Inhibitors of the human immunodeficiency virus type 1 (HIV-1) protease have entered clinical study as potential therapeutic agents for HIV-1 infection. The clinical efficacy of HIV-1 reverse transcriptase inhibitors has been limited by the emergence of resistant viral variants. Similarly, variants expressing resistance to protease inhibitors have been derived in cell culture. We now report the characterization of resistant variants isolated from patients undergoing therapy with the protease inhibitor MK-639 (formerly designated L-735,524). Five of these variants, isolated from four patients, exhibited cross-resistance to all members of a panel of six structurally diverse protease inhibitors. This suggests that combination therapy with multiple protease inhibitors may not prevent loss of antiviral activity resulting from resistance selection. In addition, previous therapy with one compound may abrogate the benefit of subsequent treatment with a second inhibitor.

Indinavir (IDV) (also called CRIXIVAN, MK-639, or L-735,524) is a potent and selective inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. During early clinical trials, in which patients initiated therapy with suboptimal dosages of IDV, we monitored the emergence of viral resistance to the inhibitor by genotypic and phenotypic characterization of primary HIV-1 isolates. Development of resistance coincided with variable patterns of multiple substitutions among at least 11 protease amino acid residues. No single substitution was present in all resistant isolates, indicating that resistance evolves through multiple genetic pathways. Despite this complexity, all of 29 resistant isolates tested exhibited alteration of residues M-46 (to I or L) and/or V-82 (to A, F, or T), suggesting that screening of these residues may be useful in predicting the emergence of resistance. We also extended our previous finding that IDV-resistant viral variants exhibit various patterns of cross-resistance to a diverse panel of HIV-1 protease inhibitors. Finally, we noted an association between the number of protease amino acid substitutions and the observed level of IDV resistance. No single substitution or pair of substitutions tested gave rise to measurable viral resistance to IDV. The evolution of this resistance was found to be cumulative, indicating the need for ongoing viral replication in this process. These observations strongly suggest that therapy should be initiated with the most efficacious regimen available, both to suppress viral spread and to inhibit the replication that is required for the evolution of resistance.

Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.

No abstract

Owing to a rise in frequency and change in pattern of cases with fungaemia at our tertiary care centre, we conducted a prospective study for 4 months to understand the epidemiology and outcome of this infection. Detailed case histories including management protocol and outcomes were noted. Records of 140 cases with fungaemia (27.1% adult and 72.9% paediatric patients) were analysed. Although C. tropicalis was the most common yeast isolated, significantly higher isolation of C. guilliermondii (30.4%) and C. pelliculosa (17.6%) was noted in paediatric patients; and C. albicans (26.3%) and C. glabrata (10.5%) in adult patients. Rare species isolated included C. ustus (0.7%) and Trichosporon asahii (2.1%). Mortality was high (56.9% and 47.4%, respectively), in both groups of patients. Resistance to azoles (fluconazole, itraconazole, voriconazole) emerged in C. albicans (12.5-18.8%) and C. tropicalis (10.2-13.6%). Antifungal susceptibility testing report modified the therapy from fluconazole to amphotericin B in 8 patients; 5 survived. In conclusion, the study highlighted the rise of non-albicans Candida species in our hospital with differential distribution in paediatric and adult wards and emergence of azole resistance.