We have correlated the in vitro results of testing the susceptibility of Cryptococcus neoformans to fluconazole with the clinical outcome after fluconazole maintenance therapy in patients with AIDS-associated cryptococcal disease. A total of 28 isolates of C. neoformans from 25 patients (24 AIDS patients) were tested. The MICs were determined by the broth microdilution technique by following the modified guidelines described in National Committee for Clinical Standards (NCCLS) document M27-A, e.g., use of yeast nitrogen base medium and a final inoculum of 10 4 CFU/ml. The fluconazole MIC at which 50% of isolates are inhibited (MIC 50 ) and MIC 90 , obtained spectrophotometrically after 48 h of incubation, were 4 and 16 g/ml, respectively. Of the 25 patients studied, 4 died of active cryptococcal disease and 2 died of other causes. Therapeutic failure was observed in five patients who were infected with isolates for which fluconazole MICs were >16 g/ml. Four of these patients had previously had oropharyngeal candidiasis (OPC); three had previously had episodes of cryptococcal infection, and all five treatment failure patients had high cryptococcal antigen titers in either serum or cerebrospinal fluid (titers, >1:4,000). Although 14 of the 18 patients who responded to fluconazole therapy had previously had OPC infections, they each had only a single episode of cryptococcal infection. It appears that the clinical outcome after fluconazole maintenance therapy may be better when the infecting C. neoformans strain is inhibited by lower concentrations of fluconazole for eradication (MICs, <16 g/ml) than when the patients are infected with strains that require higher fluconazole concentrations (MICs, >16 g/ml). These findings also suggest that the MICs determined by the modified NCCLS microdilution method can be potential predictors of the clinical response to fluconazole therapy and may aid in the identification of patients who will not respond to fluconazole therapy.Cryptococcosis is an infection caused by the ubiquitous fungus Cryptococcus neoformans, an encapsulated yeast-like fungus. The most frequent clinical presentation of the disease is meningoencephalitis (5, 6, 12, 18, 19; M. S. Saag, Editorial Response, Clin. Infect. Dis. 21:35-36, 1995); 75 to 90% of AIDS patients infected with C. neoformans will develop meningitis (5). Cryptococcosis in AIDS patients is seldom cured, and fluconazole is the drug of choice for the necessary lifelong suppressive (maintenance) therapy (17). Use of fluconazole for long-term suppressive therapy may be associated with the development of azole resistance in cryptococcal infections in AIDS patients (21).Methods for testing the antifungal susceptibility of C. neoformans could become important tools in the selection and monitoring of an appropriate antifungal drug for the treatment and prophylaxis of cryptococcal infections. Ghannoum et al. (9) developed a broth microdilution method for measuring the susceptibility of cryptococci to fluconazole, which is described as an alternative a...

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BackgroundTo assess the performance of Candida albicans germ tube antibody (CAGTA), (1 → 3)-ß-D-glucan (BDG), mannan antigen (mannan-Ag), anti-mannan antibodies (mannan-Ab), and Candida DNA for diagnosing invasive candidiasis (IC) in ICU patients with severe abdominal conditions (SAC).MethodsA prospective study of 233 non-neutropenic patients with SAC on ICU admission and expected stay ≥ 7 days. CAGTA (cutoff positivity ≥ 1/160), BDG (≥80, 100 and 200 pg/mL), mannan-Ag (≥60 pg/mL), mannan-Ab (≥10 UA/mL) were measured twice a week, and Candida DNA only in patients treated with systemic antifungals. IC diagnosis required positivities of two biomarkers in a single sample or positivities of any biomarker in two consecutive samples. Patients were classified as neither colonized nor infected (n = 48), Candida spp. colonization (n = 154) (low-grade, n = 130; high-grade, n = 24), and IC (n = 31) (intra-abdominal candidiasis, n = 20; candidemia, n = 11).ResultsThe combination of CAGTA and BDG positivities in a single sample or at least one of the two biomarkers positive in two consecutive samples showed 90.3 % (95 % CI 74.2–98.0) sensitivity, 42.1 % (95 % CI 35.2–98.8) specificity, and 96.6 % (95 % CI 90.5–98.8) negative predictive value. BDG positivities in two consecutive samples had 76.7 % (95 % CI 57.7–90.1) sensitivity and 57.2 % (95 % CI 49.9–64.3) specificity. Mannan-Ag, mannan-Ab, and Candida DNA individually or combined showed a low discriminating capacity.ConclusionsPositive Candida albicans germ tube antibody and (1 → 3)-ß-D-glucan in a single blood sample or (1 → 3)-ß-D-glucan positivity in two consecutive blood samples allowed discriminating invasive candidiasis from Candida spp. colonization in critically ill patients with severe abdominal conditions. These findings may be helpful to tailor empirical antifungal therapy in this patient population.

uAlthough epidemiological cutoff values (ECVs) have been established for Candida spp. and the triazoles, they are based on MIC data from a single laboratory. We have established ECVs for eight Candida species and fluconazole, posaconazole, and voriconazole based on wild-type (WT) MIC distributions for isolates of C. albicans (n ‫؍‬ 11,241 isolates), C. glabrata (7,538), C. parapsilosis (6,023), C. tropicalis (3,748), C. krusei (1,073), C. lusitaniae (574), C. guilliermondii (373), and C. dubliniensis (162). The 24-h CLSI broth microdilution MICs were collated from multiple laboratories (in Canada, Brazil, Europe, Mexico, Peru, and the United States). The ECVs for distributions originating from >6 laboratories, which included >95% of the modeled WT population, for fluconazole, posaconazole, and voriconazole were, respectively, 0.5, 0.06 and 0.03 g/ml for C. albicans, 0.5, 0.25, and 0.03 g/ml for C. dubliniensis, 8, 1, and 0.25 g/ml for C. glabrata, 8, 0.5, and 0.12 g/ml for C. guilliermondii, 32, 0.5, and 0.25 g/ml for C. krusei, 1, 0.06, and 0.06 g/ml for C. lusitaniae, 1, 0.25, and 0.03 g/ml for C. parapsilosis, and 1, 0.12, and 0.06 g/ml for C. tropicalis. The low number of MICs (<100) for other less prevalent species (C. famata, C. kefyr, C. orthopsilosis, C. rugosa) precluded ECV definition, but their MIC distributions are documented. Evaluation of our ECVs for some species/ agent combinations using published individual MICs for 136 isolates (harboring mutations in or upregulation of ERG11, MDR1, CDR1, or CDR2) and 64 WT isolates indicated that our ECVs may be useful in distinguishing WT from non-WT isolates.