The availability of reproducible antifungal susceptibility testing methods now permits analysis of data correlating susceptibility in vitro with outcome in vivo in order to define interpretive breakpoints. In this paper, we have examined the conceptual framework underlying interpretation of antimicrobial susceptibility testing results and then used these ideas to drive analysis of data packages developed by the respective manufacturers that correlate fluconazole and itraconazole MICs with outcome of candidal infections. Tentative fluconazole interpretive breakpoints for MICs determined by the National Committee for Clinical Laboratory Standards' M27-T broth macrodilution methodology are proposed: isolates for which MICs are < or = 8 microg/mL are susceptible to fluconazole, whereas those for which MICs are > or = 64 microg/mL appear resistant. Isolates for which the MIC of fluconazole is 16-32 microg/mL are considered susceptible dependent upon dose (S-DD), on the basis of data indicating clinical response when > 100 mg of fluconazole per day is given. These breakpoints do not, however, apply to Candida krusei, as it is considered inherently resistant to fluconazole. Tentative interpretive MIC breakpoints for itraconazole apply only to mucosal candidal infections and are as follows: susceptible, < or = 0.125 microg/mL; S-DD, 0.25-0.5 microg/mL; and resistant, > or = 1.0 microg/mL. These tentative breakpoints are now open for public commentary.

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The critical community size for measles (the size for which measles is as likely as not to fade out after a major epidemic until reintroduced from outside, corresponding to a mean time to fade-out of about two years) is found for the United States to be about 250,000 to 300,000 in terms of total population, or about 30 in terms of average weekly notifications. These figures agree broadly with English statistics, provided notifications are corrected as far as possible for unreported cases. Comparison is also made with results calculated from theoretical models. The contrasting epidemiological patterns for measles and chickenpox are noted.

Mutations in two amino-acid positions were significantly more common in AIDS patients with PCP who failed sulfa/sulfone prophylaxis. These amino acids appeared to be directly involved in both substrate and sulfa binding, based on homology to the Escherichia coli DHPS crystal structure. Thus, the results were consistent with the possibility that mutations in the P. carinii DHPS are responsible for some of the failures of sulfa/sulfone prophylaxis in AIDS patients.

We initiated a comparative study of four methods of yeast inoculum preparation: a spectrophotometric method, the Wickerham card method, a hemacytometer method, and the Prompt inoculation system. The variability in inoculum size obtained when each method was applied to two strains each of Candida albicans, Candida tropicalis, Candida parapsilosis, Torulopsis glabrata, Cryptococcus neoformans, and Saccharomyces cerevisiae was analyzed in a single laboratory. Each method was performed in triplicate on the same day and on three separate days to provide estimates of within-day and between-day variations. Inoculum size was determined by viable colony counts. The greatest range of inoculum sizes was seen with the Wickerham card method. Viable counts ranged from 1.1 x 106 to 24.2 x 106 CFU/ml among the 12 yeast isolates. The greatest variation was observed with the Prompt system. Within-day coefficients of variation averaged 19% (range, 4 to 45%), and between-day coefficients of variation averaged 22% (range, 3 to 51%). Variation between laboratories was evaluated by comparing inoculum values obtained by each method in three different laboratories for two strains of C. albicans. The spectrophotometric method was the least variable and the Wickerham card and hemacytometer methods were the most variable methods between laboratories. The spectrophotometric method is recommended as the method of choice for preparation of a standardized inoculum suspension for susceptibility testing of yeasts. * Corresponding author. for use in developing a standardized susceptibility testing method.

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Thirteen laboratories collaborated to optimize interlaboratory agreement of results of a broth macrodilution procedure for testing three classes of antifungal drugs against pathogenic yeasts. The activities of amphotericin B, flucytosine, and ketoconazole were tested against 100 coded isolates of Candida albicans, Candida tropicalis, Candida parapsilosis, Candida lusitaniae, Torulopsis (Candida) glabrata, and Cryptococcus neoformans. Two starting yeast inoculum sizes (5 x 104 and 2.5 x 103 cells per ml) were compared, and readings were taken after 24 and 48 h of incubation. All other test conditions were standardized. The resultant turbidities in all tubes were estimated visually on a scale from 0 to 4+ turbidity, and MIC-0, MIC-1, and MIC-2 were defined as the lowest drug concentrations that reduced growth to 0, 1+, or 2+ turbidity, respectively. For flucytosine, agreement among laboratories varied between 57 and 87% for different inocula, times of incubation, and end point criteria. Agreement was maximized (85%) when the lower inoculum was incubated for 2 days and the MICs were defined as 1+ turbidity or less. For amphotericin B, variations in test conditions produced much smaller differences in interlaboratory agreement. For ketoconazole, interlaboratory agreement was poorer by all end point criteria. However, MIC-2 endpoints distinguished T. glabrata as resistant compared with the other species. Overall, the studies indicated that readings from the lower inoculum obtained on the second day of reading result in the greatest interlaboratory agreement. In combination with data from previous multicenter studies (National Committee for Clinical Laboratory Standards, Antifungal Susceptibility Testing: Committee

Sulfa drugs are widely used in the treatment and prophylaxis of Pneumocystis carinii pneumonia. The nucleotide sequences of the sulfa target enzyme, dihydropteroate synthase (DHPS), differed substantially in human-, rat-, and mouse-derived P. carinii. Sequence variation also existed in the DHPSs from human-derived isolates. Six nucleotide changes were found in 6 human isolates; each was nonsynonymous and resulted in an amino acid change. Several of these changes were in highly conserved regions and are similar to those that cause sulfa resistance in other organisms. These data suggest that the human-derived P. carinii DHPS may be evolving under positive selective pressure from sulfa drugs.