amphotericin-b and Fever-of-Unknown-Origin

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

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

The incidence of systemic fungal infections, especially in immunocompromised patients, has continued to increase during the past few decades. Treatment with conventional amphotericin B has been the standard care for the majority of patients with invasive fungal infections, despite its associated toxicity. Three lipid formulations of amphotericin B have now been approved for use in the United States. The pharmacology, pharmacokinetics, clinical experience, toxicity, dosing strategies, and cost of these three preparations--amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B--were reviewed in detail in this chapter. The clinical data indicate that lipid formulations of amphotericin B represent an important therapeutic modality in the management of invasive fungal infections.

Topics: Amphotericin B; Antifungal Agents; Costs and Cost Analysis; Economics, Pharmaceutical; Fever of Unknown Origin; Humans; Immunocompromised Host; Liposomes; Mycoses

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

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

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

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

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

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

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

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

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

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

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

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

Histoplasmosis is a rare disease in nonendemic areas. We report a case of a 23-year-old male patient who presented with fever of unknown origin, cytopenias, organomegaly, and allograft dysfunction 4 months after renal transplant with father as donor. Bone marrow examination showed intracellular budding yeast cells, which was confirmed as histoplasmosis by culture of bone marrow biopsy sample. The patient was treated with intravenous liposomal amphotericin and responded well.

Topics: Administration, Intravenous; Amphotericin B; Antifungal Agents; Biomarkers; Fever of Unknown Origin; Histoplasma; Histoplasmosis; Humans; Kidney Transplantation; L-Lactate Dehydrogenase; Male; Predictive Value of Tests; Treatment Outcome; Young Adult

A 53-year-old man presented with a number of hospital admissions for investigation of fever of unknown origin. He became gradually weaker with significant weight loss, pancytopenia and progressive splenomegaly over a 6-month period of extensive investigation. This was undertaken at different NHS hospitals with involvement of multiple medical specialists. Clinical criteria for haemophagocytic lymphohistiocytosis were met. Following investigation, this was felt likely secondary to a low-grade lymphoma of the spleen, necessitating splenectomy for diagnostic and therapeutic purposes. Ultimately, this risky surgical procedure was avoided when positive

Topics: Amphotericin B; Antiprotozoal Agents; Diagnosis, Differential; Fever of Unknown Origin; Humans; Leishmaniasis, Visceral; Lymphohistiocytosis, Hemophagocytic; Male; Middle Aged; Pancytopenia; Splenomegaly; Treatment Outcome; Weight Loss

Leishmaniasis is a neglected disease that is prevalent in tropical and subtropical regions of the world. Even though cutaneous leishmaniasis is the most common form, visceral leishmaniasis is associated with high mortality. The case presented herein is a 39 year-old bed-ridden female who presented with fever of unknown origin, tachypnea and pancytopenia. She was initially misdiagnosed as having autoimmune pancytopenia elsewhere and treated with corticosteroids and intravenous immunoglobulin. She had also received wide-spectrum antibiotics for febrile neutropenia. We performed a leishmania rK39 dipstick test which turned out to be positive along with visualisation of amastigote forms of leishmania on bone marrow biopsy. Thus, we made a diagnosis of visceral leishmaniasis and treated her with liposomal amphotericin B. Her clinical course was complicated by respiratory failure necessitating invasive mechanical ventilation. She responded well to treatment and was later extubated, shortly before being discharged. At 6 months of follow-up, no sign of recurrence was observed.

Topics: Adult; Amphotericin B; Antiprotozoal Agents; Autoimmune Diseases; Biopsy; Bone Marrow; Cerebral Palsy; Chromatography, Affinity; Diagnosis, Differential; Female; Fever of Unknown Origin; Humans; Leishmaniasis, Visceral; Pancytopenia; Recurrence; Respiration, Artificial; Respiratory Insufficiency; Tachypnea; Turkey

Aureobasidium pullulans (A. pullulans) is a dematiaceous, yeast-like fungus that is ubiquitous in nature, which can colonize the human hair and skin. A. pullulans has been clinically implicated to cause skin and soft tissue infections, meningitis, splenic abscesses, and peritonitis. Herein, molecular diagnostic of internal transcribed spacer (ITS) sequencing was used to investigate a suspected case of A. pullulans infection, and the infection source had been traced. A 27-year-old female case was suspected of kala-azar due to the recurrent fever. Bone marrow specimens were analyzed. The samples were negative for Leishmania, Penicillium marneffei and Histoplasma capsulatum. DNA was extracted from the bone marrow specimens, and the 583-bp sequence was amplified with the fungal ITS universal primers. The sequence was compared by Blast query to be identified as A. pullulans. A strain of A. pullulans was also isolated from the kitchen of the patient's living room. Culture characteristics were the same as the human pathogens of A. pullulans, and the ITS sequence was identical to the bone marrow ITS amplification. In conclusion, a deep infection caused by A. pullulans is rare, often occurring in the indwelling catheter, which may cause peritonitis and other symptoms. ITS sequencing of fungi can be used as a diagnostic reference. As A. pullulans is a common fungus in environment, amplification of ITS sequence of A. pullulans in the aseptic body fluid would be necessary to make a comprehensive diagnosis based on the clinical symptoms and signs.

Topics: Adult; Amphotericin B; Antifungal Agents; Ascomycota; Base Sequence; Bone Marrow; China; DNA, Fungal; Environmental Microbiology; Female; Fever of Unknown Origin; Housing; Humans; Invasive Fungal Infections; Sequence Homology, Nucleic Acid; Species Specificity

Topics: Adolescent; Amphotericin B; Antigens, Fungal; Antiviral Agents; Biopsy; Bone Marrow; Cytomegalovirus; Cytomegalovirus Infections; Female; Fever of Unknown Origin; Graft Rejection; Histoplasma; Histoplasmosis; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphohistiocytosis, Hemophagocytic; Mycophenolic Acid; Renal Dialysis; Treatment Outcome; Viral Load

Human trypansomiasis due to infection by animal trypanosomes is rarely reported from India.. We describe clinical presentation of a 2-month-old boyfrom a rat infested house in rural Gujarat who was diagnosed to be havinginfection with the rodent parasite Trypanosoma lewisi.. The fever and parasitemia resolved on treatment with liposomal amphotericin B, Ceftriaxone and Amikacin, and there was no recurrence of parasitemia over a 2 month follow-up.. The case highlights the need for increased awareness and heightened surveillance for this rare zoonotic infection.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Fever of Unknown Origin; Humans; India; Infant; Parasitemia; Rats; Trypanosoma lewisi; Trypanosomiasis; Zoonoses

Topics: Adolescent; Amphotericin B; Antifungal Agents; Bone Marrow; Diagnosis, Differential; Fever of Unknown Origin; Fungemia; Histoplasma; Histoplasmosis; Humans; Infusions, Intravenous; Kidney Transplantation; Lung Diseases, Interstitial; Lymphohistiocytosis, Hemophagocytic; Male; Pancytopenia; Transplant Recipients

Topics: Abdominal Pain; Amphotericin B; Antibodies, Fungal; Antifungal Agents; Cerebrospinal Fluid; Child; Diagnosis, Differential; Fever of Unknown Origin; Histoplasmosis; Humans; Lung Diseases, Fungal; Male; Nausea

The authors report a clinical case of an isolated oral histoplasmosis in a hemodialysis patient that presented with fever of unknown origin and had an unremarkable physical examination. During the investigation, a Gallium scan showed uptake in the oral cavity and soon after the oral cavity examination revealed a granulomatous lesion on the tooth 26. Histopathologic findings were compatible with histoplasmosis. The treatment regimen included liposomal amphotericin B followed by itraconazole consolidation therapy, and side effects did not occur. Both clinical evolution and outcome were favorable. Oral histoplasmosis in a non-immunosuppressed patient is extremely rare.

Topics: Amphotericin B; Antifungal Agents; Fever of Unknown Origin; Gingiva; Histocytochemistry; Histoplasmosis; Humans; Itraconazole; Male; Portugal; Renal Dialysis

Clinicians have usually considered malignancies during follow up of patients who have infectious diseases as a pre-diagnosis. However, malignancy and an infectious disease are seen together more rarely, with the exception of immunosuppressed patients. This presentation is a case report followed up for fever of unknown origin. The patient was admitted to the hospital with the symptoms of fever, weight loss, abdominal pain and weakness. Anemia and hypergamaglobulinemia by biochemical analyses and splenomegaly by total body computed tomography were detected. Amastigotes were seen in bone marrow aspiration smears and promastigotes were isolated in NNN medium. At the end of the Liposomal Amphotericin B treatment, control bone marrow aspiration was applied. Leishmania amastigotes were not seen, while patient was diagnosed as diffuse B cell lymphoma pathologically.

Topics: Abdominal Pain; Amphotericin B; Anemia; Anticestodal Agents; Bone Marrow; Female; Fever of Unknown Origin; Humans; Hypergammaglobulinemia; Leishmania; Leishmaniasis, Visceral; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Splenomegaly; Tomography, X-Ray Computed; Weight Loss

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

Topics: Adolescent; Amphotericin B; Antibodies, Protozoan; Antiprotozoal Agents; Fever of Unknown Origin; Hodgkin Disease; Humans; India; Leishmaniasis, Visceral; Male; Treatment Outcome

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

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

Topics: Amphotericin B; Antiprotozoal Agents; Bone Marrow; Diagnosis, Differential; Fever of Unknown Origin; Humans; Leishmaniasis, Visceral; Lupus Erythematosus, Systemic; Male; Middle Aged; Recurrence

Activity and efficacy of liposomal amphotericin B have been established for the treatment of severe fungal infections. Nephrotoxic side effects, especially during prolonged administration, are regarded as a major disadvantage. In this study we examined the response rates and side effects, particularly nephrotoxicity, of treatment with liposomal amphotericin B in a large cohort of patients.. 406 patients treated with liposomal amphotericin B between January 1999 and August 2003 in participating German hospitals were included. Documentation included demographic and clinical data, reason for the treatment with liposomal amphotericin B, length of treatment, response to antifungal treatment and side effects.. 42.4% of the 406 patients were females. Their ages ranged from 1 day to 77 years. 83 % of the patients had malignancies and 65.5 % had fever of unknown origin (FUO). Mean duration of treatment with liposomal amphotericin B was 20 +/- 20 days, at an average dose of 2.3 mg/kg/d. 209 patients (51.5 %) showed complete response (CR),105 patients (25.9 %) partial response (PR) and 51 (12.6 %) patients died during the observation. 80.0 % of patients with FUO showed complete or partial response of symptoms. Mean serum creatinine increased from 0.9 mg/kg before start of therapy with liposomal amphotericin B to 1.1 mg/kg during treatment. Side effects (common toxicity criteria > grade 1) occurred in 94 patients (23/2 %). Among these hypokalemia (6.2 %) and liver damage (5,2 %) were the most common. Nephrotoxicity was documented in 17 patients (4.2 %).. Liposomal amphotericin B is a safe and efficacious antifungal drug in the treatment of severe invasive fungal infections and fever of unknown origin. Nephrotoxicity is usually not a limiting factor when using liposomal amphotericin B, if it is administered in approved dosage.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Cohort Studies; Female; Fever of Unknown Origin; Humans; Infant; Infant, Newborn; Kidney; Liposomes; Male; Middle Aged; Mycoses; Neoplasms; Prospective Studies; Treatment Outcome

Topics: Abscess; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Biopsy, Fine-Needle; Caspofungin; Contraindications; Cyclosporine; Delayed Graft Function; Drug Interactions; Echinocandins; Fever of Unknown Origin; Gram-Negative Bacterial Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lipopeptides; Male; Middle Aged; Mycophenolic Acid; Peptides, Cyclic; Postoperative Complications; Prednisone; Pyrimidines; Radionuclide Imaging; Stenotrophomonas maltophilia; Surgical Wound Infection; Thyroiditis; Triazoles; Ultrasonography; Voriconazole

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; Antibiotic Prophylaxis; Antifungal Agents; Drug Carriers; Fever of Unknown Origin; Humans; Liposomes; Mycoses

Topics: Agranulocytosis; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Catheters, Indwelling; Cryptococcosis; Diagnosis, Differential; Fever of Unknown Origin; Humans; Liposomes; Mucormycosis; Mycoses; Neutropenia; Risk

Topics: Adolescent; Adult; Agranulocytosis; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Bacterial Infections; Carbenicillin; Cephalothin; Child; Child, Preschool; Drug Therapy, Combination; Fever of Unknown Origin; Gentamicins; Humans; Mycoses; Neoplasms; Prospective Studies; Random Allocation

Topics: Aged; Amphotericin B; Bronchi; Female; Fever of Unknown Origin; Histoplasma; Histoplasmosis; Humans; Lung; Pulmonary Fibrosis; Radiography

Topics: Agranulocytosis; Amphotericin B; Cytarabine; Daunorubicin; Decision Making; Esophagitis; Fever of Unknown Origin; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycoses

Topics: Adult; Amphotericin B; Fever of Unknown Origin; Histoplasmosis; Humans; Immunologic Deficiency Syndromes; Male

Topics: Acute Disease; Adolescent; Adult; Aged; Amphotericin B; Aspergillosis; Autopsy; Biopsy; Candidiasis; Candidiasis, Oral; Child, Preschool; Female; Fever of Unknown Origin; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lung Diseases, Fungal; Male; Middle Aged; Mucor; Mycoses; Retrospective Studies

Topics: Adult; Amphotericin B; Fever; Fever of Unknown Origin; Histoplasmosis; Humans; Male; Middle Aged; Tuberculosis, Miliary