Adam Belley

The investigational β-lactam/β-lactamase inhibitor combination cefepime-taniborbactam is intended as therapy for serious infections caused by Gram-negative pathogens resistant to third-generation cephalosporins and carbapenems. Establishing a susceptibility testing reference method for cefepime-taniborbactam that conforms to the Clinical Laboratory Standards Institute (CLSI) M07 and International Standards Organization 20776-1:2019 standards is necessary to inform patient care. This study describes the reference broth microdilution MIC method for cefepime-taniborbactam (taniborbactam fixed at 4 µg/mL). In a CLSI M23 Tier 2 study that included nine clinical microbiology laboratories, the CTX-M-15-producer Escherichia coli NCTCC 13353 was determined to be appropriate for routine quality control (QC) as ranges for cefepime (≥64 µg/mL) and cefepime-taniborbactam (0.12 to 1 µg/mL) were non-overlapping, thereby simultaneously controlling for cefepime antibacterial activity and taniborbactam β-lactamase inhibition. Of the cefepime-taniborbactam MIC results obtained, 99.6% (269/270) were within the identified QC range; similarly, 100% (79/79) and 98.0% (98/100) of the QC values from a surveillance study and from the two central microbiology laboratories of the CERTAIN-1 Phase 3 clinical study (clintrials.gov identifier NCT03840148) were in range, respectively. Modifications to the standard medium (pH, cation content, or supplementation with human serum, albumin, polysorbate-80, or pulmonary surfactant) or assay parameters (inoculum density, incubation duration, and atmosphere) revealed that only inoculum titers (e.g., ≥5 × 10 ⁶ CFU/mL) exceeding the CLSI M07 standard (2–8 × 10 ⁵ CFU/mL) increased MIC values above the QC range. These results demonstrate the robustness and reliability of the cefepime-taniborbactam broth microdilution MIC reference method when performed following the approved standards. IMPORTANCE: This study focuses on a new antibiotic combination called cefepime-taniborbactam that is being developed to treat serious infections caused by bacteria that are often resistant to current treatments. To make sure this new antibiotic combination can be used safely and effectively once it has been approved for clinical use, we developed a standardized laboratory method to measure its activity against certain bacteria that are widely used during quality control testing. The method was assessed in multiple labs and proved to be reliable, accurate, and consistent. It also held up well under different testing conditions, showing that it is a dependable tool for guiding treatment decisions. This is an important step in meeting the challenge of antibiotic-resistant infections since it will help clinicians evaluate cefepime-taniborbactam as a potential treatment option as they strive to improve the care of patients suffering from serious infections.

The investigational β-lactam/β-lactamase inhibitor combination of cefepime (FEP)/enmetazobactam (ENM) met criteria for non-inferiority and superiority compared to piperacillin/tazobactam in a phase 3 clinical trial of adult patients with complicated urinary tract infections (cUTI)/acute pyelonephritis (AP). In this study, a population pharmacokinetic (PK) model is presented that describes FEP and ENM plasma PK in adult cUTI/AP patients. Plasma PK samples were analyzed from participants receiving FEP (n=588) and ENM (n=649) in three phase 1 (n=132), and single phase 2 (n=43) and phase 3 (n=488) clinical trials. Population PK parameters were assessed and the relationship between different covariates and model parameters were investigated. The effect of infection on disposition was assessed by testing disease covariates on fixed and random effects for all PK parameters. A two-compartment model with linear clearance of FEP (5.95 L/h) and ENM (7.68 L/h) from the central compartment best described the PK of both compounds. Common covariates for both compounds were de-indexed estimated glomerular filtration rate (eGFR), age, and body weight while ENM PK covariates also included cUTI infection and sex. Simulations showed that the only covariate requiring dose adjustment was renal function. The final model simultaneously described FEP and ENM plasma PK, which enabled estimates of the correlation of the random effects between PK parameters. Clearances and volumes of distribution (Vd) were strongly correlated within individuals between the two compounds (correlation coefficients >0.9). Variability was higher in cUTI patients although differences in mean ENM or FEP exposures between healthy subjects and cUTI patients were negligible. The total Vd was 16.9 L for FEP and 20.6 L for ENM. Clearance of both agents was found to depend on de-indexed eGFR (covariate coefficients ≥0.83), suggesting that renal filtration is the predominant clearance mechanism. The terminal elimination half-life was 2.2 h for FEP and 2.0 h for ENM. The population PK models for FEP and ENM predict exposures in cUTI patients, including subjects with renal impairment. These models support Monte-Carlo simulations and target attainment estimations in adult cUTI/AP patients. Adam Belley, PhD, Allecra Therapeutics SAS: Advisor/Consultant Patrick Velicitat, MD, Allecra Therapeutics SAS: Salary

The use of carbapenem antibiotics to treat infections caused by Enterobacterales expressing increasingly aggressive extended-spectrum β-lactamases (ESBLs) has contributed to the emergence of carbapenem resistance. Enmetazobactam is a novel ESBL inhibitor being developed in combination with cefepime as a carbapenem-sparing option for infections caused by ESBL-producing Enterobacterales .

Third-generation cephalosporin resistance among Enterobacteriaceae , mediated by the spread of extended-spectrum β-lactamases (ESBLs), is a very serious medical concern with limited therapeutic options. Enmetazobactam (formerly AAI101) is a novel penicillanic sulfone β-lactamase inhibitor active against a wide range of ESBLs. The combination of enmetazobactam and cefepime has entered phase 3 development in patients with complicated urinary tract infections.