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Concept: Amphotericin B

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Introduction: Leishmaniasis is a parasitic disease transmitted by phlebotomine sandflies. Between 700,000 and 1.2 million cases of cutaneous leishmaniasis and between 200,000 and 400,000 cases of visceral leishmaniasis (VL), which is fatal if left untreated, occur annually worldwide. Liposomal amphotericin B (LAMB), alone or in combination with other drugs, has been extensively studied as VL treatment, but data on routine field use are limited, and several challenges to patients' access to this life-saving drug remain. Areas covered: This article provides a review of clinical studies on LAMB for VL and other forms of leishmaniasis. The current development of generic versions of LAMB and related challenges are also discussed. Expert opinion: LAMB proved to be highly efficacious and safe in over 8000 VL patients treated by MÉdecins Sans Frontières in South Asia, and its use was feasible even at primary healthcare level. Despite requiring higher doses, LAMB is the drug of choice to treat vulnerable groups (e.g., pregnant or HIV positive) and relapsing VL patients in East Africa. LAMB should be included in national VL guidelines and registered in all VL endemic countries. Its cost should be further reduced and regulatory pathways to prove bioequivalence for generic LAMB products should be implemented.

Concepts: Illness, Amphotericin B, Leishmaniasis, Visceral leishmaniasis, Generic drug, Cutaneous leishmaniasis, Leishmania, Parasitic diseases

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Our goal was to improve treatment outcomes for visceral leishmaniasis by designing nanocarriers that improve drug biodistribution and half-life. Thus, long-acting mannose-anchored thiolated chitosan amphotericin B nanocarrier complexes (MTC AmB) were developed and characterized.

Concepts: Amphotericin B, Leishmaniasis, Visceral leishmaniasis

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Background Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. Methods We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. Results A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen. Conclusions One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509 .).

Concepts: AIDS, Africa, Tuberculosis, Amphotericin B, Antifungals, Flucytosine, Antifungal drug, World Health Organization essential medicines

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Pulmonary aspergillomas may cause life-threatening hemoptysis. The treatment of this condition is problematic because poor pulmonary function often precludes definitive surgical resection.

Concepts: Function, Amphotericin B, Resection, Hemoptysis, Aspergilloma

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New World cutaneous leishmaniasis is mostly acquired in the Amazon Basin of Bolivia where L viannia (V) braziliensis is endemic. Treatment with systemic pentavalent antimonial compounds has been shown to be effective in achieving clinical cure in only 75% of cases.

Concepts: Amphotericin B, Leishmaniasis, Visceral leishmaniasis, Cutaneous leishmaniasis, Leishmania, Amazon River, Sodium stibogluconate, Pentavalent antimonial

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OBJECTIVE:To report a case of accidental amphotericin B overdose that was treated with plasmapheresis.CASE SUMMARY:A 60-year-old woman with a history of kidney transplant 4 years prior to presentation for a congenital abnormality was admitted for a suspected systemic fungal infection. The patient inadvertently received intravenous amphotericin B deoxycholate 250 mg (4.3 mg/kg) over 2 hours instead of prescribed liposomal amphotericin B. The medication error was discovered 16 hours after administration. She had normal vital signs at that time and reported abdominal pain and general malaise. Results of a metabolic panel were significant for a creatinine level of 2.1 mg/dL and CO(2) of 17 mg/dL. Her serum amphotericin B concentration 33 hours after the initial dose was 4.9 μg/mL. She subsequently received 5 courses of plasmapheresis and 3 courses of hemodialysis and ultimately did not develop any further renal injury, as well as hemolysis, cardiovascular collapse, dysrhythmias, or severe electrolyte abnormalities.DISCUSSION:The dosing differences between nonliposomal and liposomal preparations of amphotericin B can be as high as 50-fold. Reported adverse events from overdose in both animal models and human case reports include renal insufficiency, hemolysis, thrombocytopenia, electrolyte abnormality, and cardiac dysrhythmias. There have been previous reports of similar errors that have led to death. Furthermore, amphotericin B has been shown to be poorly dialyzable. Our patient’s serum amphotericin B concentration decreased after she received plasmapheresis, and she did not develop severe complications.CONCLUSIONS:We describe a patient who survived a 4-fold overdose of amphotericin because of a medication error. The use of plasmapheresis may have enhanced the elimination of amphotericin and may have contributed to the positive outcome. However, the role of plasmapheresis in amphotericin overdose is not fully understood.

Concepts: Chronic kidney disease, Kidney, Nephrology, Dialysis, Report, Vital signs, Amphotericin B, Thrombocytopenia

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Recent studies have shown decreased susceptibility of Candida krusei to amphotericin B (AmB), in addition to its inherent resistance to fluconazole. The susceptibility of C. krusei to AmB was studied in the Parasitology-Mycology laboratory of Grenoble Teaching Hospital, France. Between 2003 and 2011, we analysed 200 C. krusei isolates from 130 patients. The isolates were mainly collected in intensive care, cardio-thoracic and cancer/haematology units. Minimum inhibitory concentrations (MICs) were determined by the E-test method. The modal MIC was 0.5 μg ml(-1) ; the MIC(50) and MIC(90) (MICs encompassing 50% and 90% of all isolates tested, respectively) were 0.5 μg ml(-1) and 1 μg ml(-1) . The Cuzick’s and Kendall’s tests showed a significant increase in MIC values between 2003 and 2011 (P = 0.001 and P ≤ 0.001, respectively), regardless of age or gender. No statistical difference was reached with these tests when the first 100 or 50 data were excluded. Despite the increase observed in the first period of the study, our results confirm the low AmB MICs reported in previous studies. However, some authors have recently reported much higher MICs. This discrepancy cannot be explained by method biases and could reflect C. krusei epidemiological differences among populations.

Concepts: Scientific method, Hospital, Retrospective, Amphotericin B, Cultural studies, Candida krusei

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Introduction: Leishmaniasis broadly manifests as visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). The treatment of VL is challenging. The duration of treatment is long, and drugs are toxic thereby needing monitoring and hospitalization. Areas covered: Novel therapies such as single dose of liposomal amphotericin B (L-AmB) and multidrug therapy are important breakthrough for VL in the Indian subcontinent and have been recommended as the treatment of choice in this region. African Leishmania donovani is less susceptible to L-AmB, miltefosine and paromomycin as compared to the Indian strains, and the treatment of choice remains a 17-day combination therapy of pentavalent antimonials (SB(v)) and paromomycin. L-AmB at a total dose of 18 - 21 mg/kg is the recommended regimen in the Mediterranean region and South America. It is also the treatment of choice for HIV-VL coinfection. Treatment of CL should be decided by the clinical lesions, etiological species and its potential to develop into mucosal leishmaniasis. A literature search on treatment of leishmaniasis was done on PubMed and through Google. Expert opinion: There is an urgent need for exploratory studies with short course, highly efficient regimens such as single dose L-AmB or combination therapy for all the endemic regions of VL. Shorter and more acceptable regimens are needed for the treatment of post-kala-azar dermal leishmaniasis. Treatment of CL remains one of the neglected areas of leishmaniasis as data are scarce and drawn from uncontrolled studies.

Concepts: Therapy, Amphotericin B, Leishmaniasis, Visceral leishmaniasis, Cutaneous leishmaniasis, Leishmania, Sodium stibogluconate, History of the Mediterranean region

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We aim in this study to provide levels of susceptibility of 162 bloodstream isolates of non-Candida albicans and non-C. tropicalis species from a sentinel program conducted in 11 hospitals in Brazil. Additionally, we compared the broth microdilution (BMD) method of the European Committee of Susceptibility Testing (EUCAST) with Clinical Laboratory Standards Institute (CLSI) BMD method for fluconazole, itraconazole, voriconazole, and amphotericin B. The study included 103 C. parapsilosis, 38 C. glabrata, 8 C. orthopsilosis, and 7 C. krusei isolates, and single isolates of Pichia anomala, C. famata, C. lusitaniae, C. kefyr, C. guilliermondii, and C. metapsilosis. Of note, we observed cross-resistance between fluconazole and voriconazole for two isolates being one C. parapsilosis and one C. glabrata. Good essential agreement (EA) was observed between the EUCAST and the CLSI results for C. parapsilosis and for fluconazole, itraconazole, voriconazole, and amphotericin B, respectively: 98%, 99%, 98%, and 97%. Otherwise, for C. glabrata, the EA for fluconazole was 84.2% and for voriconazole 89.4%. Because data from Brazil are scarce, our results contribute to the consolidation of the database of candidemia agents and monitoring of trends in the profile of drug resistance.

Concepts: Laboratory, Amphotericin B, The Europeans, Antifungals, Candidiasis, Ergosterol, Triazole, World Health Organization essential medicines

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We report the detection of high-titre anti-Histoplasma capsulatum IgM in the serum of three young adult males occupationally exposed to bat guano. Multidrug treatment with trimethoprim- sulfamethoxazole was started, followed by ciprofloxacin, clarithromycin, metamizole sodium, rifampicin/isoniazid/pyrazinamide, moxifloxacin and lastly amphotericin B and ceftriaxone. Despite treatment the condition of one patient deteriorated, and he died 23 days after exposure. The other two patients recovered after receiving similar therapy with the addition of voriconazole. They are currently being treated with itraconazole for a 1-year period.

Concepts: Patient, Amphotericin B, Bat, Antifungals, Ergosterol, Histoplasmosis, Guano, World Health Organization essential medicines