosis and to patient's status. Current diagnosis methods and therapeutic options are discussed.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Drug Resistance, Multiple, Fungal; Etoposide; Fatal Outcome; Female; Fusariosis; Fusarium; Humans; Immunocompromised Host; Itraconazole; Leukemia, Myeloid, Acute; Mitoxantrone; Neutropenia; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Premedication; Pyrimidines; Recurrence; Salvage Therapy; Transplantation, Homologous; Triazoles; Voriconazole

The efficacy of antifungal prophylaxis for prevention of invasive aspergillosis (IA) may depend on whether IA results from recent inhalation of spores or reactivation of latent colonisation. Compare the efficacy of liposomal amphotericin B (LAmB) for prophylaxis in acute and reactivation models of IA. In the acute model, mice immunosuppressed from day 0 were challenged at day 3 with an aerosol of Aspergillus fumigatus. LAmB (15 mg kg(-1) ) was administered at day 0 or at challenge. In the reactivation model, naïve mice exposed to A. fumigatus remained untreated until clearance of spores from the lungs, then immunosuppressed to induce reactivation. A single LAmB dose was administered at start of immunosuppression. In the acute model, a single administration of LAmB at start of immunosuppression was not effective, but an additional administration resulted in a significant decrease in lung fungal burden (P < 0.05 vs. controls). A significant prophylactic efficacy was observed when LAmB was administered once at challenge (P < 0.01). In the reactivation model, a single LAmB administration at start of immunosuppression significantly reduced both reactivation rate and fungal burden vs. controls (P < 0.01). Our results show that the conditions under which IA develop and timing of administration of LAmB were determinant variables for prophylactic efficacy.

Topics: Acute Disease; Amphotericin B; Animals; Antibiotic Prophylaxis; Antifungal Agents; Aspergillus fumigatus; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Lung; Mice; Mice, Inbred BALB C; Neutropenia; Spores, Fungal

Mucormycosis has emerged as an increasingly important infection in oncology centres with high mortality, especially in severely immunocompromised patients. We carried out a retrospective study of 11 children with mucormycosis treated in seven French oncology-haematology paediatric wards during the period from 1991 to 2011. Lichtheimia corymbifera and Mucor spp. were the predominant pathogens. Treatment regimens included antifungal therapy, reversal of underlying predisposing risk factors and surgical debridement. Although mucormycosis is associated with high mortality, this infection could be cured in eight of our cases of severely immunocompromised paediatric cancer patients.

Topics: Adolescent; Amphotericin B; Antineoplastic Agents; Child; Female; Hospitals, Pediatric; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Lung Diseases, Fungal; Male; Mucor; Mucormycosis; Neutropenia; Opportunistic Infections; Retrospective Studies; Risk Factors; Young Adult

Liposomal amphotericin B (L-AmB) is recommended as an empirical antifungal treatment for patients at increased risk of fungal infections although renal toxicity remains a clinical problem. We therefore conducted a pilot study to evaluate the safety and efficacy of low-dose L-AmB as an empirical antifungal therapy for patients with prolonged neutropenia.. High-risk patients with hematological malignancies were eligible to enroll in this study provided they had: exhibited neutropenia for at least 1 week; suffered from high-grade fever for 4 days despite treatment with a broad-spectrum antibacterial; and no identified fever-causing pathogen. Low-dose L-AmB (1 mg/kg) was administrated as empirical antifungal therapy.. Sixteen patients were registered and, of these, data from the13 patients who did not receive allogeneic stem cell transplantation were analyzed. The median duration of low-dose L-AmB treatment was 8 days. Hypokalemia was seen in one patient: administration of potassium supplements for 10 days restored potassium levels to the normal range. A two-fold increase in creatinine levels was not found in any patients even those taking concomitant nephrotoxic drugs (e.g., amynoglycoside) during the study. One patient stopped receiving the drug due to an infusion-related adverse event. No patients showed breakthrough fungal infections or died during therapy or within 7 days after the end of the study. Increase in the L-AmB dose was necessary due to persistent fever in three patients who withdrew from the study. The satisfactory response rate for low-dose L-AmB was 69 %.. This study suggests that low-dose L-AmB may be an effective option as empirical antifungal therapy for high-risk patients with febrile neutropenia.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Female; Fever; Hematologic Neoplasms; Humans; Liposomes; Male; Middle Aged; Mycoses; Neutropenia

Aspergillus terreus is considered to be resistant to amphotericin B (AMB). However, it is unknown whether higher daily doses of liposomal AMB (L-AMB) can overcome this resistance in vivo. We evaluated the efficacy and total lung homogenate AMB concentrations of escalating intravenous doses of L-AMB (3-20 mg/kg daily) versus an induction-de-escalation dosing strategy (10 mg/kg/day ×3 days, then 3 mg/kg/day) in an experimental neutropenic murine model of A. terreus pneumonia.. BALB/c mice were rendered neutropenic with cyclophosphamide and administered cortisone acetate prior to intranasal inoculation (3.5 × 10(6) conidia) with A. terreus (Etest MIC 8 mg/L). Mice were then treated with L-AMB regimens for 5-7 days. The efficacy was assessed by animal survival and quantitative PCR lung fungal burden. Total AMB lung homogenate concentrations were determined by HPLC.. Compared with untreated controls, 10 mg/kg/day L-AMB prolonged survival (mean >7 versus 3-4 days, P < 0.003) and reduced A. terreus lung fungal burden (median log10 conidial DNA 5.0 versus 6.7, P < 0.05). Daily L-AMB regimens >10 mg/kg/day were associated with poorer survival and higher lung fungal burden. The induction-de-escalation strategy of 10 mg/kg/day ×3 days followed by 3 mg/kg/day was as effective as 10 mg/kg daily dosing, and resulted in higher mean AMB lung homogenate concentrations compared with a continuous 10 mg/kg regimen (23.2 ± 6.7 versus 16.4 ± 4.4 μg/g, P = 0.09).. A high-dose induction-de-escalation L-AMB dosing strategy was an effective treatment for experimental A. terreus pneumonia in neutropenic mice.

Topics: Administration, Intravenous; Amphotericin B; Animals; Antifungal Agents; Aspergillus; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Neutropenia; Pulmonary Aspergillosis; Survival Analysis; Treatment Outcome

The in vitro susceptibility of 17 strains of Mucor circinelloides to amphotericin B and posaconazole was ascertained by using broth microdilution and disk diffusion methods and by determining the minimal fungicidal concentration (MFC). We evaluated the efficacy of posaconazole at 40 mg/kg of body weight/day and amphotericin B at 0.8 mg/kg/day in a neutropenic murine model of disseminated infection by M. circinelloides by using 6 different strains tested previously in vitro. In general, most of the posaconazole MICs were within the range of susceptibility or intermediate susceptibility, while the small inhibition zone diameters (IZDs) were indicative of nonsusceptibility for all isolates tested. The MFCs were ≥ 3 dilutions higher than the corresponding MICs. In contrast, amphotericin B showed good activity against all of the strains tested regardless of the method used. The in vivo studies demonstrated that amphotericin B was effective in prolonging survival and reducing the fungal load. Posaconazole showed poor in vivo efficacy with no correlation with the MIC values. The results suggested that posaconazole should be used with caution in the treatment of infections caused by Mucor circinelloides or by strains of Mucor not identified to the species level.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Disease Models, Animal; Drug Resistance, Fungal; Kidney; Male; Mice; Microbial Sensitivity Tests; Mucor; Mucormycosis; Neutropenia; Species Specificity; Survival Rate; Treatment Failure; Triazoles

There are limited data about the use of antifungal agents (AF) in critically ill patients and treatment trends since the inclusion of the new generation AF. The use of these agents may have a significant influence on the development of new resistances.. Observational prospective study of the systemic use of AF in patients admitted to Spanish intensive care units (ICU) participating in the ENVIN-HELICS register, from 2006 to 2010. The annual use, the indications that led to that use and, the intra-ICU infections, the AF employment related to the hospital size, and per 1000 patients/day, were compared.. Of the 8240 prescriptions for AF, fluconazole and caspofungin were the most often employed (55% and 19.5%, respectively). An increase in use was observed to the year 2008, with subsequent stabilisation. A decrease in the use of fluconazole and an increase in echinocandins consumption was observed over time. As regards the intra-ICU infections, the AF were ordered empirically in 47.9% of the indications. Fluconazole was more frequently used in medium size hospitals than in the large ones (60.4% versus 53.3%; P=.036) and the opposite occurred in the case of caspofungin (15.8% versus 21.8%; P<.001). Fluconazole was more prematurely employed (median 12 days since ICU admission) and the duration of the therapy was similar to the other AF (median 8 days). The total therapy days were 39.51 per 1000 patient/day, with predominance in fluconazole use (21.48 per 1000 patients/day).. Fluconazole is the most used antifungal agent in critically ill patients in any of the indications, although a progressive decrease in its use is observed, with a proportional increase in the use of echinocandins.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Community-Acquired Infections; Critical Illness; Cross Infection; Drug Prescriptions; Drug Utilization; Echinocandins; Female; Fluconazole; Hospital Bed Capacity; Humans; Immunocompromised Host; Intensive Care Units; Lipopeptides; Male; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Registries; Spain

The efficacy of fluconazole (FLU), amphotericin B (AMB) and caspofungin (CAS) was tested against three Candida orthopsilosis, three C. metapsilosis and two C. parapsilosis sensu stricto isolates in neutropenic mice.. Mice were immunosuppressed by 200 mg/kg cyclophosphamide. Five-day intraperitoneal treatment was started 24 h after infection. Kidney burden was analyzed using the Kruskal-Wallis test.. FLU 10 and 20 mg/kg as well as AMB 1 mg/kg significantly decreased the fungal burden (p < 0.05) for all eight isolates of the three species. CAS 2 and 5 mg/kg were efficacious against all C. orthopsilosis and C. metapsilosis isolates (p < 0.05), but only 5 mg/kg CAS was effective against C. parapsilosis isolates (p < 0.05).. The efficacy of FLU and AMB against the three species was comparable. Though the activity of CAS was higher against C. orthopsilosis and C. metapsilosis, the current treatment guidelines for C. parapsilosis sensu stricto seem to be applicable to other 'psilosis' species.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida; Caspofungin; Disease Models, Animal; Echinocandins; Female; Fluconazole; Immunocompromised Host; Kidney; Lipopeptides; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Neutropenia

To investigate the correlation between in vitro killing activity and in vivo efficacy of micafungin (MCFG) and liposomal amphotericin B (L-AMB) against Candida tropicalis in a neutropenic murine lethal infection model.. Candida albicans (one strain) and C. tropicalis (three strains) were tested in time-kill studies. Cyclophosphamide-treated mice were inoculated intravenously with each strain. One day after inoculation, antifungals were administered intravenously once daily for 1 or 3 days.. MCFG exhibited fungicidal activity against C. albicans ATCC 90029 and C. tropicalis SP-20142, and fungistatic activity against C. tropicalis ATCC 42678 and SP-20047. The ED(50)s (dosage that results in 50% survival) of MCFG for C. tropicalis ATCC 42678 and SP-20047 (4.1-50 mg/kg) were higher than those for other strains (1.6-12 mg/kg). A 1-day course of MCFG was not effective against C. tropicalis ATCC 42678 and SP-20047 at the clinical dose (5 mg/kg), which achieved an AUC level almost equal to that of 100 mg in humans, whereas a 3-day course of 5 mg/kg MCFG was efficacious against all strains. In contrast, L-AMB showed fungicidal activity against all strains tested and the ED(50)s of L-AMB were 0.08-0.65 mg/kg. In both treatment regimens, the minimum effective doses of L-AMB (≤0.5 mg/kg) were less than the clinical dosage (≤5 mg/kg).. The in vivo efficacy of MCFG and L-AMB showed a correlation with the in vitro killing activity. At the clinical dose, L-AMB exerted anti-C. tropicalis activity within a shorter treatment period than MCFG.

Topics: Amphotericin B; Animals; Antifungal Agents; Area Under Curve; Candida tropicalis; Candidiasis; Disease Models, Animal; Echinocandins; Lipopeptides; Male; Micafungin; Mice; Microbial Sensitivity Tests; Neutropenia

Hormographiella aspergillata, a filamentous basidiomycete, has rarely been involved in human infections. We describe 2 febrile neutropenic patients who developed a severe pulmonary infection due to H. aspergillata while receiving empirical caspofungin therapy for presumed fungal pneumonia. After introduction of liposomal amphotericin B, one patient, who had neutrophil recovery, presented a favorable outcome, while the other, who remained neutropenic throughout the course of infection, died. Resistant fungi, including basidiomycetes, may emerge during empirical treatment with caspofungin in febrile neutropenic patients. A rapid switch to any other potent antifungal should be rapidly considered in case of failure of caspofungin in this setting.

Topics: Adult; Amphotericin B; Antifungal Agents; Basidiomycota; Caspofungin; DNA, Fungal; Echinocandins; Female; Fever of Unknown Origin; Fungi; Humans; Lipopeptides; Lung Diseases, Fungal; Male; Molecular Sequence Data; Mycoses; Neutropenia; Sequence Analysis, DNA; Treatment Outcome

Mucormycosis is a rare but emerging group of life-threatening opportunistic mycoses. We described experience of eight patients who developed mucormycosis. These patients had developed hematologic malignancies, and none achieved complete remission. Six of the eight patients presented with neutropenia, five received corticosteroid, and four had concomitant hyperglycemia. The most frequent physical finding was fever, and five patients complained of facial pain, headache, or chest pain. Four patients presented with concomitant bacterial infection, pulmonary aspergillosis, or intestinal candidiasis. Premortal diagnosis of mucormycosis was made in only one patient. Postmortem biopsy or autopsy was the diagnostic tool for the other patients. Although patients who were treated with amphotericin B survived longer than those treated with micafungin or voriconazole, all patients died due to the progression of mucormycosis. Estimated median survival was 23 days. Premortal diagnosis was rarely achieved as biopsy of infected tissues was the only diagnostic tool, and four patients who revealed dual infection were diagnosed with aspergillosis or bacterial infections. In patients with a high risk of mucormycosis presenting with pain and uncontrollable fever, mucormycosis should be included in the differential diagnosis. High dosages of liposomal amphotericin B should be given and surgical debridement should be performed promptly in cases highly suggestive of mucormycosis.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Biopsy; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Mucormycosis; Neutropenia; Pyrimidines; Retrospective Studies; Survival Rate; Triazoles; Voriconazole

Sporopachydermia cereana is a cactophilic yeast, which is not recognised as a human pathogen. We describe two fatal infections with this fungus in profoundly neutropenic patients. S. cereana escapes detection by conventional mycological identification methods. This organism may be an under-recognised cause of fatal fungal sepsis among immunocompromised patients.

Topics: Adult; Amphotericin B; Antifungal Agents; Fatal Outcome; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses; Neutropenia; Saccharomycetales

This study aimed to determine the frequency of invasive fungal infection (IFI) in pediatric patients with hematologic malignancy who received amphotericin B oral suspension and early intravenous fluconazole during the neutropenic phase as prophylaxis for IFI. Records of 743 neutropenic episodes induced by cytotoxic chemotherapy between 1997 and 2008 were retrospectively reviewed to determine risk factors for and frequency of IFI. The overall frequency of IFI was 0.8% (n=6) and frequencies of proven, probable, and possible infections were 0.3% (n=2), 0.4% (n=3), and 0.1% (n=1), respectively. During 351 episodes of profound neutropenia (neutrophil count <500/μL for ≥ 14 d), overall incidence of IFI was 1.71% (n=6). Pulmonary aspergillosis was the most common causative agent, and no patients showed candidemia, or hepatosplenic candidiasis. Cytotoxic chemotherapy regimens for acute myelogenous leukemia and profound neutropenia were significantly associated with IFI (P=0.004 and P=0.009, respectively). No IFI-attributable deaths or breakthrough fungal infections occurred. Our results indicate that amphotericin B oral solution and early intravenous fluconazole may be effective in reducing the incidence and mortality of IFI in pediatric patients with hematologic malignancies.

Topics: Administration, Oral; Adolescent; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Candidiasis; Child; Child, Preschool; Female; Fluconazole; Humans; Incidence; Infant; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Neutropenia; Retrospective Studies; Risk Factors; Treatment Outcome

Rituximab-related late-onset neutropenia (R-LON) is an adverse event associated with rituximab. A 65-year-old woman presented with diffuse large B-cell lymphoma of the kidney without bone marrow involvement. She was treated with 4 cycles of CHOP chemotherapy consisting of doxorubicin, cyclophosphamide, vincristine, and prednisolone at 4-week intervals. Rituximab was also administrated of the second, third, fourth CHOP cycles. She developed a high fever of 38°C, nausea, and severe neutropenia following the four cycles of R-CHOP chemotherapy. Her leukocyte count was 160/μl without neutrophils. Initially, a blood and pleural fluid and cerebrospinal fluid cultures were positive for Cryptococcus neoformans. Once she became asymptomatic following treatment with fluconazole and neutropenia was recovered with lenograstim, she had neck stiffness and admitted soon. Cerebro-spinal fluid (CSF) culture was positive for Cryptococcus neoformans. Treatment with amphotericin B(AMPH-B) and flucytosine(5-FC) was initiated as diagnosis of cryptococcus meningitis. Lenograstim was administrated for 9 months, and amount of dose was 9,750 μg. Cryptococcosis with malignant lymphoma is rare disease, and previously 17 cases were reported. Of note, mortality of disseminated cryptococcosis with malignant lymphoma is 54%. The more and more rituximab is widely used; the cases of severe infection in R-LON may increase.

Topics: Aged; Amphotericin B; Antibodies, Monoclonal, Murine-Derived; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Cryptococcosis; Cryptococcus neoformans; Cyclophosphamide; Doxorubicin; Female; Fluconazole; Flucytosine; Humans; Immunologic Factors; Lymphoma, Non-Hodgkin; Neutropenia; Prednisolone; Rituximab; Treatment Outcome; Vincristine

Febrile neutropenia (FN) is a serious complication associated with morbidity and mortality. To manage infections in neutropenic patients, it is necessary to administer empirical antibiotic therapy in a timely and efficient manner. We developed an electronic critical pathway system for a computer-stored medical record system (EGMAIN-GX, Fujitsu), which matches FN patients to either: i) the first-line therapy with meropenem (3 g/day) alone, or ii) the second-line therapy with meropenem plus vancomycin (2 g/day). If patients do not respond to the first-line therapy within 72 hours, then they are provided with the second-line therapy. A total of 28 FN events were treated in 14 patients presenting with hematological malignancies. The mean and median neutrophil counts were 42 (0-300)/microl and 0/microl, respectively. The response rates with the first-line and second-line therapies were 57% and 93%, respectively. There were no serious adverse events. Meropenem is a highly effective treatment for FN. Use of an electronic critical pathway system could ensure that neutropenic patients receive this necessary empiric therapy in a timely manner so as to prevent the serious complications associated with FN.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Critical Pathways; Drug Therapy, Combination; Electronic Health Records; Female; Fever; Hematologic Neoplasms; Humans; Liposomes; Male; Meropenem; Middle Aged; Neutropenia; Thienamycins; Treatment Outcome; Vancomycin; Young Adult

Topics: Acute Disease; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Aspergillus; Caspofungin; Combined Modality Therapy; Echinocandins; Humans; Hyphae; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Leukemia, B-Cell; Lipopeptides; Male; Middle Aged; Neutropenia; Spleen; Splenectomy; Splenic Diseases; Triazoles

A number of agents are now available for empirical antifungal treatment (EAFT) of patients with persistent fever and neutropenia. We carried out a study of efficacy of antifungal drugs to prevent breakthrough invasive aspergillosis by reviewing the medical records of all consecutive patients who received EAFT from November 2005 to February 2006. Patients' characteristics and the type, dose and duration of antifungal therapy were recorded. Breakthrough invasive fungal infections were documented according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definition. Fifty-six episodes of persistent fever with neutropenia requiring EAFT were recorded among 49 patients. All patients received high-dose chemotherapy for acute myeloid leukaemia (51%), acute lymphoid leukaemia (12%), lymphoma (14%) or other haematologic conditions (22%). Fourteen (29%) and five (10%) patients were allogeneic and autologous haematopoietic stem cell transplant recipients, respectively. Caspofungin was prescribed initially in 40 episodes (71%), amphotericin B (AmB) desoxycholate and liposomal AmB being prescribed in six (10%) and ten (18%) episodes, respectively. Six patients were switched from liposomal AmB to caspofungin because of adverse events. The median duration of antifungal therapy was 9 days. During follow-up, six patients (12%) were diagnosed with invasive aspergillosis after a median of 8 days (range 3-16 days) of EAFT. Invasive aspergillosis breakthrough occurred in 6/46 (13%) caspofungin recipients and in 0/16 (0%) AmB recipients (OR 3.1, p 0.32). The observed high rate of invasive aspergillosis among caspofungin recipients requires further evaluation.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Caspofungin; Deoxycholic Acid; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Female; Fever of Unknown Origin; Hematologic Neoplasms; Humans; Immunocompromised Host; Lipopeptides; Male; Middle Aged; Neutropenia; Young Adult

We evaluated the efficacy of amphotericin B (1.5mg/kg/day), voriconazole (60mg/kg/day) and posaconazole (60mg/kg/day) in a murine model of systemic infection caused by Neoscytalidium dimidiatum. All the treatments were able to prolong survival and to reduce the tissue burden in the spleen and kidneys of infected mice. Neither voriconazole nor posaconazole improved the results achieved with amphotericin B.

Topics: Amphotericin B; Animals; Antifungal Agents; Ascomycota; Colony Count, Microbial; Disease Models, Animal; Kidney; Male; Mice; Mycoses; Neutropenia; Pyrimidines; Sepsis; Spleen; Survival Analysis; Treatment Outcome; Triazoles; Voriconazole

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Digestive System Surgical Procedures; Enterococcus faecium; Fatal Outcome; Female; Gram-Positive Bacterial Infections; Humans; Idarubicin; Leukemia, Myeloid, Acute; Middle Aged; Mucormycosis; Neutropenia; Rhinitis; Shock, Septic; Sinusitis; Typhlitis

Topics: Amphotericin B; Antifungal Agents; Cord Blood Stem Cell Transplantation; Echinocandins; Humans; Leukemia; Lung; Male; Middle Aged; Neutropenia; Postoperative Complications; Pulmonary Aspergillosis; Pyrimidines; Triazoles; Voriconazole

During the past two decades, an increasing number of unusual moulds has been reported as responsible for septicaemia and systemic or disseminated infections in immunocompromised patients. Investigation of fever in a 10-year-old boy with acute myeloblastic leukaemia, including blood cultures on selective media, allowed the diagnosis of a fungaemia due to the slow-growing fungus Acremonium strictum. The patient recovered with liposomal amphotericin B (AmB) and voriconazole, followed by voriconazole alone due to AmB resistance. Facing a neutropenic patient with fever, clinicians usually suspect bacterial or viral aetiologies. This case, however, illustrates the need for mycological analysis of blood samples in febrile neutropenic patients and for antifungal susceptibility testing.

Topics: Acremonium; Amphotericin B; Antifungal Agents; Blood; Child; Fever; Fungemia; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Neutropenia; Pyrimidines; Triazoles; Voriconazole

This study aimed to document outcome of invasive respiratory aspergillosis (IRA) in pediatric malignancy patients. Patients with febrile neutropenia episodes followed between January 2003 and May 2007 were enrolled. Antifungal therapy was added to those who were still febrile on the 5th day of febrile neutropenia treatment. Patients were screened with computerized tomographies. IRA was identified in 22 of 98 patients. There were 13 males and the mean age was 97 months. Proven infection was established in 3, probable in 7, and possible in 12 patients. Liposomal amphotericin B was administered to all patients and was successful in 10 patients. Modifications with caspofungin or voriconazole were done in liposomal amphotericin B failures. The median duration of antifungal therapy was 5.5 months. The median follow-up time was 29 months. There was no evidence of IRA in 12 patients after completion of cancer chemotherapy. Six patients died due to underlying disease, whereas IRA was either in remission or stable disease. Four patients were lost due to IRA. The remission rate for IRA was 82%. Survival at 37 months was 55% (95% confidence interval 25-47 months). The amount of time that absolute neutrophil count after initiation of treatment for IRA remained at zero was found to be an independent prognostic factor on survival (P = .01). These results suggest that early diagnosis and aggressive treatment may increase the successful outcome of IRA.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Child; Early Diagnosis; Echinocandins; Female; Fever; Hematologic Neoplasms; Humans; Lipopeptides; Male; Neutropenia; Prognosis; Pulmonary Aspergillosis; Pyrimidines; Retrospective Studies; Treatment Outcome; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fever of Unknown Origin; Humans; Immunocompromised Host; Lipopeptides; Neutropenia; Treatment Outcome

An eleven-year-old boy presented with one month's history of fever and weight loss. He was diagnosed with Acute Mycloid Leukemia (AML-M2). During treatment he developed recurrent infections with neutropenia requiring prolonged antibiotics and subsequently developed invasive aspergillosis. He was treated with amphotericin B and Voriconazole. This case shows the efficacy and safety of combined antifungal therapy, including voriconazole, for invasive aspergillosis complicating AML.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Child; Fever; Humans; Leukemia, Myeloid, Acute; Male; Neutropenia; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

We report the first case, to our knowledge, of Blastoschizomyces capitatus infection occurring in a patient receiving empirical echinocandin therapy for neutropenic fevers. Clinicians should consider B. capitatus infection in those neutropenic patients who remain febrile despite echinocandin therapy or who develop yeast bloodstream infections while receiving an echinocandin.

Topics: Aged; Antifungal Agents; Echinocandins; Fatal Outcome; Geotrichosis; Geotrichum; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Neutropenia

We compared the efficacy of combination posaconazole-liposomal amphotericin B (LAmB) therapy to monotherapy with either drug in diabetic ketoacidotic or neutropenic mice with disseminated zygomycosis caused by Rhizopus oryzae. Combination therapy was no better than LAmB alone, and posaconazole monotherapy did not improve survival or reduce fungal burden versus placebo.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Diabetic Ketoacidosis; Dose-Response Relationship, Drug; Drug Combinations; Kidney; Liposomes; Male; Mice; Mice, Inbred BALB C; Neutropenia; Rhizopus; Triazoles; Zygomycosis

New lipid-associated formulations of amphotericin B (AmB) have been developed in order to reduce toxicity and enhance the efficacy of AmB by allowing administration of higher doses of the drug. We determined the in vivo dose-response relationships of 1 day and 7 day treatment of AmB, Ambisome (AmBi) and Abelcet (ABLC) in a non-neutropenic murine model of invasive aspergillosis by using survival as an endpoint. Female CD-1 mice were infected intravenously 48 h prior to start therapy with Aspergillus fumigatus (1 x 10(7) conidia/mouse). Groups of 10 mice were treated iv for 1 day or 7 days with increasing 2-fold doses of AmB, ABLC and AmBi up to a maximum of 20 mg/kg/day. Mortality was determined twice daily until day 15. Results were analyzed using product-moment survival analysis and by determining the dose response relationships on day 15. Survival at day 15 of mice with 7 day AmBi or ABLC treatment was significantly better than that of controls or AmB. The ED50s of AmBi and ABLC were 0.06 (95% CI: 0.03-0.127) mg/kg and 0.21 (0.06-0.66) mg/kg respectively. In addition, the maximum effect was higher for AmBi than ABLC, 90% survival versus 68%, respectively. Most of the effects of treatment with AmBi were reached after 1 day of treatment, indicating that the first dose given is most important in predicting survival. This study shows that AmBi and ABLC were significantly more efficacious than AmB in a non-neutropenic murine model of invasive aspergillosis, and that the effect observed was primarily dependent on the first dose administered.

Topics: Amphotericin B; Animals; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Mice; Neutropenia; Nonlinear Dynamics; Survival Analysis

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Genetic Predisposition to Disease; Hematopoietic Stem Cell Transplantation; Humans; Neutropenia; Toll-Like Receptor 2; Toll-Like Receptor 4

Topics: Adolescent; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Aspergillus flavus; Caspofungin; Combined Modality Therapy; Debridement; Drug Therapy, Combination; Echinocandins; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunocompromised Host; Lipopeptides; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sinusitis

Cryptococcosis is a disseminated fungal disease typically associated with immunosuppression and characterized by high mortality rates. Cryptococcus neoformans has been reported to be isolated from blood cultures in around 20% of patients with cryptococcosis, and cryptococcemia has been correlated with poor prognosis. We report a case of fatal C. neoformans fungemia in a neutropenic patient with a history of chronic lymphocytic leukemia treated with alemtuzumab. The patient presented with loss of consciousness and died after 5 days of antifungal therapy with liposomal amphotericin B. The international literature regarding opportunistic infections after immunosuppressive therapy with alemtuzumab with particular attention on fungal infections has also been reviewed.

Topics: Aged; Alemtuzumab; Amphotericin B; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antifungal Agents; Antineoplastic Agents; Cryptococcosis; Cryptococcus neoformans; Fatal Outcome; Fungemia; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neutropenia; Opportunistic Infections

Topics: Adolescent; Amphotericin B; Antifungal Agents; Caspofungin; Child; Child, Preschool; Drug Therapy, Combination; Echinocandins; Female; Humans; Immunocompromised Host; Infant; Infant, Newborn; Lipopeptides; Male; Mycoses; Neutropenia; Pyrimidines; Retrospective Studies; Salvage Therapy; Triazoles; Voriconazole

Neutropenic individuals are at high risk for invasive pulmonary aspergillosis (IPA), a life-threatening infection. To evaluate the therapeutic potential of antioxidants, IPA was induced in neutropenic mice and the effect of N-acetyl-l-cysteine (NAC) on oxidative stress levels and lung injury was analyzed.. Mice were pretreated with three daily intraperitoneal injections of 150 mg/kg cyclophosphamide, followed by intratracheal inoculation with 4.5x10(6) conidia of Aspergillus fumigatus. The infected mice were then randomly assigned to an amphotericin B (AMB) group, an AMB plus NAC group, or an untreated control (C) group. In each group, the duration of treatment was 24, 48, or 72 h, and activities such as appearance, feeding, and dermal temperature were observed throughout the experiment. Sera and lung tissues were collected and analyzed by quantitative enzyme-linked immunosorbent assay (ELISA) for total protein, superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) levels. The wet/dry weight ratio of the lung was also calculated and lung sections were stained with hematoxylin-eosin for pathological examination and with methenamine silver stain for fungus detection.. Compared with the mice untreated with NAC, mice in the AMB plus NAC group had increased SOD and reduced MDA levels both systemically and locally at 24, 48, and 72 h after inoculation with conidia. NAC treatment also decreased the pulmonary protein content at 48 and 72 h and the lung wet/dry weight ratio at 24 and 48 h. Additionally, NAC enhanced pulmonary production of TNF-alpha and IL-10 at 24 h and 48 h.. In combination with antifungal therapy, NAC treatment can alleviate oxidative stress and lung injury associated with IPA in neutropenic mice.Acta Pharmacologica Sinica (2009) 30: 980-986; doi: 10.1038/aps.2009.83.

Topics: Acetylcysteine; Amphotericin B; Animals; Antifungal Agents; Disease Models, Animal; Humans; Interleukin-10; Invasive Pulmonary Aspergillosis; Lung Injury; Male; Mice; Mice, Inbred BALB C; Neutropenia; Oxidative Stress; Random Allocation; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Leishmaniases are parasitic diseases due to a flagellate protozoan of the genus Leishmania. They are transmitted from mammal to mammal by the bite of an arthropod vector: a female sandfly. Among the different clinical presentations, the zoonotic visceral leishmaniasis (ZVL) is due to Leishmania infantum. Dogs are the reservoir and can develop a deadly disease. ZVL is described in China, Pakistan, Latin America and in the Mediterranean region, particularly in the South of France. In recent years, many asymptomatic carriers have been described. Despite the fact that cases in immunocompromised adults are the majority, the classic Mediterranean ZVL in young children is still observed. The classic triad of symptoms is: fever, pallor, splenomegaly and hepatomegaly in half of the cases. The biological orientation is a low blood count (anemia, leuconeutropenia, and thrombocytopenia) and an inflammatory syndrome. Serological tests are useful, but the diagnosis is made by the identification of the parasite in a bone marrow sample. Today, the treatment is done by the liposomal amphotericin B (AmBisome) and the total dose must to be 20 mg/kg.

Topics: Amphotericin B; Anemia; Animals; Anti-Bacterial Agents; Child; Dogs; Female; Fever; Hepatomegaly; Humans; Leishmania infantum; Leishmaniasis; Leishmaniasis, Visceral; Leukopenia; Neutropenia; Splenomegaly; Thrombocytopenia; Zoonoses

In a neutropenic murine model of invasive pulmonary aspergillosis, prophylaxis with single doses of liposomal amphotericin B or micafungin at >or=5 mg/kg of body weight improved animal survival and suppressed the lung fungal burden for up to 7 days after infection, demonstrating the potential utility of infrequent dosing with these antifungals.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Colony Count, Microbial; Disease Models, Animal; Drug Administration Schedule; Echinocandins; Female; Invasive Pulmonary Aspergillosis; Lipopeptides; Liposomes; Micafungin; Mice; Mice, Inbred BALB C; Neutropenia

A nationwide questionnaire-based survey was performed to evaluate the current clinical practices for the management of neutropenic fever in hematology units and hematopoietic stem cell transplantation (HSCT) centers throughout Korea. A 86.9% response rate was obtained from a total of 46 doctors and practical policies of the 33 sites were analysed. Approximately 42.4% and 84.8% of the sites responded that they used oral fluoroquinolone as prophylaxis for neutropenic patients receiving chemotherapy and HSCT, respectively. Additionally, 42.4% of the sites responded that they used antifungal prophylaxis in the chemotherapy groups whereas 90.9% of the sites responded that they used antifungal prophylaxis in HSCT recipients. Approximately half of the responding sites prescribed combination regimen with 3rd or 4th cephalosporin plus aminoglycoside as a first-line therapy. Most of the sites considered persistent fever for 2-4 days or aggravated clinical symptoms for 1-2 days as failure of the first-line regimen, and they changed antibiotics to second-line regimens that varied widely among the sites. Twenty-seven sites (84.4%) responded that they considered adding an antifungal agent when fever persisted for 5-7 days despite antibacterial therapy. Amphotericin B deoxycholate was preferred as a first-line antifungal, which was probably due to the limitations of the national health insurance system. The role of oral antibiotics in the management of neutropenic fever still accounted for a small portion. To the best of our knowledge, this survey is the first report to examine the practical policies currently in place for the management of neutropenic fever in Korea and the results of this survey may help to establish a Korean guideline in the future.

Topics: Administration, Oral; Aminoglycosides; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Cephalosporins; Data Collection; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Fever; Fluoroquinolones; Hematopoietic Stem Cell Transplantation; Humans; Korea; Neoplasms; Neutropenia; Prospective Studies; Surveys and Questionnaires; Time Factors; Treatment Failure

A 47-year-old man with newly diagnosed acute myeloblastic leukemia and non-insulin-dependent diabetes mellitus developed Trichosporon asahii fungemia while receiving caspofungin as empirical antifungal therapy. The diagnosis was based on repeated isolation of T. asahii in culture of blood for three times. Despite treatment with amphotericin B and voriconazole, the patient died. The in vitro antifungal susceptibilities of the T. asahii isolates were only available after the patient died. In vitro antifungal susceptibility tests showed high caspofungin and amphotericin B minimal inhibitory concentrations (MICs) value for this Trichosporon strain (MICs, 16 microg/ml, and>32 microg/ml, respectively). Fluconazole, itraconazole, and voriconazole exhibited low MICs in vitro (MICs, 4 microg/ml, 0.5 microg/ml, and

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Diabetes Mellitus, Type 2; Drug Resistance, Multiple, Fungal; Echinocandins; Fatal Outcome; Fungemia; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Lipopeptides; Male; Microbial Sensitivity Tests; Middle Aged; Neutropenia; Trichosporon

Invasive aspergillosis predominantly occurs in patients with impaired host defence and is often resistant to different therapeutically strategies. However, mortality significantly increases if the central nervous system is affected. In this report, we describe a case of successful treatment of invasive aspergillosis with cerebral involvement. The treatment consists of a medication of voriconazole and lipid-associated amphotericin B as well as a stereotactic neurosurgical procedure to drain an intracranial abscess.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Drug Combinations; Drug Therapy, Combination; Female; Humans; Middle Aged; Neuroaspergillosis; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Pyrimidines; Triazoles; Voriconazole

Topics: Adolescent; Amphotericin B; Antifungal Agents; Candidiasis; Child; Child, Preschool; Drug Resistance, Fungal; Female; Fever; Fungemia; Humans; Immunocompromised Host; Male; Neutropenia

Fusarium infections are associated with high mortality after allogeneic stem cell transplantation. We report on successful treatment of a disseminated cutaneous Fusarium proliferatum infection using liposomal amphotericin B and terbinafine. In vitro susceptibility tests of antifungal drugs suggest that terbinafine is a potent additional antifungal drug for disseminated cutaneous fusariosis.

Topics: Amphotericin B; Antifungal Agents; Dermatomycoses; Drug Therapy, Combination; Female; Fusarium; Humans; Middle Aged; Naphthalenes; Neutropenia; Salvage Therapy; Stem Cell Transplantation; Terbinafine; Transplantation, Homologous; Treatment Outcome

We compared the efficacies of liposomal amphotericin B (LAmB) and an amphotericin B lipid complex (ABLC) in diabetic ketoacidotic (DKA) or neutropenic mice with disseminated zygomycosis. ABLC was as effective as LAmB in neutropenic but not DKA mice. Low-dose ABLC was less effective than LAmB at reducing brain fungal burdens in both models.

Topics: Amphotericin B; Animals; Antifungal Agents; Diabetic Ketoacidosis; Disease Models, Animal; Drug Combinations; Humans; Liposomes; Male; Mice; Mice, Inbred BALB C; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Rhizopus; Treatment Outcome; Zygomycosis

The objective of the current retrospective study was to compare the epidemiology of candidemia and its risk factors in patients who had hematologic malignancies(HM) with those in patients who had solid tumors (ST).. The medical and electronic records of all patients with cancer who had candidemia at the authors' institution from 1993 to 2003 were reviewed for demographic data and clinical information, including the use of prophylactic fluconazole, the infecting Candida species, and the source of candidemia (catheter-related vs other apparent sources).. Six hundred thirty-five patients with candidemia were analyzed. C. glabrata and C. krusei were the leading causes of candidemia in 31% and 24% of patients with HM, respectively, and in 18% and 2% of patients with ST, respectively (P < .001). A catheter was the source of candidemia in 36% of the patients with ST and in 12% of the patients with HM (P < .001). Response to antifungal therapy occurred in 73% of the ST group compared with 49% of the HM group (P < .001). Multivariate logistic regression analysis revealed that fluconazole prophylaxis was a risk factor for both C. glabrata and C. krusei candidemia. The analysis also identified neutropenia as a risk factor for all candidemia and catheter-related infection as a risk factor for C. parapsilosis candidemia.. The results of this study indicated that C. glabrata and C. krusei were the leading causes of candidemia in patients with HM. Neutropenia was the leading risk factor for all candidemia, whereas the catheter was the leading risk factor for C. parapsilosis candidemia.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Catheterization, Central Venous; Cohort Studies; Drug Resistance, Fungal; Female; Fluconazole; Fungemia; Hematologic Neoplasms; Humans; Male; Middle Aged; Neutropenia; Retrospective Studies; Risk Factors

Topics: Administration, Inhalation; Amphotericin B; Antifungal Agents; Aspergillosis; Humans; Lung Diseases, Fungal; Neutropenia

Fungal infections are a major cause of morbidity and mortality in patients during chemotherapeutic treatments and malignant hematologic disease. We present a case of a double fungal infection with disseminated Acremonium strictum (A. strictum) and pulmonary Aspergillus fumigatus (A. fumigatus) and its rapid clinical course. A 17-year-old boy with prolonged neutropenia developed a disseminated fungal infection during induction chemotherapy of his acute lymphoblastic leukemia. The infection was rapidly lethal despite neutrophil recovery and early antifungal combination therapy with amphotericin B and caspofungin. Since there are only a few reports about invasive Acremonium infections, we present this case with regard to differences in the clinic pathologic features of Aspergillosis and other opportunistic fungal infections due to Fusarium or Acremonium species.

Topics: Acremonium; Adolescent; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Burkitt Lymphoma; Caspofungin; Echinocandins; Fatal Outcome; Humans; Lipopeptides; Male; Neutropenia; Peptides, Cyclic

Disseminated candidiasis is associated with a high rate of morbidity and mortality. The presence of neutrophils and the timely administration of antifungal agents are likely to be critical factors for a favorable therapeutic outcome of this syndrome. The effect of neutropenia on the temporal profile of the burden of Candida albicans in untreated mice and those treated with amphotericin B was determined using a pharmacodynamic model of disseminated candidiasis. A mathematical model was developed to describe the rate and extent of the C. albicans killing attributable to neutrophils and to amphotericin B. The consequences of a delay in the administration of amphotericin B, flucytosine, or micafungin were studied by defining dose-response relationships. Neutrophils caused a logarithmic decline in fungal burden in treated and untreated mice. The combination of amphotericin B and neutrophils resulted in a high rate of Candida killing and a sustained anti-C. albicans effect. In neutropenic mice, 5 mg/kg of body weight of amphotericin B was required to prevent progressive logarithmic growth. An increased delay in drug administration resulted in a reduction in the maximum effect to a point at which no drug effect could be observed. Neutrophils and the timely initiation of antifungal agents are critical determinants in the treatment of experimental disseminated candidiasis.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Disease Models, Animal; Dose-Response Relationship, Drug; Echinocandins; Flucytosine; Kidney; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Microbial Sensitivity Tests; Neutropenia; Neutrophils; Peptides, Cyclic; Time Factors

Neutropenic mice with latent trichosporonemia were given various antifungal agents (amphotericin B, fluconazole, itraconazole) or saline to determine which antifungal agent could be useful for prophylaxis. The 3-week-survival rate was 80% in the fluconazole group, 50% in the amphotericin B group, 45% in the itraconazole group, and 30% in the saline group. Compared with the other antifungal agents, fluconazole offered superior prophylaxis against the progression of trichosporonosis fungemia to disseminated disease (P<0.05). These results suggest that clinical studies are warranted to investigate fluconazole prophylaxis of trichosporonosis progression in neutropenic patients, such as people receiving chemotherapy and patients who have received solid organ transplants.

Topics: Amphotericin B; Animal Structures; Animals; Antibiotic Prophylaxis; Antifungal Agents; Cyclophosphamide; Disease Models, Animal; Fluconazole; Fungemia; Itraconazole; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Survival Analysis; Treatment Outcome; Trichosporon

In spite of the development of new antifungal drugs, amphotericin B deoxycholate (d-AMB) remains the gold standard in the treatment of severe fungal infections in immunosuppressed hosts. However, d-AMB is a toxic drug, the most important dose-limiting toxicities being nephrotoxicity and infusion-related allergic reactions. Lipid and liposomal formulations of d-AMB have relatively lower toxicity and are considered alternative choices. However, the routine use of these formulations is limited by their higher cost. Using retrospective analysis, we explored the incidence of nephrotoxicity and allergic reactions requiring the cessation of conventional d-AMB in 113 cases treated with the drug. In contrast to knowledge in the relevant literature, we did not detect significant toxicity, which would have required discontinuation of the d-AMB treatment. Mean serum creatinine levels were 0.72 +/- 0.25 and 0.84 +/- 0.31 mg dl(-1) before and after therapy, respectively. Although the difference between creatinine levels before and after d-AMB is statistically significant, the creatinine level increased twofold in only eight cases. Mean serum potassium levels were 3.8 +/- 0.54 and 3.6 +/- 0.7 mmol l(-1) before and after d-AMB respectively. Potassium levels below 3 mmol l(-1) were found in 7 and 17 cases before and after d-AMB respectively. Potassium levels were statistically lower in cases with fungal mucositis. Severe infusion-related allergic reactions were observed in three cases. Antihistamine and corticosteroid were added to the treatment in these cases. With these findings, we can conclude that d-AMB is a tolerable, low cost drug which can be safely used provided there is suitable premedication and monitoring of blood urea nitrogen, serum potassium and magnesium levels.

Topics: Adolescent; Adult; Amphotericin B; Creatinine; Deoxycholic Acid; Drug Combinations; Drug Hypersensitivity; Female; Humans; Kidney; Magnesium; Male; Middle Aged; Mycoses; Neutropenia; Potassium; Retrospective Studies; Urea

An analysis was conducted that evaluated and compared the cost differences between caspofungin and liposomal amphotericin B when the medications were used as empirical antifungal therapy for persistent fever during neutropenia.. Rates of drug use and impaired renal function (IRF) were based on data from published studies. IRF was defined as a doubling of the serum creatinine level or, if the creatinine level was elevated at enrollment, an increase of at least 1 mg/dL. The estimates of the costs for drug acquisition and treating IRF were derived using published data and applied to compare caspofungin with liposomal amphotericin B. Sensitivity analyses were performed by varying the IRF and relative acquisition costs to assess the effect of these factors on the cost differences.. The acquisition costs per patient were 6942 dollars for liposomal amphotericin B and 3996 dollars for caspofungin. The estimated cost per patient from IRF was 3173 dollars for liposomal amphotericin B and 793 dollars for caspofungin. Combining drug acquisition and IRF costs, the overall treatment cost per patient for caspofungin was 5326 dollars less than for liposomal amphotericin B. In sensitivity analyses of drug costs, the price of liposomal amphotericin B would have to be 23.95 dollars per vial for the overall treatment costs to be equal.. Comparison of cost estimates derived from published data revealed that a combined estimate of acquisition costs and costs related to the treatment of IRF was lower for caspofungin than for liposomal amphotericin B for empirically treating patients with neutropenic fever.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Cost-Benefit Analysis; Drug Costs; Echinocandins; Fever; Humans; Kidney Function Tests; Lipopeptides; Liposomes; Neutropenia; Peptides, Cyclic; Renal Insufficiency; Retrospective Studies; Sensitivity and Specificity

Liposomal amphotericin B (LAmB) has demonstrated similar efficacy to conventional amphotericin B for antifungal treatment in patients with febrile neutropenia; however, it is not without toxicities and is associated with a high acquisition cost. Despite this high cost, LAmB has been shown to have a pharmacoeconomic advantage over less expensive agents. Voriconazole is a potential alternative for empirical antifungal treatment of febrile neutropenia. The objective of this study was to assess the economic outcomes of voriconazole versus LAmB in patients with fever and neutropenia.. A decision analytical model was developed from a hospital perspective based on a 2-year (2002-2003) review of outcomes and prescribing practices in febrile neutropenic patients at a tertiary care medical centre. Literature reports and expert opinion were used to further populate the model. Sensitivity analyses and Monte Carlo simulation enhanced the robustness of the model through variation of all probabilities and costs that populated the model.. Sixty-three cases were evaluated in the retrospective review. Thirty-two were initially given voriconazole and 31 were given LAmB. Patient demographic data were similar in each group. In the base case, patients initially given voriconazole displayed a 27% reduction in overall treatment cost over patients initially given LAmB (14,950 vs 20,591 $US). Sensitivity analysis determined that the cost advantage in the voriconazole arm was maintained over a wide range of costs and probabilities. Variance in the cost of nephrotoxicity and medication cost did not significantly alter results. Monte Carlo simulation determined the voriconazole arm to be the optimal path in 65% of cases.. The decision model indicated that use of voriconazole as the preferred antifungal agent in adult haematology patients with febrile neutropenia should result in lower overall treatment costs relative to LAmB.

Topics: Amphotericin B; Antifungal Agents; Decision Support Techniques; Economics, Pharmaceutical; Fever; Health Care Costs; Humans; Liposomes; Neutropenia; Pyrimidines; Retrospective Studies; Treatment Outcome; Triazoles; Voriconazole

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Dose-Response Relationship, Drug; Humans; Neutropenia; Randomized Controlled Trials as Topic

Primary cutaneous aspergillosis is a rare cutaneous disease that usually affects immunodepressed patients of any age. The most common associated disorders in children are leukemias and lymphomas although it can also occur in neonates and preterms due to their intrinsic immunological immaturity. We report the case of a 4-year-old boy diagnosed of acute lymphoblastic leukemia that, during chemotherapy, developed an ulceronecrotic inflammatory cutaneous lesion in the venopuncture area of the left forearm, and whose microbiological culture was positive for Aspergillus flavus.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Aspergillus flavus; Child, Preschool; Dermatomycoses; Humans; Immunocompromised Host; Male; Neutropenia; Opportunistic Infections; Phlebotomy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Skin Ulcer; Wound Infection

To assess the effectiveness, safety, and cost of empiric treatment of febrile neutropenia before and after implementing an algorithm in which voriconazole was substituted for liposomal amphotericin B (L-AmB).. Retrospective cohort analysis.. An 850-bed tertiary care hospital, which is also a referral site for patients with acute leukemia.. Fifty-five adult patients who started empiric antifungal therapy for febrile neutropenia between January 1, 2002, and December 31, 2003, encompassing 58 treatment episodes (defined as a hospitalization during which empiric antifungal therapy was administered).. Medical charts, including patients' pharmacy and laboratory data, were reviewed. Twenty-six and 32 episodes of L-AmB and voriconazole use, respectively, were identified. No significant differences between the L-AmB and voriconazole groups were noted at baseline. Rates of fever resolution (54% vs 59%, p=0.791) and breakthrough invasive fungal infections (11% vs 12%, p>0.999) were similar for the L-AmB and voriconazole episodes. Premature drug discontinuation due to the prescriber's perceived lack of efficacy occurred most frequently in the voriconazole group (25% vs 8%, p=0.160). Survival was significantly higher in the voriconazole than in the L-AmB group (100% vs 77%, p=0.006). Adverse effects that were significantly more common in the L-AmB group than in the voriconazole group were elevated serum creatinine levels (27% vs 3%, p=0.017) and electrolyte disturbances (19% vs 0%, p=0.014). Adverse effects reported more frequently in the voriconazole group than in the L-AmB group were visual disturbances (9% vs 0%, p=0.245) and elevated hepatic enzyme levels (9% vs 8%, p>0.999). Mean drug expenditures/episode for initial empiric antifungal therapy were lower for voriconazole than for L-AmB ($1593 vs $4144, or $153 vs $380/day).. Our institution's algorithm incorporating voriconazole into the empiric management of febrile neutropenia was associated with effectiveness outcomes comparable to those observed with L-AmB as well as a lower frequency of adverse effects and overall expenditures for antifungal drugs.

Topics: Amphotericin B; Antifungal Agents; Female; Fever; Health Care Costs; Hospitalization; Humans; Male; Middle Aged; Neutropenia; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Invasive aspergillosis (1A) is one of the most common and serious fungal infections in immuno-compromised host. Available data regarding IA among Asian patients are limited.. To determine patients' characteristics, clinical presentation, treatment, and outcomes of patients with IA in a Tertiary-care Hospital in Thailand.. The authors retrospectively reviewed medical and laboratory records of adult patients with IA from January 2000 to December 2005.. Ninety-four patients were identified and classified as proven (n = 35), probable (n = 10), and possible IA (n = 49) according to the criteria designed for cancer patients (EORTC/MSG). Mean +/- SD age was 48 +/- 19 (range, 17-89) years old and 54 patients (57%) were male. Acute leukemia was the most common underlying condition (30%). Major predisposing factors were neutropenia (39%), chemotherapy (34%), and receiving corticosteroid therapy (25%). Common sites of infection were lungs (68%), sinus (17%), and eyes (8%). Aspergillus fumigatus (67%) was the most frequently isolated species. Amphotericin B followed by itraconazole was the mainstay of treatment. Thirty-six patients (38%) had complete or partial response to therapy whereas 44 patients (47%) died due to aspergillosis. Multivariate analysis showed that corticosteroid therapy [hazard ratio (HR) 10.65; 95% confidence interval (CI) 1.03-110.15, p = 0.047] and pulmonary infection [HR 18.06; 95% CI 4.28-76.17, p < 0.001] were significant predictive factors of death.. Epidemiology and outcomes of IA among Thai patients were comparable to those in Western countries. Early diagnosis of lA in patients at risk is still essentially required in order to offer appropriate therapy, decrease morbidity, and mortality rate.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Aspergillosis; Early Diagnosis; Female; Humans; Immunocompromised Host; Itraconazole; Male; Middle Aged; Neutropenia; Proportional Hazards Models; Retrospective Studies; Risk Factors; Thailand; Treatment Outcome

In August 2002, the antifungal prophylaxis algorithm for neutropenic hematology/oncology (NHO) patients at the Medical Center was changed from conventional amphotericin (AMB) to an azole (AZ) based regimen (fluconazole [FLU] in low-risk and voriconazole [VOR] in high-risk patients). The aim of our study was to compare outcomes associated with the two regimens, including breakthrough fungal infection, adverse drug events, and costs.. Adult, non-febrile, NHO patients who received prophylactic AMB from 01 August 2001-30 July 2002 or AZ from 01 August 2002-30 July 2003 were retrospectively evaluated.. A total of 370 patients (AMB: n = 181; AZ: n = 216) associated with 580 hospitalizations (AMB: n = 259; AZ: n = 321) were included. The incidence of probable/definite breakthrough Aspergillus infections was similar among regimens (AMB: 1.9% vs AZ: 0.6%; p=0.19). A greater incidence of mild/moderate (24.7% vs. 5.3%; p < 0.0001) and severe renal dysfunction (13.5% vs. 4.4%; p < 0.0012) was observed with AMB. In contrast, patients treated with VOR were found to have an increased rate of severe hepatic toxicity (32.5%) compared with patients treated with either AMB (22.6%) or FLU (21.4%) (p = 0.05). While the AZ period was associated with a >$9,000 increase in mean total costs/hospitalization, the mean acquisition cost associated with AZ was only $947/hospitalization more than AMB.. While an AZ-based regimen is associated with increased cost, the reduced rate of nephrotoxicity and availability of oral dosage forms, suggests that azoles be used preferentially over AMB. However, an increased rate of severe hepatic toxicity may be associated with VOR.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Therapy, Combination; Female; Fluconazole; Humans; Male; Middle Aged; Mycoses; Neutropenia; Pyrimidines; Retrospective Studies; Triazoles; Voriconazole

Invasive pulmonary aspergillosis (IPA) remains a life-threatening condition despite systemic antifungal therapy.. This retrospective analysis investigated whether additional bronchoscopic instillation of amphotericin B (amB) would improve efficacy of antifungal treatment in patients with haematological malignancies suffering from IPA.. Twenty patients (40.6 +/- 14.2 years, 14 male) with preceding chemotherapy, bone marrow or stem cell transplantation complicated by severe IPA who did not respond sufficiently to systemic antifungal therapy were additionally treated by repeated bronchoscopic instillations of amB solution (91 instillations, on average 4.6 +/- 2.2 instillations per patient over a period of 24.1 +/- 21.0 days). Therapeutic response to this combined treatment regimen was monitored by chest X-ray and CT scan.. The mean infiltration sizes during systemic antifungal therapy alone (mean duration 11.9 +/- 9.9 days) did not change significantly. However, after additional bronchoscopic instillation of amB solution infiltration sizes were reduced significantly (p < 0.05). A total resolution of infiltrates was seen in 3 and a partial reduction in 13 of 20 patients. Mean duration of total antifungal treatment was 50.1 +/- 24.0 days. The mean follow-up period was 34.1 +/- 31.2 months. The IPA-related mortality rate was 18.8% (3 of 16 patients).. Additional bronchoscopic instillation of amB may improve the efficacy of systemic antifungal therapy in patients with haematological malignancies complicated by severe IPA. Bronchoscopic instillation of amB should be considered as an additional treatment option in cases with IPA unresponsive to systemic therapy.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Bronchoscopy; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Therapy, Combination; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Radiography; Retrospective Studies; Treatment Outcome

Cutaneous zygomycosis is a rare but severe fungal infection with high risk of dissemination. Early recognition, deep surgical biopsy for diagnosis, aggressive treatment with repeated surgical debridement, and targeted pharmacotherapy are essential and can prevent dissemination and fatal outcome. We present case reports of 2 patients.

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Debridement; Dermatomycoses; Female; Humans; Hyperbaric Oxygenation; Immunocompromised Host; Male; Neutropenia; Treatment Outcome; Zygomycosis

Topics: Amphotericin B; Antifungal Agents; Chin; Diabetes Complications; Ecthyma; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Middle Aged; Necrosis; Neutropenia; Zygomycosis

We conducted a dose fractionation study of neutropenic, corticosteroid-immunosuppressed mice to characterize the pharmacodynamic/pharmacokinetic (PK/PD) parameter most closely associated with amphotericin B (AMB) efficacy in the treatment of invasive pulmonary aspergillosis. Pharmacokinetic parameter estimates were determined by a nonparametric population pharmacokinetic analysis of plasma drug concentrations following single intraperitoneal doses (0.25, 1.0, and 3.0 mg/kg of body weight) of amphotericin B deoxycholate. Three dosage groups (0.5, 0.75, and 1.0 mg/kg) fractionated into three dosing intervals (every 8 h [q8h], q24h, or q72h) were tested to discriminate between the PK/PD parameters (the ratio of maximum concentration of drug in serum [Cmax]/MIC, the ratio of area under the concentration-time curve/MIC, and percentage of time above MIC) most closely associated with AMB efficacy over a range of clinically achievable exposures in humans. The efficacy of each regimen was determined by quantitative PCR and survival. Reductions in pulmonary fungal burden and improvements in survival were maximized at the highest peak plasma concentrations in each of the dosage groups. Reductions in pulmonary fungal burden and increased survival were most closely associated with Cmax/MIC, with maximal activity occurring as the Cmax/MIC approached 2.4. In our model, Cmax/MIC is the PK/PD parameter most closely associated with efficacy in the treatment of invasive pulmonary aspergillosis. These data predict that less frequently administered, higher dosages of AMB would optimize efficacy.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Deoxycholic Acid; DNA, Fungal; Drug Combinations; Female; Lung; Lung Diseases, Fungal; Mice; Microbial Sensitivity Tests; Models, Biological; Neutropenia

Evaluation of the potential of caspofungin, in relation to pharmacokinetics, in order to optimize its use in the treatment of filamentous fungal infections.. The in vitro antifungal activity, pharmacokinetics and therapeutic efficacy of caspofungin versus amphotericin B was investigated in vitro as well as in a model of aerogenic Aspergillus fumigatus infection in neutropenic rats, using rat survival and decrease in fungal burden as parameters for therapeutic efficacy.. In contrast to amphotericin B, caspofungin shows a concentration-dependent gradual decrease in fungal growth in vitro, which makes it difficult to perform visual readings of antifungal activity (CLSI guidelines). The quantitative XTT [2,3-bis(2-methoxy-4-nitro-5-[(sulphenylamino) carbonyl]-2H-tetrazolium-hydroxide] assay measuring a decrease in fungal metabolic activity seems more appropriate for caspofungin susceptibility testing. Using this assay, in vitro caspofungin was 4-fold less active than amphotericin B. In the infection model, therapy was started 16 h after fungal inoculation, and continued once daily for 10 days. Caspofungin was administered intraperitoneally at 1, 2, 3 or 4 mg/kg/day (CAS 1, 2, 3 or 4), amphotericin B at 1 mg/kg/day (AMB 1). Treatment with CAS 1 or AMB 1 provided modest prolongation of animal survival. The combination of caspofungin and amphotericin B did not show additive effects. Increasing the dosage of caspofungin to 2, 3 or 4 mg/kg/day resulted in a dose-dependent significant increase in efficacy. There was 100% survival among rats in the CAS 4 group, which was correlated with a significant decrease in fungal burden, based on the concentration of A. fumigatus galactomannan in serum and lung tissue and quantification of A. fumigatus DNA in lung tissue. Pharmacokinetic analysis suggested that the CAS 4 dose in rats produced drug exposure comparable to the human situation, visualized by similar 24 h AUC and trough concentrations.. The therapeutic efficacy of caspofungin is superior to amphotericin B, which seemed to be discrepant with their in vitro antifungal activity.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Caspofungin; Disease Models, Animal; Echinocandins; Humans; Lipopeptides; Lung; Lung Diseases, Fungal; Microbial Sensitivity Tests; Neutropenia; Peptides, Cyclic; Rats; Treatment Outcome

We describe a 57-year-old woman with acute lymphoblastic leukemia who had a cavitary lesion develop in the right upper lobe caused by Cunninghamella bertholletiae, a zygomycete. The infection was resistant to both high-dose liposomal amphotericin B and voriconazole. The current report demonstrates successful treatment, even in the setting of subsequent bone marrow transplantation and immunosuppression, using a combination of surgical resection and posaconazole therapy.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Benzamides; Bone Marrow Transplantation; Cefepime; Cephalosporins; Combined Modality Therapy; Cunninghamella; Daunorubicin; Drug Resistance, Multiple, Fungal; Female; Humans; Imatinib Mesylate; Immunocompromised Host; Lung Diseases, Fungal; Middle Aged; Neutropenia; Piperazines; Pneumonectomy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Pyrimidines; Transplantation Conditioning; Triazoles; Vancomycin; Vincristine; Voriconazole; Zygomycosis

Topics: Alternaria; Amphotericin B; Dermatomycoses; Female; Fever; Hand; Humans; Middle Aged; Neutropenia

Candidemia is often fatal, especially in patients with persistent neutropenia. New therapies are needed. We performed 24-h pharmacodynamic studies to compare the efficacies of anidulafungin, fluconazole, and amphotericin B in neutropenic mice with disseminated candidiasis caused by one of three strains of Candida glabrata. Anidulafungin produced a maximal fungal kill (E(max)) of 1.4 to 1.9 log(10) CFU/g in kidneys and was not influenced by resistance to either fluconazole or amphotericin B. Fluconazole produced an E(max) of 1.3 log(10) CFU/g in mice infected with fluconazole-susceptible C. glabrata, but the E(max) was 0 for mice infected with a C. glabrata strain that had a fluconazole MIC of >/=32 mg/liter. Amphotericin B achieved an E(max) of 4.2 log(10) CFU/g in mice infected with amphotericin B-susceptible C. glabrata, but the E(max) was 0 for mice infected with a C. glabrata strain with an amphotericin B MIC of 2 mg/liter. In all instances, anidulafungin's maximal microbial kill was superior to that of fluconazole. Next, we performed a 96-h anidulafungin pharmacokinetic-pharmacodynamic study. Anidulafungin exhibited delayed peak concentrations in kidneys compared to those in serum, after which the concentrations declined, with a serum terminal half-life of 21.6 (+/-4.6) h. This was accompanied by a persistent 96-h decrease in the kidney fungal burden after treatment with a single anidulafungin dose of >/=8 mg/kg of body weight. This pharmacokinetic-pharmacodynamic picture of anidulafungin persistence in tissues and the resultant persistent fungal decline should be exploited to improve the efficacy of anidulafungin therapy for candidemia.

Topics: Algorithms; Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Area Under Curve; Candida glabrata; Candidiasis; Colony Count, Microbial; Dose-Response Relationship, Drug; Echinocandins; Female; Fluconazole; Mice; Microbial Sensitivity Tests; Neutropenia; Peptides, Cyclic

Fusarium solani infections are notoriously difficult to treat. We compared the efficacy of polyenes and an echinocandin in treating murine fusariosis to identify the optimal therapeutic regimen.. Neutropenic mice infected intravenously with F. solani were treated with amphotericin B (AmB), liposomal AmB (LAmB), amphotericin B lipid complex (ABLC), caspofungin acetate or a combination of LAmB and caspofungin. Treatment was initiated prior to infection (prophylactic therapy), 24 h post-infection (delayed therapy) or 2 days before infection and continued for 1 day after (continuous therapy).. Prophylaxis only with LAmB significantly reduced brain or kidney fungal burden compared with placebo. No prophylactic treatment improved survival. LAmB levels in the kidneys were higher than ABLC or AmB levels, which were often undetectable. In the delayed therapy model, neither polyenes nor caspofungin improved survival. In the continuous therapy model, LAmB or LAmB plus caspofungin did not improve survival even though they did decrease fungal burden. In contrast, continuous caspofungin at 1 but not 5 mg/kg/day improved survival, but did not decrease fungal burden. Kidney inflammation and tissue necrosis were markedly decreased in mice treated with caspofungin compared with other treatments.. These studies demonstrate a dissociation between survival and tissue fungal burden during murine fusariosis. Although prophylactic LAmB may be useful at reducing tissue fungal burden, polyenes had limited survival benefit for active fusariosis. Caspofungin at 1 but not 5 mg/kg/day mediated surprising improvements in survival during active fusariosis, despite lack of reduction in fungal burden. Further studies are warranted.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Caspofungin; Drug Combinations; Echinocandins; Fusarium; Kidney; Lipopeptides; Male; Mice; Mice, Inbred BALB C; Mycoses; Neutropenia; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols

In a clinical non-trial setting, the efficacy and safety of caspofungin was compared with liposomal amphotericin B for the management of febrile neutropenia or invasive fungal infections in 73 episodes in patients with haematological malignancy. There were fewer episodes of drug toxicity with caspofungin than liposomal amphotericin B (58.3 vs 83.7 %, P=0.02). The favourable response rate for episodes of febrile neutropenia treated with caspofungin or liposomal amphotericin B was similar at 37.5 and 53.8 %, respectively, but more breakthrough fungal infections occurred with caspofungin than with liposomal amphotericin B (33.3 vs 0 %, P<0.05) in these patients who did not receive antifungal prophylaxis. None of four episodes of candidaemia or hepatosplenic candidiasis responded to caspofungin compared with three of four episodes treated with liposomal amphotericin B. Mortality was significantly higher with caspofungin treatment compared with liposomal amphotericin B (6/24 vs 2/49, P=0.01), mainly due to an excess of fungal infections (P=0.04). Caspofungin treatment was a significant independent predictor of mortality [odds ratio=7.6 (95 % confidence interval 1.2-45.5)] when sepsis severity, prolonged neutropenia and length of antifungal therapy were considered in a multiple logistic regression model. In clinical practice, there is a suggestion that caspofungin may not be as effective as liposomal amphotericin B in preventing breakthrough invasive fungal infections in febrile neutropenia or in preventing fungus-related deaths. Because of the potential biases in this observational study, these preliminary findings should be interpreted with caution and clarified with a larger cohort of patients.

Topics: Adult; Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Female; Fever; Hematologic Neoplasms; Hospitals; Humans; Lipopeptides; Liposomes; Logistic Models; Male; Mycoses; Neutropenia; Peptides, Cyclic; Retrospective Studies; Treatment Outcome; United Arab Emirates

Topics: Amphotericin B; Antifungal Agents; Brain Neoplasms; Candida; Candida albicans; Candida glabrata; Candidiasis; Caspofungin; Child, Preschool; Drug Resistance, Fungal; Echinocandins; Humans; Immunocompromised Host; Lipopeptides; Male; Neuroectodermal Tumors; Neutropenia; Peptides, Cyclic; Time Factors

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Child, Preschool; Female; Fungemia; Humans; Immunocompromised Host; Microbial Sensitivity Tests; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The efficacy of itraconazole (ITZ) solubilized in hydroxypropyl-beta-cyclodextrin (ITZ-IV) was examined in a murine model of invasive pulmonary aspergillosis (IPA). Immunosuppressed mice were infected by the intratracheal inoculation of Aspergillus fumigatus conidia (2 x 10(6) conidia/mouse). Their body weight rapidly decreased and they died within 6 days after infection. Intravenous administration of various doses of ITZ-IV was started 24 h after infection and was continued once a day for 4 days. ITZ-IV at daily doses of 10, 20, or 40 mg/kg was as effective as the intraperitoneal administration of amphotericin B (AMPH) at a dosage of 1 mg/kg daily in improving survival. ITZ-IV (20 mg/kg per day), as well as AMPH (1 mg/kg per day) significantly lowered the fungal burden in the pulmonary tissues. Histological improvement was seen within 2 days after the beginning of administration of ITZ-IV (20 mg/kg per day). In mice intravenously given a single dose of ITZ-IV (20 mg/kg), the blood level and pulmonary tissue level of ITZ plus its active metabolites, mainly hydroxyitraconazole (OH-ITZ), decreased gradually after the injection, but after 4 h their concentration was still between 1.4 microg/ml (ITZ) and 1.9 microg/ml (OH-ITZ), concentrations that were approximately 10 to 20 times greater than the minimum inhibitory concentration (MIC) of ITZ for challenging the strain of A. fumigatus (0.16 microg/ml). These results support the clinical usefulness of ITZ-IV for the treatment of IPA in immunocompromised patients.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Female; Immunocompromised Host; Infusions, Intravenous; Infusions, Parenteral; Itraconazole; Lung Diseases, Fungal; Mice; Mice, Inbred ICR; Models, Animal; Neutropenia; Survival Analysis

Invasive Acremonium infection in humans is rare. We report a patient with leukemia who developed pyomyositis due to Acremonium species. Painful cutaneous nodules and severe myalgia were the first clinical manifestations during the neutropenic stage after chemotherapy. Magnetic resonance image (MRI) revealed multiple nodular lesions scattered along the intramuscular regions of the lower legs. Culture of an aspiration grew Acremonium species. Surgical drainage was performed. Although all antifungal agents tested showed no in vitro inhibitory activity, we successfully treated this patient with amphotericin B, granulocyte colony-stimulating factor (G-CSF), and surgical drainage.

Topics: Acremonium; Acute Disease; Adolescent; Amphotericin B; Drainage; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia; Mycoses; Neutropenia; Opportunistic Infections

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Caspofungin; Echinocandins; Humans; Lipopeptides; Neutropenia; Neutrophils; Peptides, Cyclic

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fever; Humans; Lipopeptides; Mycoses; Neutropenia; Peptides, Cyclic; Risk Assessment

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fever; Humans; Lipopeptides; Mycoses; Neutropenia; Peptides, Cyclic; Triazoles

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fever; Humans; Infusions, Intravenous; Lipopeptides; Liposomes; Mycoses; Neutropenia; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fever; Humans; Lipopeptides; Mycoses; Neutropenia; Peptides, Cyclic; Pyrimidines; Survival Rate; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Deoxycholic Acid; Drug Combinations; Echinocandins; Fever; Humans; Infusions, Intravenous; Lipopeptides; Mycoses; Neutropenia; Peptides, Cyclic

Topics: Amphotericin B; Antifungal Agents; Fever; Humans; Liposomes; Meta-Analysis as Topic; Neutropenia

The recent shortage of the brand name drug Fungizone has necessitated a change to generic formulations of amphotericin B deoxycholate. Clinical trials cannot be conducted in a timely manner to provide data on the safety and efficacy of these formulations. We therefore compared generic amphotericin B and Fungizone for activity and safety in the treatment of experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. Fungizone and generic amphotericin B are similar in efficacy, pharmacokinetics, and safety in the treatment of experimental IPA.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Drugs, Generic; Lung Diseases, Fungal; Neutropenia; Rabbits

Topics: Acute Disease; Amphotericin B; Antifungal Agents; Bacterial Infections; Humans; Leukemia, Myeloid; Mycoses; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Blastoschizomyces capitatus (formerly known as Geotrichum capitatum and Trichosporon capitatum) is a rare, yet an emerging, cause of invasive infections in immunosuppressed patients. Profound and prolonged neutropenia is the crucial predisposing factor for this yeast infection. Blastoschizomyces capitatus was isolated from peripheral blood cultures of a profoundly neutropenic patient with acute myeloid leukemia (M2 FAB). Despite administration of antifungal chemotherapy with liposomal amphotericin B at 4.5 mg kg(-1) daily, the patient succumbed 4 days after initiation of treatment. Infections attributed to B. capitatus have generally a poor prognosis, although the yeast shows in vitro susceptibility to antifungal agents. Low flucytosine, caspofungin acetate, voriconazole and amphotericin B minimum inhibitory concentration values were also recorded with our isolate. The clinical relevance of the in vitro susceptibility testing against the isolate and the current antifungal chemotherapy regimens against B. capitatus systemic infections are discussed.

Topics: Aged; Amphotericin B; Antifungal Agents; Blood; Fatal Outcome; Fungemia; Geotrichosis; Geotrichum; Greece; Humans; Leukemia, Myeloid, Acute; Male; Neutropenia; Sepsis

Disseminated fusariosis in children is a rare and serious fungal infection, that occurs especially in neutropenic immunosuppressed patients, treated for malignant hemopathy, or bone marrow transplant recipient. Treatment is difficult and mortality is estimated between 50 and 70% in adult patients. CASE REPORT 1: A ten-year-old boy, treated for an acute lymphoblastic leukemia in second relapse, presented a disseminated fusarium spp infection, that occurred during neutropenia. He died due to fusariosis infection in spite of amphotericin B treatment. CASE REPORT 2: A ten-year-old neutropenic girl, treated for an acute myeloïd leukemia, presented disseminated fusariosis, uncontrolled by amphotericin B. Recovery was observed after voriconazole introduction and resolution of neutropenia. Ten months later, she presented a leukemia's relapse, treated by new intensive chemotherapy with secondary prophylaxis by voriconazole, without fusariosis's recurrence.. Voriconazole, a new triazole agent, seems to be an alternative antifungal agent to amphotericin B for disseminated fusarium infection, either at the acute phase or for secondary prophylaxis.

Topics: Amphotericin B; Antifungal Agents; Child; Drug Combinations; Fatal Outcome; Female; Fusarium; Humans; Immunocompromised Host; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Mycoses; Neutropenia; Pyrimidines; Triazoles; Voriconazole

To compare the activity of aminocandin (IP960), a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp., with that of amphotericin B and fluconazole in a temporarily immunocompromised murine model of disseminated candidiasis.. Mice were rendered neutropenic with cyclophosphamide and infected intravenously 3 days later with a fluconazole-resistant Candida tropicalis strain. Mice were treated with intraperitoneal amphotericin B (5 mg/kg/dose), oral fluconazole (50 mg/kg/dose), intravenous aminocandin (0.1--5 mg/kg/dose) or solvent control for 9 days. Mice were observed for survival and survivors were sacrificed 11 days post-infection. Kidneys, liver, brain and lungs were removed for semi-quantitative culture.. Control mice had 90--100% mortality. After infection with C. tropicalis, aminocandin 2.5 and 5 mg/kg/day and amphotericin B yielded 80% survival; aminocandin 1 mg/kg/day yielded 70% survival; aminocandin 0.25 and 0.1 mg/kg/day yielded 30% and 20% survival, respectively; and fluconazole 50 mg/kg/day and control regimens yielded 10% and 0--10% survival, respectively. Aminocandin 2.5 and 5.0 mg/kg/day and amphotericin B were superior in reducing mortality compared with aminocandin 0.25 and 0.1 mg/kg/day, fluconazole and controls (P<0.047). The only regimen to reduce organ burdens below detectable levels was amphotericin B, which cleared 40% of mice. All organ burdens in the aminocandin 1.0, 2.5 and 5.0 mg/kg/day and amphotericin B regimens were significantly lower than other groups (P<0.02).. The data demonstrate that aminocandin at doses of >or=1.0 mg/kg/day is as effective as amphotericin B at improving survival and reducing organ burdens in this murine model of disseminated C. tropicalis.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida tropicalis; Candidiasis; Cyclophosphamide; Disease Models, Animal; Drug Resistance, Fungal; Fluconazole; Immunocompromised Host; Lipopeptides; Lipoproteins; Male; Mice; Mice, Inbred Strains; Neutropenia; Survival Rate; Treatment Outcome

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Child, Preschool; Granulocyte Colony-Stimulating Factor; Humans; Male; Neutropenia; Platelet Transfusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vancomycin

Empirical antifungal therapy is the standard treatment for persistent or relapsing antibiotic-resistant neutropenic fever. However, overtreatment resulting in increased toxicity and treatment-related cost is a major shortcoming of such therapy. We assessed the feasibility of a "preemptive" approach based on the incorporation of sensitive, noninvasive diagnostic tests for consecutive high-risk neutropenic patients who had received fluconazole prophylaxis while avoiding empirical therapy.. A total of 136 treatment episodes for persons who were at risk of acquiring invasive fungal infection (IFI) were screened for the presence of galactomannan with an enzyme immunoassay. A diagnostic evaluation, which included thoracic computed tomography scanning (HRCT) and bronchoscopy with lavage, was performed on the basis of well-defined clinical, radiological, and microbiological criteria. Only seropositive patients and patients with a positive microbiological test result plus supportive radiological findings received liposomal amphotericin B.. Neutropenic fever developed in 117 episodes, of which at least 41 episodes (35%) satisfied existing criteria for empirical antifungal therapy. However, our protocol-driven preemptive approach reduced the rate of antifungal use for these episodes from 35% to 7.7% (a 78% reduction) and led to the early initiation of antifungal therapy in 10 episodes (7.3%) that were clinically not suspected of being IFI. No undetected cases of invasive aspergillosis were identified; 1 case of zygomycosis was missed. Breakthrough candidemia was diagnosed by conventional culture techniques and was treated successfully. With use of a preemptive approach, the 12-week survival rate for patients with IFI was 63.6% (it was 63.1% for those with invasive aspergillosis).. Preemptive therapy based on enzyme immunoassay and HRCT reduced the exposure to expensive and potentially toxic drugs and offered effective antifungal control, but it failed to detect non-Aspergillus IFI.

Topics: Adolescent; Adult; Aged; Algorithms; Amphotericin B; Antifungal Agents; Aspergillosis; Feasibility Studies; Female; Galactose; Humans; Lung Diseases, Fungal; Male; Mannans; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Risk Factors; Tomography, X-Ray Computed

Systemic fungal infections remain a major clinical problem in immunocompromised patients. Presumed systemic fungal infections (PSFI) are treated empirically with an intravenous antifungal agent to reduce the occurrence of documented infections and associated mortality. The objective of this study was to compare the cost-effectiveness of intravenous itraconazole (IVitra) treatment with the current first-line empirical treatment of PSFI with conventional amphotericin B (CAB) in cases of neutropenic cancer and bone marrow transplantation (BMT). Cost-effectiveness was expressed as cost per additional "responder" (defined as a patient without fever or major toxicity). We developed a medical decision analytical tree that included probabilities of toxicity, response and pathogen documentation, and second-line treatments. Clinical data were obtained from randomized clinical trials, and resource use data were obtained from a panel of clinical experts. The total cost of treating PSFI per neutropenic cancer patient was lower for IVitra than for CAB, and this lower cost resulted from a reduced need for second-line antifungals. In a cost-effectiveness analysis, IVitra treatment was superior to CAB treatment. Compared with current treatment with CAB, IVitra therapy was shown to be a cost-effective and cost-saving empirical treatment for PSFI in neutropenic cancer patients and BMT patients.

Topics: Amphotericin B; Antifungal Agents; Costs and Cost Analysis; Humans; Itraconazole; Korea; Mycoses; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic

In recent years, the incidence of HIV infection, the intensity of chemotherapy regimens for cancer and the use of bone marrow transplantation have all increased. This results in an increase in the incidence of systemic fungal infections, which are associated high rates of morbidity and mortality in this immunosuppressed population; the incidence is growing: 50% for neutropenic/transplant bone marrow patients and 5-20% for organ transplant. Fluconazole, itraconazole, amphotericin-B and, in the recent years, caspofungin and voriconazole are the most frequently used antifungal agents. However, the newly developed formulations of itraconazole and lipid-associated formulations of amphotericin-B have provide new treatment options for systemic fungal infection and have prompted a number of comparisons of the treatment costs of empirical therapy. The i.v. formulation of itraconazole may be more cost effective than either conventional or liposomial formulations of amphotericin-B when used as empirical therapy for neutropenic patients with persistent fever despite broad spectrum antibiotic therapy, but further studies are required. The lack of studies, national and international, and the small amount of available data on the cost of systemic fungal infections mean that the costs saving from prophylactic and empirical use of antifungals are difficult to estimate.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fluconazole; Humans; Immunocompromised Host; Itraconazole; Lipopeptides; Mycoses; Neutropenia; Opportunistic Infections; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

Mucormycoses are seen with an increasing incidence in immunocompromised patients. Most common presentations are rhinocerebral and pulmonary. We here report the experience of a single center with mucormycoses in patients with hematologic malignancies.. Mucormycoses were diagnosed in six patients, (median age of 52 years; range, 26-74) treated between 2001-2004. Diagnoses included acute myeloid leukemia (AML) (n=3), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1) and multiple myeloma (n=1). Mucormycosis was diagnosed in the neutropenic state following allogeneic hematopoietic cell transplantation (n=3) or intense chemotherapy (n=3). Sites of infections were rhinocerebral, facial and pulmonary involvement in one patient each and disseminated mucormycosis in three patients. The diagnosis was established by computed tomography followed by surgical interventions and histological diagnosis in 4 patients and post-mortem in two patients. Species identified were Rhizopus (n=3), Rhizomucor (n=2) and Absidia (n=1). Treatment responses were best if surgical resection was followed by aggressive antifungal chemotherapy. Five of six 6 patients died, all of complications of mucormycosis or their underlying disease. Only one patient with facial mucormycosis is still alive.. This experience demonstrates that patient with mucormycoses have a high mortality rate and early recognition followed by aggressive surgical debridement, high dose antifungal therapy and attempts to correct the underlying immunocompromised state are crucial in the treatment of this fatal infection.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Communicable Diseases, Emerging; Dermatomycoses; Disease Susceptibility; Female; Fluconazole; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Itraconazole; Lung Diseases, Fungal; Male; Middle Aged; Mucormycosis; Neutropenia; Pyrimidines; Sinusitis; Transplantation Conditioning; Triazoles; Viscera; Voriconazole

Paecilomyces variotii, an emerging hyalohyphomycetes, has been reported to be susceptible in vitro to voriconazole. We describe a case of disseminated P. variotii infection in a neutropenic child with relapsed leukaemia who was on voriconazole prophylaxis. The P. variotii isolate was resistant to voriconazole in vitro. The patient responded to liposomal amphotericin B.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Dermatomycoses; Drug Resistance, Fungal; Fungemia; Humans; Lung Diseases, Fungal; Male; Microbial Sensitivity Tests; Mycoses; Neutropenia; Paecilomyces; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Radiography; Treatment Outcome; Triazoles; Voriconazole

Intravenous amphotericin B deoxycholate (AmB-D) infusions, usually given over 4 hours, frequently induce nephrotoxicity and undesirable infusion-related side effects such as rigors and chills. There is evidence in the literature that the use of AmB-D in the form of continuous 24-hour infusion is less toxic than the usual four-hour infusion of this drug. Our objective was to evaluate the efficacy and safety of continuous infusion of AmB-D for the treatment of persistent fever in neutropenic patients with hematological malignancies after chemotherapy.. Observational retrospective analysis of our experience with continuous infusion of AmB-D, at Faculdade de Medicina da Fundação ABC and Hospital Estadual Mário Covas in Santo André.. From October 2003 to May 2004, 12 patients with hematological malignancies and chemotherapy-induced neutropenia received 13 cycles of continuous infusion of AmB-D.. The median dose of AmB-D was 0.84 mg/kg/day (0.33 to 2.30 mg/kg/day). Concomitant use of nephrotoxic medications occurred in 92% of the cycles. Nephrotoxicity occurred in 30.76% of the cycles, hypokalemia in 16.67%, hepatotoxicity in 30% and adverse infusion-related events in 23%. All patients survived for at least seven days after starting continuous infusion of AmB-D, and clinical resolution occurred in 76% of the cycles.. Continuous infusion of AmB-D can be used in our Institution as an alternative to the more toxic four-hour infusion of AmB-D and possibly also as an alternative to the more expensive liposomal formulations of the drug.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Retrospective Studies; Treatment Outcome

In May 2003, an indigenously developed liposomal amphotericin B (Fungisome) was introduced in the Indian market for the treatment of systemic fungal infections and visceral leishmaniasis. The present post marketing study assessed the safety and effectiveness of Fungisome in actual clinical practice.. Retrospective post marketing surveillance from four cities of India.. The present study was carried out for a period of 6 months (Jun-Nov 2004), a year after the introduction of the drug. A list of doctors who had prescribed and procured the drug was obtained from the distributor. Consent to participate and scrutinize the patients' source notes were obtained from the concerned doctors. All patients who had received Fungisome treatment were included. Data was collected from the patient's source notes on a predesigned proforma. They were then analyzed by descriptive statistics. Cost of Fungisome was calculated on the basis of dose used and number of days of treatment.. Data were available for 109/144 patients from 35/40 physicians. Fungisome was administered at 1-3 mg/kg/day for 7-76 days. No serious adverse events related to the drug were observed in the study. Mild infusion-related adverse events were reported in 40 (36%), moderate in 11 (10%) of patients and severe in 2 (1.8%). None of the adverse events were certain to Fungisome exposure, 12 (11%) were probable, 28 (25 %) were possible, and 13 (11.9%) were unlikely. Of the 91 assessable patients (received at least eight doses of Fungisome) for efficacy complete response was observed in 67 (73.6%), 16 (17.5%) had partial responses, and 8 (8.7%) of patients had no response. The acquisition cost per day and per course treatment of different fungal infections ranged from (apprx) Rs 4500-8000 and 0.9-2.1 lakh respectively.. This postmarketing study documents the safety, tolerability, effectiveness and cost advantage of indigenously developed liposomal amphotericin B in the treatment of systemic fungal infections and febrile neutropenia in actual clinical practice.

Topics: Adult; Amphotericin B; Antifungal Agents; Female; Fever; Humans; India; Liposomes; Male; Mycoses; Neutropenia; Product Surveillance, Postmarketing; Retrospective Studies

A case of disseminated infection with Fusarium oxysporum following chemotherapy of acute myelogenous leukemia is reported. Antifungal treatment was successful with a 13-day course of oral terbinafine 250 mg t.i.d. in combination with amphotericin B deoxycholate 1.0-1.5 mg/kg qd and subsequently intravenous liposomal amphotericin B 5 mg/kg qd. Preceding monotherapy with amphotericin B deoxycholate 1.0-1.5 mg/kg qd had not stopped the progression of infection. The combination therapy described here represents a novel approach to the treatment of Fusarium spp. in the immunocompromised host in whom Fusarium spp. are known to cause disseminated infection with high mortality.

Topics: Amphotericin B; Antifungal Agents; Dermatomycoses; Drug Therapy, Combination; Fusarium; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Microbial Sensitivity Tests; Middle Aged; Naphthalenes; Neutropenia; Terbinafine; Treatment Outcome

Ravuconazole is a new antifungal triazole with broad-spectrum activity and a long half-life in plasma. We studied the antifungal efficacy, safety, and pharmacokinetics of ravuconazole lysine phosphoester in escalating dosages for the treatment of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment groups consisted of rabbits treated with ravuconazole at 2.5 (RVC2.5), 5 (RVC5), and 10 (RVC10) mg/kg of body weight/day, rabbits treated with amphotericin B (AMB) at 1 mg/kg/day, or untreated controls. There was a dose-dependent reduction of pulmonary residual fungal burden (CFU per gram) in RVC5-, RVC10-, and AMB-treated rabbits in comparison to untreated controls (P < 0.01, P < 0.001, and P < 0.01, respectively). These findings correlated with progressive galactomannan antigenemia in untreated controls and the RVC2.5-treated rabbits, a lower galactomannan index (GMI) in RVC5- and RVC10-treated rabbits, and a similarly low GMI in AMB-treated rabbits (P < 0.01). Rabbits treated with RVC5, RVC10, and AMB also showed a reduction of organism-mediated pulmonary injury, as measured by infarct scores and lung weights, in comparison to untreated controls (P < 0.001). These results were supported by decreased pulmonary infiltrates detected by computed tomography in RVC5- and RVC10-treated rabbits in comparison to untreated controls (P < 0.05). Survival throughout the entire study was achieved in 95% of RVC5-treated rabbits (P < 0.001), 85% of RVC10-treated rabbits (P < 0.001), and 50% of AMB-treated rabbits (P < 0.05) in comparison to none of the untreated controls. Ravuconazole showed linear plasma pharmacokinetics and a large volume of distribution while maintaining concentrations in plasma above the MIC throughout the dosing interval. There was no evidence of hepatotoxicity or nephrotoxicity among ravuconazole-treated animals. Intravenously administered ravuconazole lysine phosphoester showed dose-dependent efficacy and an excellent safety profile for the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Dose-Response Relationship, Drug; Female; Galactose; Half-Life; Image Processing, Computer-Assisted; Immunosuppressive Agents; Injections, Intravenous; Lung; Mannans; Microbial Sensitivity Tests; Neutropenia; Rabbits; Survival Analysis; Tetrazolium Salts; Thiazoles; Tomography, X-Ray Computed; Triazoles

Topics: Adolescent; Amphotericin B; Anti-Bacterial Agents; Bacterial Infections; Catheterization, Central Venous; Child; Child, Preschool; Drug Resistance, Bacterial; Fever; Humans; Infant; Meropenem; Neoplasms; Neutropenia; Prospective Studies; Thienamycins; Vancomycin

Amphotericin B failure is frequently seen in patients with candidaemia caused by Candida rugosa. We evaluated amphotericin B, fluconazole, posaconazole and voriconazole as alternative treatments against infection in mice with two isolates of C. rugosa.. Neutropenic mice were inoculated intravenously with C. rugosa. Amphotericin B, fluconazole, posaconazole and voriconazole were administered for 7 days after infection. Efficacy of the antifungal treatment was assessed by survival and tissue burden of C. rugosa.. All of the four drugs significantly prolonged survival over controls. With both isolates, kidney counts were reduced significantly below controls for amphotericin B, fluconazole and posaconazole. However, voriconazole was less effective than the other antifungals.. Despite poor clinical response to amphotericin B, in vivo data indicate that amphotericin B increases organ clearance and survival over untreated controls. However, although voriconazole improved survival over controls, increased tissue clearance was not seen. This discrepancy may be caused by rapid clearance of voriconazole in mice. These studies suggest fluconazole, posaconazole or voriconazole may be useful alternatives to amphotericin B in therapy of C. rugosa infection.

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Colony Count, Microbial; Fluconazole; Kidney; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Organ Size; Pyrimidines; Spleen; Survival Analysis; Triazoles; Voriconazole

Aspergillus infection is a rare but devastating complication following organ transplantation with high mortality rate. Aspergillus fumigatus is the most common cause of invasive aspergillosis. This fungus is present in the environment worldwide. Aspergillus infection is mainly acquired by inhalation of spores and several nosocomial infections in transplant recipient have been associated with construction work at hospitals. Risk factors for invasive aspergillosis include administration of steroid boluses, history of cytomegalovirus infection, neutropenia and prolonged antibiotic use after transplantation. Successful treatment depends on three factors: early diagnosis, aggressive antifungal therapy and decrease or removal of immunosuppression. Amphotericin deoxycholate has been the standard treatment for many years but lipid preparations for amphotericin are now used due to their significantly fewer adverse effects. A number of new antifungal drugs are now being developed including new azoles such as voriconazol and echinocandin. Invasive aspergillosis has a high mortality rate more than 95% when cerebral dissemination is demonstrated. We report the case of a 47 years old woman who received a cadaveric renal graft and developed pulmonary aspergillosis with fulminant cerebral dissemination two months later. The diagnosis of pulmonary aspergillosis was by culture isolation obtained from bronchioalveolar lavage. Removal of immunosuppresive agents and liposomal amphotericin B therapy were started shortly after admission. Brain CT scan performed on the 12th day showed cerebral dissemination. The recipient died two days later. Our patient had several risk factors such as the administration of steroid boluses and cytomegalovirus infection. Invasive aspergillosis must be always included in the differential diagnosis of fever and pulmonary disease in the renal transplant recipient.

Topics: Amphotericin B; Aspergillosis; Aspergillus fumigatus; Cross Infection; Cyclosporine; Cytomegalovirus Infections; Fatal Outcome; Female; Fever; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Liposomes; Lung Diseases, Fungal; Middle Aged; Mycophenolic Acid; Neuroaspergillosis; Neutropenia; Polycystic Kidney, Autosomal Dominant; Prednisone; Risk Factors

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Caspofungin; Drug Therapy, Combination; Echinocandins; Fatal Outcome; Fever; Humans; Immunocompromised Host; Leukemia, Myeloid; Lipopeptides; Liposomes; Male; Middle Aged; Mycoses; Neutropenia; Peptides; Peptides, Cyclic; Trichosporon

The in vivo efficacy of a new amphotericin B (AmB) oil-in-water lecithin-based microemulsion delivery system (M-AmB) compared to deoxycholate-AmB (D-AmB) was studied in an immunocompetent and neutropenic murine model of systemic candidiasis. D-AmB was administered at the maximum tolerated dose of 1 mg/kg whereas M-AmB was given at the doses of 1, 2 and 3 mg/kg; doses were well tolerated due to their reduced toxicity. Both formulations were administered 24, 48 and 72 h after infection in immunocompetent mice, and 2, 6 and 24 h after infection in neutropenic mice. Kaplan-Meier survival curves showed that the M-AmB treated group had a better survival time than infected mice without treatment used as a control group (P = 4.66 x 10(-6)), and the Mann-Whitney W statistical test indicated that it reduced the percentage of mortality and fungal load in the most representative organs. This new formulation is a designed competitor which has proved to present better results than D-AmB in an established infection not only in immunocompetent but in neutropenic mice as well.

Topics: Amphotericin B; Animals; Candidiasis; Chemistry, Pharmaceutical; Deoxycholic Acid; Emulsions; Freeze Drying; Immunocompetence; Male; Mice; Neutropenia; Phosphatidylcholines

Invasive aspergillosis (IA) has emerged as a common cause of morbidity and mortality among immunocompromised patients. At The University of Texas M. D. Anderson Cancer Center (Houston, TX), Aspergillus terreus is second to A. fumigatus as the most common cause of IA. In the current study, the authors compared the risk factors and outcomes associated with IA caused by A. terreus and IA caused by A. fumigatus.. The authors retrospectively reviewed the medical records of 300 patients who received care at our institution between 1995 and 2001 and who had cultures that were positive for Aspergillus infection, including 90 patients whose cultures were positive for A. fumigatus and 70 patients whose cultures were positive for A. terreus.. Thirty-two patients with IA caused by A. terreus and 33 patients with IA caused by A. fumigatus were evaluated. The two groups were comparable in terms of age, gender, and underlying disease. Leukemia was the most common underlying malignancy (84%). More than 40% of patients in each group had undergone bone marrow transplantation. There was a trend toward a higher frequency of neutropenia among patients with IA caused by A. terreus (P = 0.12). IA caused by A. terreus was considered to be nosocomial in origin significantly more frequently compared with IA caused by A. fumigatus (P = 0.03). In vitro, A. terreus was found to be more resistant to amphotericin B (minimal inhibitory concentration [MIC90], 4.0 microg/mL) than to antifungal therapy (MIC90, 1.0 Hg/mL) in the isolates that were tested (< 50% of all isolates). The overall rate of response to antifungal therapy was 39% for patients with A. fumigatus infection, compared with 28% for patients with A. terreus infection (P = 0.43).. Despite the decreased in vitro susceptibility of A. terreus (relative to A. fumigatus) to amphotericin B, the two groups within the current patient population had comparably poor responses to amphotericin B preparation and somewhat improved responses to posaconazole.

Topics: Adult; Aged; Amphotericin B; Aspergillosis; Aspergillus; Aspergillus fumigatus; Cross Infection; Drug Resistance, Fungal; Female; Humans; Leukemia; Male; Middle Aged; Neutropenia; Opportunistic Infections; Retrospective Studies; Risk Factors; Triazoles

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fever; Humans; Lipopeptides; Liposomes; Mycoses; Neoplasms; Neutropenia; Peptides; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

In this report, a case of Fusarium fungaemia developed in an acute lymphoblastic leukemia (ALL) patient was presented. A seven year old girl who had weakness, loss of appetite, paleness and ecchymosis on legs applied to Pediatric Hematology Service and cytotoxic chemotherapy was started after she had been diagnosed as ALL-L1. Her chemotherapy was stopped because of increase in fever, leukopenia and neutropenia. Central venous catheter and peripheral blood cultures were obtained. Fusarium thapsinum was recovered from blood cultures, obtained in two consecutive days. Thereupon central venous catheter of the patient was removed and intravenous amphotericin B was added to the therapy. On the fifth day of febrile neutropenia attack, her fever was decreased after the onset of antifungal therapy. Radiological examinations were normal and no fungal growth was observed in the later blood cultures. On the 21st day of amphotericin B therapy, chemotherapy was started again and amphotericin B was changed to peroral itraconazole (200 mg/day) at the fifth week. The patient whose itraconazole therapy was stopped after three months, was still in remission and continued receiving her prolonged therapy. In conclusion, Fusarium infections which manifest with fungaemia and fever as the only symptoms, should be taken into consideration in neutropenic patients receiving immunosuppressive therapy.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Catheterization, Central Venous; Catheters, Indwelling; Child; Female; Fever; Fungemia; Fusarium; Humans; Immunosuppressive Agents; Itraconazole; Leukopenia; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Cerebral scedosporiosis is a life-threatening infection that is difficult to treat. The aim of this work was to develop a murine model of cerebral infection by Scedosporium apiospermum using intracranial inoculation and to use this model to evaluate the efficacy of amphotericin B deoxycholate and liposomal amphotericin B.. Mice were rendered neutropenic by intraperitoneal cyclophosphamide and intravenous (iv) 5-fluorouracil administration. Animals were infected with iv or intracranial inoculation of 1 x 10(4), 5 x 10(4) or 5 x 10(5) cfu of a clinical strain of S. apiospermum. Tissue burden reduction was determined in kidneys and brain 4 days after the infection. Efficacy of amphotericin B and liposomal amphotericin B (0.8 mg/kg/day intraperitoneally and 40 mg/kg/day iv, respectively) was evaluated in neutropenic mice infected iv or intracranially with 5 x 10(4) cfu. Survival was analysed with the log-rank test. Fungal burden values of different groups were compared using the Mann-Whitney U-test.. In our model, intracranial infection produced a higher fungal load in the brain and a lower fungal load in the kidney than iv inoculation. Survival of animals infected intracranially and treated with amphotericin B or liposomal amphotericin B (mean survival time = 8.3 and 9.2 days, respectively) was not different from the control group (P=0.58 and 0.85, respectively).. We have developed a murine model of cerebral scedosporiosis, which may be useful for studying various pathological aspects of this infection and evaluating new therapeutic approaches. Amphotericin B and liposomal amphotericin B were unable to resolve the infection.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Brain Diseases; Disease Models, Animal; Humans; Liposomes; Male; Mice; Mycetoma; Neutropenia; Scedosporium; Treatment Failure

In order to optimise the use of new forms of Amphotericine B (Ampho B), a decisional tree was created at the end of 2001 in the paediatric hemato-oncology unit for the empirical antifungal treatment in febrile neutropenic children: the standard remained conventional Ampho B and Abelcet was proposed in case of antecedent or occurrence of a deterioration of the renal function (DRF). In order to validate the place of Abelcet we initiated a retrospective study over year 2002.. 21 treatments were begun in 14 children for a median duration of 8 days (1-48 days). Three kind of indications were found: DRF antecedent (10 episodes: A group), DRF occurrence during a treatment with conventional Ampho B (7 episodes: B group), age lower than 1 year (3 episodes). 81% of the children were thus treated according to the decisional tree. The clinical tolerance was good in 90% of the cases, with a premedication in half of the cases. The study of the renal function showed a good renal tolerance for 6 episodes out of 9 evaluable in A group, 3 resolutions and 2 stabilisation of the renal failure for the 5 evaluable episodes of the B group. Seven to ten days of treatment by Abelcet were necessary to obtain the renal failure resolved.. This study confirms the interest of Abelcet in the empirical antifungal treatment in febrile neutropenic children and specially in children having antecedents of DRF related or not to a treatment with conventional Ampho B.

Topics: Amphotericin B; Antifungal Agents; Child; Creatinine; Drug Combinations; Fever; Hematologic Neoplasms; Humans; Kidney Function Tests; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Retrospective Studies

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fever; Humans; Infusions, Intravenous; Lipopeptides; Mycoses; Neoplasms; Neutropenia; Peptides, Cyclic

Although the most common orofacial fungal infection in immunocompromised patients is candidosis, infections caused by virulent molds, such as Aspergillus spp. and Furarium spp. are being recognized with increasing frequency. We report a case of oral Exophiala infection in a 39-year-old woman with acute myeloid leukemia.. Clinical records of the patient were reviewed and the following additional information was collected: histological and microbiological evidence; identification of the causative organism; in vitro antifungal susceptibility.. The patient developed a necrotic ulcer surrounded by a violaceous rim in the gingiva during neutropenia. Exophiala dermatitidis was identified as the causative organism by histopathological examination and culture, and finally confirmed by sequencing of the ribosomal DNA internal transcribed space domain. In vitro, amphotericin B was found to show strong activity against the Exophiala isolate while itraconazole showed less activity. The patient was successfully treated with parenteral amphotericin B and oral itraconazole in combination with surgical removal of the fungi focus.. Local excision with adequate antifungal agents can be used to treat immunocompromised patients with Exophiala stomatitis, based on early diagnosis.

Topics: Administration, Oral; Adult; Amphotericin B; Antifungal Agents; DNA, Fungal; Exophiala; Female; Humans; Immunocompromised Host; Infusions, Intravenous; Itraconazole; Leukemia, Myeloid, Acute; Mycoses; Neutropenia; Stomatitis

Pseudomembranous tracheobronchial aspergillosis coincident with systemic pulmonary aspergillosis represents a rare manifestation of fungal infection in immunocompromized hosts. We report on a patient with recurrent Hodgkin's disease, showing this infectious pattern after treatment with corticosteroids within the antineoplastic schedule, whereas neutropenia--the main risk factor for mold infections--had not occurred. An impaired number of helper T lymphocytes was merely detected as an additional, but hypothetical risk factor, when investigating the status of immunosuppression. Treated systemically with amphotericin B, the patient recovered quickly, although reported mortality rates are disastrous. What is crucial for the clinical management is an early diagnosis by bronchoscopy and cultural proof of the pathogen followed by an adequate antifungal treatment.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Bronchoscopy; Female; Hodgkin Disease; Humans; Immunocompromised Host; Lung Diseases, Fungal; Middle Aged; Neutropenia; Opportunistic Infections; Tracheal Diseases

We compared the activity of four doses of micafungin (FK463) with that of amphotericin B, liposomal amphotericin B and itraconazole in a murine model of disseminated aspergillosis. Temporarily neutropenic mice were infected with a lethal dose of either an itraconazole-resistant Aspergillus fumigatus isolate or Aspergillus terreus, a species that is less susceptible to amphotericin B. Treatment was started 24 h after infection and lasted for 7 days. Mice were treated with either amphotericin B (0.5 or 5 mg/kg), liposomal amphotericin (5 or 25 mg/kg), itraconazole (25 or 75 mg/kg) or FK463 (either 1, 2, 5 or 10 mg/kg). Treatment of the A. fumigatus model with either amphotericin B, liposomal amphotericin or FK463 prolonged survival. Doses of FK463 5 and 10 mg/kg had a 100% survival. Treatment of A. terreus infection with either itraconazole or FK463, but not amphotericin B, also prolonged survival. Doses of liposomal amphotericin of 5 and 25 mg/kg were ineffective against A. terreus infection. No treatment regime was able to totally clear the liver or kidneys in either model. The data indicate that FK463 may have a clinical role in the treatment of life-threatening invasive aspergillosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Colony Count, Microbial; Drug Resistance, Fungal; Echinocandins; Immunosuppressive Agents; Itraconazole; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Microbial Sensitivity Tests; Neutropenia; Peptides, Cyclic

Amphotericin B deoxycholate (AmB-d) remains a mainstay of antifungal therapy for immunocompromised patients, despite being associated with significant therapy-related toxicity. Because continuous infusion of AmB-d is better tolerated than traditional administration over 2-6 hours, we evaluated escalation of the AmB-d dose in 33 patients (31 of whom were neutropenic), for whom the initial dosage of AmB-d (1 mg/kg/day) was gradually increased to 2.0 mg/kg/day when renal function remained stable and the drug was tolerated. Dose escalation was possible without delay in 28 patients. Median duration of AmB-d therapy was 16 days (range, 7-72 days). Infusion-related reactions accompanied <18% of AmB-d infusions. Twenty-seven patients had a decrease in creatinine clearance while receiving AmB-d therapy. A >2-fold decrease in creatine clearance was observed in 5 patients, and the decrease was dose-limiting in only 1 patient; no dialysis was required. In conclusion, continuous infusion of AmB-d escalated to 2.0 mg/kg/day seems not to cause additional impairment of vital organ functions and to be well tolerated by most patients.

Topics: Adolescent; Adult; Aged; Amphotericin B; Cohort Studies; Deoxycholic Acid; Drug Combinations; Female; Humans; Immunocompromised Host; Infusion Pumps; Male; Middle Aged; Mycoses; Nausea; Neutropenia; Opportunistic Infections; Treatment Outcome

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Candida albicans; Candidiasis; Chemoprevention; Drug Resistance, Microbial; Female; Fluconazole; Fungemia; Humans; Leukemia; Male; Microbial Sensitivity Tests; Middle Aged; Neutropenia

Systemic fungal infections have high mortality, and therapy is often toxic. Caspofungin acetate, a new antifungal agent with minimal toxicity, may provide a better alternative to typical therapy for Candida krusei.. Case report.. Multidisciplinary intensive care unit (ICU) of a community teaching hospital.. A 22-yr-old male with acute lymphoblastic leukemia and Candida krusei fungemia failed therapy with fluconazole and amphotericin B.. Caspofungin acetate given intravenously as a 70-mg loading dose, followed up by 50 mg daily along with standard ICU care.. Survival without toxicity from therapy.. Efficacy of caspofungin acetate in a patient with life-threatening Candida Krusei infection.

Topics: Adult; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Fluconazole; Fungemia; Humans; Infusions, Intravenous; Lipopeptides; Male; Neutropenia; Opportunistic Infections; Peptides; Peptides, Cyclic; Pleural Effusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tomography, X-Ray Computed; Treatment Outcome

Fusarium infection is known to cause major morbidity and mortality in immunocompromised hosts. We report the successful treatment of disseminated Fusarium infection with skin manifestations in a severely neutropenic, immunocompromised host with voriconazole, a new second-generation triazole. Voriconazole might be an alternative therapy for patients with neutropenia who have fusariosis that is refractory or unresponsive to amphotericin B or its liposomal formulation.

Topics: Aged; Amphotericin B; Antifungal Agents; Fusarium; Humans; Immunocompromised Host; Male; Mycoses; Neutropenia; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

To study the toxicity and activity of two new amphotericin B formulations: poly(epsilon-caprolactone) nanospheres coated with poloxamer 188 (AmB-NP) and mixed micelles with the same surfactant (AmB-MM).. The toxicity of these formulations was evaluated in erythrocytes, J774.2 macrophages and LLCPK1 renal cells, as well as in mice. Activity was determined in clinical isolates and in neutropenic mice. Mice were made neutropenic with 5-fluorouracil, infected with Candida albicans and treated with the antifungal formulations for three consecutive days. AmB association in cells and accumulation in kidneys and liver of animals was quantified by HPLC.. Both formulations decreased between 8- and 10-fold the MIC of the polyene against clinical isolates of C. albicans. However, their activity was lower than or equal to that of AmB-deoxycholate when it was assessed against C. albicans-infected macrophages. When given as a single intravenous dose in mice, AmB-MM and AmB-NP had an LD50 of 9.8 and 18.6 mg/kg, respectively, compared with 4 mg/kg for AmB-deoxycholate. Comparison of residual infection burdens in the liver and kidneys showed that AmB-deoxycholate (0.5 mg/kg) was more effective and faster in eradicating yeast cells than polymeric formulations. This fact can be related to a lower AmB accumulation inside macrophages and in liver and kidneys (about 1.5 mg drug/g tissue) of mice, compared with those detected for AmB-deoxycholate (4 mg drug/g). Overall, the efficacy of these formulations at 2 mg/kg was equal to that of AmB-deoxycholate at 0.5 mg/kg.. AmB-MM and AmB-NP decreased the in vivo antifungal activity of AmB, and higher concentrations were therefore necessary to obtain a similar therapeutic effect. However, these higher concentrations were achievable owing to the reduced toxicity of these formulations.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Caproates; Cells, Cultured; Chemical Phenomena; Chemistry, Physical; Drug Carriers; Erythrocytes; Excipients; Hemoglobins; Humans; In Vitro Techniques; Lactones; Macrophages; Male; Mice; Micelles; Microspheres; Neutropenia; Particle Size; Poloxamer; Potassium; Surface-Active Agents; Survival Analysis

The kinetics of various parameters of fungal load and cytokines were investigated, in order to acquire insight into the pathogenesis of invasive pulmonary aspergillosis (IPA) during antifungal treatment with amphotericin B.. Neutropenic rats with left-sided IPA received either treatment with amphotericin B or remained untreated. At 0, 4, 8, 16, 24, 48, 72 and 120 h after fungal inoculation, the rats were dissected. The size of the macroscopic pulmonary lesions, the number of cfu and amounts of chitin were determined in the infected left lung. Galactomannan concentrations were measured both in the left lung and serum. The cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, interferon (IFN)-gamma, IL-4, IL-10, and the chemokines macrophage inflammatory protein (MIP)-2 and monocyte chemoattractant protein (MCP)-1 were determined quantitatively by ELISA in the infected left lung, uninfected right lung and serum.. Amphotericin B treatment of IPA resulted in changed aspect of pulmonary lesions and significantly reduced levels of left lung chitin (72 and 120 h), left lung galactomannan (72 and 120 h) and serum galactomannan (120 h), but not left lung cfu, compared with untreated infected rats. In addition, amphotericin B treatment resulted in a significant decrease in levels of left lung IL-6 (at 72 and 120 h), MIP-2 (at 120 h) and MCP-1 (at 120 h). No local or systemic increases in TNF-alpha, IL-1beta or IFN-gamma were observed during infection.. It is concluded that treatment with amphotericin B results in decreased fungal load in the infected lung. This reduction in fungal load probably results in a decreased local inflammatory response, as measured by decreased levels of IL-6, MIP-2 and MCP-1 in the infected lung.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Chitin; Colony Count, Microbial; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Galactose; Kinetics; Lung; Mannans; Neutropenia; Rats; Survival Analysis

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Humans; Mycoses; Neutropenia; Solubility

Voriconazole is a new triazole active orally and parenterally that recently proved effective in the treatment of invasive aspergillosis and in empirical antifungal therapy for persistently febrile neutropenic patients. Limited data are available for pediatric patients. We report our experience with voriconazole in seven children with invasive aspergillosis, i.e., four girls and three boys with a median age of 5 (range 2-13) years affected by acute lymphoblastic leukemia (3), acute myeloid leukemia (2), refractory anemia with excess of blasts (1), and severe aplastic anemia (1). First-line therapy in all patients was liposomal amphotericin B (AmBisome) administered at a dosage of 3-5 mg/kg day. Voriconazole was administered for a median 8 (range 2-15) weeks. Response was complete and partial in two patients, respectively, stable in one, and there was no response (failure) in two. The voriconazole treatment was well tolerated. Four patients died-two of progressive aspergillosis. Three patients are alive and well 6, 5, and 4 months after the diagnosis of aspergillosis. Voriconazole appears to be an effective salvage treatment for invasive aspergillosis in pediatric patients, with good responses in patients who recover from neutropenia or are not relapsing.

Topics: Adolescent; Amphotericin B; Anemia, Aplastic; Anemia, Refractory; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Bone Marrow Transplantation; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hematologic Neoplasms; Humans; Leukemia, Myelomonocytic, Acute; Male; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Time Factors; Treatment Outcome; Triazoles; Voriconazole

Topics: Amphotericin B; Antineoplastic Agents; Cladribine; Deoxycholic Acid; Drug Combinations; Fatal Outcome; Humans; Leukemia, Hairy Cell; Male; Middle Aged; Neutropenia; Zygomycosis

Deep-seated Candida infections are strongly associated with mortality and morbidity of patients, and need early diagnosis. The frequency of deep-seated fungal infection has recently been growing. We encountered a tuboovarian abscess caused by Candida glabrata after chemotherapy with an anticancer drug, methotrexate, in a febrile neutropenic patient. The susceptibilities to fluconazole and amphotericin B were 16 and 0.5 micro g/ml, respectively. Although combination therapy of fluconazole and amphotericin B was effective, left salpingectomy was laparoscopically performed because the left adnexal tumor continued to exist asymptomatically after 1 month.

Topics: Abscess; Adult; Amphotericin B; Antifungal Agents; Antimetabolites, Antineoplastic; Candida glabrata; Candidiasis; Diagnosis, Differential; Fallopian Tubes; Female; Fever; Fluconazole; Genital Diseases, Female; Granulocyte Colony-Stimulating Factor; Humans; Hydatidiform Mole; Magnetic Resonance Imaging; Methotrexate; Neutropenia; Pregnancy

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Caspofungin; Child; Drug Combinations; Drug Therapy, Combination; Echinocandins; Female; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Neutropenia; Peptides; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

A case of disseminated Aspergillus terreus infection in a patient with prolonged neutropenia after stem cell transplant for myeloma is reported. The isolate was resistant to amphotericin B in vitro, and the patient was successfully managed with surgical debridement and the recently licensed antifungal agent caspofungin. There are many challenges associated with treating invasive aspergillosis, particularly that due to A. terreus, and the early use of caspofungin should be considered.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Caspofungin; Dermatomycoses; Drug Resistance, Fungal; Echinocandins; Humans; Immunocompromised Host; Itraconazole; Lipopeptides; Male; Middle Aged; Neutropenia; Peptides; Peptides, Cyclic; Stem Cell Transplantation

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Fever; Humans; Lipids; Neutropenia

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Child; Cost-Benefit Analysis; Drug Costs; England; Humans; Liposomes; Liver Transplantation; Lung Diseases, Fungal; Medical Audit; Mycoses; Neutropenia; Organizational Policy; Postoperative Complications; Sinusitis; Treatment Outcome

Invasive pulmonary aspergillosis is frequent in neutropenic patients. Usually localized in the beginning, the disease spreads and mortality is high despite antifungal treatment. The role of early adjuvant surgery is not clear. Surgery may help to confirm fungal disease, may control fungal disease locally and may prevent systemic spreading. This study examines effects of early resection on survival and dissemination in a rat model of localized invasive pulmonary aspergillosis.. Forty persistently neutropenic male albino rats were challenged with standardized conidial aspergillus inoculum injected into peripheral lung tissue of the right upper lobe under direct vision. Animals were divided into four groups. Twenty animals were treated with amphotericin B at 1 mg/kg per day beginning 48 h after inoculation, 20 animals were left untreated. In each group half the animals underwent early resection of localized invasive aspergillosis by lobectomy. Animals were checked daily and mortality was recorded up to 28 days after which surviving animals were sacrificed.. Significantly higher survival was observed in resected animals in the non-Am B groups (survival: 10 +/- 19% without early resection and 50 +/- 32% with early resection; P = 0.044). However, early resection did not lead to improved survival in animals treated with amphotericin B (survival 70 +/- 29% without early resection and 50 +/- 32% with early resection; P = 0.316).. In this rat model of localized invasive pulmonary aspergillosis effects of early resection on survival could be demonstrated only in animals not receiving amphotericin B treatment.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Combined Modality Therapy; Disease Models, Animal; Lung Diseases, Fungal; Male; Neutropenia; Opportunistic Infections; Rats; Rats, Sprague-Dawley; Survival Rate

Micafungin is a new echinocandin with broad-spectrum in vitro and in vivo antifungal activity against both Aspergillus and Candida species. We compared the activity of micafungin with that of amphotericin B and fluconazole in a persistently immunocompromised murine model of disseminated candidiasis against a strain of Candida tropicalis that was resistant to amphotericin B and fluconazole in vitro. Mice were rendered persistently neutropenic with multiple doses of cyclophosphamide and infected intravenously with C. tropicalis. Mice were treated with either intraperitoneal amphotericin B (0.5-5 mg/kg per dose), oral fluconazole (50 mg/kg twice a day), intravenous micafungin (1-10 mg/kg per dose) or solvent control for 7 days. Mice were killed at 11 days post-infection and kidneys, lungs, brain and liver removed for quantitative culture. Overall mortality in the model was low, with rates varying between 10% and 25% in treatment groups. Micafungin at doses between 2 and 10 mg/kg were the only regimes able to reduce cfu below the level of detection of tissues infected with C. tropicalis. Micafungin was well tolerated by the mice and was much more effective than amphotericin B or fluconazole against an amphotericin B- and fluconazole-resistant C. tropicalis.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida tropicalis; Candidiasis; Disease Models, Animal; Echinocandins; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Neutropenia; Peptides, Cyclic

Primary invasive mold infection of the oral cavity is a rare but serious complication in immunocompromised hosts. We report a case of fatal Trichoderma longibrachiatum stomatitis in a 66-year-old female patient with malignant lymphoma. The infection rapidly disseminated from the oral mucosa to the lungs during neutropenia. Despite intensive antifungal therapy with amphotericin B and itraconazole, there was a fatal progression of the condition. While Trichoderma species have been recognized to be pathogenic in profoundly immunosuppressed hosts, this is the first report of the primary oral focus causing a fatal infection.

Topics: Aged; Amphotericin B; Antifungal Agents; Disease Progression; Fatal Outcome; Female; Gingivitis, Necrotizing Ulcerative; Humans; Immunocompromised Host; Itraconazole; Lung Diseases, Fungal; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Mycoses; Neutropenia; Opportunistic Infections; Stomatitis; Trichoderma

Concomitant use of allogeneic donor granulocyte transfusions and amphotericin B in febrile neutropenic recipients may be limited by the increased incidence of respiratory distress. In vitro effects of amphotericin B and AmBisome were compared on polymorphonuclear leukocyte (PMN) aggregation from PMNs isolated from granulocyte-colony-stimulating factor (G-CSF)/dexamethasone-mobilized allogeneic donors. Six allogeneic donors were mobilized with G-CSF (600 microg subcutaneously) and dexamethasone (8 mg orally) 12 hours before leukopheresis. AmBisome was associated with significantly less PMN aggregation (100 microM [microg/mL]) (0.33% +/- 0.33% vs 54.33% +/- 5.82%; P <.001) than amphotericin B. Furthermore, with the addition of the PMN agonist, FMLP, AmBisome was also associated with significantly less aggregation (100 microM [microg/mL]) (18.67% +/- 1.45% vs 54.67% +/- 2.4%; P <.001). In summary, these studies demonstrate that liposomal amphotericin is associated with significantly less in vitro PMN aggregation than amphotericin B and could possibly be administered concomitantly with mobilized allogeneic PMN infusions.

Topics: Amphotericin B; Antifungal Agents; Blood Donors; Cell Aggregation; Dexamethasone; Glucocorticoids; Granulocyte Colony-Stimulating Factor; Humans; Leukapheresis; Leukocyte Transfusion; Liposomes; Mycoses; N-Formylmethionine Leucyl-Phenylalanine; Neutropenia; Neutrophils

A common complication of the intensive therapy that children with cancer receive is infection. The Oncology Unit of The Children's Hospital at Westmead maintains a comprehensive database of all admissions for suspected sepsis. From July 1994 to June 1999 broad-spectrum antibiotics were commenced in 2331 episodes. With early and aggressive use of empirical amphotericin B, 545 courses were given. Bacteraemia was documented in 701 episodes and invasive fungal disease in 73. Trends seen during the study included: (i) the proportion of febrile neutropenic patients receiving granulocyte colony stimulating factor increased from 40% to 60%; (ii) the mean neutrophil count at cessation of antibiotics fell from 0.97 to 0.63 x 10(9) cells/L for patients not receiving growth factors; (iii) the proportion of non-albicans Candida species infections increased. In addition, an outbreak of infection caused by Scedosporium sp. was documented; (iv) first-line empirical antibiotic combinations containing vancomycin fell from 20% to 7%; and (v) the ability to maintain or escalate anti-fungal therapy with reduced nephrotoxicity through use of lipid formulations of amphotericin was increasingly apparent in high-risk patients. During the study, infection was the primary cause of death in 11 non-bone marrow transplant (BMT) patients (five fungal, four viral, one bacterial infection and one sepsis syndrome) and five BMT patients (two bacterial and three viral). A prospective randomized study of toxicity due to amphotericin B given in either lipid emulsion or dextrose showed no significant difference, but both groups showed a lower incidence of amphotericin B intolerance in comparison with the adult series. The inability to reduce toxicity of amphotericin B by simple mixing with lipid emulsion has led to increasing use of commercially available lipid formulations of amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Bacteremia; Child; Drug-Related Side Effects and Adverse Reactions; Humans; Mycoses; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic

Topics: Amphotericin B; Antifungal Agents; Fever; Humans; Mycoses; Neutropenia; Pyrimidines; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Data Interpretation, Statistical; Fever; Humans; Mycoses; Neutropenia; Pyrimidines; Research Design; Treatment Outcome; Triazoles; Voriconazole

Due to an increasing number of leukemic patients with invasive gingival aspergillosis during neutropenia (neutrophils <500 cells/microl for >10 days), we evaluated the efficacy of oral itraconazole prophylaxis for preventing this invasive infection at our hospital.. This was a retrospective, non-randomized study to analyze the onset of identified invasive gingival aspergillosis among 536 patients with acute leukemia at risk due to the presence of neutropenia from 1991 to 1998. Patients received itraconazole capsules 100 mg/day prophylactically between April 1994 and December 1996, and 200 mg/day between January 1997 and December 1998. Itraconazole serum levels at day 10 were measured in some patients.. In the 39 months prior to April 1994 without itraconazole prophylaxis, 15 cases of invasive gingival aspergillosis were detected in 192 high risk patients with 469 episodes of neutropenia (7.8% of the high risk patients). Between April 1994 and December 1996, using itraconazole prophylaxis at 100 mg/day, there was a dramatic decrease in the infections resulting in 3 of 198 high risk patients with 511 episodes of neutropenia (1.5% of the high risk patients). Furthermore, between January 1997 and December 1998, using itraconazole prophylaxis at 200 mg/day, no cases of the infection were observed in the 146 high risk patients with 380 episodes of neutropenia. The incidence of invasive gingival aspergillosis was significantly lower among patients administered itraconazole than among those without itraconazole (100 mg/day; P = 0.006 and 200 mg/day; P = 0.001). The mean itraconazole serum level in 20 patients receiving 100 mg/day was 71.78 ng/mL and in 16 patients receiving 200 mg/day was 202.67 ng/ml.. These findings suggest that oral itraconazole could be effective for preventing invasive gingival aspergillosis in neutropenic patients with acute leukemia and warrants further randomized investigation.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis, Oral; Capsules; Chi-Square Distribution; Chromatography, High Pressure Liquid; Cohort Studies; Fluconazole; Flucytosine; Gingival Diseases; Humans; Immunocompromised Host; Itraconazole; Leukemia, Myeloid, Acute; Leukocyte Count; Neutropenia; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Risk Factors; Treatment Outcome

Candida glabrata is an increasing cause of candidemia, especially at cancer and bone marrow transplant centers where fluconazole is used for antifungal prophylaxis. This yeast is less susceptible to fluconazole in vitro than is Candida albicans. We compared the characteristics of patients who had C. glabrata and C. albicans candidemia at a large cancer center.. We searched the microbiological laboratory reports and identified 116 cases of C. glabrata candidemia between 1993 and 1999. The 116 cases of C. albicans candidemia that occurred most closely in time (before or after each case of C. glabrata candidemia) served as the control group. Data were collected from patients' medical records.. When compared with patients who had C. albicans infection, patients with C. glabrata candidemia more often had an underlying hematologic malignancy (68 [59%] vs. 26 [22%], P = 0.0001), had an Acute Physiology and Chronic Health Evaluation (APACHE) II score > or =16 (55 [48%] vs. 28 [25%], P = 0.0002), and received fluconazole prophylaxis (57 [49%] vs. 8 [7%], P = 0.0001). Patients with C. albicans candidemia more often had concomitant infections (101 [87%] vs. 78 [67%], P = 0.0003) and septic thrombophlebitis (11 [10%] vs. 2 [2%], P = 0.01). Among patients treated with antifungal therapy, those with C. albicans candidemia had a significantly greater overall response to therapy (83/104 [80%] vs. 60/97 [62%], P = 0.005) and to primary therapy (74/104 [71%] vs. 45/97 [46%], P = 0.0003). Amphotericin B preparations were not more effective than fluconazole (19/45 [42%] vs. 20/38 [53%], P = 0.5) in patients with C. glabrata candidemia. Fluconazole was less effective against C. glabrata than against C. albicans (20/38 [53%] vs. 57/74 [77%], P = 0.008).. C. glabrata has emerged as an important cause of candidemia, especially among neutropenic patients who receive fluconazole prophylaxis.

Topics: Amphotericin B; Antifungal Agents; APACHE; Bone Marrow Transplantation; Candida albicans; Candidiasis; Case-Control Studies; Female; Fluconazole; Fungemia; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Postoperative Complications; Regression Analysis; Treatment Outcome

Invasive fungal infections are associated with high morbidity and mortality in immunocompromised patients. We describe an unusual case of concomitant invasive candidiasis and zygomycosis of the tongue and epiglottis that occurred in a young patient with neutropenia during chemotherapy for acute myelogenous leukemia and was successfully treated medically.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Candida; Candidiasis; Cytarabine; Epiglottis; Fungi; Humans; Idarubicin; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Neutropenia; Tongue; Tongue Diseases; Zygomycosis

In order to assess the risk factors for breakthrough candidemia (candidemia occurring in patients receiving at least 3 days of systemic fluconazole or amphotericin B), 270 cases of candidemia occurring in two tertiary hospitals were analyzed. Using multivariate analysis, profound neutropenia (<100/mm(3)) (odds ratio [OR], 9.14), use of corticosteroids (OR, 3.17), and heavy antibiotic exposure (previous use of 2 or more antibiotics for at least 14 days) (OR, 2.93) were identified as risk factors. Neither the susceptibility of the isolates nor the presence of a catheter was found to be a risk factor. These data suggest that gastrointestinal colonization plays a major role in the development of breakthrough candidemia.

Topics: Amphotericin B; Anti-Bacterial Agents; Candidiasis; Fluconazole; Fungemia; Humans; Multivariate Analysis; Neoplasms; Neutropenia; Odds Ratio; Retrospective Studies; Risk Factors

Topics: Amphotericin B; Antifungal Agents; Clinical Protocols; Data Interpretation, Statistical; Fever; Humans; Mycoses; Neutropenia; Pyrimidines; Research Design; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Fever; Humans; Mycoses; Neutropenia; Pyrimidines; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Drug Interactions; Fever; Humans; Neutropenia; Pyrimidines; Risk Factors; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Fever; Humans; Mycoses; Neutropenia; Pyrimidines; Triazoles; Voriconazole

In a patient treated for a non-Hodgkin's lymphoma, a lung abscess caused by Hormographiella aspergillata (stat. anamorph. Coprinus cinereus) was diagnosed using an ultrasound-guided puncture of the lesion. The patient appeared to respond to amphotericin B, but at the same time was also recovering from her neutropenic episode. The extent to which each of these two factors explains the complete resolution of the infection is unclear. Expert classical morphological examination and molecular typing methods were needed to identify this filamentous basidiomycetous fungus.

Topics: Adult; Amphotericin B; Antifungal Agents; Coprinus; Female; Humans; Lung Diseases, Fungal; Lymphoma, Non-Hodgkin; Neutropenia

We report the chest radiographic and CT findings in 21 immunocompromised patients with invasive pulmonary aspergillosis (IPA) and describe the outcome when the early diagnosis was linked to treatment with liposomal amphotericin B.. Chest radiographs and CT examinations were analyzed retrospectively in 53 consecutive neutropenic patients with suspected early IPA.. Twenty-one of 244 patients admitted for chemotherapy of hematologic malignancy fulfilled the definition for IPA - incidence of 8.6%. The incidence of normal and non-specific chest radiographic findings was high (29% and 71%, respectively) during the early stages of IPA. The CT halo sign was seen in 20 of the 21 patients (95%), and occurred within 5 days of neutropenic fever that was unresponsive to antibiotics in 5 patients. Crescent signs or cavitations were seen in 7 patients (33%). Treatment with liposomal amphotericin B was associated with an attributable mortality of 9.5%. Two patients died from IPA having a high fungal burden.. Early chest CT in neutropenic patients at risk for IPA is an important diagnostic and management tool and should be included in the investigative protocol even when chest radiographs are normal or non-specific.

Topics: Adolescent; Adult; Amphotericin B; Aspergillosis, Allergic Bronchopulmonary; Female; Humans; Immunocompromised Host; Leukemia; Liposomes; Male; Middle Aged; Neutropenia; Radiography, Thoracic; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome

Though liposomal amphotericin B has been available in Germany since 1992, efficacy and safety of this formulation of amphotericin B are still not well-documented in children. As far as gastrointestinal side-effects are concerned, an elevated alkaline phosphatase and elevated transaminases have been reported. In our department, liposomal amphotericin B had been used since 1994 to treat patients with proven or suspected fungal infections in a daily dose of 1-3 mg kg-1. Additionally, patients with high-dose chemotherapy and autologous stem cell support received liposomal amphotericin B prophylactically in a dose of 1 mg kg(-1) three times per week. We performed a retrospective analysis of all 31 patients who had received liposomal amphotericin B by 1999. In five patients, an isolated transient elevation of the serum lipase level during, or shortly after, the therapy with liposomal amphotericin B was detected. Three of these patients showed clinical signs of pancreatitis, with one patient displaying slightly elevated transaminases. So far, elevated levels of serum lipase have not been described as a possible side-effect of a liposomal amphotericin B therapy. The pathogenesis of this elevation is unclear. As possible reasons, an enzyme induction due to fat overload or a toxic damage of the pancreatic tissue by the liposomes or amphotericin B itself are discussed.

Topics: Adolescent; Amphotericin B; Child; Child, Preschool; Female; Humans; Infant; Lipase; Liposomes; Male; Mycoses; Neoplasms; Neutropenia; Pancreatitis; Pancrelipase; Retrospective Studies

The role of antifungal prophylaxis remains controversial and concerns exist that the use of azoles may potentiate the emergence of resistant Candida species. We used a strategy of combining the latest azole/triazole with oral amphotericin B to reduce this risk. We analysed data on Candida colonization and candidaemia in neutropenic patients from four prophylaxis periods (1985/6: ketoconazole and amphotericin B suspension; 1991/2 & 1997: fluconazole and amphotericin B suspension; 1998/9: itraconazole) to look for evidence of the emergence of potentially resistant species. Overall, the percentage of patients colonized with Candida fell significantly (69.3%, 57.5%, 43.2% and 46%, respectively, P < 0.001) due to a decrease in colonization with C. albicans (49%, 23.1%, 22.2% and 25.2%, respectively, P < 0.001). However, in 1998/9, increased colonization, particularly with C. glabrata in the lower gastrointestinal tract, was noted to coincide with the omission of oral amphotericin B. Despite an increasing population of 'high risk' patients, the incidence of candidaemia has not changed significantly (2%, 1.4%, 1.2% and 2% respectively). However, species causing candidaemia have changed, with resistant organisms now predominating. Our findings support the use of azole prophylaxis although, in view of the trends noted when itraconazole was used alone, we would recommend the additional use of oral amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Azoles; Bone Marrow Transplantation; Candida; Candidiasis; Drug Resistance, Microbial; Drug Therapy, Combination; Fluconazole; Hematologic Neoplasms; Humans; Itraconazole; Ketoconazole; Neutropenia; Prospective Studies; Retrospective Studies

Candida lusitaniae is an infrequent cause of fungemia. We identified 12 cases of C. lusitaniae fungemia that occurred at the University of Texas M. D. Anderson Cancer Center from 1988 to 1999. The mean age of patients was 48 years (range 20--70 years). Eight patients had hematologic malignancy or had received a bone marrow transplant, and 4 had a solid tumor. Most patients (75%) were neutropenic (<10(3)/mm(3)). Treatment with amphotericin B alone failed for 3 of 6 patients, irrespective of neutropenic status. Fluconazole was effective as a single agent in 3 patients with solid tumors. The combination of amphotericin B plus fluconazole was effective treatment for two-thirds of patients with hematologic malignancy, despite persistence of neutropenia. The mortality rate associated with C. lusitaniae infection was 25%. C. lusitaniae presents as breakthrough fungemia in immunocompromised patients and is associated with failure of amphotericin B therapy. Fluconazole may be a useful agent in the treatment of this infection.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Candida; Candidiasis; Drug Therapy, Combination; Female; Fluconazole; Fungemia; Hematologic Neoplasms; Humans; Immunocompromised Host; Male; Middle Aged; Neoplasms; Neutropenia; Treatment Failure

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Deoxycholic Acid; Drug Combinations; Fever; Fluconazole; Humans; Mycoses; Neutropenia

In vivo pharmacodynamic parameters have been described for a variety of antibacterials. These parameters have been studied in correlation with in vivo outcomes in order to determine which dosing parameter is predictive of outcome and the magnitude of that parameter associated with efficacy. Very little is known about pharmacodynamics for antifungal agents. We utilized a neutropenic mouse model of disseminated candidiasis to correlate pharmacodynamic parameters (percent time above MIC [T > MIC], area under the concentration time curve [AUC]/MIC ratio, and peak serum level/MIC ratio) for amphotericin B in vivo with efficacy, as measured by organism number in homogenized kidney cultures after 72 h of therapy. Amphotericin B was administered by the intraperitoneal route. Drug kinetics for amphotericin B in infected mice were nonlinear. Serum half-lives ranged from 13 to 27 h. Infection was achieved by intravenous inoculation with 10(6) CFU of yeast cells per ml via the lateral tail vein of neutropenic mice. Groups of mice were treated with fourfold escalating total doses of amphotericin B ranging from 0.08 to 20 mg/kg of body weight divided into 1, 3, or 6 doses over 72 h. Increasing doses produced concentration-dependent killing, ranging from 0 to 2 log(10) CFU/kidney compared to the organism number at the start of therapy. Amphotericin B also produced prolonged dose-dependent suppression of growth after serum levels had fallen below the MIC. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Peak serum level in relation to the MIC (peak serum level/MIC ratio) was the parameter best predictive of outcome, while the AUC/MIC ratio and T > MIC were only slightly less predictive (peak serum level/MIC ratio, coefficient of determination [R(2)] = 90 to 93%; AUC/MIC ratio, R(2) = 49 to 69%; T > MIC, R(2) = 67 to 85%). The total amount of drug necessary to achieve various microbiological outcomes over the treatment period was 4.8- to 7.6-fold smaller when the dosing schedule called for large single doses than when the same amount of total drug was administered in 2 to 6 doses. Given the narrow therapeutic window of amphotericin B and frequent treatment failures, these results suggest the need for a reevaluation of current dosing regimens.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Colony Count, Microbial; Disease Models, Animal; Female; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia

Between September 1993 and December 1993, during extensive hospital construction and indoor renovation, a nosocomial outbreak of invasive pulmonary aspergillosis occurred in acute leukemia patients treated in a regular ward that has only natural ventilation. The observed infection rate was 50%. Chemoprophylaxis with intravenous continuous low-dose amphotericin B was then instituted as a preventive measure. During the next 18 months invasive pulmonary aspergillosis developed in 43% of acute leukemia patients. After that period a new hematology ward was opened with an air filtration system through high-efficiency particulate air filtration (HEPA) filters, and a bone marrow transplantation program was started on the hematology service. During the following three years, none of the acute leukemia or bone marrow transplantation patients who were hospitalized exclusively in the hematology ward developed invasive pulmonary aspergillosis, although 29% of acute leukemia patients who were housed in a regular ward, because of shortage of space in the new facility, still contracted invasive pulmonary aspergillosis. Overall, 31 patients were diagnosed with invasive pulmonary aspergillosis during almost five years: 74% of patients recovered from invasive pulmonary aspergillosis, and 42% are long-term survivors; 26% of patients died of resistant leukemia with aspergillosis, but no one died of invasive pulmonary aspergillosis alone. In conclusion, during an on-going construction period, an extremely high incidence rate of invasive pulmonary aspergillosis in acute leukemia patients undergoing intensive chemotherapy was observed. Institution of low-dose intravenous amphotericin B prophylaxis marginally reduced the incidence rate of invasive pulmonary aspergillosis. Keeping patients in a special ward with air filtration through a HEPA system eliminated invasive pulmonary aspergillosis completely. Among patients who developed invasive pulmonary aspergillosis, early diagnosis and treatment are probably the explanation for the favorable outcome.

Topics: Adult; Air Microbiology; Air Pollution, Indoor; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Aspergillus; Cross Infection; Disease Susceptibility; Filtration; Hematology; Hospital Design and Construction; Hospital Units; Hospitals, Teaching; Humans; Immunocompromised Host; Incidence; Israel; Leukemia; Lung Diseases, Fungal; Neutropenia; Patients' Rooms; Spores, Fungal; Treatment Outcome; Ventilation

Pulmonary mucormycosis is a usually fatal opportunistic infection in immunocompromised patients. We describe the first case of an adult patient with hematological malignancy and profound neutropenia to survive a disseminated pulmonary Rhizomucor pusillus infection. Early diagnostic procedures combined with high doses of liposomal amphotericin B and surgical resection may have contributed to the successful outcome.

Topics: Amphotericin B; Antifungal Agents; Combined Modality Therapy; Humans; Leukemia-Lymphoma, Adult T-Cell; Liposomes; Lung Diseases, Fungal; Male; Middle Aged; Mucormycosis; Neutropenia; Pneumonectomy; Radiography; Rhizomucor; Treatment Outcome

The aim of the present study was to evaluate the diagnostic significance of the D-arabinitol/L-arabinitol ratio in urine of neutropenic patients with suspected fungal infection. D-arabinitol/L-arabinitol ratios were determined in 373 serial urine samples of 104 patients with haematological malignancies receiving empirical amphotericin B treatment for suspected invasive fungal infection. Twenty-eight (8%) urine samples obtained from 17 (16%) patients were positive (ratio > or =4). Eight (47%) patients had positive urine samples at the initiation of empirical amphotericin B treatment and the rest from 7 to 30 days after empirical therapy was started. Several urine samples were positive in six patients. Only one of the five patients with candidemia had elevated D-arabinitol/L-arabinitol ratios (persistent Candida krusei fungaemia). Four patients with transient candidemia and seven patients with invasive mould infections were negative. Patients who died during the study period had significantly higher D-arabinitol/L-arabinitol ratios than patients who survived (P=0.0002). Pneumonia was the most common manifestation of infection (53% of patients with elevated D-arabinitol/L-arabinitol ratios) and was associated with an especially high mortality (67%). The present study shows that elevated urine D-arabinitol/L-arabinitol ratios are common in febrile, neutropenic patients. However, the urine arabinitol test did not detect transient candidemia at elevated levels during the course of infection. Furthermore, D-arabinitol/L-arabinitol ratios were often elevated in the late phase of infection only. This contests the use of this test in guiding the initiation of antifungal therapy. The detection of elevated arabinitol levels in neutropenic patients during empirical amphotericin B treatment is associated with poor prognosis.

Topics: Adult; Aged; Amphotericin B; Antiviral Agents; Candida; Candidiasis; Female; Fungemia; Humans; Male; Middle Aged; Neutropenia; Sugar Alcohols

Patients treated for cancer with chemotherapy and other cytoreductive therapy often develop serious bacterial, viral, and fungal infections due to B- and T-cell depletion, neutropenia and decreased barrier function of mucosal membranes. In patients with neutropenic fever not responding to broad spectrum antibiotic therapy there is a high risk of fungal infection. In a Cochrane Library meta-analysis of the effect of prophylactic and empirical antifungal treatment, amphotericin B was found to be the only drug affecting total mortality. Fluconazole, ketoconazole and itraconazole affected risk of colonization and invasive infection, but not the total risk of death. We agree with these conclusions, but emphasize that the appropriate time to initiate empirical antifungal therapy is still not settled. We also believe that azoles may be of value in the therapy of symptomatic mucositis.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Drug Resistance, Microbial; Evidence-Based Medicine; Fever; Humans; Meta-Analysis as Topic; Mycoses; Neutropenia; Radiography; Randomized Controlled Trials as Topic

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Cryptococcosis; Fluconazole; Flucytosine; Histoplasmosis; Humans; Immunosuppression Therapy; Mycology; Mycoses; Neutropenia; Prognosis; Risk Factors; Travel

To present a case of rhino-orbital mucormycosis in a patient with AIDS and neutropenia managed without exenteration.. Case report.. A 60-year-old African-American man with AIDS developed neutropenia that was probably secondary to antiretroviral therapy. He developed right rhino-orbital mucormycosis and was treated with right partial ethmoidectomy with debridement and liposomal amphotericin B. The infection was cured without need for orbital exenteration, although visual acuity in his right eye ultimately was no light perception.. Rhino-orbital mucormycosis is uncommon in patients with AIDS. When rhino-orbital mucormycosis occurs, patients require a careful search for an underlying metabolic derangement such as neutropenia. Treatment should be aggressive, but these patients may not require orbital exenteration.

Topics: Acquired Immunodeficiency Syndrome; Amphotericin B; Antifungal Agents; Debridement; Eye Infections, Fungal; Humans; Leukocyte Count; Liposomes; Magnetic Resonance Imaging; Male; Middle Aged; Mucormycosis; Neutropenia; Orbital Diseases; Paranasal Sinus Diseases; Risk Factors; Visual Acuity

Topics: Amphotericin B; Antifungal Agents; Drug Combinations; Fever; Humans; Liposomes; Mycoses; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Administration, Oral; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Deoxycholic Acid; Drug Combinations; Fever; Humans; Infusions, Intravenous; Itraconazole; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Risk Factors; Treatment Failure

Invasion of the major airways is a rare manifestation of respiratory tract involvement by Aspergillus sp. and is seen almost exclusively in immunocompromised patients. We present calcification as a new feature of this condition and its demonstration by ultrasound in a 15-year-old boy with severe neutropenia secondary to aplastic anaemia.

Topics: Adolescent; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillosis; Calcinosis; Humans; Immunocompromised Host; Male; Neutropenia; Trachea; Tracheal Diseases; Ultrasonography

The incidence of disseminated infection with Scedosporium species is increasing in patients with haematological malignancy. Two fatal cases are reported of patients with acute myeloid leukaemia and neutropenia who presented with Scedosporium endophthalmitis. Diagnosis of fungal infection was delayed as blood and vitreous cultures were positive only after 3 days in patient 1 and blood culture was positive at 7 days in patient 2. Despite antifungal therapy with amphotericin B and additional fluconazole in patient 2, both patients died of overwhelming fungal septicaemia. Post-mortem examination of the right globe in patient 1 showed haemorrhagic necrotizing chorioretinitis with numerous fungal hyphae in choroidal vessels, choroid, retina and vitreous. Scedosporium species are often resistant to conventional antifungal therapy including amphotericin B. Diagnosis is difficult and mortality in disseminated infection is high.

Topics: Acute Disease; Adult; Amphotericin B; Antifungal Agents; Endophthalmitis; Eye Infections, Fungal; Fatal Outcome; Female; Fluconazole; Fungemia; Humans; Leukemia, Myeloid; Male; Middle Aged; Mycetoma; Neutropenia; Scedosporium

Amphotericin B lipid complex (ABLC) has been investigated as an empirical antifungal treatment for neutropenic patients with persistent fever of unknown origin (FUO). We studied the safety and efficacy of low dose ABLC (1 mg/kg/day) for empirical treatment of neutropenic FUO. Sixty-one patients with hematologic malignancies developing 69 episodes of neutropenic FUO after chemotherapy or hematopoietic stem cell transplantation were included in the study. The median patient age was 47 years (18-68). The median duration of neutropenia (< 0.5 x 10(9)/l) was 17 days (7-45) and the median duration of ABLC therapy was 8 days (2-19). Thirteen patients (19%) suffered from mild to moderate infusion-related adverse events. Creatinine levels were stable in 42 cases (61%), improved in 9 (13%) and deteriorated in 18 (26%), with no other significant toxicities. Among 67 evaluable episodes, the response rate (resolution of fever during the period of neutropenia without developing a fungal infection) was 67%, while 33% were treatment failures. Low-dose ABLC is safe, well tolerated and seems to be at least as effective as c-AmB for empirical antifungal therapy of FUO. Randomized trials at this dose level comparing ABLC with c-AmB or other lipid formulations are warranted.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antiviral Agents; Drug Combinations; Female; Fever; Hematologic Neoplasms; Humans; Hypokalemia; Kidney; Liver; Male; Middle Aged; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols

Fusarium is a newly emerging fungal pathogen associated with significant morbidity and mortality in the immunocompromised host. We have reviewed our hospital's experience with Fusarium between 1985 and 1995. Fusarium species were isolated from 22 specimens, representing 11 patients. Cases were not clustered by time period. The median age of the patients was 36.5 years (range 17-69 years). The sources of the organism were 12 skin lesions from eight patients, seven blood cultures from two patients and one specimen each from a Hickman catheter tip, nail clippings and a bronchoalveolar lavage. Seven of the patients had chemotherapy-induced neutropenia when the Fusarium was isolated. Five of them developed invasive fusarosis during acute leukaemia induction treatment. They remained neutropenic, and none survived. The other two patients recovered from neutropenia and were treated successfully for this infection. The remaining four patients were not neutropenic or immunocompromised. Three grew Fusarium from skin or nail clippings and one from bronchial alveolar lavage (BAL). There was no evidence of invasive disease in any of the four. None of them received antifungal therapy, and they were all alive at last follow-up. We conclude that Fusarium is a newly emerging infection in neutropenic patients. A high index of suspicion, especially for skin lesions, will help in early diagnosis before systemic and visceral dissemination. Excision of the initial focus of infection and antifungal therapy, aided by speedy neutrophil recovery, are likely to protect patients threatened with these fatal infections. Fusarium isolated from non-neutropenic, non-immunosuppressed patients is not significant and does not merit systemic antifungal treatment.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Dermatomycoses; Female; Foot Dermatoses; Fusarium; Humans; Immunocompromised Host; Leukemia; Male; Middle Aged; Necrosis; Neutropenia; Retrospective Studies; Skin

Infections due to Candida species are the most common of the fungal infections. Candida species produce a broad range of infections, ranging from nonlife-threatening mucocutaneous illnesses to invasive process that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. This document summarizes current knowledge about treatment of multiple forms of candidiasis and is the guideline of the Infectious Diseases Society of America (IDSA) for the treatment of candidiasis. Throughout this document, treatment recommendations are scored according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the underlying data. The document covers 4 major topical areas. The role of the microbiology laboratory. To a greater extent than for other fungi, treatment of candidiasis can now be guided by in vitro susceptibility testing. The guidelines review the available information supporting current testing procedures and interpretive breakpoints and place these data into clinical context. Susceptibility testing is most helpful in dealing with infection due to non-albicans species of Candida. In this setting, especially if the patient has been treated previously with an azole antifungal agent, the possibility of microbiological resistance must be considered. Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis, the guidelines review strategies for treatment of 15 other forms of invasive candidiasis. Extensive data from randomized trials are really available only for therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of therapy for other forms of candidiasis is based on case series and anecdotal reports. In general, both amphotericin B and the azoles have a role to play in treatment. Choice of therapy is guided by weighing the greater activity of amphotericin B for some non-albicans species (e.g., Candida krusei) against the lesser toxicity and ease of administration of the azole antifungal agents. Flucytosine has activity against many isolates of Candida but is not often used. Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is dominated by the azole antifungal agents. These drugs may be used topically or systemically and have been proven safe and efficacious. A significant problem with mucosal disease is the propensity for a small proportion of patients to suffer repeated relapses.

Topics: Adult; Amphotericin B; Antifungal Agents; Candida; Candidiasis; Child; Child, Preschool; Cost-Benefit Analysis; Female; Fever; Humans; Microbial Sensitivity Tests; Neutropenia; Outcome Assessment, Health Care

Invasive sinonasal fungal disease is a potentially fatal complication of chemotherapy-induced immunosuppression and neutropenia. We reviewed the outcomes of seven cancer patients who had been diagnosed with invasive fungal sinusitis; six patients had hematologic malignancies and one had breast cancer. At the time of their sinus diagnosis, all patients had been hospitalized and were receiving combination chemotherapy for their underlying malignancy. Impairment of their immune function was characterized by an absolute neutrophil count of less than 1,000/mm3. Aggressive management of their sinonasal fungal disease consisted of surgical debridement and systemic amphotericin B for all patients, and treatment with granulocyte colony-stimulating factor for two patients. Invasive Aspergillus infection was identified in six patients and invasive Candida albicans infection in one. Although the prognosis for these patients was poor and two patients died of the fungal infection, the aggressive treatment strategy resulted in long-term survival for the remaining five patients.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Aspergillus; Candida albicans; Child; Combined Modality Therapy; Debridement; Female; Fever; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses; Neutropenia; Paranasal Sinuses; Retrospective Studies; Sinusitis; Treatment Outcome

To investigate diagnostic aspects of invasive aspergillosis (IA) in allogeneic BMT recipients, the charts of 22 consecutive patients with IA transplanted in 1989-1995 were reviewed. IA was diagnosed 69-466 days (median 131 days) post BMT. In 16 patients (73%), a definite or probable diagnosis of IA was made during life. Respiratory symptoms were the presenting feature in half of the patients followed by neurological symptoms (27%). Chest X-ray revealed single or multiple nodular lesions in 10 patients; cavitation was observed in five patients. Tissue biopsy was the most common method of diagnosis (nine patients: lungs 6, liver 1, subcutaneous tissue 1, brain 1). Five IA cases were detected by nine guided fine needle lung biopsies in eight patients and without complications. Bronchoalveolar lavage was performed in 14 patients with findings suggestive of invasive pulmonary aspergillosis in eight cases. Lungs were the most common organ affected (90%) followed by central nervous system (41%). The diagnosis of IA is still difficult, and a large number of patients have advanced infection at diagnosis. Methods for early diagnosis are needed. Patients with a clinical suspicion of IA should be treated vigorously with antifungal agents during the diagnostic work-up.

Topics: Adolescent; Adult; Amphotericin B; Aspergillosis; Aspergillus flavus; Aspergillus fumigatus; Aspergillus niger; Autopsy; Biopsy, Needle; Bone Marrow Transplantation; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Cohort Studies; Female; Fever; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Hemoptysis; Humans; Lung; Male; Middle Aged; Nervous System Diseases; Neutropenia; Radiography, Thoracic; Respiratory Tract Diseases; Tomography, X-Ray Computed; Transplantation, Homologous

The aim of this study was to investigate the relationship between phenotypes of Candida albicans strains isolated from clinical specimens and the susceptibility of the strains to three antifungal agents, fluconazole, amphotericin B and flucytosine. Oropharyngeal, gastrointestinal and urogenital tract specimens were collected from 122 neutropenic patients who had received no previous prophylactic treatment. Each of 122 C. albicans strains recovered was found to express one of the six phenotypes: smooth, fuzzy, irregular, star, ring and stipple. The mean minimum inhibitory concentrations (MICs) of fluconazole was consistently higher for C. albicans strains expressing the stipple phenotype. The mean MICs for the six phenotypes of C. albicans strains ranged between 1.22 and 7.94 micrograms ml-1 for fluconazole, 0.99 and 2.55 micrograms ml-1 for amphotericin B and 1.23 and 1.83 micrograms ml-1 for flucytosine. The antifungal susceptibility of the stipple phenotype requires attention, especially in patients who are clinically unresponsive to fluconazole chemotherapy or in cases of life-threatening C. albicans infections of immunocompromised hosts. Long-term use of fluconazole may explain the outcome of the resistant stipple phenotype.

Topics: Amphotericin B; Antifungal Agents; Candida albicans; Candidiasis; Digestive System; Fluconazole; Flucytosine; Humans; Microbial Sensitivity Tests; Neutropenia; Oropharynx; Phenotype; Urogenital System

A 73-y-old female with a history of adenocarcinoma of colon and refractory anemia developed febrile neutropenia following chemotherapy. Therapy with iv infusion of amphotericin B deoxycholate (AmBd) was initiated on day 8 of hospital admission. Premedications included acetaminophen, diphenhydramine and meperidine. Patient developed rigor, chill and elevated temperature approximately 100 min into the infusion. The infusion was temporarily discontinued and rigors subsided following administration of 25 mg meperidine im. Infusion was continued after cessation of the rigors with no further sequelae. During each infusion of AmBd over the next 3 d, the patient developed rigor, chill and elevated temperature which was managed with meperidine. However, on day 4 she developed respiratory distress, bronchospasm and visible cyanosis with oxygen saturation of 88% while on 2 L oxygen. The infusion was stopped and the symptoms subsided with administration of albuterol via nebulizer. Amphotericin lipid formulation infusion was reinstituted after 3 d because of the patient's worsening clinical status. However, the patient developed severe respiratory distress approximately 130 min into the infusion. The infusion was discontinued and she was treated with albuterol via nebulizer. Itraconazole therapy was instituted without any adverse sequelae. Clinicians should be aware of this potential adverse event since it can occur with all formulation of amphotericin.

Topics: Adenocarcinoma; Aged; Amphotericin B; Anemia; Antifungal Agents; Colonic Neoplasms; Drug Combinations; Female; Fever; Humans; Infusions, Intravenous; Leukemia, Myeloid, Acute; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Respiratory Distress Syndrome

Fungal colonization during cytotoxic chemotherapy was studied in 42 patients with a recent diagnosis of a haematological malignancy. In total, 2759 surveillance cultures were taken from the nostrils, throat, urine, stool and perineal region. Seven hundred and ninety-six positive surveillance cultures (28.9%) yielded 968 fungal isolates. The rate of fungal colonization did not differ between patients with acute leukaemia, patients with other haematological malignancies and control patients in the same ward at admission (71% vs. 67% vs. 80%). Patients with acute leukaemia were colonized at a significantly lower rate in samples from the throat (32%), urine (10%), stool (45%) and perineum (29%) taken during hospitalization when compared with other haematological patients (respective values 58%, 21%, 67% and 45%; P-values 0.001). This could be attributed to differences in the use of antifungal drugs. Although 21/42 (50%) of our patients had multiple-site fungal colonization at the end of follow-up, only one systemic Candida infection was diagnosed. Extensive use of antifungal treatment may have influenced the low incidence of systemic fungal infections during the follow-up. In addition to Candida species, Malassezia furfur, Geotrichum candidum and Saccharomyces cerevisiae were frequently isolated. The rate of S. cerevisiae isolation increased significantly over time after admission (1%, vs. 18% of isolates, P<0.001), suggesting hospital-acquired transmission. These isolates were highly resistant to azole antifungals (MIC90 128 microg/mL for fluconazole and 16 microg/ml, for itraconazole), and caused persistent multiple site colonization in 12 patients. Extensive use of antifungal agents in a haematological ward may keep the incidence of invasive fungal infections low in spite of heavy fungal colonization. However, there may be a risk of emergence of resistant fungal strains.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Cross Infection; Drug Resistance, Microbial; Female; Finland; Fluconazole; Hematologic Neoplasms; Hospital Units; Humans; Infection Control; Itraconazole; Male; Microbial Sensitivity Tests; Middle Aged; Mycoses; Neutropenia; Saccharomyces cerevisiae

Blastoschizomyces capitatus (BC), a filamentous fungus of genus Trichosporum, is as an important opportunistic pathogen in the compromised host. Within the past 10 years, 47 cases of BC infection have been published. Most of the patients had acute leukemia (AL) or related disorders and had received chemotherapy treatment. Due to BC's resistance to currently used antifungal agents, this infection represents a therapeutic challenge and serious complication in the treatment of hematology malignancies. Here we report our experience with BC infection in four patients with acute leukemia or related disorders.

Topics: Acute Disease; Adult; Amphotericin B; Antifungal Agents; Female; Humans; Immunosuppression Therapy; Leukemia; Male; Middle Aged; Mycoses; Neutropenia; Trichosporon

Candida krusei is inherently resistant to fluconazole and is emerging as a frequent cause of fungemia in patients with hematologic malignant neoplasms.. To determine the risk and prognostic factors associated with C krusei fungemia in comparison with Candida albicans fungemia in patients with cancer.. Retrospective study of 57 cases of C krusei fungemia occurring at the M. D. Anderson Cancer Center, Houston, Tex, from 1989 to 1996. The C krusei cases were compared with 57 cases of C albicans fungemia with respect to demographics, underlying cancer, Acute Physiology and Chronic Health Evaluation II score, immunosuppression status, chemotherapy, and the use of central venous catheters, as well as fluconazole prophylaxis.. At our institution, C krusei accounted for 5% of fungemias during 1989 through 1992 and for 10% during 1993 through 1996. Patients with C krusei fungemia more often had leukemia than patients with C albicans (77% vs 11%; P =.02), whereas catheter-related infections were more common among patients with C albicans fungemia (42% vs 0%; P<.001). Patients with C krusei fungemia had a lower response rate (51% vs 69%; P =.05), largely because they more frequently were neutropenic and had disseminated infection. Mortality related to fungemia was 49% in the cases with C krusei vs 28% in C albicans. Multiple logistic regression analysis showed that persistent neutropenia (P =.02) and septic shock (P =.002) were predictors of poor prognosis.. In neutropenic patients, C krusei fungemia is associated with high mortality. It should be suspected in patients with leukemia who are receiving fluconazole prophylaxis and should be treated aggressively with an amphotericin B regimen.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Candida albicans; Case-Control Studies; Catheterization, Central Venous; Catheters, Indwelling; Child; Child, Preschool; Drug Resistance, Microbial; Female; Fluconazole; Fungemia; Hematologic Neoplasms; Humans; Immunocompromised Host; Immunosuppressive Agents; Infant; Logistic Models; Male; Middle Aged; Neutropenia; Prognosis; Retrospective Studies; Risk Factors; Shock, Septic; Treatment Outcome

Topics: Amphotericin B; Antifungal Agents; Fever; Fluconazole; Humans; Mycoses; Neutropenia

The outcome of invasive aspergillosis (IA) has been considered poor in allogeneic BMT recipients. We analyzed retrospectively the treatment and outcome of IA diagnosed during life in a recent cohort of 20 allogeneic BMT recipients. All patients were initially treated with amphotericin B (AmB) (conventional 16, liposomal 4). Due to toxicity, conventional AmB was changed to a liposomal preparation in 10 patients. Five patients also received itraconazole and three underwent surgery. Of 19 evaluable patients, two patients achieved a complete response and a partial response was observed in five patients (response rate 37%). The median survival was 37 days after the diagnosis. Only two patients (10%) were cured. The prognosis of allogeneic BMT recipients with IA has remained poor. Although treatment responses are common, immunosuppression aggravated by GVHD and its treatment, as well as the commonly disseminated presentation of IA, seem to be major obstacles to the success of therapy. Bone Marrow Transplantation (2000) 26, 759-762.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Autopsy; Bone Marrow Transplantation; Cohort Studies; Female; Humans; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Retrospective Studies; Survival Rate; Transplantation, Homologous; Treatment Outcome

Topics: Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Clinical Protocols; Humans; Kidney; Liposomes; Mycoses; Neutropenia; Randomized Controlled Trials as Topic; Safety

We have used a new, commercial enzyme-linked immunosorbent assay (ELISA, Platelia Aspergillus) to detect Aspergillus antigen in serum, urine and bronchoalveolar lavage (BAL) samples of 105 haematological patients who received empirical amphotericin B treatment for suspected fungal infection. 14% (60/419) of serum and 5% (18/373) of urine samples were positive. Ten-fold concentration of urine increased the number of positive samples to 31 (8%). The antigen was detected in 5 of 20 BAL samples, but fungal culture was negative in all of them. 22 patients had positive antigen test. Serum was positive in 17, urine in 7 and concentrated urine in 12 patients. Six patients had confirmed invasive aspergillosis. In all these patients, antigen was detected in serum, but urine was positive in only 2 patients. Patients whose antigen test turned negative during the amphotericin B treatment had significantly lower mortality than patients with persistently positive antigen test (2/10 vs. 8/8, p = 0.002). We conclude that Aspergillus galactomannan can be detected by ELISA in serum, urine and BAL samples of haematological patients, but the higher sensitivity of serum testing makes it preferable for screening. Disappearance of the antigen during antifungal therapy seems to correlate with good, and persistence with poor, clinical outcome.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Antigens, Fungal; Aspergillosis; Aspergillus; Bronchoalveolar Lavage Fluid; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Neutropenia; Sensitivity and Specificity; Treatment Outcome

Invasive fungal infections are a major cause of mortality in neutropenic cancer patients. To determine whether a polymerase chain reaction (PCR)-based assay enabled the identification of patients at risk for invasive fungal infections, a prospective monitoring once per week was performed during 92 neutropenic episodes in patients receiving chemotherapy for acute leukaemia or high-dose therapy followed by allogeneic or autologous stem cell transplantation, with the investigators blinded to clinical and microbiological data. PCR positivity was documented in 34 out of 92 risk episodes. All patients developing proven invasive fungal infection were found PCR positive, and PCR was found to be the earliest indicator of invasive fungal infection preceding clinical evidence by a mean of 5.75 d (range 0-14 d). In febrile neutropenic patients without a prior history of invasive fungal infection, a sensitivity of 100% and a specificity of 73% of the PCR assay for the development of proven or probable invasive fungal infection was documented. In conclusion, panfungal PCR performed prospectively once a week enabled the identification of patients at high risk for invasive fungal infections.

Topics: Acute Disease; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candidiasis; Female; Fever of Unknown Origin; Genes, Fungal; Hematopoietic Stem Cell Transplantation; Humans; In Situ Hybridization; Leukemia, Myeloid; Liver Diseases; Lung Diseases, Fungal; Male; Middle Aged; Monitoring, Physiologic; Neutropenia; Polymerase Chain Reaction; Sensitivity and Specificity

Topics: Amphotericin B; Drug Interactions; Humans; Hypokalemia; Mineralocorticoid Receptor Antagonists; Neutropenia; Potassium; Spironolactone

Twelve cases of Trichosporon spp. fungemias occurring in a national cancer institution within 10 years are described. The trend of hematogenous trichosporonosis within the last 10 years is increasing. While no cases occurred in 1988-1991, after 1991, Trichosporon spp. was the most common species among non-Candida spp. fungemias in 1993-1997. The 12 cases of fungemia included 5 that started while the patients were receiving prophylaxis with oral itraconazole, and 2 appeared despite empiric therapy with amphotericin B. Five of the 12 fungemias were catheter associated. Risk factors for fungemia were: central venous catheter, broad-spectrum antibiotics (third-generation cephalosporins plus aminoglycoside); all but 1 had neutropenia and were receiving antineoplastic chemotherapy. All but 2 of the patients died of systemic fungal infection (83.3% mortality). Amphotericin B was administered to all but 1 patient, who was not treated because he died the day after his culture was found to be positive for T. beigelii, before antifungals were administered. All cases infected with T. pullulans were catheter related, and all these patients died. One of the remaining 9 fungemias was caused by T. capitatum (Blastoschizomyces capitatus), and 8 by T. beigelii. Only 2 patients were cured, 1 with a combination therapy with amphotericin B plus fluconazole, and 1 with amphotericin B monotherapy. Several risk factors (neutropenia, acute leukemia, prior therapy or prophylaxis with antifungals and catheter as source of fungemia, breakthrough fungemia) were significantly associated with Trichosporon spp. fungemia, in comparison to 63 C. albicans candidemia occurring in the same period at the same institution. Attributable mortality of hematogenous trichosporonosis was also significantly higher (83.3% vs. 15.8%, P<0.001) than that of hematogenous candidiasis.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Aminoglycosides; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Candidiasis; Catheterization, Central Venous; Catheterization, Peripheral; Cause of Death; Cephalosporins; Chemoprevention; Female; Fungemia; Humans; Itraconazole; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Risk Factors; Trichosporon

Topics: Amphotericin B; Antifungal Agents; Cost-Benefit Analysis; Humans; Liposomes; Mycoses; Neutropenia

The aim of this study was to evaluate the relevance of in vitro antifungal susceptibility to clinical response in neutropenic patients with invasive oral aspergillosis.. Nine isolates of Aspergillus species were obtained from invasive oral infections in 9 patients with hematologic malignancies and tested for their in vitro susceptibility to amphotericin B, fluconazole, miconazole, 5-fluorocytosine, and itraconazole. Minimal inhibitory concentration values of the 5 drugs were obtained for each fungus through use of a microdilution broth method. The patients were treated with intravenous amphotericin B (30-50 mg/day) in combination with oral 5-fluorocytosine (3000-6000 mg/day) and/or oral itraconazole (200 mg/day).. Amphotericin B and itraconazole were found to be very active, with minimal inhibitory concentration values of 0.861 and 0.194 microg/mL, respectively. Miconazole and 5-fluorocytosine showed minimal inhibitory concentration values of 1.72 and 3.56 microg/mL, respectively. On the other hand, fluconazole FCZ showed low activity, with a minimal inhibitory concentration value in excess of 64.0 microg/mL. During neutropenia, combined antifungal chemotherapy stabilized oral aspergillosis and prevented the spread of oral lesions in 8 patients in whom neutrophil counts eventually recovered.. The results imply that in vitro susceptibility testing may serve as an informative parameter with respect to the efficacy of these antifungals in the treatment of invasive oral aspergillosis, inducing fungal stasis until the neutrophils recover.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Aspergillus; Drug Combinations; Drug Evaluation; Female; Fluconazole; Flucytosine; Humans; Immunocompromised Host; Itraconazole; Leukemia; Lymphoma; Male; Miconazole; Microbial Sensitivity Tests; Middle Aged; Mouth Diseases; Neutropenia

Voriconazole (UK-109,496) is a new triazole with in vitro activity against a wide spectrum of fungi including yeasts intrinsically resistant to fluconazole such as Candida krusei. In this study the efficacy of voriconazole was compared to amphotericin B and fluconazole in a neutropenic guinea pig model of hematogenously disseminated C. krusei infection. In guinea pigs, neutropenia was established by using cyclophosphamide (intraperitoneally, i.p., 100 mg/kg on day 1 and 4), and dexamethasone (orally, 2 mg/kg/day, for 8 days). Neutropenic guinea pigs were infected with 0.5 ml of yeast cell suspension (1 x 10(8) CFU) intravenously. Challenged animals were treated with antifungals starting 1 h postinfection for 7 days. The animals were divided into five groups: untreated control, amphotericin B (1 mg/kg i.p. on alternate days), fluconazole (20 mg/kg orally twice daily), and voriconazole (two groups: 5 and 10 mg/kg orally twice daily) groups. Guinea pigs were sacrificed 1 day after the last treatment. Brain, liver, and kidneys were removed and weighed, tissues were homogenized and fungal burden determined by serial quantitative counts. Voriconazole at dosages of 5 or 10 mg/kg b.i.d. was shown to be significantly more efficacious than either amphotericin B or fluconazole in eradicating C. krusei from brain, liver and kidney tissue. These data indicate that voriconazole could be efficacious for the treatment of infections caused by fluconazole-resistant Candida, such as C. krusei.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida; Candidiasis; Disease Models, Animal; Drug Resistance, Microbial; Fluconazole; Guinea Pigs; Male; Neutropenia; Pyrimidines; Random Allocation; Triazoles; Voriconazole

Blood samples were drawn daily from 72 patients who had hematological malignancies, neutropenia, and fever and who had failed to respond to broad-spectrum antibiotics. Each sample was used for conventional fungal blood cultures and for detection and identification of Candida DNA by a PCR method with subsequent restriction enzyme analysis (REA) recently developed in our laboratory. The PCR method was able to detect five CFU of Candida spp. per ml of blood, and subsequent REA of the amplicons allowed the identification of the Candida species most commonly implicated in cases of candidiasis. Thirty-one patients were PCR-REA positive, and four of these patients were also culture positive. The ultimate diagnosis for 13 of these patients and 1 patient who was PCR-REA negative was disseminated candidiasis (confirmed by clinical data, multiple cultures, histology, autopsy, and/or ultrasonographic evidence of hepatosplenic candidiasis). The molecular method is significantly more sensitive than conventional fungal blood cultures and has a high negative predictive value (97.5%) for the development of disseminated candidiasis in neutropenic patients.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; DNA, Fungal; Female; Fever; Hematologic Neoplasms; Humans; Male; Mycology; Mycoses; Neutropenia; Polymerase Chain Reaction; Prohibitins; Reproducibility of Results; Restriction Mapping; Sensitivity and Specificity

In invasive aspergillosis, the duration of neutropenia is an accepted risk factor, and recovery from neutropenia is generally associated with a favourable outcome. However, the rapidity of granulocyte recovery may rarely be associated with adverse sequelae. The purpose of this study was to define the relationship between neutrophil (polymorphonuclear, PMN) recovery after chemotherapy-induced bone marrow aplasia and the occurrence of severe pulmonary complications (haemoptysis, pneumothorax and death) in patients with haematological malignancies who developed invasive fungal pneumonias.. Twenty consecutive patients were retrospectively studied; eight of them had developed pulmonary events between 5 and 11 days after neutrophil recovery that followed deep neutropenia (PMN < 100 microL-1).. Five patients had haemoptysis (one of these also had pneumothorax) and three had pneumothorax. According to the multiplicative logistic model, the odds of occurrence of a pulmonary event increased significantly with increasing PMN count on the fifth day (P < 0.001). Five of the eight patients who had pulmonary complications died. Also, the risk of death was larger in the presence of rapid neutrophil recovery, although the difference was not statistically significant (P = 0.111). Analysis of clinical and laboratory data showed that the risk of pulmonary complications significantly increased when the neutrophil concentration was > 4500 microL-1 on day 5 after deep granulocyte neutropenia (PMN < 100 microL-1). There was no correlation between pulmonary complications, dosage of amphotericin B and deaths.. The occurrence of life-threatening complications in patients with invasive fungal pneumonia is closely related to rapid PMN recovery.

Topics: Adolescent; Adult; Aged; Amphotericin B; Aspergillosis; Female; Granulocytes; Hemoptysis; Humans; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Neutrophils; Pneumothorax; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

The activity of liposomal nystatin against invasive pulmonary aspergillosis was investigated in persistently neutropenic rabbits. Treatment groups included liposomal nystatin at dosages of 1, 2 and 4 mg/kg/day intravenously, or amphotericin B deoxycholate 1 mg/kg/day administered intravenously after normal saline loading. As compared with untreated controls, liposomal nystatin administered at 2 and 4 mg/kg/day prolonged survival and reduced fungus-mediated tissue injury and excess lung weight at post-mortem in a similar manner to amphotericin B. Although amphotericin B was superior in clearing infected lung tissue, treatment with all regimens of liposomal nystatin led to a significant reduction in pulmonary fungal tissue burden. During treatment, ultrafast CT-scan demonstrated ongoing resolution of pulmonary lesions at 2 and 4 mg/kg/day, but not at 1 mg/kg/day. With the exception of mild increases in blood urea nitrogen (BUN) and serum creatinine values during treatment at 2 and 4 mg/kg/day, which were similar to those found in amphotericin B-treated rabbits, liposomal nystatin was well tolerated. Preliminary pharmacokinetic studies in non-infected animals established linear drug disposition of liposomal nystatin in plasma over the investigated dosage range and peak plasma levels above the MIC for the test strain after multiple daily dosing for 7 days. Liposomal nystatin increased survival and provided reduced tissue injury, effective microbiological clearance and tolerable side effects in experimental pulmonary aspergillosis in persistently neutropenic rabbits, thus providing a rational basis for further investigations in clinical trials.

Topics: Amphotericin B; Animals; Antifungal Agents; Area Under Curve; Aspergillosis; Blood Urea Nitrogen; Creatinine; Drug Carriers; Female; Half-Life; Liposomes; Lung; Lung Diseases, Fungal; Neutropenia; Nystatin; Organ Size; Rabbits; Radiography; Survival Rate

Hepatosplenic candidiasis following granulocytopenic periods is a relatively recently recognised problem in immunocompromised patients, particularly in those with acute leukaemia. We present three patients in whom diagnosis of hepatosplenic candidiasis was suspected on the basis of ultrasonographic (US), computed tomographic (CT) findings and confirmed by laparoscopy and biopsy of liver lesions. All three patients were successfully treated briefly with amphotericin B, followed by a longer period of fluconazole. In one patient laparotomy and surgical evacuation of abscesses was performed. This condition could be more often recognised by careful follow-up of liver function test, C-reactive protein level, ultrasonography, CT and MRI after recovery from chemotherapy-induced neutropenia.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Candidiasis; Female; Fluconazole; Humans; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Liver Diseases; Male; Middle Aged; Neutropenia; Opportunistic Infections; Splenic Diseases

The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocandin, were studied against disseminated candidiasis in persistently neutropenic rabbits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic rabbits suggested a linear relationship between dose and area under the curve (AUC). The times spent above the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected rabbits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 10(3) Candida albicans blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. Rabbits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. albicans from the liver, spleen, kidney, lung, vena cava, and brain in comparison to that for UCs. There was a dose-dependent clearance of C. albicans from tissues in response to LY. Among rabbits treated with LY0.1 there was a significant reduction of C. albicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues but the brain. By comparison, LY0.5 and LY1 cleared all tissues, including the brain, of C. albicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was observed among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated rabbits than in UCs and LY- and FLU-treated rabbits. LY0.5 and LY1 were well tolerated, displayed predictable pharmacokinetics in plasma, and had activities comparable to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic rabbits.

Topics: Amphotericin B; Analysis of Variance; Anidulafungin; Animals; Antifungal Agents; Candida albicans; Candidiasis; Creatinine; Dose-Response Relationship, Drug; Echinocandins; Female; Fluconazole; Metabolic Clearance Rate; Microbial Sensitivity Tests; Neutropenia; Peptides, Cyclic; Potassium; Rabbits

The effects of the hematoregulatory peptide SK&F 107647 were examined in a persistently and profoundly neutropenic rabbit model of disseminated candidiasis in order to determine its potential to enhance resistance against infection and its role as an adjunct to conventional antifungal chemotherapy. In healthy animals, SK&F 107647 elicited a time-dependent increase in CD11b-positive monocytes and neutrophils. When administered to neutropenic rabbits infected with Candida albicans, no significant differences in the number of CFU per gram in any of the tissues tested compared with the number in untreated control rabbits were detected. However, when SK&F 107647 was administered in combination with low doses of amphotericin B, there was a significant reduction in organism burden in the lungs, liver, spleen, and kidneys compared with the burdens in the organs of untreated control animals and in the lungs and kidneys compared with the burdens in the lungs and kidneys of animals treated with amphotericin B alone. These data suggest a potential role for this peptide as adjunctive therapy in combination with conventional antifungal agents in the treatment of disseminated candidiasis in the setting of profound and persistent neutropenia.

Topics: Adjuvants, Immunologic; Amphotericin B; Animals; Antifungal Agents; Candidiasis; Cytarabine; Drug Therapy, Combination; Female; Neutropenia; Oligopeptides; Rabbits

A retrospective study of 76 episodes of candidemia in 73 patients with underlying hematological malignancy, from 1988 until 1997, has been conducted to evaluate the clinical characteristics and to ascertain the variables related to the onset and the outcome of candidemia. The most frequent malignancy was acute myeloid leukemia (29 episodes). Candidemia developed mainly during aplasia in patients refractory to chemotherapy (42%). In 65 episodes (86%) the patients were neutropenic (ANC <1 x 10(9)/l) before the candidemia diagnosis for a median time of 13 d, and in 53 episodes (70%) at microbiological diagnosis of candidemia ANC was <1 x 10(9)/l. Candida albicans was the most frequently isolated etiologic agent (31 episodes), but C. non-albicans species sustained the majority of candidemia. Seventeen candidemias developed during azoles prophylaxis. One month after the diagnosis of candidemia, 26 patients died. In 19 cases, death was attributable to candidemia. The case-control study demonstrated, at univariate analysis, that the colonization with Candida. spp. (p=0.004), antimycotic prophylaxis (p=0.01), presence of central venous catheter (p=0.01), neutropenia (p=0.002), and the use of glycopeptide (p=0.0001) increased the risk of candidemia. Using multivariate regression analysis only colonization with Candida spp. and the previous therapy with glycopeptide were associated with a significantly increased risk. Acute mortality, expressed by a cumulative probability of survival at 30 d from diagnosis of candidemia, was 0.67 (95% C.I. 0.55-0.77) and was significantly reduced in patients with neutrophils <1 x 10(9)/l when compared to those with neutrophils >1 x 10(9)/l (p at Mantel-Cox=0.029). Overall cumulative probability of survival at 1 yr was 0.38 (95% C.I. 0.27-0.49) and only the treatment with Amfotericin B significantly reduced the risk of death.

Topics: Adolescent; Adult; Aged; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Candidiasis; Case-Control Studies; Catheterization, Central Venous; Female; Fungemia; Glycopeptides; Hematologic Neoplasms; Humans; Life Tables; Male; Middle Aged; Neutropenia; Parenteral Nutrition, Total; Proportional Hazards Models; Regression Analysis; Retrospective Studies; Risk Factors; Superinfection; Survival Analysis; Survival Rate; Treatment Outcome

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Candidiasis; Drug Carriers; Fluconazole; Humans; Liposomes; Mycoses; Neutropenia

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Drug Carriers; Drug Costs; Fever; Humans; Liposomes; Mycoses; Neutropenia

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Drug Carriers; Drug Costs; Fever; Humans; Liposomes; Mycoses; Neutropenia

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Drug Carriers; Fever; Humans; Liposomes; Middle Aged; Neutropenia; Research Design

Forty-five cases of fungaemia due non-albicans Candida spp. (NAC) in a single National Cancer Institution within 10 years were analysed for aetiology, risk factors and outcome. There had been 12 cases of fungaemia that were due to C. krusei, 14 due to C. parapsilosis, 7 due to C. (T.) glabrata, 6 to C. tropicalis, 2 to C. guillermondii, 2 to C. lusitaniae, 1 to C. stellatoidea, and 1 to C. rugosa. Comparison of 45 NAC fungaemia with 75 episodes of C. albicans fungaemia revealed differences only in two risk factors: previous empiric therapy with amphotericin B (16.0 vs 2.2%, P<0.01) appeared more frequently in cases of C. albicans fungaemia, and prior prophylaxis with fluconazole (8.9 vs 0%, P<0.02) was conversely more frequently observed with NAC. The incidence of other risk factors, such as underlying disease, chemotherapy, antibiotic prophylaxis or therapy, treatment with corticosteroids, catheter insertion, mucositis, cytotoxic chemotherapy, and neutropenia, was similar in both groups. There was no difference either in attributable or in overall mortality between NAC and C. albicans fungaemia in our cancer patients.

Topics: Adrenal Cortex Hormones; Amphotericin B; Anti-Bacterial Agents; Antibiotic Prophylaxis; Antifungal Agents; Antineoplastic Agents; Candida; Candida albicans; Candidiasis; Catheterization; Chi-Square Distribution; Cross Infection; Fluconazole; Fungemia; Humans; Incidence; Neoplasms; Neutropenia; Outcome Assessment, Health Care; Prospective Studies; Risk Factors; Slovakia

Using an isolate of Aspergillus fumigatus that is less susceptible in vivo to amphotericin B than most other isolates, we compared different doses of liposomal nystatin (L-nystatin), liposomal amphotericin B (L-amphotericin), and amphotericin B lipid complex (ABLC) with amphotericin B deoxycholate. Four experiments with intravenously infected neutropenic mice were conducted. A dose of L-nystatin at 10 mg/kg of body weight was toxic (the mice had fits or respiratory arrest). The optimal dosage of L-nystatin was 5 mg/kg daily on days 1, 2, 4, and 7 (90% survival). This was superior to L-amphotericin (5 mg/kg [P = 0.24] and 1 mg/kg [P < 0.0001]), ABLC (5 mg/kg [P = 0.014] and 1 mg/kg [P < 0.0001]), and amphotericin B deoxycholate (5 mg/kg [P = 0.008]). In terms of liver and kidney cultures, L-nystatin (5 mg/kg) was superior to all other regimens (P = 0.0032 and <0.0001, respectively). Higher doses of L-amphotericin (25 and 50 mg/kg) in one earlier experiment were more effective (100% survival) than 1 mg of L-amphotericin per kg and amphotericin deoxycholate (5 mg/kg) in terms of mortality and both liver and kidney culture results and to L-amphotericin (5 mg/kg) in terms of liver and kidney culture results only. ABLC (25 mg/kg) given daily for 7 days was superior to ABLC (50 mg/kg [P = 0.03]) but not to ABLC at 5 mg/kg or amphotericin B deoxycholate in terms of mortality, although it was in terms of liver and kidney culture results. No dose-response for amphotericin B (5 and 1 mg/kg) was demonstrable. In conclusion, in this stringent model, high doses of L-amphotericin and ABLC could overcome reduced susceptibility to amphotericin B deoxycholate, but all were inferior to 5- to 10-fold lower doses of L-nystatin.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Colony Count, Microbial; Cyclophosphamide; Deoxycholic Acid; Drug Carriers; Drug Combinations; Drug Resistance, Microbial; Immunosuppressive Agents; Liposomes; Mice; Neutropenia; Nystatin

Meta-analyses may become biased if the reported data in the individual trials are biased and if overlap among trials cannot be identified. We describe the unanticipated problems we encountered in collecting data for a meta-analysis comparing a new antifungal agent, fluconazole, with amphotericin B in patients with cancer complicated by neutropenia. In 3 large trials that comprised 43% of the patients identified for the meta-analysis, results for amphotericin B were combined with results for nystatin in a "polyene" group. Because nystatin is recognized as an ineffective drug in these circumstances, this approach creates a bias in favor of fluconazole. Furthermore, 79% of the patients were randomized to receive oral amphotericin B, which is poorly absorbed and not an established treatment, in contrast to intravenous amphotericin B, which was administered in 4 of 5 placebo-controlled trials, or 86% of patients. It was unclear whether there was overlap among the "polyene" trials, and it is possible that results from single-center trials were included in multicenter trial reports. We were unable to obtain information to clarify these issues from the trial authors or the manufacturer of fluconazole. Two of 11 responding authors replied that the data were with the drug manufacturer and two indicated that they did not have access to their data because of change of affiliation. In the meta-analyses, fluconazole and amphotericin B (mostly given orally) had similar effects (13 trials), whereas nystatin was no better than placebo (3 trials). Since individual trials are rarely conclusive, investigators, institutions, and pharmaceutical companies should provide essential details about their work to ensure that meta-analyses can accurately reflect the studies conducted and that patients will realize maximum benefits from treatments. We recommend that investigators keep copies of their trial data to help facilitate accurate and unbiased meta-analyses.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Meta-Analysis as Topic; Mycoses; Neoplasms; Neutropenia; Nystatin; Opportunistic Infections; Publication Bias; Randomized Controlled Trials as Topic; Research Design

Topics: Amphotericin B; Antifungal Agents; Child; Cytarabine; Female; Fusarium; Hematologic Neoplasms; Humans; Mycoses; Neutropenia; Opportunistic Infections

Topics: Amphotericin B; Anti-Bacterial Agents; Colloids; Fever; Humans; Neutropenia

Topics: Amphotericin B; Anti-Bacterial Agents; Humans; Neutropenia

The impact of intranasal amphotericin B and high-efficiency particulate air (HEPA) filtration on the incidence of invasive aspergillosis was reviewed in patients from 1977 to 1994 undergoing intensive chemotherapy. Overall, the incidence of proven invasive aspergillosis was reduced from 24.4% (1977-1984) to 7.1% (1985-1991) (P < 0.001) following the introduction of intranasal prophylaxis, but when probable cases of aspergillosis were included and lymphoma cases excluded, there was no change in incidence. Following the introduction of HEPA filtration, patient exposure to aspergillus spores as measured by air sampling was markedly reduced and there were no new cases of invasive aspergillosis. HEPA filtration proved effective in reducing invasive aspergillosis and has allowed increasingly aggressive treatment regimens to be introduced.

Topics: Administration, Intranasal; Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Combined Modality Therapy; Environment, Controlled; Female; Filtration; Hematologic Neoplasms; Hospital Units; Humans; Male; Neutropenia; Treatment Outcome

LY303366 is a novel antifungal echinocandin with excellent in vitro activity against Aspergillus spp. We compared four doses (1, 2.5, 10, and 25 mg/kg of body weight) of LY303366 with amphotericin B (0.5 to 5 mg/kg) in a temporarily neutropenic murine model of invasive aspergillosis against an amphotericin B-susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus fumigatus isolate based on in vivo response. Mice were immunosuppressed with cyclophosphamide (200 mg/kg) and infected 3 days later. Treatment started 18 h after infection and lasted for 10 days. LY303366 was given once daily intravenously for 10 days, and amphotericin B (at 0.5, 2, and 5 mg/kg) was given once daily intraperitoneally for 10 days, or only on days 1, 2, 4, and 7 (at 5 mg/kg). Kidneys and lungs from survivors were cultured on day 11. Control mice in both experiments had 90 to 100% mortality. Amphotericin B at 0.5 mg/kg and LY303366 at 1 mg/kg yielded 10 to 20% survival rates for mice infected with either AF210 or AF65. Amphotericin B at 2 and 5 (both regimens) mg/kg yielded a 70 to 100% survival rate for mice infected with AF210 but a 10 to 30% survival rate for mice infected with AF65 (P = 0.01 to 0.04 compared with AF210). Against AF210 and AF65, LY303366 at 2.5, 10, and 25 mg/kg produced a survival rate of 70 to 80%, which was as effective as amphotericin B for AF210, but superior to amphotericin B for AF65 (P < 0.03 to 0.0006). For AF65, LY303366 at 10 and 25 mg/kg/day was superior to amphotericin B at 2 and 5 mg/kg/day in reducing tissue colony counts (P = 0.01 to 0.003), and for AF210, amphotericin B at 5 mg/kg/day and at 5 mg/kg in four doses was more effective than all four regimens of LY303366 in reducing renal culture counts (P = 0.01 to 0.0001). The present study shows, for the first time, that in vivo resistance of A. fumigatus to amphotericin B exists, although this could not be detected by in vitro susceptibility assays. Furthermore, LY303366 appears to be effective against amphotericin B-susceptible and -resistant A. fumigatus infection in this model and should be further evaluated clinically.

Topics: Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Colony Count, Microbial; Cyclophosphamide; Drug Resistance, Microbial; Echinocandins; Immunocompromised Host; Immunosuppressive Agents; Male; Mice; Microbial Sensitivity Tests; Neutropenia; Peptides, Cyclic

We report the first case of invasive disease caused by Fusarium chlamydosporum. The patient had aplastic anemia with prolonged neutropenia and was treated with immunosuppressive therapy. While she was receiving empirical amphotericin B, a dark crusted lesion developed on her nasal turbinate. Histologic analysis revealed invasive hyaline hyphae and some darkly pigmented structures that resembled conidia of dematiaceous molds. Only after the mold was grown in culture were characteristic colonial morphology, phialides, conidia, and chlamydospores evident, thus permitting the identification of F. chlamydosporum. This case illustrates the ever-increasing spectrum of pathogenic Fusarium spp. in immunocompromised patients and emphasizes the potential pitfalls in histologic diagnosis, which may have important treatment implications.

Topics: Adult; Amphotericin B; Anemia, Aplastic; Female; Fusarium; Humans; Immunocompromised Host; Mycoses; Neutropenia; Nose

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.

Topics: Adult; Amphotericin B; Antifungal Agents; Drug Carriers; Female; Humans; Liposomes; Male; Middle Aged; Neutropenia

LY303366 is a novel semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1,3)-beta-D-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In rabbits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured by the number of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. Rabbits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparable therapeutic efficacies by all parameters with the exception of reduction in tissue burden of A. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels above the MIC for 18 h, and dosages of >/=5 mg/kg maintained plasma drug levels above the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated rabbits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic rabbits.

Topics: Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Dose-Response Relationship, Drug; Echinocandins; Female; Lung Diseases, Fungal; Neutropenia; Peptides, Cyclic; Rabbits

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Drug Carriers; Humans; Liposomes; Neutropenia; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome

Patients with hematology disease in post-chemotherapy medullary aplasia are susceptible to life-threatening bronchopulmonary mycoses, especially aspergillosis. Other less common pulmonary mycoses are also observed. We report 4 cases due to Penicillium purpurogenum, Acromonium strictum and Scedosporium apiospermum (n = 2) infections. These unusual fungi appear to be emerging as pathogens in this population. They have common ubiquitous, opportunistic and low pathogenicity characteristics in immunocompetent subjects. The major risk factor is neutropenia. Isolating one of these fungi in an immunodepressed patient modifies management protocols since certain unusual fungi such as Scedosporium are resistant to amphotericin B.

Topics: Acremonium; Adolescent; Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Bone Marrow Transplantation; Female; Hematologic Neoplasms; Humans; Imidazoles; Leukemia, Myeloid, Acute; Lung; Lung Diseases, Fungal; Male; Middle Aged; Multiple Myeloma; Neutropenia; Penicillium; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pseudallescheria; Pyrimidines; Risk Factors; Triazoles; Voriconazole

Sixty four episodes of bacteraemia that appeared during antimicrobial prophylaxis with an oral quinolone plus an azole in neutropenic cancer patients were compared with 128 cases of bacteraemia in a cohort of controls matched for age, sex, underlying disease, neutropenia and vascular catheter in situ to assess differences in aetiology, cost of therapy and outcome. Patients who received prophylaxis had breakthrough bacteraemias of a different aetiology compared with the control group: they had significantly fewer multiply-resistant strains (21.9 vs. 51.5, P < 0.04) and a longer afebrile neutropenic period (9.55 days vs. 4.1, P < 0.001). Patients who received prophylaxis also had bacteraemias that were significantly more frequently caused by viridans streptococci (9.4%, vs. 1.7%, P < 0.01), enterococci (15.6% vs. 7.2%, P < 0.05) and Stenotrophomonas maltophilia (17.2% vs. 3.4%, P < 0.01). The cost of antimicrobial therapy per case (37401 SKK (1091 USD) vs. 31808 SKK (899 USD), P < 0.05) was also significantly higher in cases than controls; however, the number of administered antibiotics (4.18 vs. 3.21 per case, P = NS) was similar in both groups. There were no differences in outcome between both groups. However patients who received prophylaxis had significantly longer periods of afebrile neutropenia (9.55 days vs. 4.1, P < 0.001) and bacteraemia developed later than in controls. Also, the incidence of polymicrobial bacteraemia caused by multiresistant strains was lower among cases (21.9 vs. 51.5, P < 0.04).

Topics: Amikacin; Amphotericin B; Antibiotic Prophylaxis; Bacteremia; Bacterial Infections; Case-Control Studies; Catheters, Indwelling; Ceftazidime; Drug Therapy, Combination; Enterococcus; Female; Fluconazole; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Male; Neoplasms; Neutropenia; Ofloxacin; Retrospective Studies; Streptococcal Infections; Treatment Outcome; Vancomycin; Xanthomonas

Primary invasive aspergillosis of the oral cavity is a rare but serious complication in immunocompromised patients. We report a case of gingival Aspergillus infection in a neutropenic patient with acute myelogenous leukemia, who was successfully treated by an early surgical approach in combination with antifungal medication and granulocyte colon stimulating factors.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Female; Fluconazole; Flucytosine; Gingival Diseases; Granulocyte Colony-Stimulating Factor; Humans; Immunocompromised Host; Itraconazole; Leukemia, Myeloid, Acute; Neutropenia

Amphotericin B can cause significant toxicity but this can be reduced by direct dilution into a fat emulsion (Intralipid). To investigate the potential use of amphotericin B diluted in Intralipid, a study was made of its activity in the treatment of subacute disseminated candidiasis in persistently granulocytopenic rabbits, compared with the same dose of amphotericin B diluted in dextrose. Amphotericin-B-fat emulsion was at least as effective as amphotericin-B-dextrose. Amphotericin-B-fat emulsion was significantly more effective than amphotericin-B-dextrose therapy in reducing candida colony counts in both kidney and liver tissues (P < 0.05). Furthermore, amphotericin-B-fat emulsion was found less toxic on the renal function than conventional amphotericin B (P < 0.05). From these experimental results, we conclude that amphotericin-B-fat emulsion (Intralipid) was at least as effective and less toxic than conventional amphotericin B.

Topics: Amphotericin B; Animals; Candidiasis; Creatinine; Fat Emulsions, Intravenous; Glucose; Kidney; Male; Neutropenia; Rabbits; Urea

A PCR assay was developed for the detection and identification of Candida and Aspergillus species. The design of the oligonucleotide primer pair as well as the species-specific probes used for species identification was derived from a comparison of the sequences of the 18S rRNA genes of various fungal pathogens. The primers targeted a consensus sequence for a variety of fungal pathogens. The assay was tested for sensitivity and specificity with 134 fungal and 85 nonfungal isolates. To assess clinical applicability, 601 blood samples from four defined groups were tested: group A (n = 35), controls; groups B to D (n = 86), patients with febrile neutropenia, without fungal colonization (group B; n = 29) and with fungal colonization (group C; n = 36); and patients with documented invasive fungal infection (IFI) (group D; n = 21). The assay detected and, by species-specific hybridization, identified most of the clinically relevant Candida and Aspergillus species at 1 CFU/ml of blood. Amplification was 100% sensitive for all molds and yeasts tested, with Histoplasma capsulatum being the only non-Aspergillus species hybridizing with the Aspergillus spp. probe. None of 35 group A patients and only 3 of 65 group B and C patients were PCR positive. The sensitivity of the assay for specimens from patients with IFI (21 patients in group D) was 100% if two specimens were tested. For specificity, 3 of 189 specimens from patients at risk but with negative cultures were positive by the assay, for a specificity of 98%. PCR preceded radiological signs by a median of 4 days (range, 4 to 7 days) for 12 of 17 patients with hepatosplenic candidiasis or pulmonary aspergillosis. For the 10 patients with IFI responding to antifungal therapy, PCR assays became persistently negative after 14 days of treatment, in contrast to the case for 11 patients, who remained PCR positive while not responding to antifungal therapy. Thus, the described PCR assay allows for the highly sensitive and specific detection and identification of fungal pathogens in vitro and in vivo. Preliminary data from the screening of a selected group of patients revealed some value in the early diagnosis and monitoring of antifungal therapy.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; DNA, Fungal; Fluconazole; Fungemia; Fungi; Humans; Molecular Sequence Data; Neutropenia; Oligonucleotide Probes; Polymerase Chain Reaction; RNA, Ribosomal, 18S; Sensitivity and Specificity

Although there are an increasing number of new antifungal agents available, the morbidity and mortality due to invasive mycoses remain high. The high rates of polyene toxicities and the development of azole resistance have raised the issue of using antifungal agents of these classes in combination, despite theoretical concerns regarding antagonism between such agents. This study was designed to evaluate the in vivo efficacy of combined therapy with amphotericin B and fluconazole against Candida albicans. Two distinct animal models were used in this study: a neutropenic-mouse model of hematogenously disseminated candidiasis and the infective-endocarditis rabbit model. Treatment efficacy was assessed by determining reductions in mortality as well as decreases in tissue fungal densities. In the neutropenic-mouse model, amphotericin B, as well as combination therapy, significantly prolonged survival compared to untreated controls (P < 10(-5) and P = 0.001, respectively). The fungal densities in the kidneys of neutropenic mice were significantly reduced with either amphotericin B monotherapy or amphotericin B-fluconazole combined therapy compared to those of controls (P < 10(-6)). Fluconazole monotherapy also reduced fungal densities in the kidneys; however, this decrease was not statistically significant (P = 0.17). In contrast, treatment with either fluconazole alone or combined with amphotericin B (but not amphotericin B monotherapy) significantly decreased fungal densities in the brain (P = 0.025). In the rabbit endocarditis model, amphotericin B monotherapy or combined therapy significantly decreased fungal densities in cardiac vegetations (P < 0.01 versus the controls). Although no significant antagonism was seen when fluconazole was given in combination with amphotericin B, combination therapy did not augment the antifungal activity of amphotericin B.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Endocarditis; Female; Fluconazole; Male; Mice; Mice, Inbred BALB C; Neutropenia; Rabbits

Topics: Amphotericin B; Antifungal Agents; Humans; Neoplasms; Neutropenia

The purpose of this study was to examine the activity of liposomal nystatin against a disseminated Aspergillus fumigatus infection in neutropenic mice. Mice were made neutropenic with 5-fluorouracil and were administered the antifungal drug intravenously for 5 consecutive days beginning 24 h following infection. Liposomal nystatin, at doses as low as 2 mg/kg of body weight/day, protected neutropenic mice against Aspergillus-induced death in a statistically significant manner at the 50-day time point compared to either the no-treatment, the saline, or the empty-liposome group. This protection was approximately the same as that for free nystatin, a positive control. Histopathological results showed that liposomal nystatin cleared the lungs, spleen, pancreas, kidney, and liver of Aspergillus and that there was no organ damage at the day 5 time point, which was after only three doses of liposomal nystatin. Based on these results in mice, it is probable that liposomal nystatin will be effective against Aspergillus infection in humans.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Drug Carriers; Liposomes; Male; Mice; Mice, Inbred Strains; Microbial Sensitivity Tests; Neutropenia; Nystatin; Organ Culture Techniques

Aspergillus sinusitis is usually a lethal condition in bone marrow transplanted patients. We report the case of a patient known to have a sinus infection with Aspergillus flavus before treatment with allogenic bone marrow transplantation for a refractory acute myelogenous leukemia. Exacerbation of the sinusitis during the neutropenic period required a multidisciplinary approach. Cure was achieved after treatment with a combination of surgery (Caldwell-Luc procedure), long term ABCD (amphotericin B colloidal dispersion) therapy (7 months) and granulocyte transfusions during the period preceding engraftment. The use of granulocyte transfusion in this salvage setting is discussed. Aggressive multimodality management of aspergillus sinusitis in immunosuppressed patients may lead to a cure and might not preclude allogenic transplantation.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Female; Granulocytes; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Leukocyte Transfusion; Neutropenia; Sinusitis

Phialophora is a dematiaceous fungus isolated from soil and wood. Human infections including chromoblastomycosis, mycotic keratitis, cutaneous infections, and prosthetic valve endocarditis have been reported. We report a case of fatal hemorrhage due to Phialophora verrucosa in a patient with prolonged neutropenia undergoing autologous bone marrow transplant (BMT) for acute myelogenous leukemia (AML). Bacterial infections complicated induction and consolidation chemotherapies. Liposomal amphotericin B (LAMB) was given from day +33 to day +72 for febrile neutropenia. Death occurred on day +74 due to tracheal hemorrhage. Autopsy revealed granulation tissue on the posterior wall of the trachea with fungal hyphae on histopathology; the tissue grew Phialophora verrucosa. In vitro susceptibility studies revealed a minimum inhibitory concentration to AmB of 0.1 microg/ml. This represents the first reported case of invasive P. verrucosa in a BMT patient leading to fatal hemorrhage, despite large cumulative doses of LAMB to which the organism remained susceptible.

Topics: Adult; Amphotericin B; Antifungal Agents; Antiprotozoal Agents; Bone Marrow Transplantation; Female; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Liposomes; Mycoses; Neutropenia; Phialophora; Trachea

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Anti-Infective Agents; Humans; Infections; Lymphoma, AIDS-Related; Male; Neutropenia; Prototheca; Skin Diseases, Infectious

Invasive fungal infections occur frequently in neutropenic patients although only in recent years has the role of emerging fungi been clearly established. We describe two cases of fungemia caused by Trichosporon beigelii and Rhodotorula glutinis respectively in two neutropenic patients with hematological malignancies who were treated with amphotericin B. The first patient, with refractory multiple myeloma, died following massive pneumonia despite therapy with amphotericin B and granulocyte-colony stimulating factor (G-CSF); the second patient, with relapsed acute lymphatic leukemia and persistent fever without any other clinical evidence, finally recovered. Amphotericin B continues to be considered the "gold standard" in the treatment of invasive mycoses although other approaches need to be tested for refractory infections.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Female; Fungemia; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neutropenia; Pneumonia, Bacterial; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pseudomonas Infections; Rhodotorula; Treatment Outcome; Trichosporon

To evaluate the effect of total bowel decontamination (TD) and selective bowel decontamination (SD) in a non-protective environment clinical and laboratory data of children treated for acute leukaemia between 1983 and 1991 were analysed retrospectively. From 1983 until 1989 34 patients [18 acute non-lymphoblastic leukaemia (ANLL) patients, 16 acute lymphoblastic leukaemia (ALL) patients] received TD and 31 patients (8 ANLL patients, 23 ALL patients) received SD from 1987 until 1991. TD consisted of colistin sulphate, neomycin, cephaloridine and amphotericin B orally as well as Orabase and sterilized food, while the patients were nursed in a single room. SD consisted of oral colistin sulphate, neomycin and amphotericin B. Those patients with ANLL were nursed in a single room; patients with ALL were nursed in a single room during remission induction therapy only. All patients except those with ANLL receiving TD received Pneumocystis carinii pneumonia prophylaxis with cotrimoxazole. Because the two groups were heterogeneous for diagnosis and chemotherapy the occurrence of fever (central body temperature at least 38.5 degrees C) and major infections (septicaemia of infections of the deep tissues or organs) were registered during periods of neutropenia (neutrophilic granulocytes < or = 500/mm3 for at least 8 days). Patients on TD had 55 periods of neutropenia, patients on SD 80. Patients on TD had 89.1 periods of fever/100 periods of neutropenia whereas patients on SD had 56.3. Also patients on TD had 27.3 major infections/100 periods of neutropenia whereas patients on SD had 11.3. Major infections predominantly consisted of septicaemia caused by gram-positive bacteria. We conclude that, in this study, TD in a non-protective environment does not offer better protection against major infections that SD in patients with ALL or ANLL.

Topics: Adolescent; Amphotericin B; Anti-Bacterial Agents; Bacteremia; Bacterial Infections; Carboxymethylcellulose Sodium; Cephaloridine; Cephalosporins; Child; Child, Preschool; Colistin; Drug Therapy, Combination; Food Handling; Gram-Negative Bacterial Infections; Humans; Infant; Intestines; Leukemia, Myeloid, Acute; Neomycin; Neutropenia; Pneumonia, Pneumocystis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Sterilization; Trimethoprim, Sulfamethoxazole Drug Combination

When a diagnosis of invasive candidiasis has been made, treatment with toxic fungicidal agents is inevitable. The crucial decision of when to stop such treatment is difficult to make, because cultures are often negative despite ongoing invasive candidiasis and can therefore not be used as a reliable parameter of effective therapy. In the present study, the use of PCR in monitoring the therapeutic efficacy of antifungal treatment with liposomal amphotericin B was evaluated by using neutropenic mice with systemic candidiasis. Blood cultures of infected mice treated with different doses of liposomal amphotericin B were only positive at the early onset of the infection process and became sterile within 3 days; this was true even with mice treated with 1 mg of liposomal amphotericin B per kg of body weight that experienced a relapse of infection 14 days later. A significant correlation between presence of Candida albicans in the kidneys and PCR results obtained with blood was demonstrated. Thus, PCR results obtained with blood samples correlated well with the therapeutic efficacy of antifungal treatment.

Topics: Amphotericin B; Animals; Antifungal Agents; Base Sequence; Candida albicans; Candidiasis; DNA Primers; DNA, Fungal; Evaluation Studies as Topic; Female; Fungemia; Liposomes; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Mycology; Neutropenia; Polymerase Chain Reaction; Time Factors

The authors report three cases of fusarial infection in neutropenic patients with hematologic malignancies. The first patient was affected by a cutaneous extensive fusariosis. The second patient developed a fusarial lung infection during a multiple organ failure following allogenic bone marrow transplantation. The third patient who presented with refractory acute myelogenous leukemia, developed fusarial skin lesions, and died from pulmonary failure. The treatment of fusarial infection is disappointing and requires amphotericin B, in association with hematopoietic growth factors. The role of new agents, or combination chemotherapy remains to be determinated. The recovery of adequate neutrophil levels is the most important factor in the resolution of fusarial infection.

Topics: Adult; Amphotericin B; Antifungal Agents; Dermatomycoses; Female; Fusarium; Humans; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia

This paper reports a simultaneous pulmonary infection due to Aspergillus fumigatus and Rhizomucor pusillus which evolved to disseminated aspergillosis and mucormycosis in a leukaemic and neutropenic 40-year-old woman. Both fungi were cultured ante mortem from bronchial secretion. Although high doses of intravenous amphotericin B were administered, the course of the infection was fatal. At autopsy, aspergilli were demonstrated by histology in lungs and brain, and zygomycetes were found to have invaded liver and kidneys.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Autopsy; Candida; Fatal Outcome; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mucorales; Mucormycosis; Neutropenia

We report a case of Fusarium solani infection in a 2 1/2-year-old girl with acute lymphoblastic leukemia and severe neutropenia. The infection, initially limited to her sinuses, became disseminated, as evidenced by the development of a characteristic cutaneous lesion on her left leg after a cumulative dose of amphotericin B of 18.3 mg/kg. Amphotericin B lipid complex (ABLC), 5 mg/kg/day, in conjunction with repeated surgical debridement of the sinuses and correction of neutropenia with granulocyte colony stimulating factor (GCSF), led to clinical and mycologic cure.

Topics: Amphotericin B; Antifungal Agents; Child, Preschool; Dermatomycoses; Drug Combinations; Drug Resistance, Microbial; Female; Fusarium; Humans; Immunocompromised Host; Mycoses; Neutropenia; Paranasal Sinus Diseases; Phosphatidylcholines; Phosphatidylglycerols; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Cutaneous mucor infection developed in two children who had undergone bone marrow transplantation for treatment of leukemia. One infection occurred before transplantation, and the other occurred during the period of profound neutropenia after transplantation. Both children were treated with an extensive wide excision of the infected area, and there was no evidence of mucor along the resected edges of tissue. Both patients received extensive treatment with either amphotericin (case 1) or amphotericin and itraconazole (case 2). These two cases represent aggressive management of cutaneous mucor infections, which is believed to be required for the successful completion of a marrow transplantation procedure.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Child; Dermatomycoses; Female; Humans; Itraconazole; Leukemia, Myeloid, Acute; Male; Mucormycosis; Neutropenia; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rhizopus

Blastoschizomyces capitatus (Trichosporon capitatum) is an uncommon fungal pathogen. Infections have mostly been seen in immunocompromised patients and use of broad spectrum antibiotics was identified as a risk factor. Treatment has been extremely difficult. A report is presented about a case of fatal B. capitatum infection with clinical septicemia and multiorgan failure during intravenous liposomal amphotericin B therapy.

Topics: Adult; Amphotericin B; Drug Carriers; Fatal Outcome; Humans; Leukemia, Lymphoid; Liposomes; Male; Mycoses; Neutropenia; Treatment Failure; Trichosporon

We undertook a retrospective review of all patients with hematologic malignancies in whom candidemia developed during chemotherapy-induced neutropenia in 1989 and 1990. Candidemia developed in 11 patients; five were receiving therapeutic doses of amphotericin B at the time of infection. Disseminated infection occurred in 2 of 5 patients with breakthrough infection and 3 of 6 patients with candidemia before receipt of amphotericin B. Among patients with breakthrough candidemia there was a trend toward more-prolonged neutropenia prior to infection (P = .069), but otherwise they were indistinguishable from other candidemic patients with regard to risk factors for candidemia. Amphotericin B-susceptible Candida albicans was isolated from two patients and Candida krusei from three patients with breakthrough infection. All patients were treated with amphotericin B; all breakthrough infections responded to treatment. Neutropenic patients with breakthrough candidemia were clinically similar to those whose candidemia preceded amphotericin B therapy, and there was no increase in morbidity and mortality among individuals with breakthrough infection.

Topics: Acute Disease; Adult; Aged; Amphotericin B; Candida; Candida albicans; Candidiasis; Fatal Outcome; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Treatment Failure

Topics: Adult; Amphotericin B; Antifungal Agents; Fusarium; Humans; Immunocompromised Host; Leukemia, Myelomonocytic, Acute; Male; Mycoses; Neutropenia; Onychomycosis

We describe five patients with acute leukemia who during the period of chemotherapy-induced neutropenia developed invasive pulmonary aspergillosis. Amphotericin B was initiated early in the febrile neutropenic episode at a dose of 1-1.5 mg/kg per day. Four of the five patients had normal chest films at the time amphotericin B was started and only later developed infiltrates, which subsequently progressed to cavitation formation with resolution of the infiltrates around the cavitations. This is compatible with primary aspergilloma or invasive pulmonary aspergillosis. The patients experienced partial (2 patients) or complete resolution (3 patients) of the process, and none died of the fungal infection. In the past, infection with invasive aspergillosis carried a high mortality. We believe that this positive outcome constitutes a change in the natural history of invasive pulmonary aspergillosis in neutropenic patients as a result of the early initiation of high dose amphotericin B. We recommend the early empiric use of amphotericin B therapy in febrile neutropenic patients not responding to broad-spectrum antibiotics, and that the minimal initial dose be 1 mg/kg per day especially in institutions carrying a high incidence of aspergillosis.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Female; Humans; Leukemia, Myeloid, Acute; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

A 52-year-old male diagnosed with acute myeloid leukemia (AML) developed an invasive middle-ear mucormycosis during the neutropenic period after consolidation chemotherapy which resolved successfully with surgery and antifungal therapy. The patient underwent autologous peripheral blood stem cell transplantation (APBSCT) in first complete remission with antifungal prophylaxis with liposomal amphotericin B (AmB). There was no clinical, radiological or microbiological data of mycotic reactivation. This is the first reported stem cell transplantation (SCT) in a patient with prior invasive mucormycosis.

Topics: Acute Disease; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Facial Paralysis; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Leukemia, Myeloid; Male; Mastoid; Middle Aged; Mitoxantrone; Mucormycosis; Myringoplasty; Neutropenia; Otitis Media, Suppurative; Remission Induction; Transplantation Conditioning; Transplantation, Autologous

The aim of this study was to review the eight histopathologically proven cases of invasive fungal sinusitis that occurred at the Toronto Hospital for Sick Children between 1985 and 1995, seven of which that clustered between March 1990 and February 1992.. A retrospective review of the relevant cases and a review of the literature are presented.. A clinical review of this rare, life-threatening entity, occurring almost exclusively in severely neutropenic patients is presented and compared to the relevant clinical findings from an analysis of this series, the largest reported to date and first to document a significant clustering (p < .01).. We conclude, based on epidemiologic evidence, that this clustering was directly related to the release of airborne fungal spores from dormant soil reservoirs disturbed during hospital construction. Therefore, we strongly advocate increased vigilance with respect to precautions against airborne pathogens wherever severely neutropenic hosts are treated.

Topics: Adolescent; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillus; Child; Female; Humans; Leukemia, Myeloid, Acute; Male; Mucor; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Sinusitis; Wilms Tumor

The use of high-dose chemotherapy and the subsequent prolonged neutropenia in patients with haematological diseases have resulted in an increased incidence of fungal infections. These infections are associated with a high mortality rate. There are several predisposing factors including broad-spectrum antibiotic, central venous access. Diagnosis remains difficult. Characteristic clinical manifestations are not constant and they appear only after neutrophil recovery. Responsible organisms are infrequently isolated. The use of invasive procedures is far from being justified in patients who suffering usual severe thrombocytopenia. The unique drug with proven efficiency in the treatment of fungal infections is amphotericin B or liposomal amphotericin B. A favourable outcome strongly correlated with complete leukemia remission. We describe our findings in seven leukemic patients with fungal infections.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Child; Female; Humans; Immunocompromised Host; Leukemia; Lung Diseases, Fungal; Male; Middle Aged; Mycoses; Neutropenia; Retrospective Studies; Thrombocytopenia

A 35-year-old man from Central America with a history of AIDS and numerous opportunistic infections presented with progressive neutropenia and thrombocytopenia despite having been stable for a period of 6 months. Cessation of antiviral medications did not stop his neutropenia, nor did use of folinic acid, G-CSF, or erythropoietin. The failure of these measures required repeated blood transfusions. Although the physical examination was relatively unremarkable, hematology and blood chemistries indicated that the patient needed urgent hospitalization due to fever and neutropenia. Neutropenia within HIV infection can be confusing, since it may be a result of the infection itself, an adverse effect of drug therapy, or from an opportunistic infection or malignancy. If the cause is not evident, it is wise to seek the etiology first rather than immediately use bone marrow stimulants, such as G-CSF. In this case, an infectious disease specialist made a diagnosis of disseminated histoplasmosis, after which the patient was treated with amphotericin B and released on itraconazole maintenance therapy.

Topics: Acquired Immunodeficiency Syndrome; Adult; Amphotericin B; Antifungal Agents; Erythropoietin; Fever; Granulocyte Colony-Stimulating Factor; Histoplasmosis; Humans; Male; Mucous Membrane; Neutropenia

Topics: Amphotericin B; Dermatomycoses; Female; Fusarium; Humans; Leukemia, Myeloid, Acute; Liposomes; Middle Aged; Neutropenia

Topics: Aged; Amphotericin B; Anaphylaxis; Asthma; Candidiasis; Desensitization, Immunologic; Drug Resistance, Microbial; Emergency Medical Services; Female; Humans; Leukemia, Myeloid, Acute; Neutropenia

In neutropenic patients, one way of improving invasive pulmonary aspergillosis (IPA) prognosis is an earlier initiation of the antifungal treatment. We report our experience with 36 cases of IPA in 35 patients with haematological malignancies. When aspergillosis was diagnosed, all but 2 patients were neutropenic (PMN < 500; median duration = 20 days). The most frequent clinical signs were cough (100%), chest pain (78%) and haemoptysis (58%). Before the diagnosis of IPA, Aspergillus antibody test was positive in 60% of cases. A thoracic CT-scan was performed in 23 patients and demonstrated highly suggestive images in 22 cases (96%) with presence of CT halo sign (n = 13) or CT air-crescent sign (n = 9). Moreover, Aspergillus antigen test was positive in 13 of 28 tested patients. IPA diagnosis was determined to be definite in 23 cases and probable or possible in 13 cases. Thirty-five patients were treated: in 3 cases with amphotericin B (2 failures) and in 32 cases with itraconazole (7 failures and 25 successes or improvements). In 7 cases (including 5 emergencies) surgical resection was successfully combined with the medical treatment. In neutropenic patients with fever, we consider that thoracic CT-scan and repeated biological tests (Aspergillus antibody and antigen tests) can be used to establish the diagnosis of aspergillosis. Early treatment with itraconazole and surgical resection appears to improve prognosis.

Topics: Adult; Aged; Amphotericin B; Aspergillosis, Allergic Bronchopulmonary; Female; Humans; Itraconazole; Male; Middle Aged; Neutropenia; Prognosis; Radiography, Thoracic; Retrospective Studies; Time Factors; Tomography, X-Ray Computed

Herein we report the successful treatment of invasive aspergillosis with the liposomal amphotericin B (AMB) formulation, Amphotericin B Lipid Complex (ABLC). This investigational compound was employed in a 50-year-old patient with acute myelomonocytic leukemia complicated by prolonged, treatment-induced granulocytopenia and documented Aspergillus flavus sinusitis with signs of disseminated aspergillosis. The patient demonstrated radiographic signs of pulmonary aspergillosis and biochemical signs of hepatic involvement that were resistant to a 23 day course of conventional AMB (Fungizone) therapy. Following therapy with ABLC her fever abated, her chest X-ray findings improved, and her hepatic function tests improved with eventual resolution.

Topics: Adult; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Female; Humans; Leukemia, Myeloid, Acute; Liposomes; Lung Diseases, Fungal; Neutropenia; Time Factors

Pulmonary infiltrates in neutropenic hosts with invasive aspergillosis are due to vascular invasion and hemorrhagic infarction. In order to measure the effect of antifungal compounds on this organism-mediated tissue injury, we monitored the course of pulmonary infiltrates by serial ultrafast computerized tomography (UFCT) in persistently granulocytopenic rabbits with experimental invasive pulmonary aspergillosis. The course of pulmonary lesions measured by serial UFCT scans was compared with those measured by conventional chest radiography, histopathological resolution of lesions, and microbiological clearance of Aspergillus fumigatus. Treatment groups included either amphotericin B colloidal dispersion in dosages of 1, 5, and 10 mg/kg of body weight per day intravenously or conventional desoxycholate amphotericin B at 1 mg/kg/day intravenously. Therapeutic monitoring of pulmonary lesions by UFCT demonstrated a significant dose-response relationship. Lesions continued to progress in untreated controls, whereas lesions in treated rabbits initially increased and then decreased in response to antifungal therapy in a dosage-dependent manner (P < or = 0.05 to P < or = 0.005, depending upon the groups compared). This same trend of resolution of lesions in response to antifungal therapy was also demonstrated by postmortem examination and by microbiological clearance of the organism. These data indicated that amphotericin B colloidal dispersion at 5 and 10 mg/kg/day exerted a more rapid rate of clearance of lesions than conventional amphotericin B. UFCT was more sensitive than conventional chest radiography in detecting lesions due to invasive pulmonary aspergillosis (P < 0.05 to P < 0.005, depending upon the groups compared). These findings establish a correlation among UFCT-defined lesions, microbiological response, and resolution of pathologically defined lesions in experimental invasive pulmonary aspergillosis. Serial monitoring of UFCT-defined lesions of aspergillosis provides a novel system for determining the antifungal response of organism-mediated tissue injury.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Female; Immunosuppression Therapy; Liposomes; Lung; Neutropenia; Rabbits; Tomography, X-Ray Computed

A study was performed to assess the in vivo relevance of the in vitro antagonism between fluconazole and amphotericin B against Candida albicans. Combinations of fluconazole and amphotericin B were explored for their efficacies against acute (100% mortality in 2 to 5 days) or less acute (100% mortality in 30 days) invasive candidiasis infections in mice with healthy immune systems and immunocompromised mice. Treatment efficacy was assessed by protection from mortality and/or a reduction in the fungal burden in tissue. In models of acute infection in mice with healthy immune systems or less acute infection in immunocompromised mice, combinations of fluconazole and amphotericin B were superior to fluconazole alone, and the effects were at least additive. Combination therapy was at least as efficacious as amphotericin B alone. In a different model of less acute infection in mice with healthy immune systems, combinations of fluconazole and amphotericin B showed no interactions and were no better than either drug alone. We conclude that combination therapy with fluconazole and amphotericin B is not antagonistic in vivo, in contrast to published in vitro studies, and, consequently, suggest that combination therapy should be considered in the management of clinical candidiasis.

Topics: Amphotericin B; Animals; Candidiasis; Cyclophosphamide; Drug Combinations; Female; Fluconazole; Kidney; Male; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Neutropenia

Candida krusei is increasingly recognized as an opportunistic pathogen in immunocompromised patients and is inherently resistant to fluconazole. We tested the in vivo efficacy of SCH 51048, an investigational antifungal triazole, in experimental hematogenous murine infection caused by two C. krusei isolates and compared its activity with those of amphotericin B and fluconazole. CF1 mice were immunosuppressed with cyclophosphamide and cortisone acetate and were challenged intravenously with infecting inocula of each C. krusei isolate. Treatment with SCH 51048 (50 or 100 mg/kg of body weight per day orally) or amphotericin B (2 mg/kg/day intraperitoneally) significantly prolonged the survival of infected mice and significantly reduced fungal titers in the kidneys (P < or = 0.05). Treatment with fluconazole (100 mg/kg/day orally) had no effect. Both dosages of SCH 51048 were as effective as amphotericin B in improving survival, but the higher dosage was significantly (P < or = 0.05) better in reducing the fungal burden in the kidneys of infected animals. A dose-dependent response was observed with SCH 51048 treatment, especially in organ clearance. Our results indicate that SCH 51048 is the first triazole that has in vivo activity against experimental infection with C. krusei and deserves further evaluation.

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Fluconazole; Immunosuppression Therapy; Kidney; Male; Mice; Mice, Inbred Strains; Neutropenia; Triazoles

Mortality due to Invasive Pulmonary Aspergillosis (IPA) remains high in neutropenic patients due to pulmonary haemorrhage. The aim of this study was to evaluate the emergency surgical management of IPA. Seven neutropenic patients, with a mean age of 47 years (range: 30-64) (4 women and 3 men) were treated for (6 cases) acute leukaemia one Myeloma (1 case). Presumptive diagnosis of IPA was based on: Halo sign (n = 6) or air-crescent sign (n = 1) on CT scan, positive serology (n = 4), positive antigenemia (n = 3) and positive broncho-alveolar lavage (n = 1). In 2 cases, IPA diagnosis was only based on CT scan. In all cases, aspergillosis lesions were located near the left (n = 5) or right (n = 2) pulmonary artery. The type of pulmonary resection was: left superior lobectomy in 3 cases, left superior lobectomy and Fowler's segmentectomy in 1 case, Left inferior lobectomy in 1 case, right superior lobectomy in 1 case and middle lobectomy and paracardiac segmentectomy. Sleeve resection of the pulmonary artery was performed in two patients. There were no deaths or major postoperative complications. Mean hospital stay after surgery was 12 days (rang: 8-19). Histological examination confirmed the diagnosis of IPA. CT is essential to determine the optimal timing for surgery.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Combined Modality Therapy; Emergency Medicine; Female; Hemoptysis; Humans; Itraconazole; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Pneumonectomy; Preoperative Care

60 patients undergoing bone marrow or stem cell transplantation were treated with liposomal Amphotericin-B for documented or suspected mycosis. 34 patients had a prior course of conventional Amphotericin-B with the following adverse effects: increasing creatinine above 1.4 mg/dl (n = 17), increasing creatinine below 1.5 mg/dl (n = 9), no response (n = 6), and clinical side-effects (n = 4). Liposomal Amphotericin-B failed in 6/7 patients with culture-proven mycosis who died from infection with Aspergillus (n = 2) and Candida (n = 4), respectively. One patient with Candida lambica sepsis was cured. No patient with clinically or serologically suspected or diagnosed infection died from mycosis. Liposomal Amphotericin-B was well tolerated in 57 patients, even after side-effects of the conventional formulation. Adverse effects occurred in three cases, requiring the withdrawal of the drug in one patient. Due to toxic side-effects of the high-dose therapy and transplant-related complications, it was difficult to evaluate the influence of liposomal Amphotericin-B on laboratory parameters. Eight patients showed a decrease of creatinine levels, which had increased above normal values under preceding therapy with conventional Amphotericin-B. Liposomal Amphotericin-B is well tolerated in patients undergoing high-dose therapy and bone marrow transplantation. The efficacy of liposomal Amphotericin-B needs to be investigated in randomized studies in comparison with conventional Amphotericin-B.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lung Diseases, Fungal; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Treatment Outcome

Mucormycosis is a rare fungal infection that has been described mainly in oncologic and diabetic patients. We here report the cases of two leukaemic patients in whom pulmonary mucormycosis was diagnosed. Prompt diagnosis, therapy with amphotericin B and surgery when possible, are the cornerstones in the treatment of this fungal infection. Although infrequent, this infection must be suspected in oncohaematological patients with lung infiltrates.

Topics: Adult; Aged; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Factors; Itraconazole; Leukemia, Promyelocytic, Acute; Lung Diseases, Fungal; Male; Mercaptopurine; Methotrexate; Mitoxantrone; Mucormycosis; Neutropenia; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Amphotericin B; Drug Therapy, Combination; Female; Fusarium; Granulocyte Colony-Stimulating Factor; Humans; Infant; Mycoses; Neutropenia

The use of high dose chemotherapy in the treatment of solid tumors is associated with prolonged neutropenia and, consequently, in some patients, systemic candidiasis. The authors describe their experience with a clinicoradiologic syndrome developing after high dose chemotherapy was administered to patients with breast cancer.. The authors evaluated the clinical and radiologic records of 12 patients in whom hepatic, splenic, or renal candidiasis developed.. Three patients had positive blood cultures for candida tropicalis. One of these patients and two others had fungal organisms identified with special stains of an organ aspirate. Most patients were asymptomatic, and most of them were treated successfully with antifungal agents, although untreated patients also recovered. There were no fatalities due to the candidiasis.. A radiographic syndrome resembling hepatic, splenic, or renal candidiasis is described, which occurred after high dose chemotherapy was administered and autologous bone marrow transplantation was performed on patients with breast cancer. This syndrome has a favorable prognosis. Conclusions as to the more indolent nature of this syndrome cannot be made; however, this topic warrants further investigation.

Topics: Adult; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Breast Neoplasms; Candidiasis; Combined Modality Therapy; Female; Fluconazole; Fungemia; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Kidney Diseases; Liver Diseases; Middle Aged; Neutropenia; Retrospective Studies; Splenic Diseases; Syndrome; Tomography, X-Ray Computed; Transplantation, Autologous

Immunosuppressed CF1 mice were infected intravenously with two strains of Candida krusei and four strains of Candida lusitaniae (two of which were resistant to amphotericin B). Mice were treated with 1 or 2 mg of amphotericin B desoxycholate per kg of body weight per day or escalating doses of liposomal amphotericin B (8 to 30 mg/kg/day) or were left untreated. Higher doses of liposomal amphotericin B were as effective as standard dose of amphotericin B desoxycholate in prolonging survival but were significantly more effective in reducing the fungal burden in the kidneys of animals infected with both C. krusei strains and the C. lusitaniae strains that were susceptible to amphotericin B desoxycholate. This advantage of liposomal amphotericin B therapy could not be demonstrated in mice infected with the C. lusitaniae strains that were resistant to amphotericin B desoxycholate.

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Carriers; Drug Combinations; Immunosuppression Therapy; Liposomes; Male; Mice; Microbial Sensitivity Tests; Neutropenia; Random Allocation

Liposomal amphotericin B (AmBisome) was used for suspected or confirmed fungal infection complicating 133 neutropenic episodes in 116 patients not tolerating, or not responding to, conventional amphotericin. Adverse effects were infrequent and no significant renal impairment resulted. Acute reactions occurred in five patients, reversible hepatic dysfunction in 23, and hypernatraemia in 17. The putative mycosis resolved with AmBisome treatment in 81 episodes (61%) and progressed with fatal outcome in 25 (19%), but the diagnosis was equivocal in most, and in 27 episodes (20%) evidence indicating nonfungal pathogenesis emerged. Treatment efficacy is, however, evaluable in those with proven aspergillosis. 13/17 patients with confirmed invasive aspergillosis responded to AmBisome (77%), conventional amphotericin having failed in 11. Treatment was successfully discontinued when the neutrophil count was < 1 x 10(9)/l in eight responders (61%). In four further patients treated for suspected aspergillosis, disseminated infection was documented at post-mortem, but the true incidence is unknown. This analysis confirms that AmBisome is well tolerated and effective against invasive mycoses in neutropenic patients, and may salvage patients when conventional amphotericin proves excessively toxic or ineffective.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antineoplastic Agents; Aspergillosis; Candidiasis; Child; Drug Carriers; Female; Humans; Liposomes; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Opportunistic Infections; Retrospective Studies

Topics: Adult; Amphotericin B; Candidiasis; Fluconazole; Fungemia; Humans; Neutropenia

Mucor circinelloides form circinelloides has rarely been associated with human disease, even in immunocompromised patients. We report a case of cutaneous zygomycosis caused by M. circinelloides in a 23-year-old neutropenic woman receiving consolidation chemotherapy for acute myelogenous leukemia. The organism was exquisitely susceptible to amphotericin B. Despite the fact that the patient was profoundly neutropenic for an additional 3 weeks, the lesions began to resolve during therapy, and no surgical debridement was required.

Topics: Adult; Amphotericin B; Antineoplastic Agents; Dermatomycoses; Drug Resistance, Microbial; Female; Humans; Leukemia, Myeloid, Acute; Mucor; Mucormycosis; Neutropenia; Opportunistic Infections

The incidence of invasive fungal infections after bone marrow transplantation (BMT) was analyzed in 303 consecutive marrow graft recipients (allogeneic n = 271, autologous n = 27, syngeneic n = 5). All patients received inhalations with amphotericin B (10 mg twice daily) during neutropenia. The overall incidence of invasive fungal infections within the first 120 days after transplant was 3.6% (11/303; aspergillosis: 6; yeast infection: 5). Four of the 11 cases occurred early, and seven cases were observed after neutrophil recovery and discontinuation of amphotericin B inhalation treatment. Late infection was significantly associated with the development of acute graft-versus-host disease. Four of the 11 infections (early 2/4; late: 2/7) were observed in patients with a history of previous fungal infection. Other patient and treatment characteristics were not helpful in defining potential risk factors. In particular, the incidence of invasive fungal infections did not differ between patients with more or less strict reverse isolation measures. Occasional side effects such as initial mild cough and bad taste were rare, usually disappeared during continued administration, and were in no case the reason for discontinuation of treatment. These data suggest that aerosolized amphotericin B may be a useful, convenient, and efficient prophylactic antifungal regimen in BMT.

Topics: Administration, Inhalation; Adolescent; Adult; Aerosols; Amphotericin B; Bone Marrow Transplantation; Female; Humans; Incidence; Male; Middle Aged; Mycoses; Neutropenia; Survival Analysis

Three children who developed pulmonary aspergillosis while being treated for leukaemia or non-Hodgkin's lymphoma. Each child continued with intensive myelosuppressive chemotherapy regimens during the infection and each was successfully treated with antifungal prophylaxis based on itraconazole by mouth. Amphotericin B was also given during periods of severe neutropenia. No reactivation of the fungal infection was seen.

Topics: Amphotericin B; Antineoplastic Agents; Aspergillosis; Child, Preschool; Drug Therapy, Combination; Humans; Itraconazole; Lung; Lung Diseases, Fungal; Male; Neutropenia; Opportunistic Infections; Radiography

This is a retrospective study comparing the methods of preventing fungal infection in a total of 420 episodes of chemotherapy-induced neutropenia of more than 10 days' duration between 1986 and 1992 in 104 patients with acute leukemia and 62 patients who underwent bone marrow transplantation. The episodes were divided into five groups according to the prophylactic regimens (group 1, oral amphotericin B (OA) only; 2, OA and nebulization of amphotericin B (NA); 3, OA and NA with a laminar air flow system (LAF); 4, oral fluconazole (OF) and NA; 5, OF, NA, and LAF. The total numbers of neutropenic episodes were 115, 141, 95, 37, and 32, respectively. A total of 15 episode of invasive fungal infections were documented. Aspergillosis was seen on two occasions each in groups 1 and 2, while none was seen in the patients who were under the LAF system. Nebulization of amphotericin B did not have a significant preventive effect in this study and it needs to be evaluated further by a randomized study.

Topics: Acute Disease; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Aspergillosis; Bone Marrow Transplantation; Fluconazole; Humans; Leukemia; Middle Aged; Neutropenia; Retrospective Studies

The study objective was to identify prognostic factors associated with survival in patients treated for acute leukemias who developed invasive aspergillosis (IA) during induction therapy. This retrospective analysis involved 21 patients treated in two hematologic centers over a six-year period. All were treated in protective isolated rooms with high-dose amphotericin B as soon as fungal infection was suspected. Ten (45%) of the twenty-one patients died. There was no statistical difference between the patients who survived and those who died in relation to the mean time of onset of IA or the total and mean daily dose of amphotericin B. On the other hand a favourable outcome correlated strongly with complete leukemic remission (p < 0.0001): all but one of the patients with objective residual leukemia died of IA, whereas all those who achieved complete hematological remission survived. In conclusion, it seems that the main vital prognostic factor in these leukemic patients with IA was the achievement of complete remission. We were unable to control IA in 10 of 11 patients with refractory leukemia, regardless of neutropenic status, despite early administration of high-dose amphotericin B. All the patients who achieved complete remission were successfully treated with amphotericin B.

Topics: Acute Disease; Adolescent; Adult; Aged; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Humans; Leukemia; Lung Diseases, Fungal; Middle Aged; Neutropenia; Patient Isolation; Prognosis; Remission Induction; Retrospective Studies; Risk Factors; Survival Analysis; Treatment Outcome

Candida krusei is reported to cause serious infections in immunocompromised patients, particularly those receiving prophylaxis with antifungal azoles. Treatment of this infection can be very challenging. The efficacy of amphotericin B, liposomal amphotericin B (three dosages), fluconazole, and D0870 (a new experimental oral bis-triazole) was assessed in a CF1 mouse model of hematogenous C. krusei infection. Increased survival time and reduced kidney fungal burden were achieved with treatment with amphotericin B at 2 mg/kg/day and liposomal amphotericin B at 8 and 15 mg/kg/day. D0870 at 25 mg/kg/day increased survival time but had no effect on clearance from organs, while the survival and clearance from organs of mice treated with fluconazole at a dose of 100 mg/kg/day did not differ from those of untreated animals. These findings suggest that deoxycholate and liposome-encapsulated amphotericin B are active against disseminated C. krusei infection in neutropenic mice and confirm the in vitro and in vivo resistance of this species to fluconazole.

Topics: Amphotericin B; Animals; Candidiasis; Fluconazole; Hematopoiesis; Immunosuppression Therapy; Liposomes; Male; Mice; Neutropenia; Survival Analysis

Because the use of fluconazole prophylaxis had been associated with an increased rate of Candida krusei infections at The John Hopkins Oncology Center, early empiric amphotericin B plus flucytosine were given to febrile neutropenic patients colonized by C. krusei. By this practice, the proportion of fungemias attributable to C. krusei was low (12.5%) in patients receiving fluconazole over a 6-month interval. However, Torulopsis (Candida) glabrata assumed a much higher proportion of fungemias (75%) among patients receiving fluconazole. In vitro susceptibility testing combined with this clinical experience suggests that some T. glabrata isolates are not susceptible to fluconazole and can cause breakthrough infections in patients receiving fluconazole.

Topics: Amphotericin B; Bacterial Infections; Bone Marrow Transplantation; Candida; Candidiasis; Fluconazole; Flucytosine; Humans; Leukemia; Microbial Sensitivity Tests; Neutropenia

Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in patients with neutropenia. Two severe complications with poor outcome can be observed after apparently successful IPA medical treatment: severe hemoptysis and IPA relapse during subsequent cytotoxic treatments. Early surgical therapy has not been considered routinely in the management of localized IPA.. Six consecutive patients (four women, two men; median age, 52 years) with localized cavitating IPA diagnosed during chemotherapy-induced aplasia were treated with early surgical resection after hematologic recovery.. All patients received a lobectomy. Surgery was uneventful. This procedures allows patients to proceed with further intensive chemotherapy and/or bone marrow transplantation without IPA reactivation.. For selected patients, surgical resection of localized IPA with unique cavitating lesion, which prevents hemoptysis and IPA recurrence and allows for subsequent cytotoxic treatment, may be recommended.

Topics: Adult; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Female; Follow-Up Studies; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Pneumonectomy; Survival Rate; Time Factors

Efficacy of immunoglobulin G (IgG) bearing liposomal amphotericin B (LAMB-IgG), liposomal amphotericin B without IgG (LAMB) or free amphotericin B (fAMB/Fungizone) was investigated in the treatment of systemic candidiasis in a neutropenic mouse model. Treatment with a single dose (0.6 or 0.9 mg amphotericin B per kg body weight) of LAMB-IgG resulted in a significant increase in the survival rate of neutropenic mice infected with 3 x 10(5) cfu of Candida albicans compared to untreated controls, mice injected with IgG, or liposome alone. Survival was also better in neutropenic mice treated with LAMB-IgG than in neutropenic mice treated with the same dose of LAMB or fAMB. Moreover, 65% of all mice survived the infection after treatment with a single dose of 0.6 mg AMB of the LAMB-IgG formulation. Quantitative culture counts of organs showed that both fAMB and LAMB-IgG formulations even at a dose of 0.3 mg AMB/kg, cleared C. albicans from the spleens, livers, and lungs but not from the kidneys. However, a decreased number of C. albicans cells was recovered from the kidneys of mice that survived the infection. Results of the study suggest that LAMB-IgG is more effective than LAMB or fAMB in the therapy of disseminated candidiasis in neutropenic mice.

Topics: Amphotericin B; Animals; Candidiasis; Combined Modality Therapy; Drug Evaluation, Preclinical; Evaluation Studies as Topic; Female; Immunoglobulin G; Liposomes; Mice; Neutropenia; Opportunistic Infections

The incidence of candidal infections in patients with cancer is increasing, and drug-resistant fungi are being isolated more frequently. Diagnosis of hematogenously disseminated candidiasis remains difficult. Characteristic clinical presentations, such as endophthalmitis and chronic hematogenously disseminated candidiasis, are inconstant and may not develop until after neutrophil recovery. Blood cultures are insensitive for detecting candidemia. Growth of Candida species in even one blood culture is strongly suggestive of hematogenously disseminated candidiasis. Serological tests to diagnose this disease remain experimental. Whenever feasible, central venous catheters should be removed from patients with candidemia. Amphotericin B is the treatment of choice for acute and chronic hematogenously disseminated candidiasis. The roles of azoles and liposomal amphotericin B in treating these diseases are currently undefined. Prophylactic use of antifungal agents decreases the incidence of documented fungal infections in neutropenic patients but does not improve overall survival and may increase the likelihood of infections by resistant fungi.

Topics: Amphotericin B; Candidiasis; Fluconazole; Humans; Itraconazole; Ketoconazole; Neutropenia

Inhaled amphotericin was administered to 29 patients with prolonged neutropenia and toxicity was analyzed. Treatment consisted of 30 mg of amphotericin B administered by nebulizer once daily via either a hand-held nebulizer or face mask. The mean duration of treatment was 16 days. Toxicity was minimal and patient had significant toxic reaction to the inhaled medication. This study documents that nebulized amphotericin B has less than 10% incidence of severe toxicity with 95% confidence level. Guidelines for future trials and use are suggested.

Topics: Administration, Inhalation; Adult; Amphotericin B; Humans; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Pneumonia

The efficacy and tolerance of a new amphotericin B lipid emulsion (AmB-IL) in which amphotericin B was diluted in a lipid solution for parenteral nutrition (Intralipid) was assessed in fourteen episodes of candidaemia occurring in neutropenic patients. The strains isolated were Candida krusei (nine cases), Candida albicans (three cases), Candida parapsilosis (one case) and Candida lusitaniae (one case). An AmB-IL was administered at a mean dosage of 1.18 mg/kg/day (range 0.73-1.55) for 22 days (range 6-62). Flucytosine was added to AmB-IL in 12 patients (mean duration 10.6 days). Chills were noted in only 3/306 infusions of AmB-IL. A mild increase of serum creatinine level from 9.3 +/- 3 mg/L (baseline) to 10.9 +/- 3 mg/L (after completion of AmB-IL) and mild decrease of creatinine clearance from 83 +/- 28 mL/min to 56 +/- 21 mL/min were observed. These changes did not correlate with either daily or total dose of AmB-IL or length of therapy. Seven patients were cured and six improved (patients who subsequently died due to nonfungal cause) with AmB-IL. One patient died due to C. krusei pneumonia. In conclusion AmB-IL is a well-tolerated method of amphotericin B administration. It could facilitate the use of amphotericin B without impairing its efficacy for the treatment of candidaemia in neutropenic patients.

Topics: Adult; Aged; Amphotericin B; Candida; Candidiasis; Fat Emulsions, Intravenous; Female; Flucytosine; Humans; Infusions, Intravenous; Male; Middle Aged; Neutropenia; Species Specificity

A 13-year-old Moroccan boy in The Netherlands developed fever and a lesion resembling ecthyma gangrenosum on the abdomen during cytostatic drug treatment for a lymphoblastic B-cell lymphoma. Scytalidium dimidiatum was cultured from blood and the abdominal skin lesion. The patient was successfully treated with amphotericin B. The fungus Scytalidium dimidiatum is a fairly common plant pathogen in tropical and subtropical countries and is known to cause dermatomycoses in humans in these areas. This case demonstrates that it is necessary to be aware that immigrants from these areas can import their own fungal flora, some members of which may cause life-threatening disease in the case of patients with immune suppression.

Topics: Adolescent; Amikacin; Amphotericin B; Ceftazidime; Drug Therapy, Combination; Humans; Immunocompromised Host; Lymphoma, B-Cell; Male; Mitosporic Fungi; Morocco; Mycoses; Netherlands; Neutropenia; Vancomycin

Invasive Trichosporon capitatum infections are seldom reported. We present here five cases of septicemia. All patients had an acute myeloblastic leukemia and were severely neutropenic. They have also been treated before the onset of the fungal infection with broad-spectrum antibiotherapy and also with an oral azole antifungal agent. The role of this antifungal therapy in the development of T. capitatum infection is discussed. The prognosis of T. capitatum infections is severe. Eight of the 10 published cases had a fatal outcome and one of our patients died of the fungal infection in spite of the treatment.

Topics: Adult; Amphotericin B; Bone Marrow Transplantation; Female; Graft vs Host Disease; Humans; Immunocompromised Host; Leukemia, Myeloid; Male; Middle Aged; Mycoses; Neutropenia; Prognosis; Sepsis; Trichosporon

KW-2228, a mutationally modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), possesses some excellent properties such as high specific activity in stimulating granulocyte colony-formation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support such an application on human infectious diseases. In this paper, we examined combination effect of KW-2228 with various chemotherapeutic drugs in experimental infectious in mice. A combination effect of KW-2228 with ceftazidime (CAZ) was evaluated in a systemic infection with Pseudomonas aeruginosa in normal mice. Combination effects of KW-2228 with CAZ, astromicin and amphotericin B were also evaluated in experimental systemic infections caused by P. aeruginosa, Serratia marcescens and Candida albicans in immunosuppressed mice treated with cyclophosphamide. Synergistic effects were generally observed at KW-2228 doses from 1 to 5 micrograms per mouse with all combinations. We concluded that combination therapies of KW-2228 with various chemotherapeutic drugs in experimental infections in mice showed that it should be effective in normal and immunosuppressed host. These results of our laboratory studies suggest that KW-2228 in combination with antibiotics would be useful in the clinical treatment of microbial infections. Recently, clinical efficacy studies of KW-2228 have been initiated in Japan.

Topics: Aminoglycosides; Amphotericin B; Animals; Anti-Bacterial Agents; Candidiasis; Ceftazidime; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Male; Mice; Mice, Inbred Strains; Neutropenia; Pseudomonas Infections; Recombinant Proteins; Serratia Infections

There is insufficient in vivo data on the efficacy of new antifungal agents against invasive Candida tropicalis infection. Disseminated infection with Candida tropicalis in neutropenic mice was treated with cilofungin, fluconazole, or amphotericin B intraperitoneally, and compared to untreated controls. Early survival rates at the end of treatment (day 10) were similar for amphotericin B (97.5%) and fluconazole (100%), and superior to cilofungin (62.6%) which was better than no treatment (0%). Late survival rates (day 31) were highest for amphotericin B (95%), and significantly lower for cilofungin (48.7%) and fluconazole (43.9%), p = 0.0001. Rates of sterilization of the lung, liver, and spleen were high in survivors for all regimens (85.1-100%) but lower for the kidneys: fluconazole, 21.3%; amphotericin B, 39.3%; and cilofungin, 65.5%. Amphotericin B was the most effective agent in this study of disseminated Candida tropicalis (C. tropicalis) infection.

Topics: Amphotericin B; Animals; Candida; Candidiasis; Echinocandins; Female; Fluconazole; Injections, Intraperitoneal; Kidney; Liver; Lung; Mice; Neutropenia; Peptides, Cyclic; Spleen

We reviewed all 155 episodes of central venous catheter-associated fungemia among inpatients at the National Cancer Institute during a 10-year period. Candida species accounted for 98% of episodes. Fungemia was documented by culture of blood drawn through catheters in 50% of cases and by culture of both catheter-drawn and peripheral blood in 39%; mortality and the rate of dissemination were similar for these two groups. Four management strategies were used: catheter removal, antifungal therapy (with amphotericin B), both, or neither; indications for the use of both modes of treatment included fever, neutropenia, long-term indwelling catheterization, positive cultures of both catheter-drawn and peripheral blood, isolation of Candida tropicalis, and fungal isolation from two or more blood cultures. Disseminated fungal infection was documented in 82% of cases with these features but also in 35% of the less severe cases treated only with catheter removal. In addition, nine (82%) of 11 cases managed only with antifungal therapy had a negative outcome (either death from disseminated infection or the recurrence of fevers and/or fungemia), a finding suggesting that intravascular catheters should be removed in fungemia. Virtually all cases of catheter-associated fungemia in patients with cancer are clinically significant and require prompt therapy with amphotericin B.

Topics: Adolescent; Adult; Aged; Amphotericin B; Candidiasis; Catheterization, Central Venous; Catheters, Indwelling; Chemotherapy, Adjuvant; Child; Child, Preschool; Cross Infection; Female; Fungemia; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Retrospective Studies

We describe a case of proven invasive pulmonary aspergillosis in a neutropenic patient in whom disease progression occurred during treatment with conventional amphotericin B despite neutrophil recovery. Treatment with liposomal encapsulated amphotericin B resulted in clinical and radiological improvement and the clearance of aspergillus spores from the sputum.

Topics: Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Aspergillus flavus; Aspergillus fumigatus; Drug Carriers; Humans; Liposomes; Lung Diseases, Fungal; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neutropenia

Topics: Adult; Aged; Amphotericin B; Candidiasis; Fluconazole; Humans; In Vitro Techniques; Neutropenia

Topics: Adult; Amphotericin B; Candidiasis; Fluconazole; Humans; Male; Neutropenia

Fifty-three patients undergoing autologous bone marrow transplantation received antimicrobial prophylaxis with ciprofloxacin with or without erythromycin and low dose intravenous amphotericin B. Eight patients remained afebrile throughout the neutropenic period. All other patients had one or more febrile episodes. The median time to fever after the onset of neutropenia was 7 days. There were no gram-negative organisms isolated from blood cultures during any of these episodes whereas gram-positive organisms were isolated in 28. There was one death in this series associated with sepsis. The use of low-dose prophylactic parenteral amphotericin did not prevent the subsequent successful use of full dose amphotericin for antibiotic-resistant fever. Ciprofloxacin effectively prevents gram-negative sepsis. The addition of erythromycin does little to prevent gram-positive sepsis. The use of regimens with agents with activity against gram-positive organisms is appropriate initial treatment of all febrile neutropenic episodes.

Topics: Adolescent; Adult; Amphotericin B; Bacteremia; Bacterial Infections; Bone Marrow Transplantation; Ciprofloxacin; Drug Therapy, Combination; Erythromycin; Female; Humans; Male; Middle Aged; Mycoses; Neutropenia; Transplantation, Autologous; Vancomycin

The use of high-dose chemotherapy and the subsequent prolonged neutropenia in patients with haematological diseases has resulted in an increased incidence of fungal infections. The diagnosis and treatment of these infections in neutropenic patients pose major therapeutic problems. The only drug with proven efficacy in the treatment of deep-seated fungal infections, including invasive aspergillosis, is amphotericin B. Unfortunately, this drug has adverse side effects, most importantly dose-dependent nephrotoxicity; furthermore, some patients fail to show a response to amphotericin B. We have treated 20 patients undergoing myeloablative chemotherapy and/or bone marrow transplantation for haematological diseases with liposomal amphotericin (AmBisome) for proven or suspected aspergillosis. Eighteen patients had diffuse interstitial pneumonitis and two patients had suspected fungal liver abscesses. Five patients had mycologically proven fungal infection and of these, three patients (60%) showed a complete response to liposomal amphotericin. Eleven patients received liposomal amphotericin because of the failure of conventional amphotericin B to eradicate proven or suspected fungal infection. Five of these 11 patients (45%) showed a complete clinical response to liposomal amphotericin. Eight patients received liposomal amphotericin because of pre-existing renal impairment or nephrotoxicity caused by conventional amphotericin B. Four of these patients (50%) showed a response to liposomal amphotericin. Recovery from probable fungal infection in this group of patients occurred when there was complete remission of underlying disease and recovery of neutrophil counts, when they were concurrently treated with liposomal amphotericin.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antineoplastic Agents; Child; Drug Carriers; Female; Humans; Liposomes; Male; Middle Aged; Mycoses; Neutropenia

A case of disseminated Scedosporium inflatum infection occurring in a neutropenic patient with acute myeloblastic leukemia is reported. Scedosporium inflatum was isolated from skin lesions, blood, urine and vitreous cultures. Amphotericin B treatment was ineffective in avoiding hematogenous spread. At autopsy, hyphae and ovoid conidia with truncate bases consistent with the morphology of Scedosporium inflatum were found in the lungs, kidneys, myocardium, liver, thyroid, spleen, lymph nodes, brain and the left eye. This is the first report of disseminated Scedosporium inflatum infection and the first time this organism has been isolated from a patient in Europe.

Topics: Aged; Amphotericin B; Humans; Leukemia, Myeloid, Acute; Male; Mitosporic Fungi; Mycoses; Neutropenia; Spain

The efficacy of liposomal amphotericin B bearing anticandidal antibodies (LAMB-Ab) was investigated in the treatment of systemic candidiasis in a murine model made neutropenic by an intraperitoneal injection of cyclophosphamide. Treatment with a single dose (0.6 mg amphotericin B kg-1 body weight) of LAMB-Ab resulted in an improved survival of neutropenic mice infected with Candida albicans compared to neutropenic mice treated with identical doses of liposomal amphotericin B or free amphotericin B.

Topics: Amphotericin B; Animals; Antibodies, Fungal; Candida albicans; Candidiasis; Disease Models, Animal; Liposomes; Mice; Neutropenia

To retrospectively study the prophylaxis of invasive aspergillosis in neutropenic patients and to relate the frequency of this fungal disease to any causal or modifying factors that could be identified.. Between 1977 and 1988, 130 patients underwent 158 intensive treatment episodes to control acute leukemia, lymphoma, and aplastic anemia, and the frequency of complicating aspergillus infection was determined.. Proven invasive aspergillus infections occurred in 22 cases, 12 of which were fatal. Invasive aspergillosis was suspected in a further 16 cases and all these patients recovered with amphotericin B treatment. Colonization by Aspergillus in the absence of clinically significant infection was seen in 31 treatment episodes. Invasive aspergillosis involved mainly the upper and lower respiratory tract and skin. Control of the infection was closely related to the control of the underlying disease, with subsequent return of normal marrow function and resolution of neutropenia. The incidence of aspergillus infection has decreased dramatically since 1985, most probably due to the introduction of intranasal amphotericin B. This occurred despite the persistence of aspergillus spores in the hematology ward air during the 1986 to 1988 period.. Intranasal aerosolized amphotericin B may protect against invasive aspergillosis, even when neutropenic patients are cared for in conventional wards without HEPA filtration.

Topics: Administration, Intranasal; Adolescent; Adult; Aged; Air Microbiology; Amphotericin B; Aspergillosis; Child, Preschool; Environmental Monitoring; Female; Humans; Leukemia; Lung Diseases, Fungal; Male; Middle Aged; Nasal Mucosa; Neutropenia; Retrospective Studies

Topics: Adult; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Appendicitis; Appendix; Aspergillosis; Combined Modality Therapy; Cytarabine; Daunorubicin; Humans; Ileal Diseases; Iliac Vein; Intestinal Perforation; Ischemia; Leukemia, Myeloid, Acute; Male; Mitoxantrone; Neutropenia; Thrombosis

Fungal infections are increasingly being reported in patients with acute leukaemia on intensive induction chemotherapy protocols. The common fungi seen are candida, aspergillus and mucormycosis. We have seen 3 cases of mucormycosis over the last 4 years. All 3 patients had acute leukaemia-two had acute lymphoblastic and one acute myeloid leukaemia. All patients were in neutropenic phase after induction chemotherapy. Features suggestive of fungal infection were fever and development or progression of pulmonary infiltrates despite antibiotic therapy. Repeated body fluid cultures were negative in two patients. In the first patient, the diagnosis was confirmed after biopsy of a palatal mass; he was treated successfully with amphotericin-B. In two patients the diagnosis was confirmed at autopsy. A high degree of suspicion in febrile, neutropenic cancer patients on chemotherapy and early administration of amphotericin-B may improve the outcome. With dissemination, the prognosis is poor.

Topics: Adolescent; Adult; Amphotericin B; Female; Humans; Infusions, Intravenous; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Myeloid, Acute; Male; Middle Aged; Mucormycosis; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiography

A 46-year-old male was admitted to our hospital because of relapse of acute myeloblastic leukemia (M2). Remission was successfully reinduced after reinduction chemotherapy consisting of daunorubicin, cytosine arabinoside, etoposide and vincristine, but was complicated by neutropenia. After the therapy, the patient had persistent fever of about 38 degrees C despite broad-spectrum antibiotics therapy and the patient developed pain in the right quadrant of the abdomen. The white blood cell count rose to 23000/mm3. Liver function tests showed abnormal findings mainly consisting of an elevated serum alkaline phosphatase level. Ultrasonography showed multiple hypoechoic lesions in the liver and CT scans also revealed multiple low density areas. Therefore he was suspected of having a complication of liver abscesses. Amphotericin B was administered 75 mg/day intravenously every other day. A percutaneous liver biopsy was performed, but was not diagnostic. Blood cultures were negative for pathogens. Amphotericin B was administered up to a cumulative dosage of 2.3 g, but the patient remained febrile. Then he had an exploratory laparotomy and an open liver biopsy. The liver biopsy samples showed fungal elements proved by PAS staining. A catheter was inserted into the portal vein. Administration of Amphotericin B was started 20 mg daily through the catheter. The temperature fell to normal after institution of this therapy. The abnormal findings in CT scans almost disappeared and the inflammatory findings became negative after he had received intraportal administration of Amphotericin B over three months. Through the analysis of this case study, we confirmed that the intraportal administration of Amphotericin B was effective to the intractable liver abscesses due to fungi.

Topics: Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Humans; Infusions, Intravenous; Leukemia, Myeloid, Acute; Liver Abscess; Male; Middle Aged; Mycoses; Neutropenia; Portal Vein; Remission Induction

Topics: Agranulocytosis; Amphotericin B; Fever; Humans; Neutropenia

We compared the efficacies of the new triazole antifungal drugs fluconazole and itraconazole with that of amphotericin B in vitro and in an animal model of systemic candidiasis in normal and neutropenic mice. Antifungal treatment with fluconazole (2.5 to 20 mg/kg orally twice daily), itraconazole (10 to 40 mg/kg orally twice daily), or amphotericin B (0.1 to 4 mg/kg intraperitoneally once daily) was started 1 day after intravenous injection of 10(4) Candida albicans into normal mice or 10(3) C. albicans into neutropenic mice; the drugs were administered for 2 days. In normal mice the efficacy of treatment, which was assessed on the basis of the number of C. albicans cultured from the kidney, was greater for amphotericin B than for the triazoles. Fluconazole was more potent than itraconazole on the basis of equivalent doses, although itraconazole was more potent on the basis of the amount of free drug that was available. In neutropenic mice amphotericin B was less effective than it was in normal mice, whereas the triazoles were equally effective in normal and neutropenic mice. This was not expected, since in vitro data showed that amphotericin B was highly fungicidal, whereas both fluconazole and itraconazole had only a minimal effect on the growth of C. albicans in vitro.

Topics: Agranulocytosis; Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Fluconazole; Half-Life; Itraconazole; Ketoconazole; Male; Mice; Neutropenia; Triazoles

A retrospective analysis was carried out of the results of 115 intensively-treated cancer inpatients receiving 91 treatment courses of amphotericin B given in an empirical fashion. Amphotericin B was administered over 1.5 to 2 hours at a dose of 0.6 to 0.7 mg/kg/day. Median duration of neutropenic fever before amphotericin B administration was 5 days (range 1 to 32 days) and median total amphotericin B dose was 480 mg (range 10 to 2450 mg). In 56 (61%) of 91 amphotericin B courses, neutropenic fevers resolved; this occurred a median of 3 days (range 1 to 15 days) after amphotericin B was begun and at a median dose of 120 mg (range 10 to 850 mg). Response to amphotericin was independent of positive cultures for fungus or sites of positive culture. Adverse reactions to amphotericin B included rigors (89% of courses), fever (23%), bronchospasm (9%), and transient hypotension (9%). Median increase above baseline serum creatinine in patients given amphotericin B was 0.5 mg/dl (range 0 to 2.6 mg/dl) compared to a median of 0.1 mg/dl (range 0 to 2.9 mg/dl) in a similar group of intensively-treated cancer patients who did not receive amphotericin B. Amphotericin B was well tolerated when given by rapid infusion and was associated with prompt resolution of neutropenic fever in the majority of patients.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amphotericin B; Female; Fever; Humans; Infusions, Intravenous; Male; Middle Aged; Neutropenia

A 21-year-old man with acute myeloid leukaemia developed cavitating pneumonia while neutropenic and on broad spectrum antibiotics following induction chemotherapy. Trichosporon beigelii was isolated from several samples of sputum. He was successfully treated with amphotericin B. Previous reports of lung infection with this organism are reviewed.

Topics: Adult; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Myeloid; Lung Diseases, Fungal; Male; Mitosporic Fungi; Neutropenia; Pneumonia; Sputum; Trichosporon

The results of surveillance cultures in 424 neutropenic patients with hematologic malignancies were analyzed to evaluate the relationship between colonization and infection by Candida species. Eighteen (32%) of 56 patients with multiple noncontiguous colonized sites developed proven (13 cases) or probable (five cases) systemic candidiasis, versus two patients with proven candidiasis (1.2%) of 170 with one colonized site (P less than 0.00000001), and one patient with proven candidiasis (0.5%) of 198 without any evidence of Candida colonization (P less than 0.00000001). Twenty-two patients with multiple colonized sites who developed a febrile episode resistant to antibiotics were treated with empiric amphotericin B. Nine of 11 given empiric amphotericin B within day 6 survived versus three of 11 receiving antifungal therapy after day 6 (P = 0.014). The above data seem to justify further prospective studies on Candida colonization as indication to early antifungal therapy in febrile neutropenic patients.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amphotericin B; Candidiasis; Female; Humans; Male; Middle Aged; Neutropenia; Retrospective Studies

The diagnostic efficiency of a serum Candida antigen detection test Cand-Tec test) was prospectively investigated in 104 leukemic patients treated by intensive chemotherapy or allogeneic bone marrow transplantation. Candida antigen titers were determined on admission and then weekly as long as patients remained neutropenic. Nine patients had a proven disseminated yeast infection (diagnosed only at autopsy in five cases). The highest Candida antigen titers were 1:2 in two patients and 1:4 or more in seven patients (sensitivity: 76% for this last titer). This highest titer was observed 12 days before to 3 days after the diagnosis. Seven out of the 97 patients without proven deep candidiasis had a maximum titer of 1:4 (specificity: 93%). The positive predictive value was 50% for a titer of 1:4 and 24% for a titer of 1:2, whereas the negative predictive value was 100% for a titer of 1:4 and 97% for a titer of 1:2. Patients with elevated titers were mostly treated by chemotherapy, were older and had a worse prognosis than those with negative titers, although the duration of neutropenia was similar. It is concluded that Candida antigen detection is a reliable method of diagnosis of deep candidiasis in neutropenic patients. The clinical interest in this test, with special regard to empiric antifungal therapy, is discussed.

Topics: Agranulocytosis; Amphotericin B; Antigens, Fungal; Candidiasis; Female; Humans; Latex Fixation Tests; Male; Neutropenia; Predictive Value of Tests; Prospective Studies

A rate on autopsy of up to 30% systemic fungal infections and difficulties in diagnosing systemic mycosis antemortem have led to the empiric use of amphotericin B in patients with hematological malignancies, prolonged fever, and neutropenia. Routine empiric antifungal treatment was initiated in our institution in 1982. Amphotericin B was given to granulocytopenic patients with hematological malignancies with (a) unremitting fever after 48-72 h of antibiotic treatment, (b) recurrent fever during antibiotic treatment, or (c) with newly detected pulmonary infiltrates, sinusitis, skin and retinal lesions suggestive of a fungal infection. With this approach the rate of systemic fungal infections decreased significantly from 10% (27 of 270 patients; 1973-1981) to 4% (6 of 153 patients; 1982-1986, P less than 0.02). The reduction of systemic fungal infections was most prominent in patients with acute myelogenous leukemia, where its proportion decreased from 16% (16 of 98 patients; 1973-1981) to 4% (2 of 50 patients; 1982-1986, P less than 0.023). Our data support the hypothesis that the incidence of systemic fungal infections in patients with hematological malignancies and especially in acute myelogenous leukemia can be reduced significantly by empirical treatment with amphotericin B.

Topics: Adult; Aged; Agranulocytosis; Amphotericin B; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Leukemia; Lung Diseases, Fungal; Lymphoma; Male; Middle Aged; Mycoses; Neutropenia; Retrospective Studies

Systemic yeast infections are a major cause of morbidity and mortality in severely immunocompromised patients. The in vitro susceptibility to amphotericin B of 29 yeasts causing fungemia was examined in 26 patients undergoing allogeneic or autologous bone marrow transplantation and/or myelosuppressive chemotherapy. The minimal inhibitory concentrations (MICs) of amphotericin B observed with blood isolates from these patients were significantly higher than those observed with blood, sputum, or skin isolates from non-immunocompromised patients (p less than 0.01). All episodes (10 of 10) of bloodstream infection in immunocompromised patients caused by isolates with MICs greater than 0.8 micrograms/ml were fatal, versus eight of 17 episodes of bloodstream infection caused by yeasts with MICs of 0.8 micrograms/ml or less (p = 0.04). Although 15 of 26 patients received empiric treatment with amphotericin B before laboratory evidence of fungemia developed, the amphotericin B susceptibilities of their isolates were not significantly different from those of patients who had not received empiric amphotericin B treatment. It is concluded that yeast fungemia in severely immunocompromised patients is often caused by organisms resistant to the usual concentrations of amphotericin B obtainable in vivo, and that this finding is clinically significant.

Topics: Adult; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Candida; Candidiasis; Drug Resistance, Microbial; Humans; Immune Tolerance; Microbial Sensitivity Tests; Neutropenia

We developed an experimental model of candidiasis in rabbits with prolonged neutropenia. Rabbits were made neutropenic with cytosine arabinoside (Ara-C) administered through an indwelling silastic catheter that had been surgically implanted in the external jugular vein. Neutropenia was sustained with intravenous Ara-C, and bacterial complications were prevented with parenteral ceftazidime plus ampicillin. Candidiasis was established by intravenously administering Candida albicans or Candida tropicalis (1-2 x 10(5) colony-forming units) and resulted in hepatic and splenic lesions that mimicked those associated with hepatosplenic candidiasis in humans. The kidney proved to be the site most refractory to eradication of Candida spp. and offered a target organ for assessing antifungal therapy. We evaluated amphotericin B, 5-flucytosine, ketoconazole, and rifampin, alone and in combination. Although each agent reduced the colony counts of Candida in the liver, spleen, and lung, the combination of amphotericin B and 5-flucytosine was the only regimen effective in eradicating renal candidiasis.

Topics: Agranulocytosis; Amphotericin B; Animals; Antifungal Agents; Candidiasis; Cytarabine; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Flucytosine; Ketoconazole; Neutropenia; Rabbits; Rifampin

Topics: Agranulocytosis; Amphotericin B; Anemia, Hemolytic, Autoimmune; Cryptococcosis; Female; Flucytosine; Humans; Meningitis; Middle Aged; Neutropenia; Prednisolone; Purpura, Thrombocytopenic

Topics: Agranulocytosis; Amphotericin B; Female; Humans; Ketoconazole; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycoses; Neutropenia

Candida krusei infections are increasing in neutropenic patients. This is the first report of a case of C. krusei arthritis in a neutropenic leukemic patient. The organism colonized the patient's respiratory tract and most likely seeded the right knee by hematogenous spread. Knee swelling and tenderness were minimal. Joint fluid Gram stain and fungal smears did not show the organism despite positive results on cultures. With therapy, the joint fluid converted from neutrophilic predominance to lymphocytic predominance. Despite sterilization of knee fluid, clinical relapse occurred after therapy with 256 mg of systemic amphotericin B; the infection was cured after a total dose of 456 mg.

Topics: Adult; Agranulocytosis; Amphotericin B; Arthritis, Infectious; Candida; Candidiasis; Humans; Knee Joint; Leukemia, Myeloid, Acute; Male; Neutropenia

The empirical use of amphotericin B in febrile leukemic patients not responding to antimicrobial agents has previously led to a significant decrease in fatal fungal infections and a significant increase in complete remissions. In this series of 66 patients receiving induction therapy for acute myelogenous leukemia (AML), 49 (74%) received amphotericin B. The median interval between institution of antibiotics and amphotericin B was ten days. Fifteen patients had clinical evidence of fungal infection, but only two (3%) died of fungal infection during induction therapy for AML. We discontinued amphotericin B upon granulocyte recovery (greater than 500/cu mm) unless a pulmonary infiltrate was present. Even though only five of 15 patients with probable fungal infection received more than 1,000 mg of amphotericin B, no patient had recurrent fungal disease while in remission. The incidence of clinically suspected fungal pneumonia during consolidation therapy and reinduction therapy also suggested that our therapy was adequate. An increased incidence of late fungal pneumonia in patients receiving reinduction was associated with prolonged neutropenia (greater than 50 days). This study supports the empirical use of amphotericin B during induction therapy for AML, and suggests that doses can be smaller than those generally recommended for fungal infection.

Topics: Aged; Amphotericin B; Anti-Bacterial Agents; Aspergillosis; Cytarabine; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Infusions, Parenteral; Leukemia, Myeloid, Acute; Lung Diseases, Fungal; Male; Middle Aged; Neutropenia; Pneumonia; Retrospective Studies; Time Factors

Topics: Agranulocytosis; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Catheters, Indwelling; Cryptococcosis; Diagnosis, Differential; Fever of Unknown Origin; Humans; Liposomes; Mucormycosis; Mycoses; Neutropenia; Risk

The potential of ketoconazole prophylaxis to antagonize the activity of amphotericin B against aspergilli was investigated in vitro and in neutropenic mice. Exposure of Aspergillus fumigatus (six strains) and of Aspergillus flavus or Aspergillus niger to ketoconazole resulted in a uniform increase of the minimal fungicidal activity of amphotericin B, from 0.15-0.63 mg/liter to greater than 2.5 mg/liter in a microwell assay. To test the relevance of this antagonism in vivo, we challenged neutropenic mice iv with a lethal dose of conidia from two strains of A. fumigatus and then treated the mice first with ketoconazole and then with amphotericin B or amphotericin B plus ketoconazole. Pretreatment with ketoconazole for 48 hr completely abolished the protective effect of a subsequent therapy with amphotericin B, whether ketoconazole therapy was stopped (P less than .001) or not (P less than .001). Ketoconazole given alone had no significant effect on survival. Our data show that ketoconazole not only antagonized the fungicidal activity of amphotericin B in vitro but also abolished in vivo the protective effect of the only drug shown to be useful in the therapy of aspergillosis. The clinical importance of this antagonism, which is not limited to Aspergilli in vitro, requires careful consideration before ketoconazole prophylaxis can be recommended for patients at high risk of developing invasive opportunistic fungal infections.

Topics: Amphotericin B; Animals; Aspergillosis; Disease Models, Animal; Female; Humans; In Vitro Techniques; Ketoconazole; Liver Diseases; Mice; Neutropenia; Premedication

Two hundred thirty-five fungal infections occurred in patients with malignant diseases over a four-year period. One hundred eighty-eight were due to Candida species and Torulopsis glabrata and are reviewed herein. The frequency was highest in patients with acute leukemia (11.9 per 100 registrations) with a frequency of 0.8 per 100 registrations in all cancer patients at this institution. Three or more predisposing factors were present in more than 50 percent of the cases; antecedent myelosuppression, chemotherapy, and antibiotic therapy were most common. Blood cultures were positive in only 35 percent of patients with disseminated candidiasis. Twenty-nine of 55 patients (53 percent) had candidemia without identifiable organ infection recovered. Eleven were given no systemic antifungal therapy and recurrence of infection was documented in two patients. Only six (4.5 percent) of 133 patients with proved deep organ infections recovered. Respiratory failure was the clinical cause of death in 62 percent of patients. Clinical features, cultures, and serologic tests were usually of no assistance in establishing the diagnosis early in the course of the infection.

Topics: Acute Disease; Amphotericin B; Bacterial Infections; Bacteriological Techniques; Candida; Candidiasis; Cytomegalovirus Infections; Humans; Ketoconazole; Leukemia; Lymphoma; Miconazole; Mycoses; Neoplasms; Neutropenia

The relative efficacies of free amphotericin B (Amp B) and liposome-encapsulated Amp B (L-AmpB) in the treatment of established Candida albicans infection in mice rendered neutropenic with cyclophosphamide were studied. AmpB was entrapped in multilamellar liposomes composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol in a molar ratio of 7:3. Infected mice treated with single doses of 3 mg L-AmpB/kg of body weight had an increased survival time compared with those injected with either single (dose, 0.8 mg/kg) or multiple doses (dose, 0.8 mg/kg daily for five days) of free AmpB. When treatment was delayed beyond three days postinfection, neither single nor multiple doses of free AmpB resulted in increased survival, whereas treatment with single-dose L-AmpB (dose, 4 mg/kg) showed efficacy when delayed as much as four days postinfection. Five days postinfection only higher doses (dose, 5.6 mg-11.2 mg/kg) of L-AmpB improved survival time and the renal impairment present in the infected animals. These data provided a rational basis for using high-dose L-AmpB to treat fungal diseases in humans, particularly in neutropenic patients.

Topics: Agranulocytosis; Amphotericin B; Animals; Candidiasis; Dose-Response Relationship, Drug; Liposomes; Mice; Neutropenia

Topics: Administration, Intranasal; Agranulocytosis; Amphotericin B; Aspergillosis; Humans; Lung Diseases, Fungal; Neoplasms; Neutropenia

The authors described a 6 years old boy suffering from acute lymphoblastic leukemia and treated by the B.F.M. protocol who presented during intensive chemotherapy period a aspergillus renal abscess apparently unique. During the postoperative period the evolution was progressively favorable under prolonged anti-fungal treatment. The different clinical features, the non facilities of diagnosis and the mean possibility of treatment in aspergillus infection in immunodeficient patients are reviewed.

Topics: Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Child; Humans; Kidney; Kidney Diseases; Leukemia, Lymphoid; Male; Neutropenia

The efficacy of liposome-encapsulated amphotericin B in the prophylaxis of disseminated Candida albicans infections in neutropenic mice was studied. The administration of liposome-encapsulated amphotericin B was associated with protection against infection with C. albicans when used at doses of greater than or equal to 2 mg of amphotericin B per kg of body weight. Neither empty liposomes nor free amphotericin B showed prophylactic efficacy.

Topics: Agranulocytosis; Amphotericin B; Animals; Candidiasis; Cyclophosphamide; Injections, Intravenous; Liposomes; Mice; Neutropenia

Topics: Agranulocytosis; Amphotericin B; Antifungal Agents; Fever; Humans; Neutropenia

Invasive fungal infections are becoming increasingly frequent among immunocompromised patients and especially among cancer patients. The most common pathogens identified are Candida species, Aspergillus species, Cryptococcus neoformans, and Mucor species. Amphotericin B remains the mainstay of antifungal therapy. However, the toxicity of this drug may limit its use and, in addition, both failures and relapses have been reported. 5-Fluorocytosine and imidazoles, such as miconazole and ketoconazole, have been shown to be active, mainly on yeast organisms. The emergence of 5-fluorocytosine-resistant strains warrants caution for its administration as a single agent. The specific role of ketoconazole has not yet been established in large studies. In our experience, ketoconazole seems to be effective in the treatment of severe oral candidiasis in non-neutropenic cancer patients. Moreover, ketoconazole administered prophylactically to neutropenic patients decreases the number of positive surveillance cultures in these patients. The rare incidence of major toxicity and the ability to administer ketoconazole orally represent also major arguments for further investigation of ketoconazole activity by prospective controlled studies.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Candidiasis, Oral; Drug Therapy, Combination; Humans; Imidazoles; Ketoconazole; Lung Diseases, Fungal; Miconazole; Microbial Sensitivity Tests; Mycoses; Neoplasms; Neutropenia; Piperazines

Topics: Agranulocytosis; Amphotericin B; Anti-Bacterial Agents; Bacterial Infections; Blood Transfusion; Drug Therapy, Combination; Fever; Granulocytes; Humans; Neutropenia

A retrospective evaluation was made on the value of amphotericin B lozenges in the selective elimination of yeasts from the oropharynx. Four different groups of severely granulocytopenic patients were studied. All 77 patients received amphotericin B orally as a suspension or as tablets. Four amphotericin B lozenges were also administered daily for topical antimycotic decontamination of the oropharynx. This was done in the presence of colonization-resistance decreasing factors such as a nasogastric tube (Group I, 19 patients) or mucosal damage (Group III, 25 patients) and in patients with four or more consecutive throat swab cultures with yeasts (Group IV, 11 patients). The 22 patients in Group II did not receive lozenges. The addition of lozenges resulted in a decrease in the mean "growth density" of Candida cells in the oropharynx. This reduction was significant in Group III (p less than 0.01) and Group IV (p less than 0.02) and became evident during the first week of treatment. In patients with a nasogastric tube, however, 51.8% of the throat swab cultures revealed yeasts. Increasing the dose of the lozenges might improve the results in these patients. Topical treatment of the oropharynx with amphotericin B lozenges is advocated for patients who are susceptible to Candida infections.

Topics: Amphotericin B; Candida; Candidiasis, Oral; Dosage Forms; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Neutropenia; Oropharynx; Retrospective Studies

Rhinocerebral mucormycosis is, with few exceptions, only reported in patients with severe metabolic or immunologic imbalances. Factors which may predispose to the development of mucormycosis are reviewed. These factors include ketoacidosis and immunologic deficiency states due either to the primary disease or to the treatment for other diseases. An appreciation for these predisposing factors is very important in order that aggressive diagnosis and therapy be undertaken without delay.

Topics: Acidosis; Adrenal Cortex Hormones; Aged; Amphotericin B; Anemia; Brain Diseases; Diabetes Complications; Humans; Immunologic Deficiency Syndromes; Keto Acids; Leukemia; Male; Mucormycosis; Neutropenia; Nose Diseases; Turbinates; Uremia

One hundred and ninety-five series of granulocyte transfusions in 144 patients were evaluated with respect to possible severe pulmonary toxicity from concomitant administration of granulocytes and amphotericin B. Dyspnea as a side effect of granulocyte transfusion was equally common among patients receiving amphotericin B and those in a matched control group not receiving amphotericin B. Granulocyte transfusions and amphotericin B were given simultaneously in 35 transfusion series, involving 32 patients. Respiratory deterioration, defined as the appearance of new pulmonary infiltrates on chest x-ray, occurred in 11 of these 35 episodes. Patients developing respiratory deterioration were similar to those not developing respiratory deterioration in age, diagnosis, disease status, duration of concomitant therapy, and outcome, but more often had positive fungal cultures as an indication for treatment (91% versus 58%; p = 0.1). In 8 patients, the episodes of respiratory deterioration were readily explained by congestive heart failure, by simultaneous bacteremia or fungemia, or by fungal pneumonia discovered at autopsy. One patient had a leukoagglutinin reaction (responsive to steroids) and the other 2 had unexplained, but reversible respiratory deterioration. We concluded that concomitant administration of granulocyte transfusions and amphotericin B is not associated with unexpected or rapidly fatal pulmonary toxicity and when appropriate, can be safely accomplished.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amphotericin B; Candidiasis; Child; Child, Preschool; Dyspnea; Escherichia coli Infections; Granulocytes; Humans; Lung; Middle Aged; Neutropenia; Pseudomonas Infections; Time Factors

Amphotericin B is used increasingly in high-risk patients with profound neutropenia and suspected sepsis. We have observed serious pulmonary reactions characterized by acute dyspnea, hypoxemia, and interstitial infiltrates on chest films in patients receiving amphotericin B and leukocyte transfusions. We reviewed 6 1/2 years of experience at the National Institutes of Health to determine whether this combination was associated with pulmonary toxicity not characteristic of either therapy alone. Amphotericin was used during 22 of 57 leukocyte-transfusion courses. Acute respiratory deterioration occurred during 14 (64 per cent) of these courses but in only two (6 per cent) of 35 courses without amphotericin (P less than 0.01). In seven cases, respiratory deterioration began during or immediately after amphotericin infusion, and it contributed to death in five patients. Diffuse intraalveolar hemorrhage was found when lung biopsy or autopsy was performed. Acute respiratory deterioration was not observed in comparably neutropenic patients given amphotericin but not leukocyte transfusions during the same period. It was mot common when amphotericin was begun with or after institution of daily leukocyte transfusions. Leukocyte transfusions may cause changes in the lungs that amplify the acute toxicity of amphotericin, thereby permitting severe pulmonary reactions.

Topics: Adolescent; Adult; Amphotericin B; Child; Dyspnea; Female; Humans; Hypoxia; Leukocyte Transfusion; Lung Diseases; Male; Middle Aged; Neutropenia; Sepsis; Transfusion Reaction

The pattern of amphotericin B toxicity was assessed retrospectively in a group of 20 children with cancer who had received one or more courses of the drug for treatment of systemic fungal infection. Azotemia was the most frequent complication, developing during 23 of 24 treatment courses. Other major toxic effects, in decreasing order of frequency, were anemia, hypokalemia, thrombocytopenia, and neutropenia. Infusion side effects, including drug-related fever, chills, and nausea, were also frequently seen. Seventeen of 20 patients were treated for disseminated histoplasmosis. Nineteen of 20 patients had acute leukemia. Although interaction with other agents could not be excluded, amphotericin B appeared to be the major causative agent for the toxic reactions noted. In no patient, however, was administration of amphotericin B stopped because of drug toxicity.

Topics: Adolescent; Amphotericin B; Anemia; Child; Child, Preschool; Female; Heart; Humans; Hypokalemia; Infant; Kidney; Liver; Male; Mycoses; Neoplasms; Neutropenia; Thrombocytopenia