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Cefepime-enmetazobactam is a novel β-lactam–β-lactamase inhibitor combination with broad-spectrum antimicrobial activity against a range of multidrug-resistant Enterobacteriaceae. This agent is being developed for a range of serious hospital infections. An understanding of the extent of partitioning of β-lactam–β-lactamase inhibitor combinations into the human lung is required to better understand the potential role of cefepime-enmetazobactam for the treatment of nosocomial pneumonia. A total of 20 healthy volunteers were used to study the intrapulmonary pharmacokinetics of a regimen of 2 g cefepime-1 g enmetazobactam every 8 h intravenously (2 g/1 g q8h i.v.). Each volunteer contributed multiple plasma samples and a single epithelial lining fluid (ELF) sample, obtained by bronchoalveolar lavage. Concentrations of cefepime and enmetazobactam were quantified using liquid chromatography-tandem mass spectrometry. The pharmacokinetic data were modeled using a population methodology, and Monte Carlo simulations were performed to assess the attainment of pharmacodynamic targets defined in preclinical models. The concentration-time profiles of both agents in plasma and ELF were similar. The mean ± standard deviation percentage of partitioning of total drug concentrations of cefepime and enmetazobactam between plasma and ELF was 60.59% ± 28.62% and 53.03% ± 21.05%, respectively. Using pharmacodynamic targets for cefepime of greater than the MIC and free enmetazobactam concentrations of >2 mg/liter in ELF of 20% of the dosing interval, a regimen of cefepime-enmetazobactam of 2 g/0.5 g q8h i.v. infused over 2 h resulted in a probability of target attainment of ≥90% for Enterobacteriaceae with cefepime-enmetazobactam MICs of ≤8 mg/liter. This result provides a rationale to further consider cefepime-enmetazobactam for the treatment of nosocomial pneumonia caused by multidrug-resistant Enterobacteriaceae.

Background There is a critical need for carbapenem-sparing therapies for infections caused by extended spectrum β-lactamase (ESBL)-producing Enterobacterales. Enmetazobactam is a novel ESBL inhibitor combined with the cephalosporin cefepime. Treatment outcomes of cefepime-enmetazobactam (FPE) versus piperacillin-tazobactam (PTZ) were assessed in subgroups of patients with ESBL-producing baseline uropathogens (ESBL-BU) in the ALLIUM phase 3 trial of complicated urinary tract infections (cUTI)/acute pyelonephritis (AP). Methods 1034 cUTI/AP patients randomized 1:1 in a double-blind, multicenter trial received either 2 g cefepime/0.5 g enmetazobactam or 4 g piperacillin/0.5 g tazobactam q8h by 2h infusion for 7 to 14 days. Enterobacterales with MICs ≥1 µg/ml to ceftazidime, ceftriaxone, cefepime, meropenem, or FPE were genotyped for β-lactamases. In addition to the primary analysis (by stratified Newcombe) of overall success (combination of clinical cure and microbiological eradication) in the microbiological modified intent to treat population (mMITT) at test-of-cure (TOC), subgroup analyses were performed on patients with ESBL-BU non-resistant to FPE (MIC≤8 µg/ml) and PTZ (MIC≤64 µg/ml) and a subgroup (mMITT+R) that also included the ESBL-BU resistant to either agent (FPE MIC ≥16 µg/ml or PTZ MIC≥128 µg/ml). Results In mMITT, FPE (273/345, 79.1%) demonstrated superiority to PTZ (196/333, 58.9%) at TOC (difference, 21.2%; 95% CI: 14.3, 27.9). The prevalence rate of ESBL-BU was 20.9% (142/678), with 99.3% (141/142) expressing a CTX-M-type (-1, -3, -9, -14, -15, -27, -55, -91, -169) and 3.5% (5/142) co-expressing AmpC (CMY-2/-59). FPE (56/76, 73.7%) demonstrated superiority to PTZ (34/66, 51.5%) in this subgroup at TOC (difference 30.2%; 95% CI: 13.4, 45.1; Table). In mMITT+R, the ESBL-BU prevalence rate was 22.3% (172/771), with 6.4% (11/172) co-expressing AmpC (CMY-2/-4/-59/-99), 4.7% (8/172) co-expressing a metallo-β-lactamase (VIM-1, NDM-1), and 2.3% (4/172) co-expressing OXA-48. Superiority of FPE (67/91, 73.6%) compared to PTZ (41/81, 50.6%) was also observed at TOC despite inclusion of ESBL-BU resistant to either agent (difference 30.0%; 95% CI: 14.9, 43.3). Table Conclusion FPE may represent a new empiric carbapenem-sparing option in settings where ESBL are endemic. Disclosures Adam Belley, PHD, Allecra Therapeutics SAS (Consultant) Philip Barth, MD, Allecra Therapeutics SAS (Consultant) Shikhar Kashyap, n/a, Allecra Therapeutics SAS (Consultant)Allecra Therapeutics SAS (Consultant) Omar Lahlou, PhD, Allecra Therapeutics SAS (Employee) Paola Motta, PhD, Allecra Therapeutics SAS (Employee) Patrick Velicitat, MD, Allecra Therapeutics SAS (Employee)

Molsidomine, a long-acting vasodilator mainly used as an antianginal agent, was reported to decrease the portohepatic venous pressure gradient in patients with alcoholic cirrhosis. This study investigated the effects of linsidomine, the active metabolite of molsidomine, on systemic and splanchnic hemodynamics in rats with CCl4-induced cirrhosis using the microsphere technique. Compared with placebo-treated rats, linsidomine-treated animals were found to have a significant decrease in portal venous pressure (-18%, p less than 0.01) and in mean arterial pressure (-16%, p less than 0.01), smaller peripheral resistances (p less than 0.01), greater portal venous inflow (p less than 0.05), smaller splanchnic arteriolar resistances (p less than 0.01) and smaller protocol-lateral resistances (p less than 0.05). Cardiac output, hepatic arterial blood flow, portal blood flow and estimated hepatic blood flow were not significantly different between the two groups of animals. Linsidomine-treated rats exhibited a trend toward greater collateral blood flow compared with controls, but this difference was not significant. We conclude that linsidomine decreases portal venous pressure by reducing portocollateral resistances without affecting liver blood flow. These effects should be beneficial for patients with cirrhosis and portal hypertension.