Background The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. Methods Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5–21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. Results Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, –27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, –46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drug-related deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively. Conclusions Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections. Clinical Trials Registration NCT02452047.

Background This is an ongoing follow-up study (NCT02723773) evaluating persistence of efficacy and immune responses for six additional years in adults vaccinated with the glycoprotein E (gE)-based adjuvanted recombinant zoster vaccine (RZV) at ≥50 years of age in two pivotal efficacy trials (ZOE-50/70). The present interim analysis was performed after ≥2 additional years of follow-up (between 5.1 and 7.1 years [mean] post-vaccination) and includes partial data for year (Y)8 post-vaccination. Methods Annual assessments were performed for efficacy against herpes zoster (HZ) from Y6 post-vaccination onwards, and for anti-gE antibody concentrations and gE-specific CD4[2+] T-cell (expressing ≥2 of four assessed activation markers) frequencies from Y5 post-vaccination onwards. Results Of 7413 participants enrolled for the long-term efficacy assessment, 7277 (mean age at vaccination: 67.2 years), 813, and 108 were included in the cohorts for the evaluation of efficacy, humoral immune responses, and cell-mediated immune responses, respectively. Efficacy of RZV against HZ through this interim analysis was 84.0% (95% confidence interval [CI]: 75.9-89.8) from the start of this follow-up study and 90.9% (95%CI: 88.2-93.2) from vaccination in ZOE-50/70. Annual vaccine efficacy estimates were >84% for each year since vaccination and remained stable during this follow-up study through the interim analysis. Anti-gE antibody geometric mean concentrations and median frequencies of gE-specific CD4[2+] T cells had plateaued throughout this follow-up study up to the interim analysis, at ~6-fold above pre-vaccination levels. Conclusion Efficacy against HZ and immune responses to RZV remained high, suggesting that the clinical benefit of RZV in older adults is sustained for at least seven years post-vaccination.

This is a repository copy of Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials.

Approximately 10 years after vaccination with the recombinant zoster vaccine (RZV), an interim analysis of this follow-up study of the ZOE-50/70 trials demonstrated that efficacy against herpes zoster remained high. Moreover, the safety profile remained clinically acceptable, suggesting that the clinical benefit of the RZV in ≥50-year-olds is sustained up to 10 years.

Background Vancomycin (VAN) therapy for C. difficile infection (CDI) is effective with > 80% clinical response (CR) but is associated with 20–30% recurrence rate (rCDI). Secondary bile acids (2° BAs) inhibit C. difficile germination and help prevent rCDI. VAN depletes the gut microbiome decreasing the conversion of primary bile acids to 2° BAs. Ridinilazole (RDZ) is a highly selective anti-CDI, DNA-binding antibiotic in development for the treatment of CDI and prevention of rCDI. Methods A global, double-blinded, randomized Phase 3 trial assessed a 10-day treatment with RDZ 200 mg BID vs VAN 125 mg QID for CDI. The primary endpoint was sustained clinical response (SCR) defined as CR and no rCDI through 30 days post-end of treatment (EOT). Other endpoints included rCDI, microbiome diversity and composition, and microbiome-derived 2° BAs concentration. rCDI was defined as a new episode of diarrhea with confirmed positive free toxin test (FTT), requiring additional CDI therapy. All participants were monitored for treatment emergent adverse events (TEAE). Results Of the 759 patients (pts) enrolled, 745 were included in the mITT population (RDZ n=370, VAN n=375). RDZ achieved a numerically higher SCR rate than VAN (73.0% vs 70.7%) p=0.4672. RDZ resulted in a significant reduction in rCDI rate (8.1% vs 17.3%, p=0.0002) (Fig 1). In a pre-specified subpopulation, this was most notable in pts not receiving other antibiotics (rCDI 6.7% in RDZ vs 16.5% in VAN, p=0.0005). Microbiome alpha diversity was higher for RDZ vs VAN at EOT and EOT+30d (p< 0.0001 and p≤ 0.0007 respectively, Fig 2) as were relative abundance (p< 0.0001 and p=0.0203 respectively), and concentrations of 2° BAs (Fig 3). Higher microbiome diversity and concentrations of 2° BAs at EOT were associated with both lower rCDI and higher SCR rates. RDZ was well tolerated (pts with ≥ 1 TEAE: RDZ 36.4% vs VAN 35.5%, treatment discontinuation due to TEAE: RDZ 0.8% vs. VAN 2.9%). Conclusion RDZ was effective for sustained clinical response and safe for the treatment of patients with CDI. This was most notable in pts not receiving antibiotics. Compared to VAN, RDZ patients had faster recovery of fecal 2° BA, consistent with the preservation of microbiome diversity, resulting in a significantly lower rate of rCDI. Disclosures Pablo C. Okhuysen, MD, AstraZeneca: Stocks/Bonds|Beam Therapeutics: Stocks/Bonds|Biontech: Stocks/Bonds|Deinove: Grant/Research Support|Ferring: Advisor/Consultant|Glaxo Smith Kleine: Stocks/Bonds|Johnson and Johnson: Stocks/Bonds|Melinta: Grant/Research Support|Merck Sharp & Dohme Corp: Grant/Research Support|Moderna: Stocks/Bonds|Napo Pharmaceuticals: Advisor/Consultant|Napo Pharmaceuticals: Grant/Research Support|Novavax: Stocks/Bonds|Pfizer: Stocks/Bonds|Summit: Advisor/Consultant|Summit: Grant/Research Support Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support Thomas J. Louie, MD, adiso therapeutics: Advisor/Consultant|adiso therapeutics: Grant/Research Support|crestone: Advisor/Consultant|crestone: Grant/Research Support|Finch: Advisor/Consultant|Finch: Grant/Research Support|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Seres Therapeutics: Honoraria|summit plc: Grant/Research Support|vedanta biosciences: Advisor/Consultant|vedanta biosciences: Grant/Research Support Jianling LI, MS, Abbott: Stocks/Bonds|Abbvie: Stocks/Bonds|ALX Oncology: Stocks/Bonds|BioNTech: Stocks/Bonds|Bluebird Bio: Stocks/Bonds|Cytokinetics: Stocks/Bonds|I-Mab: Stocks/Bonds|Johnson & Johnson: Stocks/Bonds|Moderna: Stocks/Bonds|TG Therapeutics: Stocks/Bonds Esther Duperchy, PhD, Summit Plc: Employee Jose G. Montoya, MD, Summit: Honoraria|Summit: Stocks/Bonds Lori Styles, MD, Abbvie: Stocks/Bonds|Summit Therapeutics: employee|Summit Therapeutics: Stocks/Bonds Fong Clow, Sc. D, Summit Therapeutics: Employee Danelle James, MD, Summit Therapeutics: Employee.