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Amphotericin B deoxycholate
(AMB)
Amphotericin B is a polyene antifungal agent, first isolated by Gold et al from Streptomyces nodosus in 1955. It is an amphoteric compound composed of a hydrophilic polyhydroxyl chain along one side and a lipophilic polyene hydrocarbon chain on the other. Amphotericin B is poorly soluble in water [2232].
Amphotericin B is now available in four formulations. The classic amphotericin B deoxycholate (Fungizone™) formulation has been available since 1960 and is a colloidal suspension of amphotericin B. A bile salt, deoxycholate, is used as the solubilizing agent.
This preparation has a number of toxicities that are partially ameliorated when a lipid carrier is used. Thus, three lipid preparations of amphotericin B have been licensed and are currently available [1044]. These are:
Amphotericin B Colloidal Dispersion (ABCD; Amphocil™ or Amphotec™)
Amphotericin B Lipid Complex (ABLC; Abelcet™)
Liposomal Amphotericin B (L-AMB; Ambisome™)
Susceptibility patterns, usual doses, side effects and current status reviewed on this page are of the conventional amphotericin B formulation, unless otherwise is noted. For detailed information on these issues for the lipid formulations, refer to the corresponding page(s).
Amphotericin B binds to sterols, preferentially to the primary fungal cell membrane sterol, ergosterol. This binding disrupts osmotic integrity of the fungal membrane, resulting in leakage of intracellular potassium, magnesium, sugars, and metabolites and then cellular death. The mechanism of action is the same for all the preparations and is due to the intrinsic antifungal activity of amphotericin B [2232].
A standard method of NCCLS is available for testing in vitro susceptibility to amphotericin B [1622, 1623]. However, it lacks ability to readily discriminate the resistant isolates from the susceptible ones. While some investigators have reported the use of Antibiotic Medium 3 to be useful in this respect [1379, 1905], data obtained in other studies do not always support this theory [1639]. Using various modifications of the NCCLS methodology, moderately strong correlations between MIC and/or MLC (minimum lethal concentrations) and outcome have been reported [445] [1639].
Generally speaking, amphotericin B has a very broad range of activity and is active against most pathogenic fungi. Notable exceptions include Trichosporon beigelii [2365], Aspergillus terreus [2203], Pseudallescheria boydii [2353], Malassezia furfur [755], and Fusarium spp. [119].
On occasion, however, isolate of any species may be found to be resistant. Among the Candida spp., isolates of C. albicans,
C. guilliermondii,
C. lipolytica,
C. lusitaniae,
C. norvegensis,
C. tropicalis,
C. glabrata, and
C. krusei have been reported to be relatively resistant to amphotericin B [1156, 1157, 1527, 2232]. Reduced susceptibility has been observed specifically at fungicidal levels for C. parapsilosis [2074].
For amphotericin B MICs obtained for various types of fungi, see susceptibility patterns and the susceptibility database.
Amphotericin B deoxycholate is administered by intravenous infusion at doses ranging from 0.3 to 1.5 mg/kg and over 1-4 h [1527, 1685].
The most commonly observed infusion-related side effects of amphotericin B deoxycholate are fever, chills, and myalgia. These can be partially overcome by premedication with diphenhydramine and/or acetaminophen [873].
Nephrotoxicity is the major adverse effect limiting the use of amphotericin B. The manifestations of nephrotoxicity are azotemia, decreased glomerular filtration, loss of urinary concentrating ability, renal loss of sodium and potassium, and renal tubular acidosis [1527]. The renal injury reduces erythropoietin production and leads to a normochromic normocytic anemia [1346].
Thrombophlebitis may occur at the site of infusion. Thrombocytopenia may rarely be observed [413].
Amphotericin B and its lipid formulations are administered intravenously.
Amphotericin B still remains as the mainstay of antifungal therapy. Its lipid formulations, on the other hand, are promising due to their ability to reduce the toxicity of amphotericin B. They are currently licensed for use when amphotericin B therapy fails or is unacceptably toxic. The use of lipid formulations in specific clinical settings is under continuing investigation [2454].
Please also see our discussion on cost analysis and pharmacoeconomic analysis of antifungal therapy.
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References
119. Arikan, S., M. Lozano-Chiu, V. Paetznick, S. Nangia, and J. H. Rex. 1999. Microdilution susceptibility testing of amphotericin B, itraconazole, and voriconazole against clinical isolates of Aspergillus and Fusarium species. J Clin Microbiol. 37:3946-3951.
413. Chan, C. S. P., C. U. Tuazon, and L. S. Lessin. 1982. Amphotericin B-induced thrombocytopenia. Ann. Intern. Med. 96:332-333.
445. Clancy, C. J., and M. H. Nguyen. 1999. Correlation between in vitro susceptibility determined by E test and response to therapy with amphotericin B: Results from a multicenter prospective study of candidemia. Antimicrob. Agents Chemother. 43:1289-1290.
755. Francis, P., and T. J. Walsh. 1992. Approaches to management of fungal infections in cancer patients. Oncology. 6:133-44.
873. Goodwin, S. D., J. D. Cleary, C. A. Walawander, J. W. Taylor, and T. H. Grasela, Jr. 1995. Pretreatment regimens for adverse events related to infusion of amphotericin B. Clin. Infect. Dis. 20:755-761.
1044. Hiemenz, J. W., and T. J. Walsh. 1996. Lipid formulations of amphotericin B: Recent progress and future directions. Clin. Infect. Dis. 22:S133-S144.
1156. Karyotakis, N. C., and E. J. Anaissie. 1994. Efficacy of escalating doses of liposomal amphotericin B (AmBisome) against hematogenous Candida lusitaniae and Candida krusei infection in neutropenic mice. Antimicrob. Agents Chemother. 38:2660-2662.
1157. Karyotakis, N. C., E. J. Anaissie, R. Hachem, M. C. Dignani, and G. Samonis. 1993. Comparison of the efficacy of polyenes and triazoles against hematogenous Candida krusei infection in neutropenic mice. J. Infect. Dis. 168:1311-1313.
1346. Lin, A. C., E. Goldwasser, E. M. Bernard, and S. W. Chapman. 1990. Amphotericin B blunts erythropoietin response to anemia. J. Infect. Dis. 161:348-51.
1379. Lozano-Chiu, M., S. Arikan, F. M. Martin-Diez, V. Paetznick, J. L. Rodriguez-Tudela, and J. H. Rex. 1998. A two-center study of Antibiotic Medium 3 (AM3) broth for detection of amphotericin B (amB)-resistant isolates of Candida species (CAND) and Cryptococcus neoformans (CNEO). 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract No.
1527. Meyer, R. D. 1992. Current role of therapy with amphotericin B. Clin. Infect. Dis. 14(Suppl 1):S154-S160.
1622. National Committee for Clinical Laboratory Standards. 1998. Reference method for broth dilution antifungal susceptibility testing of conidium-forming filamentous fungi; proposed standard. NCCLS document M38-P. National Committee for Clinical Laboratory Standards, Wayne, Pa.
1623. National Committee for Clinical Laboratory Standards. 1997. Reference method for broth dilution antifungal susceptibility testing of yeasts; Approved standard NCCLS document M27-A. National Committee for Clinical Laboratory Standards, Wayne, Pa.
1639. Nguyen, M. H., C. J. Clancy, V. L. Yu, Y. V. Yu, A. J. Morris, D. R. Snydman, D. A. Sutton, and M. G. Rinaldi. 1998. Do in vitro susceptibility data predict the microbiologic response to amphotericin B? Results of a prospective study of patients with Candida fungemia. J. Infect. Dis. 177:425-430.
1685. Oldfield, E. C., 3rd, P. D. Garst, C. Hostettler, M. White, and D. Samuelson. 1990. Randomized, double-blind trial of 1- versus 4-hour amphotericin B infusion durations. Antimicrob. Agents Chemother. 34:1402-1406.
1905. Rex, J. H., C. R. Cooper, Jr., W. G. Merz, J. N. Galgiani, and E. J. Anaissie. 1995. Detection of amphotericin B-resistant Candida isolates in a broth-based system. Antimicrob. Agents Chemother. 39:906-909.
2074. Seidenfeld, S. M., B. H. Cooper, J. W. Smith, J. P. Luby, and P. A. Mackowiak. 1983. Amphotericin B tolerance: a characteristic of Candida parapsilosis not shared by other Candida species. J. Infect. Dis. 147:116-119.
2203. Sutton, D. A., S. E. Sanche, S. G. Revankar, A. W. Fothergill, and M. G. Rinaldi. 1999. In vitro amphotericin B resistance in clinical isolates of Aspergillus terreus, with a head-to-head comparison to voriconazole. J Clin Microbiol. 37:2343-2345.
2232. Terrell, C. L., and C. E. Hughes. 1992. Antifungal agents used for deep-seated mycotic infections. Mayo Clin Proc. 67:69-91.
2353. Walsh, M., L. White, K. Atkinson, and A. Enno. 1992. Fungal Pseudoallescheria boydii lung infiltrates unresponsive to amphotericin B in leukaemic patients. Aust N Z J Med. 22:265-8.
2365. Walsh, T. J., G. P. Melcher, M. G. Rinaldi, J. Lecciones, D. A. McGough, P. Kelly, J. Lee, D. Callender, M. Rubin, and P. A. Pizzo. 1990. Trichosporon beigelii, an emerging pathogen resistant to amphotericin B. J. Clin. Microbiol. 28:1616-1622.
2454. Wong-Beringer, A., R. A. Jacobs, and B. J. Guglielmo. 1998. Lipid formulations of amphotericin B: Clinical efficacy and toxicities. Clin. Infect. Dis. 27:603-618.
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