Suboptimal Clinical Response Rates with Newer Antibiotics Among Patients with Moderate Renal Impairment: Review of the Literature and Potential Pharmacokinetic and Pharmacodynamic Considerations for Observed Findings.

A number of antibacterial agents have emerged into the U.S. market in the last 2 decades to address growing concerns of antimicrobial resistance. These agents have demonstrated noninferiority to comparators for treatment of a range of complicated infections in their respective clinical trials. However, with select agents, a trend of reduced therapeutic efficacy was observed among study patients with baseline renal impairment. This phenomenon was seen in phase III studies involving ceftazidime-avibactam, ceftolozane-tazobactam, daptomycin, and telavancin. Although these were largely post hoc findings among small subpopulations, this observation is still concerning, given that renal impairment is a common occurrence among patients in real-world care settings. Cautions for use in this population are featured in the prescribing information of all four agents. Although well-defined reasons for these findings across trials are diverse or unknown, several potential pharmacokinetic and pharmacodynamic explanations for these discordant response rates exist. In this review, we summarize the phase III studies that observed lower response rates with ceftazidime-avibactam, ceftolozane-tazobactam, daptomycin, and telavancin relative to their comparators among patients with moderate renal impairment, discuss potential explanations for the observed findings, provide considerations for future antibiotic development, and offer strategies for optimizing antibiotic dosage selection among patients with moderate renal impairment in clinical settings. Although all of these agents are discussed, ceftazidime-avibactam is used as a motivating example to demonstrate the implications of inappropriate dosage selection.