This phase 3 trial compared ceftolozane/tazobactam plus metronidazole vs meropenem for the treatment of complicated intra-abdominal infections. Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem. High rates of presumed microbiological eradication of Enterobacteriaceae and Pseudomonas aeruginosa were found with both regimens.

The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a ␤-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.T he emergence of drug resistance in common pathogens has become a major medical issue; increased resistance in Gram-negative pathogens, such as Pseudomonas aeruginosa and extended-spectrum ␤-lactamase (ESBL)-producing Enterobacteriaceae, is especially concerning due to the increased morbidity and mortality associated with such infections (5). However, the number of antimicrobial products currently being developed to address these unmet medical needs appears to be limited (1).Ceftolozane-tazobactam, formerly referred to as CXA-201, is a novel oxyimino-aminothiazolyl cephalosporin (ceftolozane) and ␤-lactamase inhibitor (tazobactam) combination being developed for the treatment of serious Gram-negative infections (6,7,8). The addition of tazobactam extends its spectrum of activity to cover ESBL-producing organisms. The pharmacokinetics (PK) and safety of multiple doses of ceftolozane alone has already been established (3) but needs to be investigated for the coadministration of ceftolozane and tazobactam. In the present study, the PK and safety of single and multiple doses of ceftolozane and tazobactam alone and in combination at a 2:1 ratio were investigated in healthy adult subjects. MATERIALS AND METHODSStudy population and study design. Healthy male and female subjects, 18 to 65 years of age, were enrolled in a single-center, prospective, randomized, double blind study of single ascending doses (part 1) and multiple ascending doses (part 2) of intravenous (i.v.) ceftolozane, tazobactam, and ceftolozane-tazobactam. In part 1, t...

Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra‐abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma‐to‐epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a >90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma‐to‐ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve >90% PTA for nosocomial pneumonia. For example, a 3‐g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a >90% PTA (actual 98%) for the 1‐log kill target against pathogens with an MIC of ≤8 mg/L in ELF, compared with the 1.5‐g dose approved for cIAIs and cUTIs.

Ceftolozane-tazobactam is a novel antipseudomonal cephalosporin with a ␤-lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, openlabel studies, a single dose of ceftolozane-tazobactam was administered as a 1-h intravenous infusion to 24 subjects with normal, mild, or moderate renal impairment (1,000/500 mg) and six subjects with severe renal impairment (500/250 mg). Six subjects with end-stage renal disease (ESRD) received two doses of ceftolozane-tazobactam (500/250 mg each), pre-and posthemodialysis (post-HD). PK parameters were determined by noncompartmental methods. Plasma exposure to ceftolozane-tazobactam increased as renal function declined with only slightly increased exposures in subjects with mild renal impairment; the median area under the concentration-time curve from time zero to infinity (AUC 0-ؕ ) for ceftolozane and tazobactam increased 1.4-and 1.2-fold, respectively. In subjects with moderate renal impairment, the AUC 0-ؕ increased 2.5-and 2.2-fold for ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC 0-ؕ for ceftolozane and tazobactam increased 4.4-and 3.8-fold, respectively. In ESRD subjects, ceftolozane and tazobactam concentrations declined rapidly following the start of HD, with approximately 66 and 56% reductions in overall exposure based on the AUC 0-ؕ before and after dialysis. Slight increases in exposure with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on HD require a decrease in the dose, a change in the frequency of administration, or both to achieve exposures within the established safety and efficacy margins of ceftolozane-tazobactam. Ceftolozane-tazobactam was well tolerated by all renal impairment groups. C eftolozane-tazobactam is a novel antibacterial with activity against Pseudomonas aeruginosa, including drug-resistant strains, and other common Gram-negative pathogens, including most extended-spectrum ␤-lactamase (ESBL)-producing Enterobacteriaceae (1, 2). Ceftolozane exerts its bactericidal activity by inhibiting essential penicillin-binding proteins, resulting in inhibition of cell wall synthesis and subsequent cell death (Cubist Pharmaceuticals, data on file, 2009). Tazobactam, an inhibitor of most class A ␤-lactamases and some class C ␤-lactamases, protects ceftolozane from hydrolysis and broadens its coverage to include most ESBL-producing members of the family Enterobacteriaceae (Cubist Pharmaceuticals, data on file, 2006, 2013).The pharmacokinetics (PK) of ceftolozane-tazobactam in patients with normal renal function are linear across a wide range of doses (up to 3,000 mg/1,500 mg as a single dose). The terminal elimination half-life (t 1/2 ) is approximately 2.5 h for ceftolozane and 1 h for tazobactam. Both compounds exhibit low protein binding (approximately 20% for ceftolozane and 30% for tazobactam) and are...

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