Safety and efficacy of ceftolozane/tazobactam plus metronidazole versus meropenem from a phase 2, randomized clinical trial in pediatric participants with complicated intra-abdominal infection

BACKGROUND: Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed. METHODS: This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (\u3c18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points. RESULTS: The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol. CONCLUSION: Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious

Subgroup analysis of phase 2 study of ceftolozane/tazobactam in neonates and young infants with pyelonephritis.

Ceftolozane/tazobactam is approved for the treatment of patients from birth to <18 y old with complicated urinary tract infections (cUTI). This post hoc analysis evaluated the safety, efficacy, and pharmacokinetics (PK) of ceftolozane/tazobactam compared with meropenem in neonates and young infants. NCT03230838 was a phase 2, randomized, active comparator-controlled, double-blind study of patients from birth to <18 y of age with cUTI, including pyelonephritis, given ceftolozane/tazobactam or meropenem in a 3:1 ratio. This subset analysis included only neonates and young infants < 3 mo of age. The microbiologic modified intent-to-treat population (mMITT) included 20 patients (ceftolozane/tazobactam, n = 14; meropenem, n = 6). All patients had pyelonephritis at baseline; two patients in each treatment group had bacteremia (overall 4/20, 20%). Escherichia coli was the most common baseline pathogen (overall 16/20, 80%). Safety and efficacy results were similar between treatment groups and consistent with the overall pediatric population. There were no serious drug-related adverse events (AEs), no discontinuations due to AEs, and no AEs leading to death in either treatment group. For the ceftolozane/tazobactam and meropenem treatment groups, clinical cure rates in the mMITT population were 92.9% and 100%, respectively. The population PK analysis of neonates and young infants demonstrated similar ceftolozane and tazobactam exposures to those of adults, achieving pharmacodynamic targets associated with clinical and microbiologic cure. Ceftolozane/tazobactam has a favorable safety profile and achieves high clinical cure and microbiologic eradication rates in neonates and young infants < 3 mo of age with cUTI and pyelonephritis. IMPORTANCE Extrapolation of antibacterial agent pharmacokinetics from adults to newborns and young infants may not be appropriate; similarly, the clinical manifestations of infectious diseases and outcomes following antibacterial treatment may not be similar. Ceftolozane/tazobactam is an antibacterial drug combination active against Pseudomonas aeruginosa and other multidrug-resistant gram-negative bacteria. A clinical study led to the approval for ceftolozane/tazobactam in patients from birth to 18 y of age who have complicated urinary tract infections, including those with serious kidney infections. Based on data collected during that clinical study, we compared newborns and young infants who were treated with ceftolozane/tazobactam (14 patients) and those who were treated with meropenem (6 patients). We found that ceftolozane/tazobactam treatment of newborns and young infants up to 3 mo of age who have complicated urinary tract infections demonstrated a favorable safety profile and high clinical cure and microbiologic eradication rates, similar to meropenem

Disruption of Poly(ADP-Ribose) Homeostasis Affects Spermiogenesis and Sperm Chromatin Integrity in Mice1

The major function of sperm is the delivery of the paternal genome to the metaphase II oocyte, ensuring transmission of the genetic information to the next generation. For successful fertilization and healthy offspring, sperm DNA must be protected from exogenous insults. This is achieved by packaging the sperm DNA into a condensed protamine-bound form, preceded by the precisely orchestrated removal of histones and intermittent insertion and removal of transition proteins. This remodeling process requires relaxation of supercoiled DNA by transient formation of physiological strand breaks that spermatids, being haploid, cannot repair by homologous recombination. In somatic cells, the presence of DNA strand breaks rapidly induces the formation of poly(ADP-ribose) by nuclear poly(ADP-ribose) polymerases, which in turn facilitates DNA strand break signaling and assembly of DNA repair complexes. We reported earlier that chromatin remodeling steps during spermiogenesis trigger poly(ADP-ribose) (PAR) formation. Here, we show that knockout mice deficient in PARP1, PARG (110-kDa isoform), or both display morphological and functional sperm abnormalities that are dependent on the individual genotypes, including residual DNA strand breaks associated with varying degrees of subfertility. The data presented highlight the importance of PAR metabolism, particularly PARG function, as a prerequisite of proper sperm chromatin quality