Ceftazidime-avibactam with or without renal modification in first 48 hours in patients with sepsis and acute kidney injury (CAR SAKI): An Open-Label Randomized Controlled Trial

Ceftazidime avibactam has become a widely utilized antibiotic in the management of Carbapenem resistant gram-negative bacterial sepsis. The early and appropriate management of sepsis is crucial to prevent the development of septic shock with multi-organ failure, which can result in increased mortality. Ceftazidime avibactam is primarily eliminated by the kidneys and has a wide therapeutic index, with relatively few safety concerns when administered at the maximum dose, as compared to other antimicrobial classes. However, the data on the dosing strategy in AKI patients within the first 48 hours of sepsis and its impact on outcomes is inconclusive. Thus, we hypothesized that dose adjustment could be deferred until 48 hours after initiation of therapy. The aim of renal dosage adjustments is to achieve equivalent exposures in patients with and without renal impairment, thereby minimizing toxicity without compromising efficacy. However, a recent meta-analysis showed that, compared to subjects receiving the full dose of ceftazidime-avibactam, those undergoing renal dose modifications had almost a two-fold increased risk of mortality. Such a deferred dose adjustment strategy could be employed in clinical trials and practice to ensure pharmacodynamic targets are met during this critical period in therapy. The study will provide clarity on adequate early antibiotic therapy with ceftazidime avibactam by optimizing the pharmacokinetic-pharmacodynamic targets, a primary driver of outcomes, thus justifying the need for the study.