amphotericin-b--deoxycholate-drug-combination and Candidiasis

This drug utilization evaluation aims to review current evidence on safety and efficacy of using liposomal amphotericin B (LAMB) in newborns with candidiasis, and compare it to the conventional preparation. Conventional amphotericin B deoxycholate (DAMB) is more commonly used in newborns, but dose-limiting adverse effects may compromise its efficacy. This review will examine the advantages and disadvantages of liposomal amphotericin B and define its place in current practice.. The terms 'AmBisome' or 'liposomal amphotericin B' and 'neonatal candidiasis' were entered in both PubMed and Ovid; studies included focused on safety and efficacy of liposomal amphotericin B in newborns with candidiasis, as well as studies comparing the conventional and the liposomal formulations in newborns as monotherapy. Pertinent references obtained from this search were also included. Additionally, pharmacokinetic studies were reviewed to include available data on dosing. Single case reports were not included in the review due to the limited conclusions that can be drawn from such sample sizes and quality of data.. Although liposomal amphotericin B may be better tolerated and as efficacious as the conventional formulation based on the published literature, the weakness of the studies available on the subject cannot be overlooked. Additional randomized controlled trials are needed to determine the true benefits of this medication.

Topics: Amphotericin B; Candidiasis; Deoxycholic Acid; Drug Combinations; Drug Utilization Review; Humans; Infant, Newborn

Candida infections are a source of significant mortality and morbidity in the neonatal intensive care unit. Treatment strategies continue to change as additional antifungals become available and studies in neonates are performed. Amphotericin B deoxycholate has been favored for many years, but fluconazole has the most data supporting its use in neonatal Candida infections and is often employed for prophylaxis as well as treatment. Voriconazole and posaconazole have limited utility in the nursery and are rarely used. The echinocandins are increasingly administered for invasive Candida infections, although higher doses are required in neonates than in older children and adults.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Combinations; Echinocandins; Fluconazole; Humans; Infant, Newborn; Infant, Newborn, Diseases; Intensive Care Units, Neonatal; Neonatology; Pyrimidines; Triazoles; Voriconazole

Invasive candidiasis is a common nosocomial infection among critically ill patients, constitutes an important cause of sepsis, and is associated with significant morbidity and mortality. The Infectious Diseases Society of America (IDSA) has created evidence-based guidelines for the management of invasive candidiasis. However, several new antifungal agents with excellent activity against Candida spp. and favourable safety profiles have been introduced successfully in the clinical setting since the IDSA guidelines were published in late 2003. Further, the role of antifungals is not entirely clear in the intensive care unit (ICU) setting. Therefore, this article discusses daily problems in the prophylaxis and treatment of invasive candidasis in interdisciplinary ICUs.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Cross Infection; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Echinocandins; Fluconazole; Humans; Intensive Care Units; Itraconazole; Pyrimidines; Risk Factors; Triazoles; Voriconazole

Fungal urinary tract infections (funguria) are rare in community medicine, but common in hospitals where 10 to 30% of urine cultures isolate Candida species. Clinical features vary from asymptomatic urinary tract colonization (the most common situation) to cystitis, pyelonephritis, or even severe sepsis with fungemia. The pathologic nature of funguria is closely related to host factors, and management depends mainly on the patient's underlying health status. Microbiological diagnosis of funguria is usually based on a fungal concentration of more than 10(3)/mm(3) in urine. No cutoff point has been defined for leukocyte concentration in urine. Candida albicans is the most commonly isolated species, but previous antifungal treatment and previous hospitalization affect both species and susceptibility to antifungal agents. Treatment is recommended only when funguria is symptomatic or in cases of fungal colonization when host factors increase the risk of fungemia. The antifungal agents used for funguria are mainly fluconazole and amphotericin B deoxycholate, because other drugs have extremely low concentrations in urine. Primary and secondary preventions are essential. The reduction of risk factors requires removing urinary catheters, limiting antibiotic treatment, and optimizing diabetes mellitus treatment.

Topics: Aged; Amphotericin B; Antifungal Agents; Candida albicans; Candidiasis; Cross Infection; Cystitis; Deoxycholic Acid; Drug Combinations; Female; Fluconazole; Fungemia; Fungi; Health Status; Hospital Mortality; Humans; Male; Mycoses; Primary Prevention; Pyelonephritis; Risk Factors; Urinary Catheterization; Urinary Tract Infections; Urine

Renal, liver, heart and lung transplantation are now considered to be the standard therapeutic interventions in patients with end-stage organ failure. Infectious complications following transplantation are relatively common due to the transplant recipients overall immunosuppressed status. The incidence of invasive mycoses following solid organ transplant ranges from 5 to 42% depending on the organ transplanted. These mycoses are associated with high overall mortality rates. Candida and Aspergillus spp. produce most of these infections. This article will review the risk factors, clinical presentation and treatment of invasive fungal infections in solid organ transplant patients, and evaluate the role of prophylactic therapy in this group of patients.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Clinical Trials as Topic; Cryptococcosis; Deoxycholic Acid; Drug Combinations; Echinocandins; Fluconazole; Humans; Incidence; Lipopeptides; Organ Transplantation; Peptides, Cyclic; Postoperative Complications; Premedication

Amphotericin B deoxycholate has been the 'gold standard' treatment for invasive fungal infections for over 40 years. Driven to improve on the renal toxicity of amphotericin B deoxycholate, extensive pharmaceutical research has led to the development of several new antifungals including lipid formulations of amphotericin B, broad-spectrum azoles and echinocandins. Compared with amphotericin B deoxycholate, the lipid formulations of amphotericin B (amphotericin B lipid complex, amphotericin B colloidal dispersion and liposomal amphotericin B) share distinct advantages in improved drug safety, in particular reduced incidence and severity of amphotericin B deoxycholate-related nephrotoxicity. However, the lipid formulations of amphotericin B are significantly more expensive than amphotericin B deoxycholate and, as for many of these new antifungals, there are as yet insufficient published studies to guide clinicians. This paper examines aspects of safety, efficacy, and health economic data for the lipid formulations of amphotericin B in particular, in order to provide a rationale to justify substituting amphotericin B deoxycholate with the lipid formulations of amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Chemistry, Pharmaceutical; Colloids; Deoxycholic Acid; Drug Combinations; Humans; Liposomes; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

The high morbidity, mortality, and healthcare costs associated with the invasive fungal infections, especially in the critical care setting, is of importance since the prophylactic, empiric, and pre-emptive therapy interventions, based on early identification of risk factors, is of common occurrence. In the last years alone there have been important developments in antifungal pharmacotherapy. Evidence-based studies using new antifungal agents are now emerging as important players in the pharmacotherapy of invasive fungal infections in seriously ill and difficult patients. However, data on critically ill patients are more limited and usually recovered from general studies. This study shows the benefits obtained by the new antifungal agents on different clinical situations in critical care units. The increasing number of non-C. albicans species and the high mortality rates in these settings suggest that the application of early de-escalation therapy in critically ill patients with fungal infection should be mandatory. The possibility of using antifungal combination therapy in these types of patients should be considered.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Critical Illness; Cross Infection; Deoxycholic Acid; Drug Combinations; Fluconazole; Humans; Intensive Care Units; Mycoses; Pyrimidines; Randomized Controlled Trials as Topic; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Deoxycholic Acid; Drug Combinations; Echinocandins; Hematologic Neoplasms; Humans; Itraconazole; Lipopeptides; Liposomes; Mycoses; Organ Transplantation; Peptides, Cyclic; Pyrimidines; Risk Factors; Stem Cell Transplantation; Triazoles; Voriconazole; Zygomycosis

The incidence of candidiasis has risen in neonatal intensive care units as advances in medical therapy have allowed for increased survival of extremely preterm neonates. The mortality of candidiasis has been reported to be 20% by several multi-centre studies. Definitive guidance for prophylaxis and treatment is hindered by lack of large, multi-centre, randomised controlled trials. Systemic prophylaxis is currently not recommended for any neonatal population, and amphotericin B deoxycholate continues to be used as first-line therapy for the treatment of invasive disease.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Deoxycholic Acid; Drug Combinations; Fluconazole; Humans; Infant, Low Birth Weight; Infant, Newborn; Randomized Controlled Trials as Topic; Risk Factors

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

Considering the significant morbidity and mortality associated with invasive fungal infections in immunocompromised patients, it is particularly important to make the diagnosis as early as possible and to make best use of the available antifungal drugs for prophylaxis and treatment. The newer antifungal drugs include the lipid products of amphotericin B, such as amphotericin B lipid complex (ABLC) and liposomal amphotericin B; voriconazole (a triazole); and caspofungin (an echinocandin). ABLC and liposomal amphotericin B are as effective as amphotericin B deoxycholate but are less nephrotoxic; ABLC is probably the drug of choice for zygomycosis. Voriconazole is approved for use in the treatment of invasive aspergillosis and may have a role in preventing breakthrough fungal infections in patients with persistent fever and neutropenia. Caspofungin is effective against both invasive aspergillosis and invasive candidiasis.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Liposomes; Mycoses; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Pyrimidines; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Triazoles; Voriconazole; Zygomycosis

Despite significant advances in the management of immunosuppressed patients, invasive fungal infections remain an important life-threatening complication. In the last decade several new antifungal agents, including compounds in pre-existing classes (new generation of triazoles, polyenes in lipid formulations) and novel classes of antifungals with a unique mechanism of action (echinocandins), have been introduced in clinical practice. Ongoing and future studies will determine their exact role in the management of different mycoses. The acceleration of antifungal drug discovery offers promise for the management of these difficult to treat opportunistic infections.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Candidiasis; Deoxycholic Acid; Drug Combinations; Echinocandins; Fungal Proteins; Humans; Immunocompromised Host; Mycoses; Peptides; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Triazoles

Systemic fungal infections cause almost 25% of the infection-related deaths in leukaemic patients. Particularly those with prolonged neutropenia are at risk but mycoses also feature in critically ill intensive care patients and in individuals who are treated for solid tumours and AIDS, or who received an organ transplant. The spread of AIDS and the more aggressive cytotoxic chemotherapy in combination with an improved management of haemorrhages and bacterial infections in leukaemic and other cancer patients facilitated the occurrence of these invasive fungal infections. These life-threatening complications remain both difficult to diagnose and to treat and therefore carry a poor prognosis. For many years, the only realistic option to treat systemic infections was amphotericin B, whose administration was known to be associated with numerous adverse effects. Now less toxic formulations of amphotericin have become available for clinical use, as well as several new triazoles that appear to provide an effective and less toxic alternative for the treatment of certain fungal infections.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Cryptococcosis; Deoxycholic Acid; Drug Combinations; Fluconazole; Flucytosine; Fungemia; Histoplasmosis; Humans; Immunocompromised Host; Mycoses; Zygomycosis

Candida parapsilosis produces biofilm, which colonizes catheters and other invasive medical devices that are manipulated by health care workers. In previous studies, C. parapsilosis in vitro biofilms have exhibited high resistance rates against conventional antifungals, but susceptibility to both echinocandins and lipid formulations of amphotericin B (lipid complex and liposomal). However, a recent study showed good activity of amphotericin B deoxycholate on the biomass of C. parapsilosis biofilms. Although moderate activity of echinocandins has been demonstrated against low metabolic activity biofilms of C. parapsilosis, few studies have analyzed the action of these drugs on high metabolic activity biofilms. Moreover, high biofilm-forming isolates have been associated with central venous catheter-related fungemia outbreaks and higher mortality rates. Therefore, it is relevant to verify the activity of the main antifungal drugs against high metabolic activity biofilms of C. parapsilosis. Our study aimed to evaluate the in vitro activity of amphotericin B deoxycholate, anidulafungin, caspofungin, and micafungin against high biofilm-forming and high metabolic activity clinical isolates of C. parapsilosis. Our results showed good activity of amphotericin B against C. parapsilosis biofilms, but none of the echinocandin drugs was effective. This suggests that amphotericin B deoxycholate may be a better choice than echinocandins for the treatment of biofilm-associated infections by C. parapsilosis, mainly in countries with insufficient health care resources to purchase lipid formulations of amphotericin B. These results warn of the possibility of persistent catheter-related candidemia caused by high biofilm-forming C. parapsilosis strains when treated with echinocandin drugs.

Topics: Amphotericin B; Antifungal Agents; Biofilms; Candida parapsilosis; Candidemia; Candidiasis; Catheter-Related Infections; Deoxycholic Acid; Drug Combinations; Drug Evaluation, Preclinical; Echinocandins; Humans; Microbial Sensitivity Tests

Candida sp. osteoarticular infection is rare and most often due to hematogenous seeding during an episode of candidemia in immunocompromised patients. However, the diagnosis can be delayed in patients with subtle symptoms and signs of joint infection without a concurrent episode of candidemia.. A 75-year-old woman presented with a three-year history of pain and swelling of the left knee. Candida pelliculosa was detected from the intraoperative tissue when the patient had undergone left total knee arthroplasty 32 months ago, but no antifungal treatment was performed. One year after the total knee arthroplasty, C. pelliculosa was repeatedly isolated from the left knee synovial fluid and antifungal treatment comprising amphotericin B deoxycholate and fluconazole was administered. However, joint infection had extended to the adjacent bone and led to progressive joint destruction. The patient underwent surgery for prosthesis removal and received prolonged antifungal treatment with micafungin and fluconazole.. This case shows that C. pelliculosa, an extremely rare non-Candida albicans sp., can cause fungal arthritis and lead to irreversible joint destruction owing to delayed diagnosis and treatment.

Topics: Aged; Amphotericin B; Antifungal Agents; Arthritis, Infectious; Arthroplasty, Replacement, Knee; Candida; Candidemia; Candidiasis; Deoxycholic Acid; Device Removal; Drug Combinations; Female; Fluconazole; Humans; Intraoperative Care; Joint Prosthesis; Knee; Micafungin; Osteomyelitis

This study reports design and evaluation of chitosan-based microparticle activity against Candida glabrata in vitro and in vivo in immunocompetent mice model artificially maintained in oestrus state. Because their flattened shape, chitosan microparticles are called here micro-platelets. They were obtained by self-association of oleoyl chitosan and α-cyclodextrin in water. A mixture of amphotericin B-deoxycholate (Fungizone

Topics: Amphotericin B; Animals; Antifungal Agents; Candida glabrata; Candidiasis; Chitosan; Cyclodextrins; Deoxycholic Acid; Drug Combinations; Immunocompromised Host; Mice; Mucous Membrane

The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity.. Micro-platelets were obtained by mixing oleoyl chitosan and α-cyclodextrin in water. The formulation is specifically-engineered for mucosal application by dispersing chitosan micro-platelets into thermosensitive pluronic. These results demonstrate for the first time the ability of flattened chitosan micro-platelets to have synergistic activity with AmB-DOC against C. albicans candidiasis and highlight the importance of rheological and mucoadhesive behaviors of hydrogels in the efficacy of the treatment.

Topics: alpha-Cyclodextrins; Amphotericin B; Animals; Antifungal Agents; Blood Platelets; Candida albicans; Candidiasis; Chemistry, Pharmaceutical; Chitosan; Deoxycholic Acid; Disease Models, Animal; Drug Combinations; Female; Hydrogels; Mice; Mice, Inbred BALB C; Mucous Membrane; Nanoparticles; Poloxamer; Swine

Current guidelines for treatment of Candida osteoarticular infections (COAIs) recommend a prolonged course of antifungal therapy (AFT) of 6-12 months. Based upon strategies developed at the Hospital for Special Surgery (HSS), we hypothesized that the duration of antifungal therapy may be substantially reduced for management of COAI.. This was a retrospective chart review of cases of COAI treated at the HSS for the past 14 years. COAI was documented by open biopsy and direct culture in all cases. The mean (95% confidence interval, CI) duration of documented follow-up was 39 (16-61) months.. Among the 23 cases of COAI, the median age was 62 years (range 22-83 years) with 61% having no underlying condition. Orthopedic appliances, including joint prostheses and fracture hardware, were present in 74% of cases. All patients had COAI as the first proven site of candidiasis. Candida albicans and Candida parapsilosis were the most common species. Hip, knee, foot, and ankle were the most common sites. All patients received aggressive surgical intervention followed by AFT administered for a mean (95% CI) duration of 45 (38-83) days. Systemic AFT consisted principally of fluconazole alone (65%) or in combination with other agents (26%). Adjunctive intraoperative amphotericin B irrigation was used in 35%. Among eight cases of CAOI that required placement of a new prosthetic joint, all were successfully treated. There were no microbiologic failures.. Candida osteoarticular infections may be successfully treated with substantially limited durations of AFT when combined with a thorough surgical approach.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candida; Candida albicans; Candidiasis; Combined Modality Therapy; Deoxycholic Acid; Drug Combinations; Female; Humans; Male; Middle Aged; Orthopedic Procedures; Osteomyelitis; Prosthesis-Related Infections; Retrospective Studies; Young Adult

Larger populations at risk, broader use of antibiotics and longer hospital stays have impacted on the incidence of Candida sp. bloodstream infections (CBSI).. To determine clinical and epidemiologic characteristics of patients with CBSI in two tertiary care reference medical institutions in Mexico City.. Prospective and observational laboratory-based surveillance study conducted from 07/2008 to 06/2010.. All patients with CBSI were included. Identification and antifungal susceptibility were performed using CLSI M27-A3 standard procedures. Frequencies, Mann-Whitney U test or T test were used as needed. Risk factors were determined with multivariable analysis and binary logistic regression analysis.. CBSI represented 3.8% of nosocomial bloodstream infections. Cumulative incidence was 2.8 per 1000 discharges (incidence rate: 0.38 per 1000 patient-days). C. albicans was the predominant species (46%), followed by C. tropicalis (26%). C. glabrata was isolated from patients with diabetes (50%), and elderly patients. Sixty-four patients (86%) received antifungals. Amphotericin-B deoxycholate (AmBD) was the most commonly used agent (66%). Overall mortality rate reached 46%, and risk factors for death were APACHE II score ≥ 16 (OR = 6.94, CI95% = 2.34-20.58, p<0.0001), and liver disease (OR = 186.11, CI95% = 7.61-4550.20, p = 0.001). Full susceptibility to fluconazole, AmBD and echinocandins among C. albicans, C. tropicalis, and C. parapsilosis was observed.. The cumulative incidence rate in these centers was higher than other reports from tertiary care hospitals from Latin America. Knowledge of local epidemiologic patterns permits the design of more specific strategies for prevention and preemptive therapy of CBSI.

Topics: Adult; Aged; Amphotericin B; Candida; Candida albicans; Candida glabrata; Candida tropicalis; Candidiasis; Deoxycholic Acid; Drug Combinations; Female; Fluconazole; Humans; Incidence; Male; Mexico; Middle Aged; Proportional Hazards Models; Prospective Studies; Regression Analysis; Risk Factors; Tertiary Care Centers; Treatment Outcome

Candida spp. are frequently cultured from the respiratory tract in critically ill patients. Most intensivists start amphotericin-B deoxycholate (ABDC) inhalation therapy to eradicate Candida spp. from the respiratory tract. However, the safety and efficacy of this treatment are not well established. The purpose of this study was to assess the safety and efficacy of ABDC inhalation for the treatment of respiratory Candida spp. colonization in critically ill patients.. All non-neutropenic patients admitted into the intensive care unit (ICU) of a university hospital from December 2010-2011, who had positive Candida spp. cultures of the respiratory tract for more than 1 day and required mechanical ventilation >48 h were retrospectively included. The decision to start ABDC inhalation had been made by attending intensivists on clinical grounds in the context of selective decontamination of the digestive tract. Infection characteristics and patient courses were assessed.. Hundred and thirteen consecutive patients were studied. Fifty-one of them received ABDC inhalation and their characteristics at baseline and day 1 of respiratory colonization did not differ from those of colonized patients not receiving treatment (n = 62). The ABDC-treated group had a similar Candida spp. load but did not decolonize more rapidly as compared to untreated patients. The clinical pulmonary infection and lung injury scores did not decrease as in the untreated group. In a Cox proportional hazard model, the duration of mechanical ventilation was increased (P < 0.003) by ABDC treatment independently of other potential determinants and Candida spp. colonization. No differences in ventilator-associated pneumonia or in overall mortality (up to day 90) were observed.. Treatment of respiratory Candida spp. colonization in non-neutropenic critically ill patients by inhaled ABDC may not affect respiratory colonization but may increase duration of mechanical ventilation, because of direct toxicity of the drug on the lung.

Topics: Administration, Inhalation; Adult; Aged; Amphotericin B; Candida; Candidiasis; Critical Illness; Deoxycholic Acid; Drug Combinations; Female; Humans; Intensive Care Units; Male; Middle Aged; Pneumonia, Ventilator-Associated; Respiration, Artificial; Respiratory Tract Infections; Retrospective Studies

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Creatinine; Critical Illness; Cross Infection; Deoxycholic Acid; Drug Combinations; Fluconazole; Humans; Intensive Care Units; Practice Patterns, Physicians'; Renal Insufficiency

In recent decades the incidence of Candida endocarditis has increased dramatically. Despite the application of surgery and antifungal therapy, Candida endocarditis remains a life-threatening infection with significant morbidity and mortality. We report a 37-year-old male drug abuser presenting with high fever, chest pain, loss of appetite and cardiac failure. His echocardiography revealed mobile large tricuspid valve vegetations. Fungal endocarditis was confirmed by culturing of the resected vegetation showing mixed growth of Candida albicans and Candida tropicalis, although three consecutive blood cultures were negative for Candida species. Phenotypic identification was reconfirmed by sequencing of the internal transcribed spacer (ITS rDNA) region. The patient was initially treated with intravenous fluconazole (6 mg kg(-1) per day), followed by 2 weeks of intravenous amphotericin B deoxycholate (1 mg kg(-1) per day). Although MICs were low for both drugs, the patient's antifungal therapy combined with valve replacement failed, and he died due to respiratory failure.

Topics: Adult; Amphotericin B; Antifungal Agents; Candida albicans; Candida tropicalis; Candidiasis; Coinfection; Deoxycholic Acid; DNA, Fungal; DNA, Ribosomal Spacer; Drug Combinations; Drug Users; Echocardiography; Endocarditis; Fatal Outcome; Fluconazole; Humans; Male; Molecular Sequence Data; Mycological Typing Techniques; Sequence Analysis, DNA; Substance-Related Disorders; Tricuspid Valve

Systemic candidiasis causes significant mortality in patients despite amphotericin B (AMB) therapy. Mycograb C28Y variant, a human recombinant antibody fragment to heat shock protein 90, is closely related to Mycograb, which showed a survival advantage in combination with AMB in a phase III human trial. The Mycograb C28Y variant could potentially increase the antifungal effect of AMB. In our study, the interaction between AMB-desoxycholate (DAMB) and the Mycograb C28Y variant was characterized in vitro by using a checkerboard method. Quantitative cultures of kidneys, livers, and spleens of neutropenic mice with systemic Candida albicans infections were used to assess the in vivo interaction between 1.4 mg/kg of body weight/day of DAMB and 0.15, 1.5, and 15 mg/kg/day of the Mycograb C28Y variant after 1, 3, and 5 days of therapy. DAMB and Mycograb C28Y variant monotherapies, vehicle, and a no-treatment arm served as controls. Also, single- and multidose pharmacokinetics for the Mycograb C28Y variant were determined. Indifference or synergy between DAMB and the Mycograb C28Y variant was seen in two trials by the checkerboard method. The pharmacokinetics of the Mycograb C28Y variant was best described by a 2-compartment model with a median serum t(1/2)(α) of ~0.198 h and a t(1/2)(β) of ~1.77 h. In mice, DAMB together with the Mycograb C28Y variant was no more effective than AMB alone (P > 0.05 by analysis of variance). The Mycograb C28Y variant alone had no antifungal activity. We therefore conclude that the Mycograb C28Y variant in combination with DAMB offered no benefit over DAMB monotherapy in a neutropenic murine model of systemic candidiasis.

Topics: Amphotericin B; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antifungal Agents; Candidiasis; Deoxycholic Acid; Drug Combinations; Female; HSP90 Heat-Shock Proteins; Humans; Mice; Microbial Sensitivity Tests

Intracranial fungal masses are uncommon diseases, but their incidence is increasing, most often due to the prolonged survival of patients with different immunodeficiencies. The management of patients with intracranial fungal masses included stereotactic biopsy for diagnosis, partial or radical surgery excision and prolonged antifungal therapy.. We report the case of a 51-year-old diabetic man with a history of psoas abscess due to Candida albicans 1 year before the onset of neurological symptoms, including headache and generalized tonoclonic seizures.. Magnetic resonance imaging showed a single lesion located in the right parietal lobe with mass effect, surrounding edema and enhancement after injection of gadolinium. The material was purulent.. Direct microscopic examination showed hyaline, branched and septate hyphae compatible with fungal elements.. Fungal infections, especially due to Candida species, should be considered in diabetic patients with parenchymal brain abscesses. Radical excision followed by prolonged antifungal therapy based on fluconazole or amphotericin B is necessary to improve the prognosis of this type of patients.

Topics: Amphotericin B; Antifungal Agents; Brain Abscess; Candida albicans; Candidiasis; Combined Modality Therapy; Craniotomy; Deoxycholic Acid; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Fluconazole; Humans; Hyphae; Magnetic Resonance Imaging; Male; Mannitol; Middle Aged; Parietal Lobe; Psoas Abscess

Topics: Amphotericin B; Antifungal Agents; Brain; Brain Abscess; Candidiasis; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Echoencephalography; Female; Flucytosine; Follow-Up Studies; Fungemia; Humans; Infant; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Magnetic Resonance Imaging

The prevalence of nephrotoxicity in neonates receiving amphotericin B deoxycholate (amphoB) is not well-defined. While some studies report a lack of toxicity, others claim a frequency as high as 85%.. We reviewed medical records of all infants < or = 90 days of age in the neonatal intensive care unit who received at least 3 doses of amphoB between January 1990 and December 2004. A standardized form was used to collect demographic, therapeutic, microbiologic, and laboratory data for each patient. Nephrotoxicity was defined as a rise in serum creatinine (SCr) of at least 0.4 mg/dL any time during amphoB therapy.. A total of 92 infants met entry criteria. Median gestational age was 26 (range: 23-41) weeks and median birth weight was 863 (range: 546-4000) grams. Overall, 15 (16%) infants experienced nephrotoxicity, and 16 (17%) developed hypokalemia (<3.0 mmol/L). There were no differences between infants who did or did not develop nephrotoxicity in terms of gestational age, birth weight, gender, underlying medical conditions, or use of other potentially nephrotoxic medications. AmphoB exposure and duration of therapy were similar between infants who developed nephrotoxicity and those who did not, with a mean cumulative dose of 13.5 +/- 9.6 mg/kg and duration of 16.3 +/- 10.4 days. With the exception of 1 infant, the elevated SCr values resolved in all infants by the end of amphoB therapy.. AmphoB administration does not appear to be associated with lasting measurable nephrotoxicity in neonates. Because of changes in serum creatinine and potassium, renal function and potassium levels should be monitored closely in infants receiving amphoB.

Topics: Amphotericin B; Candidiasis; Creatinine; Deoxycholic Acid; Drug Combinations; Humans; Infant, Newborn; Kidney; Kidney Diseases; Retrospective Studies; Statistics, Nonparametric

Recent open label studies have suggested that dosing amphotericin B (AMB) by continuous infusion (CI) may reduce drug-associated infusion reactions and nephrotoxicity. In vitro and in vivo pharmacodynamic (PD) data, however, do not consistently support the concept of CI dosing based on the concentration-dependent activity of this agent and in vitro studies with AMB rarely account for the drug's high degree of protein binding. Therefore, we compared the PD activity of simulated continuous versus rapid infusion strategies of AMB in killing of AMB-susceptible and -resistant Candida species using an in vitro pharmacodynamic model.. Time-kill curves were performed with Candida albicans (Etest MIC 0.38 mg/L) and Candida lusitaniae (MIC 1.5 mg/L) at AMB concentrations between 0 and 16 mg/L in the absence and presence of 4 and 8% human serum albumin (HSA). A one-compartment in vitro pharmacodynamic model was used to simulate the steady-state PK parameters of bolus and CI AMB.. The fungicidal activity of AMB was attenuated by the presence of HSA for both Candida species tested. The EC50 for each isolate significantly increased in the presence of 4% HSA (P<0.05), and fungicidal activity was completely abated for C. lusitaniae when HSA concentrations were increased to 8%. No substantial differences in the rate or extent of AMB killing were observed between rapid infusion or CI dosing and neither regimen produced fungicidal activity in the presence of HSA.. The presence of HSA changes the in vitro PD of AMB. In our model, CI and rapid infusion dosing of AMB exhibited similar activity when attempts were made to correct for protein binding that is likely to occur in vivo.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Combinations; Half-Life; Humans; In Vitro Techniques; Infusions, Intravenous; Microbial Sensitivity Tests; Models, Biological; Serum Albumin

In the present study we evaluated the pharmacokinetics and toxicity of amphotericin B in immunomodulator tuftsin-loaded liposomes in a murine model.. Stability of amphotericin B liposomes was tested by incubating one volume of liposomal formulations of amphotericin B with nine volumes of serum. The pharmacokinetics of amphotericin B in Candida albicans-infected mice treated with conventional and tuftsin-loaded amphotericin B liposomes was evaluated over a period of 24 h. In vitro toxicity of amphotericin B deoxycholate, as well as amphotericin B liposomes, was tested by incubation with human erythrocytes for 1 h at 37 degrees C. To assess amphotericin B-induced in vivo toxicity, BALB/c mice were injected with three doses of amphotericin B deoxycholate, as well as amphotericin B liposomal formulations on days 1, 2 and 3 post C. albicans infection. Blood from treated mice was taken by retro-orbital puncture to test renal function parameters such as serum creatinine and urea.. In vitro stability studies revealed that tuftsin-bearing amphotericin B liposomes released only 11% of the total liposomal amphotericin B in the serum, while it was found to be 19% from identical tuftsin-free amphotericin B liposomes. Both tuftsin-loaded as well as tuftsin-free liposomal formulations of amphotericin B induced approximately 20% haemolysis of erythrocytes at a dose of 40 mg/L, while the same amount of drug in amphotericin B deoxycholate caused 100% lysis of the erythrocytes. Pharmacokinetic studies revealed that subsequent to administration of various formulations of amphotericin B, there was 32 mg/L amphotericin B in the systemic circulation of mice treated with tuftsin-bearing amphotericin B liposomes, while it was 25 mg/L for amphotericin B liposomes, 4 h post drug administration. In vivo toxicity studies demonstrated that the amphotericin B deoxycholate formulation induced elevations in serum creatinine (approximately 300% of control) and blood urea (approximately 380% of control) values, while these values were substantially less (blood urea approximately 150% of control and serum creatinine approximately 210% of control) in the animals treated with the tuftsin-loaded amphotericin B liposomal formulation. Further, the administration of amphotericin B deoxycholate (1 mg/kg) in BALB/c mice at a dose of 1 mg/kg body weight led to the accumulation of 18.6 +/- 5.25 g/kg (of amphotericin B) in kidneys. On the other hand, administration of liposomal amphotericin B and tuftsin-bearing liposomal amphotericin B at a dose of 5 mg/kg body weight resulted in accumulation of 8.8 +/- 2.0 and 4.0 +/- 1.6 g/kg of amphotericin B, respectively, in the kidneys of treated animals.. Co-administration of immunomodulator tuftsin along with liposomal formulations of amphotericin B successfully minimizes toxicity, as well as other side effects of the drug. Interestingly, tuftsin also increased the stability of liposomal amphotericin B. Superior efficacy, reliable safety and favourable pharmacodynamics of tuftsin-loaded amphotericin B liposomes suggest their potential therapeutic value in the management of fungal infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Combinations; Drug Stability; Immunologic Factors; Liposomes; Mice; Mice, Inbred BALB C; Tuftsin

A 53-year-old woman with an intraabdominal infection secondary to Candida albicans experienced hyperbilirubinemia after receiving amphotericin B in two different formulations--amphotericin B deoxycholate and amphotericin B lipid complex. Only a few case reports of amphotericin B-induced hyperbilirubinemia have been documented in the literature, each with different patterns of corresponding abnormalities in liver function tests. The unpredictable nature of this adverse effect warrants monitoring of bilirubin levels and liver function at baseline and potentially during therapy with amphotericin B, regardless of formulation, dosage, or duration of therapy.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Carcinoma, Non-Small-Cell Lung; Deoxycholic Acid; Drug Combinations; Female; Humans; Hyperbilirubinemia; Liver; Middle Aged; Phosphatidylcholines; Phosphatidylglycerols

The strategy of combining antifungal drugs in a treatment regimen may improve the outcome of invasive candidiasis. Using a well-validated pharmacodynamic murine model of invasive candidiasis, we defined the effect of the combination of amphotericin B deoxycholate (AmB) and 5-fluorocytosine (5FC) by use of the Greco model of drug interaction. The combination was additive, meaning that the experimental effect did not deviate in a statistically significant manner from the null reference model (or additive surface) of the combined effect. From a clinical perspective, the addition of 5FC to a regimen of AmB may enable the near-maximum effect to be reached in circumstances in which the administration of a given dose of AmB alone produces a submaximum effect but an increase in the dose is not possible, because of dose-related toxicity. Our methods provide a way in which some of the complex issues surrounding antifungal combination treatment can be addressed.

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Drug Therapy, Combination; Flucytosine; Male; Mice; Microbial Sensitivity Tests; Models, Biological

Fungal infections cause serious morbidity and mortality in lung transplant recipients. Expensive lipid formulations of amphotericin B (AmB) are generally used because of fear of adverse effects due to concomitant cyclosporine A and other nephrotoxic drugs. However, a 24-hour dosing regimen of AmB may be well tolerated even in these patients.. In an open pilot study 6 out of 94 lung transplant recipients with invasive or semi-invasive bronchopulmonary azole-resistant candidal infections (3 paraspilosis, 2 glabrata, 1 krusei) were treated for 40 (17-73) days by 24-hour continuous infusions of AmB 1 mg/kg. Additionally, patients received at least 1000 ml of 0.9% saline intravenously per day. Beside cyclosporine A at serum trough levels of 240 (195-273) microg/l, five patients additionally received aminoglycosides for at least 2 weeks, and 4 were treated with ganciclovir.. Calculated creatinine clearance decreased from 57 (43-73) ml/min to a nadir of 35 (28-39) and recovered to 52 (33-60) after cessation of therapy. One patient needed temporary haemofiltration for 7 days after 30 days of AmB, most probably because of the use of contrast media in conjunction with furosemide and hypovolaemia. Besides three episodes of mild hypokalaemia no other side effects attributable to AmB were recorded. While in one case an asymptomatic candidal colonisation persisted for 10 months, the other 5 were cured from their infection.. These preliminary data show that conventional AmB administered by 24-hour infusion is well tolerated, safe, and efficacious in lung transplant recipients receiving cyclosporine A and other nephrotoxic substances.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Azoles; Candidiasis; Child; Creatinine; Deoxycholic Acid; Drug Administration Schedule; Drug Combinations; Female; Humans; Infusions, Intravenous; Lung Diseases, Fungal; Lung Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Pilot Projects

The LD50 determined in rats for the potent antifungal amphotericin B (AB) increased from 4.2 to 12.0 when the conventional AB-deoxycholate (DOC) was compared with AB associated with a triglyceride-rich emulsion (AB-emulsion). The reduction in amphotericin B toxicity is not due to a modification in plasma clearance, as both formulations seem to be removed from plasma at the same rate. Major differences in amphotericin B tissue distribution were not seen for kidney and liver but were seen for the lung. After 24 h administration of a single amphotericin B dose (2.0 mg/kg body weight) 23.78 +/- 11.71 mg/kg tissue was recovered from the lung of animals treated with AB-DOC whereas for AB-emulsion only 5.19 +/- 2.50 mg/kg tissue was recovered. The higher lethality of AB-DOC may be related to the higher concentration of amphotericin B in the lung. The therapeutic efficacy of AB-emulsion was similar to that of AB-DOC as attested by survival curves obtained after treatment of mice infected by Candida albicans. This is highly relevant, as the same is not necessarily found for other less toxic proposed vehicles. The equivalent efficacy and the increment in the LD50 will result in an important improvement in the therapeutic activity of amphotericin B. Furthermore, some data related to storage and stability indicate the clinical utility of this type of drug delivery.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Deoxycholic Acid; Drug Combinations; Erythrocytes; Fat Emulsions, Intravenous; Lethal Dose 50; Male; Mice; Mice, Inbred BALB C; Potassium; Rats; Rats, Wistar; Tissue Distribution

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Deoxycholic Acid; Drug Combinations; Humans; Male; Middle Aged; Phosphatidylcholines; Phosphatidylglycerols; Respiration Disorders

Heat-induced 'superaggregation' of deoxycholate-amphotericin B (AmB-DOC, Fungizone) was shown previously to reduce the in-vitro toxicity of this antifungal agent. We compared AmB-DOC with the formulation obtained by heating the commercial form (Fungizone, Bristol Myers Squibb, Paris, France) for 20 min at 70 degrees C, in the treatment of murine infections. An improvement of antifungal activity was obtained with heated AmB-DOC formulations due to a lower toxicity which allowed the administration of higher drug doses than those achievable with the commercial preparation. Single intravenous injections of heated AmB-DOC solutions were demonstrated to be two-fold less toxic than unheated ones to healthy mice. For mice infected with Candida albicans, the maximum tolerated dose was higher with heated than with unheated AmB-DOC solutions. In the model of murine candidiasis, following a single dose of heated AmB-DOC 0.5 mg/kg, 85% of mice survived for 3 weeks, whereas at this dose the immediate toxicity of the standard formulation in infected mice restricted the therapeutic efficacy to 25% survival. Both formulations were equally effective in increasing the survival time for murine cryptococcal pneumonia and meningoencephalitis. Injection of heated AmB-DOC solutions at a dose two-fold higher than the maximal tolerated dose observed with the unheated preparation (1.2 mg/kg) increased the survival time by a factor of 1.4 in cryptococcal meningoencephalitis. These results indicate that mild heat treatment of AmB-DOC solutions could provide a simple and economical method to improve the therapeutic index of this antifungal agent by reducing its toxicity on mammalian cells.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Chemistry, Pharmaceutical; Cryptococcosis; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Hot Temperature; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mycoses

Amphotericin B colloidal dispersion (ABCD) is a novel lipid formulation of amphotericin B designed to diminish toxic effects of the drug. In the following report, nine cases of suspected (n = 4) and proven (n = 5) deep Candida infection, treated sequentially with amphotericin B deoxycholate and ABCD, are presented. The treatment was successful in seven cases. During treatment with amphotericin B deoxycholate, a rise in serum creatinine was observed in seven patients, hypokalemia in five, and metabolic acidosis in four. After replacing amphotericin B deoxycholate with ABCD, laboratory parameters improved in four of the seven patients with increased creatinine, in four of the five patients with hypokalemia, and in two of the four patients with metabolic acidosis. Infusion-related rigors were observed in four patients receiving amphotericin B deoxycholate and in one patient treated with ABCD. Reversible elevation of liver enzymes was found in one patient receiving ABCD. In this study ABCD proved less toxic than amphotericin B deoxycholate. The efficacy of ABCD alone cannot be assessed because of previous treatment with amphotericin B deoxycholate, but sequential treatment of deep Candida infections with amphotericin B deoxycholate and ABCD seems to be an effective therapeutic modality, especially in patients requiring prolonged administration of amphotericin B.

Topics: Acidosis; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candidiasis; Creatinine; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Female; Humans; Hypokalemia; Male; Middle Aged; Treatment Outcome

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

In the quest for safer and more effective antifungal agents, amphotericin B (AMB) has been placed in a variety of lipid preparations. In this study, we examined the efficacy of amphotericin B lipid complex (ABLC) on experimental cryptococcal meningitis and disseminated candidosis. This formulation is relatively safe compared to the parent compound, and therefore doses ten times greater than the commercial amphotericin B deoxycholate can be given to rabbits. Although at equal doses the ABLC preparation is less potent than AMB, a higher dose of ABLC was rapidly fungicidal in the contexts of both a central nervous system infection with Cryptococcus neoformans during immune suppression, and a heart and kidney infection with Candida albicans. Rapid sterilization of tissue should be a goal of antifungal drug therapy, particularly in the immune compromised host. From these studies, this AMB lipid formulation has the ability to produce rapid fungicidal activity in vivo, but it requires higher doses than AMB deoxycholate. Clinical trials in humans must examine carefully the therapeutic-toxic ratio in dose-escalation protocols to determine the optimal dosage strategy for this agent.

Topics: Amphotericin B; Animals; Blood Vessels; Candidiasis; Colony Count, Microbial; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Endocarditis; Kidney; Liposomes; Male; Meningitis, Cryptococcal; Rabbits

The in-vitro activities of amphotericin B-desoxycholate (AmB-DOC), liposomal amphotericin B (L-AmB) and fluconazole were determined against a single strain of Candida albicans. In addition, the efficacies of these agents in the treatment of systematic candidosis in both immunocompetent and leucopenic mice were compared. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of AmB-DOC and L-AmB were similar, but on the basis of time-kill studies, the fungicidal activity of L-AmB was significantly less than that of AmB-DOC. In immunocompetent mice, the dosage of AmB-DOC was limited by toxicity, resulting in a maximum tolerated dosage (MTD) of 0.4 mg/kg/day during treatment for 5 days; L-AMB was less toxic, the MTD being 7 mg/kg/day following a treatment period of the same duration. Both AmB-DOC and L-AmB led to significant reductions in the numbers of C. albicans in the kidneys of these mice and prevented relapse of infection after completion of treatment. Fluconazole in dosages of 0.4 and 64 mg/kg/day resulted in initial reductions in the numbers of cfu but failed to prevent relapse. In leucopenic mice, treatment for 5 days with AmB-DOC in a dosage of 0.3 mg/kg/day resulted in survival of the animals and a significant reduction in the numbers of cfu in the liver, spleen and lungs. However, there was no reduction in the number of cfu in the kidneys and this led to relapse of infection once therapy was terminated. Fluconazole in a dosage of 64 mg/kg/day produced effects which were similar to those of AmB-DOC; prolonged treatment with fluconazole for 18 days did not improve the efficacy of this agent. Only treatment with high-dosage (7 mg/kg/day) L-AmB was effective in significantly reducing the numbers of cfu of C. albicans in the kidneys and other organs of leucopenic mice, as well as preventing relapse, even in severely infected animals.

Topics: Amphotericin B; Animals; Candidiasis; Deoxycholic Acid; Drug Carriers; Drug Combinations; Female; Fluconazole; Immunocompetence; Leukopenia; Liposomes; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests