Correlation of In Vitro Fluconazole Susceptibility with Clinical Outcome for Severely Ill Patients with Oropharyngeal Candidiasis

144

Recent studies of nonneutropenic patients with candidemia or candidiasis suggest that fluconazole pharmacodynamic parameters correlate with clinical outcomes; however, additional data of correlation to mortality in patients with candidemia would be valuable. We assessed the impact of MICs for Candida, fluconazole pharmacodynamics, and patient characteristics on all-cause mortality with use of a prospective cohort of 96 hospitalized patients with candidemia. Among 84 patients for whom Candida isolates were available for testing, the most frequent Candida species isolated were Candida albicans (44%), followed by Candida parapsilosis (20.2%), and Candida glabrata (20.2%). Fluconazole resistance (MIC of >64 g/ml) was present in 7 (8.3%) to 10 (11.9%) of 84 isolates, depending on the MIC endpoint determination method (50% or 80% inhibition read at 24 or 48 h). Overall mortality occurred in 27 (28.1%) of 96 patients, and nonsurvivors were more likely to have fluconazole-resistant isolates (25% versus 6.7%; P ‫؍‬ 0.02). Multivariable analysis demonstrated an association between fluconazole resistance and mortality, but it did not reach statistical significance (odds ratio, 5.3; 95% confidence interval, 0.8 to 33.4; P ‫؍‬ 0.08). By pharmacodynamic analysis, a fluconazole area under the concentration-time curve/MIC of <11.5 or MIC of >64 was associated with increased patient mortality (P < 0.09). These data support previous findings of an antifungal exposure-response relationship to mortality in patients with candidemia. In addition, similar MICs were obtained using a 24-or 48-h MIC endpoint determination, thus providing the opportunity to assess earlier the impact of isolate susceptibility on therapy.

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confidence: 75%

Section: Vol 52 2008 Fluconazole Pharmacodynamics 3025mentioning

confidence: 99%

Association of Fluconazole Pharmacodynamics with Mortality in Patients with Candidemia

Baddley

Patel

Bhavnani

et al. 2008

144

“…tested against fluconazole were established and studies to evaluate the correlation between in vitro MICs and in vivo outcome were initiated (1,17). While good correlation has been demonstrated in cases involving AIDS patients with oropharyngeal candidiasis (2,16), the results have emphasized that an MIC determination is very method dependent and that minor variations in the M27-A method or the breakpoints used to define resistance can significantly alter the resulting MIC and subsequent susceptibility interpretation and therefore the correlation to in vivo outcome (13,14).…”

Section: Discussionmentioning

confidence: 99%

Quantitation of Candida albicans Ergosterol Content Improves the Correlation between In Vitro Antifungal Susceptibility Test Results and In Vivo Outcome after Fluconazole Treatment in a Murine Model of Invasive Candidiasis

Arthington-Skaggs

Warnock

Morrison

2000

132

115

MIC end point determination for the most commonly prescribed azole antifungal drug, fluconazole, can be complicated by "trailing" growth of the organism during susceptibility testing by the National Committee for Clinical Laboratory Standards approved M27-A broth macrodilution method and its modified broth microdilution format. To address this problem, we previously developed the sterol quantitation method (SQM) for in vitro determination of fluconazole susceptibility, which measures cellular ergosterol content rather than growth inhibition after exposure to fluconazole. To determine if SQM MICs of fluconazole correlated better with in vivo outcome than M27-A MICs, we used a murine model of invasive candidiasis and analyzed the capacity of fluconazole to treat infections caused by C. albicans isolates which were trailers (M27-A MICs at 24 and 48 h, <1.0 and >64 g/ml, respectively; SQM MIC, <1.0 g/ml), as well as those which were fluconazole sensitive (M27-A and SQM MIC, <1.0 g/ml) and fluconazole resistant (M27-A MIC, >64 g/ml; SQM MIC, 54 g/ml). Compared with the untreated controls, fluconazole therapy increased the survival of mice infected with a sensitive isolate and both trailing isolates but did not increase the survival of mice infected with a resistant isolate. These results indicate that the SQM is more predictive of in vivo outcome than the M27-A method for isolates that give unclear MIC end points due to trailing growth in fluconazole.

“…NCCLS conditions attempt to reflect in vivo conditions resembling systemic infections. Accordingly, MICs generated with these tests show reasonable correlation with patient outcome in FLZ-treated systemic infections (1,2,11,22,39,48,51). It is generally assumed that FLZ is fungistatic for Candida species in vivo, inhibiting growth and allowing or aiding the body's defenses that eliminate the infection (10,14,17,29,49,50).…”

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confidence: 89%

Fungicidal Activity of Fluconazole against Candida albicans in a Synthetic Vagina-Simulative Medium

Moosa¹,

Sobel²,

Elhalis

et al. 2004

Fluconazole (FLZ) has emerged as a highly successful agent in the management of systemic infections of Candida. Cure rates for symptomatic candidiasis following single 150-mg FLZ dose therapy exceed 90%. In vitro, however, FLZ is fungistatic only in a narrow pH range and is not effective at vaginal pH, 4.2. This study evaluated the effect of FLZ on Candida albicans under in vitro conditions resembling the vaginal microenvironment, using vagina-simulative medium (VS). We found that FLZ was fungicidal for C. albicans in VS, but not in other media at the same pH, 4.2. In VS, FLZ was fungicidal at concentrations of >8 g/ml and reduced viability by greater than 99.9%. Analysis of the components of VS indicated that 17 mM acetic acid, a concentration achieved in the vagina, was responsible for the synergistic, fungicidal effect. This effect was not seen at neutral pH. Other substrates were not effective substitutes for acetic acid; however, short-chained carboxylic acids, glyoxylate and malonate, were effective. Most strains of C. albicans that were resistant to FLZ under standard conditions were killed by FLZ plus acetate. Other species of Candida were also killed, except C. krusei and C. glabrata. This study shows that FLZ has fungicidal activity for Candida species under in vitro conditions that mimic the vaginal microenvironment. This raises the possibility that FLZ may also have fungicidal effects during treatment of vaginal candidiasis. Elucidating the mechanism by which FLZ and acetate interact may disclose vulnerable pathways that could be exploited in drug development.