Current levels of resistance to penicillin and cephalosporin by S. pneumoniae are not associated with increased mortality in patients with pneumococcal pneumonia. Hence, these antibiotics remain the therapy of choice for this disease.

Early failure is infrequent but is associated with high morbidity and mortality rates. Its detection and management require careful clinical assessment. Most cases occur because of inadequate host-pathogen responses. Discordant therapy is a less frequent cause of failure, which may be preventable by rational application of the current antibiotic guidelines.

Background. Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability.Methods. We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebocontrolled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4 ϩ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens.Results. During the first 4 weeks, increases in CD4 ϩ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lowerdosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4 ϩ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-chain DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment.Conclusions. In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established. (N Engl J Med 1995;333:1528-33.)