Fluconazole MIC and the Fluconazole Dose/MIC Ratio Correlate with Therapeutic Response among Patients with Candidemia

Abstract

We tested 32 Candida isolates recovered in the early 1990s from the bloodstreams of patients with candidemia for in vitro susceptibility to fluconazole and determined if MIC and/or the daily dose of fluconazole/MIC ratio correlated with the response to therapy. This is a unique data set since 87.5% (28/32) of patients were treated with fluconazole doses now considered to be inadequate (<200 mg), which contributed to high therapeutic failure rates (53% [17/32]). The geometric mean MIC and dose/MIC ratio for isolates associated with therapeutic failure (11.55 g/ml and 14.3, respectively) differed significantly from values associated with therapeutic success (0.95 g/ml and 219.36 [P ‫؍‬ 0.0009 and 0.0004, respectively]). The therapeutic success rates among patients infected with susceptible (MIC < 8 g/ml), susceptible-dose dependent (S-DD) (MIC ‫؍‬ 16 or 32 g/ml), and resistant (MIC > 64 g/ml) isolates were 67% (14/21), 20% (1/5), and 0% (0/6), respectively. A dose/MIC ratio >50 was associated with a success rate of 74% (14/19), compared to 8% (1/13) for a dose/MIC ratio <50 (P ‫؍‬ 0.0003). Our data suggest that both fluconazole MIC and dose/MIC ratio correlate with the therapeutic response to fluconazole among patients with candidemia. In clinical practice, dose/MIC ratio might prove easier to interpret than breakpoint MICs, since it quantitates the effects of increasing fluconazole doses that are alluded to in the S-DD designation.Candida spp. emerged as common causes of mucosal and systemic diseases with the onset of the AIDS epidemic and increasing populations of immunosuppressed individuals (18). The introduction of fluconazole revolutionized the therapy of candidal infections in the 1990s by offering a well-tolerated alternative to amphotericin B, the long-standing and significantly toxic antifungal of choice (23). Despite the recent development of newer antifungal drugs, fluconazole remains an attractive front-line agent against candidiasis because of its excellent oral bioavailability and overall clinical efficacy.The increasing importance of candidal infections created the need for reliable methods of testing clinical isolates for susceptibility to fluconazole and other antifungal agents. After 15 years of collaborative research, the National Committee for Clinical Laboratory Standards (NCCLS) approved a standardized reference method for testing of yeasts that demonstrated excellent intra-and interlaboratory reproducibility (17). With this method, the NCCLS proposed interpretive breakpoint MICs of fluconazole that correlated with the response to therapy in vivo, largely based upon the experience in treating human immunodeficiency virus (HIV)-infected patients with oropharyngeal candidiasis caused by Candida albicans (27). Since their publication, the NCCLS interpretative breakpoints have been supported by further data on oropharyngeal candidiasis (5-7, 21, 22, 25, 30, 34). A correlation between in vitro susceptibility and the response to therapy of nonmucosal candidiasis has been demonstrated in some studi...

Variation in Susceptibility of Bloodstream Isolates ofCandida glabratato Fluconazole According to Patient Age and Geographic Location in the United States in 2001 to 2007

“…However, as shown in the present study, resistance to fluconazole among isolates of C. glabrata is not predictable, and therefore antifungal susceptibility testing is needed to ensure optimal antifungal treatment of C. glabrata BSI (7,21,29,59). Indeed, several authors have now demonstrated the importance of the relationship between the daily dose of fluconazole and the in vitro susceptibility of the organisms to fluconazole as a predictor of therapeutic success or failure (4,10,18,29). Baddley et al (10) recently demonstrated that a fluconazole area under the concentration curve-to-MIC ratio of Ͻ11.5 or a MIC of Ն64 mg/ml was associated with increased mortality among patients with candidemia treated with fluconazole.…”

“…In institutions that have lower rates of infection with C. glabrata or in patients for whom infection due to fluconazole-resistant C. glabrata is less likely, fluconazole may still be appropriate as initial therapy for patients who are not critically ill and do not have prior fluconazole exposure (56)(57)(58)80). In such settings, however, it is important to pay strict attention to the appropriate utilization of fluconazole (10,18,29,41,59,90).…”

Epidemiology, species distribution, antifungal susceptibility, and ERG11 mutations of Candida species isolated from pregnant Chinese Han women

“…Fluconazole is the first drug of choice for the treatment of vaginitis in most parts of the world in accordance with recommended guidelines (Maertens, 2004). However, fluconazole resistance has been reported in both C. albicans and non-albicans species (Clancy et al, 2005;Liu et al, 2009). Approximately 11.5% of the isolates identified as C. albicans were found to be susceptible (in a dose-dependent manner), and 12 isolates were found to be resistant, to fluconazole.…”

Susceptibility To Caspofungin And Fluconazole And Als1/Als3 Gene Expression In Biofilm And Dispersal Cells Of Candida Albicans / Profil Osjetljivosti Na Kaspofungin I Flukonazol I Ekspresija Gena Als1 I Als3 U Stanicama Biofilma Te Planktonskim Stanicama Vrste Candida Albicans

“…The yeast C. albicans is the most common source of nosocomial bloodstream infections (4), mostly associated with the use of medical devices. FLC is often used to treat acute or chronic vaginal candidiasis and fungal infections in hospitalised patients or to prevent fungal infections in AIDS patients (27)(28)(29). However, the number of azoleresistant, mainly non-C. albicans isolates has increased in hospital care (30), limiting its application.…”