Correlation of fluconazole MICs with clinical outcome in Cryptococcal infection

We have correlated the in vitro results of testing the susceptibility of Cr yptococcus neoformans to fluconazole with the clinical outcome after flucon azole maintenance therapy in patients,vith AIDS-associated cryptococcal dis ease, A total of 28 isolates of C. neoformans from 25 patients (24 AIDS pat ients) were tested. The MICs were determined by the broth microdilution tec hnique 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 w hich 50% of isolates are inhibited (MIC50) and MIC90, obtained spectrophoto metrically after 48 h of incubation, a ere I and 16 mu g/ml, respectively, Of the 25 patients studied, 4 died of active cryptococcal disease and 2 die d of other causes, Therapeutic failure was observed in five patients who we re infected with isolates for which fluconazole MICs were greater than or e qual to 16 mu g/ml. Four of these patients had previously had oropharyngeal candidiasis (OPC); three had previously had episodes of cryptococcal infec tion, 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 inf ection. 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 mu g/ml) than when the patients are infected with strains that require higher flucon azole concentrations (MICs, greater than or equal to 16 mu g/ml). These fin dings also suggest that the MICs determined by the modified NCCLS microdilu tion method can be potential predictors of the clinical response to flucona zole therapy and may aid in the identification of patients who will not res pond to fluconazole therapy.