Identification of Patients with Acute AIDS-Associated Cryptococcal Meningitis Who Can Be Effectively Treated with Fluconazole: The Role of Antifungal Susceptibility Testing

Abstract

No method currently exists to predict which patients with acute AIDS-associated cryptococcal meningitis can be effectively treated with fluconazole. The objective of this study was to determine the relationship of cryptococcal susceptibility to fluconazole, along with clinical variables, to the risk of treatment failure for patients with acute AIDS-associated cryptococcal meningitis. Results of in vitro fluconazole susceptibility testing of cryptococcal isolates and data from two clinical trials were analyzed. Susceptibility to fluconazole was determined by means of both microtiter and macrobroth (M27-P) dilution methods. Treatment was defined as successful if the patient was alive at 10 weeks and if a cerebrospinal fluid culture was sterile at that time. Seventy-six patients receiving fluconazole +/- flucytosine were included; therapy failed for 19. Patients whose therapy failed were more likely to have a positive blood and urine culture and a higher titer in serum and cerebrospinal fluid of cryptococcal antigen, and the MIC of fluconazole against their isolates (as determined by the microtiter method) was more likely to be higher; they were less likely to have received flucytosine. Logistic regression modeling revealed that a negative blood culture, a low MIC of fluconazole (per the microtiter method), and treatment with flucytosine were factors independently associated with successful treatment.

Different culture media applied to the study of Cryptococcus neoformans susceptibility to amphotericin B and fluconazole

“…The C. neoformans susceptibility to fluconazole could be an important predictor of treatment success and MICs can be useful to monitor possible development of resistance during therapy and to identify primary resistance (1,3,4,13,14,15,19). Table 2 shows that YNB-1 provided higher MICs than RPMI 1640 medium.…”

In vitro antifungal susceptibility profiles and genotypes of 308 clinical and environmental isolates of Cryptococcus neoformans var. grubii and Cryptococcus gattii serotype B from north-western India

“…All of the patients whose serial isolates showed an increase in azole and amphotericin B MICs were HIV-positive. It may be added in this context that relapses in patients with AIDSassociated cryptococcosis are often due to deterioration of the host immune function rather than to an increase in MICs (Witt et al, 1996). However, a rising MIC of fluconazole has been implicated in clinical relapse in patients with AIDS-associated cryptococcal meningitis (Paugam et al, 1994;Birley et al, 1995;Currie et al, 1995;Armengou et al, 1996;Berg et al, 1998;Davey et al, 1998;Aller et al, 2000).…”

Combination Antifungal Therapy

“…In contrast to experience with amphotericin B, the addition of flucytosine to fluconazole in clinical studies has resulted in less-clear-cut benefits. In an observational study of HIV-infected individuals with cryptococcal meningitis, the addition of flucytosine to fluconazole for the treatment of subjects with a range of levels of illness consistently reduced the failure rate (222). In a small, randomized trial performed in Uganda, the addition of flucytosine to fluconazole for the first 2 weeks of induction therapy for the treatment of HIV-infected subjects with cryptococcal meningitis was associated with increased 6-month survival rates (32 versus 12% [P ϭ 0.022]) without a high frequency of serious toxicities (124).…”