Mechanisms and clinical significance of antifungal resistance

Abstract

For fungal as well as bacterial infections, treatment failure — often called clinical resistance — should be clearly distinguished from microbial resistance. The former can be due to many causes pertaining to the host, the offender or the therapy itself, whereas the latter usually is due either to a native or intrinsic state of in vitro resistance, or to the development de novo or the expression of an acquired mechanism of resistance during therapy. Only microbial resistance will be considered here. In vitro determination of susceptibility or resistance to antifungal agents is still far behind that of antibacterial agents. However, for a few years now a standardised broth dilution method has been available which has the great merit of allowing reproducible results and inter-laboratory comparisons [1]. An increase in the number and spectrum of fungal infections, boosted by the AIDs pandemic and advances in anticancer chemotherapy and transplantation medicine has attracted new interest in the development of new compounds with antifungal activity. However, only three families of antifungal agents are still commonly used today; they are polyenes (amphotericin B), 5-fluorocytosine and azole derivatives (especially fluconazole and itraconazole). In vitro intrinsic resistance to amphotericin B is still a rare event, described mainly in some species of Candida (C. lusitaniae, C. guillermondii, and in some molds (Fusarium spp. P. boydii ). It is important to note that the current in vitro testing methodology [1] may underestimate the number of strains resistant or of reduced susceptibility to amphotericin B. Cases of documented acquired resistance to amphotericin B are even more limited up to now, having been described essentially with Cryptococcus neoformans. The clinical significance of in vitro resistance to amphotericin B is poorly documented, but a recent observational study of Candida spp bloodstream infections by Clancy and Nguyen suggests that the risk of failure is higher in patients infected with Candida strains having a MIC for amphotericin B higher than 0.38 mg/l at 48 h. rather than a lower value (56% failure rate vs. 16%, rr:3.5) [2]. For 5 FC, the picture is very different. Primary or intrinsic resistance is common in C. albicans (about 10% of the clinical isolates being natively resistant), and is known among Aspergillus spp., C. neoformans, and non-albicans Candida. This resistance is attributed to a defect in cytosine deaminase. Acquired resistance during treatment is so common (at least 30% of C. albicans) that monotherapy with 5 FC is strongly not recommended. Resistance to azole compounds is of high interest for two main reasons. One is the number and importance of yeasts (C. krusei, C. glabrata to some extent) and fungi (in particular Aspergillus spp and fluconazole) which are intrinsically not susceptible to these antifungal drugs. The second consists of acquired resistance to azoles, mainly in C. albicans. This phenomenon has been observed with an increasing frequency, particularly among HIV infected and AIDs patients suffering from oropharyngeal candidiasis and treated by recurrent courses of azoles. This acquired resistance has been correlated to a previous exposure to azoles and advanced immunosuppression and especially to a cumulative dose of fluconazole exceeding 10 g [3]. Before the availability of HAART treatment, clinical and microbiological failure of oral or oesophageal candidiasis was a frequent (up to 30%) problem. The correlation between in vitro resistance and in vivo clinical failure was well documented. Since the advent of HAART therapy, both the incidence of oropharyngeal candidiasis and that of azole resistant C. albicans episodes have dropped [4]. * Tel.: +41-21-3144057; fax: +41-21-3144060. E-mail address: jacques.bille@chuv.hospvd.ch (J. Bille).