STABLE PHENOTYPIC RESISTANCE OF CANDIDA SPECIES TO AMPHOTERICIN-B CONFERRED BY PREEXPOSURE TO SUBINHIBITORY LEVELS OF AZOLES

The fungicidal activity of amphotericin B (AmB) was quantitated for se veral Candida species. Candida albicans and C, tropicalis were consist ently susceptible to AmB, with less than 1% survivors after 6 h of exp osure to AmB. C. parapsilosis and variants of C. lusitaniae and C. gui lliermondii were the most resistant, demonstrating 50 to 90% survivors in this time period and as high as 1% survival after a 24-h exposure time. All Candida species were killed (<1% survivors) after 24 h of ex posure to AmB. In contrast, overnight exposure to either fluconazole o r itraconazole resulted in pronounced increases in resistance to subse quent exposures to amB. Most dramatically, C. albicans was able to gro w in AmB cultures after azole preexposure. Several other Candida speci es did not grow in AmB but showed little or no reduction in viability after up to 24 h in AmB. Depending on the growth conditions, Candida c ells pl preexposed to azoles may retain AmB resistance for days after the azoles have been removed. If this in vitro antagonism applies to t he clinical setting, treatment of patients with certain antifungal com binations may not be beneficial. The ability of some Candida isolates to survive transient exposures to AmB was not reflected in the in vitr o susceptibility changes as measured by standard MIC assays, This find ing should be considered in studies attempting to correlate patient ou tcome with in vitro susceptibilities of clinical fungal isolates. Pati ents who fail to respond to AmB may be infected with isolates that are classified as susceptible by standard in vitro assays but that may be resistant to transient antifungal exposures which may be more relevan t in the clinical setting.