Efficacy of bezlotoxumab in participants receiving metronidazole, vancomycin, or fidaxomicin for treatment of Clostridioides (Clostridium) difficile infection

Background: In phase 3 MODIFY I/II trials, bezlotoxumab significantly reduced recurrence of Methods: In MODIFY I/II (NCT01241552/NCT01513239), participants received a single infusion of bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment. Using pooled data from MODIFY I/II, initial clinical cure (ICC) and rCDI were assessed in metronidazole-, vancomycin-, and fidaxomicin-treated subgroups. Results: Of 1554 participants in MODIFY I/II, 753 (48.5%) received metronidazole, 745 (47.9%) vancomycin, and 56 (3.6%) fidaxomicin. Fewer participants receiving metronidazole had a prior CDI episode in the previous 6 months (12.9%) or ≥1 risk factor for rCDI (66.0%) vs participants receiving vancomycin (41.2% and 83.6%, respectively) and fidaxomicin (55.4% and 89.3%, respectively). ICC rates were similar in the bezlotoxumab (metronidazole, 81.0%; vancomycin, 78.5%; fidaxomicin, 86.7%) and placebo groups (metronidazole, 81.3%; vancomycin, 79.6%; fidaxomicin, 76.9%). In placebo-treated participants, the rCDI was lower in the metronidazole subgroup vs the vancomycin and fidaxomicin subgroups (metronidazole, 28.0%; vancomycin, 38.4%; fidaxomicin, 35.0%). When analyzed by subsets based on history of CDI, rCDI rates were similar in the metronidazole and vancomycin groups. rCDI rates were lower in all antibiotic subgroups for bezlotoxumab vs placebo (metronidazole: rate difference [RD], -9.7%; 95% confidence interval [CI], -16.4% to -3.1%; vancomycin: RD, -15.4%; 95% CI, -22.7% to -8.0%; fidaxomicin: RD, -11.9%; 95% CI, -38.1% to 14.3%). Conclusion: Bezlotoxumab reduces rCDI vs placebo in participants receiving metronidazole and vancomycin, with a similar effect size in participants receiving fidaxomicin

Effect of fecal microbiota, live-jslm (REBYOTA [RBL]) on health-related quality of life in patients with recurrent Clostridioides difficile infection: Results from the PUNCH CD3 clinical trial

BACKGROUND: Recurrence of METHODS: This was a secondary analysis of a randomized, double-blind, placebo-controlled phase 3 study (PUNCH CD3). The disease-specific RESULTS: Findings were analyzed in a total of 185 patients (RBL, n = 128 [69.2%]; placebo, n = 57 [30.8%]) with available Cdiff32 data. Patients from both arms showed significant improvements in Cdiff32 scores relative to baseline across all outcomes and at all time points (all CONCLUSIONS: In a phase 3 double-blinded clinical trial, RBL-treated patients reported more substantial and sustained disease-specific HRQL improvements than placebo-treated patients. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT03244644 (https://clinicaltrials.gov/ct2/show/NCT03244644)

Fecal Pharmacokinetics and Gut Microbiome Effects of oral Omadacycline Versus Vancomycin in Healthy Volunteers

BACKGROUND: Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults. METHODS: This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations were assessed, and microbiome changes were compared. RESULTS: Sixteen healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years were enrolled; 62.5% were male, and participants\u27 mean body mass index was 23.5 (SD, 4.0) kg/m2. Omadacycline was well tolerated with no safety signal differences between the 2 antibiotics. A rapid initial increase in fecal concentrations of omadacycline was observed compared to vancomycin, with maximum concentrations achieved within 48 hours. A significant difference in alpha diversity was observed following therapy in both the omadacycline and vancomycin groups (P \u3c .05). Bacterial abundance and beta diversity analysis showed differing microbiome changes in subjects who received omadacycline versus vancomycin. CONCLUSIONS: Subjects given omadacycline had high fecal concentrations with a distinct microbiome profile compared to vancomycin. CLINICAL TRIALS REGISTRATION: NCT06030219

Real-world Multicenter Analysis of Clinical Outcomes and Safety of Meropenem-Vaborbactam in Patients Treated for Serious Gram-Negative Bacterial Infections

Fourty patients were treated with meropenem-vaborbactam (MEV) for serious Gram-negative bacterial (GNB) infections. Carbapenem-resistant Enterobacteriaceae (CRE) comprised 80.0% of all GNB infections. Clinical success occurred in 70.0% of patients. Mortality and recurrence at 30 days were 7.5% and 12.5%, respectively. One patient experienced a probable rash due to MEV

Características clínicas, microbiología y resultados de una cohorte de pacientes tratados con ceftolozane/tazobactam en centros de hospitalización de cuidados agudos, Houston, Texas, EE.UU

Antecedentes Ceftolozane/tazobactam es una combinación de β-lactámico/β-inhibidor de lactamasa con actividad contra una variedad de bacterias Gram-negativas, incluyendo Pseudomonas aeruginosa MDR. Este agente está aprobado para la neumonía bacteriana adquirida en el hospital y asociada a la ventilación mecánica. Sin embargo, la mayoría de los datos de resultados en el mundo real proceden de pequeñas cohortes observacionales. Por lo tanto, se trató de evaluar la utilización de ceftolozane/tazobactam en múltiples hospitales terciarios en Houston, TX, EE.UU.. Métodos Realizamos un estudio retrospectivo multicéntrico de pacientes que recibieron al menos 48 h de terapia con ceftolozano/tazobactam desde enero de 2016 hasta septiembre de 2019 en dos sistemas hospitalarios en Houston. Se recopilaron datos demográficos, clínicos y microbiológicos, incluido el aislado bacteriano infectante, cuando estaba disponible. El resultado primario fue el éxito clínico compuesto al alta hospitalaria. Los resultados secundarios incluyeron la mortalidad intrahospitalaria y la disposición clínica a los 14 y 30 días después del inicio de ceftolozane/tazobactam. Se utilizó un análisis de regresión logística multivariable para identificar los factores predictivos del resultado primario y la mortalidad. Los aislados recuperados se sometieron a pruebas de sensibilidad a ceftolozano/tazobactam y a WGS. Resultados Se incluyó a un total de 263 pacientes, y se alcanzó el éxito clínico compuesto en 185 pacientes (70,3%). La gravedad de la enfermedad fue el factor predictivo más consistente del éxito clínico. El tratamiento combinado con ceftolozane/tazobactam y otro agente Gram negativo activo se asoció a una reducción de las probabilidades de éxito clínico (OR 0,32; IC del 95%: 0,16-0,63). Se observó resistencia a ceftolozano/tazobactam en el 15,4% de los aislados disponibles para WGS; las mutaciones en ampC y ftsI fueron frecuentes pero no se agruparon con una ST concreta. Conclusiones La tasa de éxito clínico entre esta cohorte de pacientes tratados con ceftolozane/tazobactam fue similar en comparación con experiencias anteriores. Ceftolozane/tazobactam sigue siendo un agente alternativo para el tratamiento de aislados susceptibles de P. aeruginosaBackground Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination with activity against a variety of Gram-negative bacteria, including MDR Pseudomonas aeruginosa. This agent is approved for hospital-acquired and ventilator-associated bacterial pneumonia. However, most real-world outcome data come from small observational cohorts. Thus, we sought to evaluate the utilization of ceftolozane/tazobactam at multiple tertiary hospitals in Houston, TX, USA. Methods We conducted a multicentre retrospective study of patients receiving at least 48 h of ceftolozane/tazobactam therapy from January 2016 through to September 2019 at two hospital systems in Houston. Demographic, clinical and microbiological data were collected, including the infecting bacterial isolate, when available. The primary outcome was composite clinical success at hospital discharge. Secondary outcomes included in-hospital mortality and clinical disposition at 14 and 30 days post ceftolozane/tazobactam initiation. Multivariable logistic regression analysis was used to identify predictors of the primary outcome and mortality. Recovered isolates were tested for susceptibility to ceftolozane/tazobactam and underwent WGS. Results A total of 263 patients were enrolled, and composite clinical success was achieved in 185 patients (70.3%). Severity of illness was the most consistent predictor of clinical success. Combination therapy with ceftolozane/tazobactam and another Gram-negative-active agent was associated with reduced odds of clinical success (OR 0.32, 95% CI 0.16–0.63). Resistance to ceftolozane/tazobactam was noted in 15.4% of isolates available for WGS; mutations in ampC and ftsI were common but did not cluster with a particular ST. Conclusions Clinical success rate among this patient cohort treated with ceftolozane/tazobactam was similar compared with previous experiences. Ceftolozane/tazobactam remains an alternative agent for treatment of susceptible isolates of P. aeruginosa

Real-world, Multicenter Experience With Meropenem-Vaborbactam for Gram-Negative Bacterial Infections Including Carbapenem-Resistant Enterobacterales and Pseudomonas Aeruginosa

Background: We aimed to describe the clinical characteristics and outcomes of patients treated with meropenem-vaborbactam (MEV) for a variety of gram-negative infections (GNIs), primarily including carbapenem-resistant Enterobacterales (CRE). Methods: This is a real-world, multicenter, retrospective cohort within the United States between 2017 and 2020. Adult patients who received MEV for ≥72 hours were eligible for inclusion. The primary outcome was 30-day mortality. Classification and regression tree analysis (CART) was used to identify the time breakpoint (BP) that delineated the risk of negative clinical outcomes (NCOs) and was examined by multivariable logistic regression analysis (MLR). Results: Overall, 126 patients were evaluated from 13 medical centers in 10 states. The most common infection sources were respiratory tract (38.1%) and intra-abdominal (19.0%) origin, while the most common isolated pathogens were CRE (78.6%). Thirty-day mortality and recurrence occurred in 18.3% and 11.9%, respectively. Adverse events occurred in 4 patients: nephrotoxicity (n = 2), hepatoxicity (n = 1), and rash (n = 1). CART-BP between early and delayed treatment was 48 hours (P = .04). MEV initiation within 48 hours was independently associated with reduced NCO following analysis by MLR (adusted odds ratio, 0.277; 95% CI, 0.081-0.941). Conclusions: Our results support current evidence establishing positive clinical and safety outcomes of MEV in GNIs, including CRE. We suggest that delaying appropriate therapy for CRE significantly increases the risk of NCOs

Combating resistance while maintaining innovation: the future of antimicrobial stewardship

Antimicrobial resistance represents a significant global health threat. However, a commercial model that does not offer a return on investment resulting in a lack of investment in antibiotic R&D, means that the current pipeline of antibiotics lacks sufficient innovation to meet this challenge. Those responsible for defining, promoting and monitoring the rationale use of antibiotics (the antimicrobial stewardship programme) are key to addressing current shortcomings. In this personal perspective, we discuss the future role stewardship can play in stimulating innovation, a need to move away from a pharmacy budget dominated view of antibiotic use, and the impact of the ever-increasing sophistication and interdisciplinary nature of antimicrobial control programs. Changes are needed to optimize clinical outcomes for patients

Ridinilazole: A novel therapy for Clostridium difficile infection

Clostridium difficile infection (CDI) is the leading cause of infectious healthcare-associated diarrhoea. Recurrent CDI increases disease morbidity and mortality, posing a high burden to patients and a growing economic burden to the healthcare system. Thus, there exists a significant unmet and increasing medical need for new therapies for CDI. This review aims to provide a concise summary of CDI in general and a specific update on ridinilazole (formerly SMT19969), a novel antibacterial currently under development for the treatment of CDI. Owing to its highly targeted spectrum of activity and ability to spare the normal gut microbiota, ridinilazole provides significant advantages over metronidazole and vancomycin, the mainstay antibiotics for CDI. Ridinilazole is bactericidal against . C. difficile and exhibits a prolonged post-antibiotic effect. Furthermore, treatment with ridinilazole results in decreased toxin production. A phase 1 trial demonstrated that oral ridinilazole is well tolerated and specifically targets clostridia whilst sparing other faecal bacteria. Phase 2 and 3 trials will hopefully further our understanding of the clinical utility of ridinilazole for the treatment of CDI