Title: Use of amphotericin B with azole antifungal drugs: what are we doing?
Abstract: Since the 1950s, the standard agent prescribed for systemic antifungal therapy has been amphotericin B (36). Its broad spectrumofactivitymakesitanattractiveagentfortheempiric treatment of patients who may be infected with yeasts or molds.Itstrackrecordastheprimarytherapyformostinvasive mycosesiswellestablished,anditisstillwidelyregardedasthe agent of choice for the treatment of many patients with invasive mycoses. However, the toxicity of amphotericin B is well appreciatedandisoftenresponsibleforlimitingtheamountof drugthatcanbeadministered.Giventheimportanceofserious mycoses in clinical medicine and the need for alternative therapies for use in patients with fungal infections, research designed to identify new antifungal drugs has accelerated. The azole antifungal drugs are one example of the fruits of these efforts. Ketoconazole, fluconazole, and itraconazole have extended the ability to treat a variety of fungal infections with oral regimens (9, 11), without the toxicity of amphotericin B. One of the questions that has arisen following increasing experience with the azoles is whether they can be combined with amphotericin B to achieve synergy, to broaden their combined spectrum of activity, or to lower the dose of amphotericin B. Certainly, the availability of different antifungal drugs makes the administration of combinations of drugs not only possible but even desirable. Thus, combinations of amphotericin B with flucytosine have been suggested to be as effective andlesstoxicthanamphotericinBusedalone,especiallyinthe treatment of cryptococcal meningitis (6). Because ketoconazolecouldonlybegivenorallyanditsspectrumofactivitywas rather narrow, the use of combinations of amphotericin B with ketoconazolewerenotcommonlyencounteredinclinicalmedicine. Furthermore, studies by Schaffner and Frick (29) suggested that this combination might be antagonistic when used to treat aspergillosis. This observation supported the theoretical concerns that combinations of polyene antifungal drugs, which bind to ergosterol in the fungal cell membrane, and azoles, which inhibit the synthesis of ergosterol, would be antagonistic, irrespective of the fungal infection. Thus, with the