Pharmacology of amphotericin B
- Richard H Drew, PharmD, MS, FCCP
Richard H Drew, PharmD, MS, FCCP
- Professor, Campbell University College of Pharmacy and Health Sciences
- Associate Professor and Clinical Pharmacist, Infectious Diseases
- Duke University Medical Center
Amphotericin B is a polyene antifungal agent with activity in vitro against a wide variety of fungal pathogens . Amphotericin B exerts its antifungal effect by disruption of fungal cell wall synthesis because of its ability to bind to sterols, primarily ergosterol, which leads to the formation of pores that allow leakage of cellular components. This affinity may also account for its toxic effects against select mammalian cells. Amphotericin B is generally considered cidal against susceptible fungi at clinically relevant concentrations.
Despite the introduction of newer antifungal agents for the treatment of systemic mycoses, amphotericin B remains the standard treatment for many severe, invasive fungal infections. However, because of toxicities associated with its intravenous use, along with the expanded availability of safer treatment options, it is frequently reserved for patients who have severe, life-threatening invasive fungal infections or who are unable to tolerate alternative antifungal agents.
The pharmacology of amphotericin B will be reviewed here. The nephrotoxicity and the clinical uses of amphotericin B are discussed in detail elsewhere. (See "Amphotericin B nephrotoxicity" and "Treatment of candidemia and invasive candidiasis in adults" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)" and "Candida infections of the bladder and kidneys" and "Candida osteoarticular infections" and "Treatment of endogenous endophthalmitis due to Candida species" and "Treatment of exogenous endophthalmitis due to Candida species" and "Candida endocarditis and suppurative thrombophlebitis" and "Mucormycosis (zygomycosis)" and "Treatment and prevention of invasive aspergillosis" and "Treatment and prevention of Fusarium infection" and "Treatment of Cryptococcus neoformans meningoencephalitis and disseminated infection in HIV seronegative patients" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients" and "Cryptococcus neoformans infection outside the central nervous system" and "Treatment of blastomycosis" and "Diagnosis and treatment of pulmonary histoplasmosis" and "Diagnosis and treatment of disseminated histoplasmosis in HIV-uninfected patients" and "Diagnosis and treatment of histoplasmosis in HIV-infected patients" and "Management of pulmonary sequelae and complications of coccidioidomycosis" and "Manifestations and treatment of extrapulmonary coccidioidomycosis" and "Coccidioidomycosis in compromised hosts" and "Coccidioidal meningitis" and "Treatment of sporotrichosis".)
SPECTRUM OF ACTIVITY
Activity of amphotericin B has been demonstrated in vitro against a wide variety of clinical fungal isolates, including most Candida spp, Aspergillus spp, the Mucorales, all of the endemic mycoses, and most hyaline and brown-black molds. Activity has also been demonstrated against Leishmania spp .
Organisms that are usually resistant to amphotericin B include the organisms that cause chromoblastomycosis, Aspergillus terreus, Candida lusitaniae, Scedosporium spp, and some Fusarium spp [2-6].
- Dismukes WE. Antifungal therapy: lessons learned over the past 27 years. Clin Infect Dis 2006; 42:1289.
- McEvoy, G (Ed). American Hospital Formulary Service — 1996. American Society of Health System Pharmacists, Bethesda, MD, 1996.
- Kontoyiannis DP, Lewis RE. Antifungal drug resistance of pathogenic fungi. Lancet 2002; 359:1135.
- Steinbach WJ, Benjamin DK Jr, Kontoyiannis DP, et al. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin Infect Dis 2004; 39:192.
- Meletiadis J, Meis JF, Mouton JW, et al. In vitro activities of new and conventional antifungal agents against clinical Scedosporium isolates. Antimicrob Agents Chemother 2002; 46:62.
- Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev 2007; 20:695.
- Daneshmend TK, Warnock DW. Clinical pharmacokinetics of systemic antifungal drugs. Clin Pharmacokinet 1983; 8:17.
- Perfect JR, Klotman ME, Gilbert CC, et al. Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients. J Infect Dis 1992; 165:891.
- Riley DK, Pavia AT, Beatty PG, et al. The prophylactic use of low-dose amphotericin B in bone marrow transplant patients. Am J Med 1994; 97:509.
- Infectious Diseases Society of America. http://www.idsociety.org/Index.aspx (Accessed on April 16, 2015).
- Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Rev Infect Dis 1990; 12:308.
- Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ 2001; 322:579.
- Leu HS, Huang CT. Clearance of funguria with short-course antifungal regimens: a prospective, randomized, controlled study. Clin Infect Dis 1995; 20:1152.
- Jacobs LG, Skidmore EA, Freeman K, et al. Oral fluconazole compared with bladder irrigation with amphotericin B for treatment of fungal urinary tract infections in elderly patients. Clin Infect Dis 1996; 22:30.
- Jacobs LG. Fungal urinary tract infections in the elderly: treatment guidelines. Drugs Aging 1996; 8:89.
- Fan-Havard P, O'Donovan C, Smith SM, et al. Oral fluconazole versus amphotericin B bladder irrigation for treatment of candidal funguria. Clin Infect Dis 1995; 21:960.
- Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62:e1.
- Stevens DA, Shatsky SA. Intrathecal amphotericin in the management of coccidioidal meningitis. Semin Respir Infect 2001; 16:263.
- Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005; 41:1217.
- Keane JR. Cisternal puncture complications. Treatment of coccidioidal meningitis with amphotericin B. Calif Med 1973; 119:10.
- Drew RH. Aerosol and other novel administrations for prevention and treatment of invasive aspergillosis. Med Mycol 2009; 47 Suppl 1:S355.
- Safdar A, Rodriguez GH. Aerosolized amphotericin B lipid complex as adjunctive treatment for fungal lung infection in patients with cancer-related immunosuppression and recipients of hematopoietic stem cell transplantation. Pharmacotherapy 2013; 33:1035.
- Hayes D Jr, Murphy BS, Lynch JE, Feola DJ. Aerosolized amphotericin for the treatment of allergic bronchopulmonary aspergillosis. Pediatr Pulmonol 2010; 45:1145.
- Hanada S, Uruga H, Takaya H, et al. Nebulized liposomal amphotericin B for treating Aspergillus empyema with bronchopleural fistula. Am J Respir Crit Care Med 2014; 189:607.
- Gigliotti F, Shenep JL, Lott L, Thornton D. Induction of prostaglandin synthesis as the mechanism responsible for the chills and fever produced by infusing amphotericin B. J Infect Dis 1987; 156:784.
- Falci DR, da Rosa FB, Pasqualotto AC. Hematological toxicities associated with amphotericin B formulations. Leuk Lymphoma 2015; 56:2889.
- Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis 1998; 27:603.
- Slain D. Lipid-based amphotericin B for the treatment of fungal infections. Pharmacotherapy 1999; 19:306.
- Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis 1996; 22 Suppl 2:S133.
- Graybill JR. Lipid formulations for amphotericin B: does the emperor need new clothes? Ann Intern Med 1996; 124:921.
- Walsh TJ, Hiemenz JW, Seibel NL, et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis 1998; 26:1383.
- Mistro S, Maciel Ide M, de Menezes RG, et al. Does lipid emulsion reduce amphotericin B nephrotoxicity? A systematic review and meta-analysis. Clin Infect Dis 2012; 54:1774.
- Bowden R, Chandrasekar P, White MH, et al. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis 2002; 35:359.
- Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002; 137:105.
- Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med 1999; 340:764.
- Wingard JR, White MH, Anaissie E, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin Infect Dis 2000; 31:1155.
- White MH, Anaissie EJ, Kusne S, et al. Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis 1997; 24:635.
- Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 2007; 369:1519.
- Roden MM, Nelson LD, Knudsen TA, et al. Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics. Clin Infect Dis 2003; 36:1213.
- Farmakiotis D, Tverdek FP, Kontoyiannis DP. The safety of amphotericin B lipid complex in patients with prior severe intolerance to liposomal amphotericin B. Clin Infect Dis 2013; 56:701.
- Food and Drug Administration. AmBisome (amphotericin B) liposome for injection. Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – March 2012. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm299520.htm.
- Weiler S, Bellmann-Weiler R, Joannidis M, Bellmann R. Penetration of amphotericin B lipid formulations into pleural effusion. Antimicrob Agents Chemother 2007; 51:4211.
- Cornely OA, Maertens J, Bresnik M, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007; 44:1289.
- Giannella M, Ercolani G, Cristini F, et al. High-dose weekly liposomal amphotericin b antifungal prophylaxis in patients undergoing liver transplantation: a prospective phase II trial. Transplantation 2015; 99:848.
- Cordonnier C, Mohty M, Faucher C, et al. Safety of a weekly high dose of liposomal amphotericin B for prophylaxis of invasive fungal infection in immunocompromised patients: PROPHYSOME Study. Int J Antimicrob Agents 2008; 31:135.
- Cagnoni PJ, Walsh TJ, Prendergast MM, et al. Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients. J Clin Oncol 2000; 18:2476.
- Sievers TM, Kubak BM, Wong-Beringer A. Safety and efficacy of Intralipid emulsions of amphotericin B. J Antimicrob Chemother 1996; 38:333.
- SPECTRUM OF ACTIVITY
- AMPHOTERICIN B DEOXYCHOLATE
- - Absorption
- - Distribution
- - Metabolism/elimination
- Method of administration
- - Intravenous
- - Bladder irrigation
- - Intraperitoneal
- - Intrathecal
- - Intravitreal
- - Aerosolized/nebulized
- Adverse effects
- - Infusion-related reactions
- - Nephrotoxicity
- - Electrolyte abnormalities
- - Other reactions
- Patient monitoring
- LIPID-BASED AMPHOTERICIN B FORMULATIONS
- Safety and efficacy
- Amphotericin B plus fat emulsions
- DRUG INTERACTIONS