Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Factors associated with risk of surgical wound infections.

Surgical wound infections are the most common hospital-acquired infections among patients who undergo inpatient surgery. Risk of infection is a function of both patient susceptibility and exposure. The authors studied all discharges in Pennsylvania from October 1, 2004, through September 30, 2005, in which a circulatory (n= 65 940), neurological (n= 6706), or orthopedic (n = 107 825) procedure was performed using data from the Pennsylvania Health Care Cost Containment Council. They estimated the impact of patient-specific factors on risk of infection and compared the ability of these factors to predict infections relative to hospital effects. Results suggested that for all 3 types of procedures, patient-specific factors were a significant determinant of risk of surgical wound infection. However, prediction of infection was improved by 23% to 33% when hospital fixed effects were included. Although patient-specific factors had a statistically significant association with risk of infections, much of the risk of surgical wound infections is determined by hospital factors.

Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy.

The virological response of multiple protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor-naive, HIV-1-infected subjects was examined with respect to baseline viral phenotype and genotype through 72 weeks of therapy with lopinavir/ritonavir plus efavirenz and nucleoside reverse transcriptase inhibitors (Study M98-957). Using a 'dropouts as censored' analysis, plasma HIV RNA < or = 400 copies/ml was observed in 93% (25/27), 73% (11/15) and 25% (2/8) of subjects with <10-fold, 10- to 40-fold, and >40-fold reduced susceptibility to lopinavir at baseline, respectively. In addition, virological response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) of subjects with baseline lopinavir mutation score of 0-5, 6-7 and > or = 8, respectively. Through 72 weeks, all subjects experiencing virological failure whose baseline isolates contained six or more protease inhibitor mutations had a common genotypic pattern, with mutations at positions 82, 54 and 10, along with a median of four additional mutations in protease. However, an equal number of subjects with a similar genotypic pattern experienced virological response. Further analysis revealed the baseline phenotypic susceptibility to lopinavir to be an additional covariate predicting response in this subset of subjects. In multivariate analyses, baseline susceptibility to lopinavir was associated with response at each time point examined (weeks 24, 48 and 72). These results provide guidance for clinically relevant interpretation of phenotypic and genotypic resistance tests when applied to lopinavir/ritonavir.