Risk Factors for Nephrotoxicity in Methicillin-Resistant Staphylococcus aureus Bacteraemia: A Post Hoc Analysis of the CAMERA2 Trial

Abstract

Background Clinical risk factors for nephrotoxicity in Staphylococcus aureus bacteraemia remain largely undetermined, despite its common occurrence and clinical significance. In an international, multicentre, prospective clinical trial (CAM-ERA2), which compared standard therapy (vancomycin monotherapy) to combination therapy (adding an anti-staphylococcal beta-lactam) for methicillin-resistant S. aureus bacteraemia, significantly more people in the combination therapy arm experienced acute kidney injury compared with those in the monotherapy arm (23% vs 6%). Objective The aim of this post hoc analysis was to explore in greater depth the risk factors for acute kidney injury from the CAMERA2 trial. Methods Among participants of the CAMERA2 trial, demographic-related, infection-related and treatment-related risk factors were assessed for their relationship with acute kidney injury by univariable and multivariable logistic regression. Acute kidney injury was defined by a modified-KDIGO (Kidney Disease: Improving Global Outcomes) criteria (not including urinary output). Results Of the 266 participants included, age (p = 0.04), randomisation to combination therapy (p = 0.002), vancomycin area under the concentration-time curve (p = 0.03) and receipt of (flu)cloxacillin as the companion beta-lactam (p < 0.001) were significantly associated with acute kidney injury. On a multivariable analysis, concurrent use of (flu)cloxacillin increased the risk of acute kidney injury over four times compared with the use of cefazolin or no beta-lactam. The association of vancomycin area under the concentration-time curve with acute kidney injury also persisted in the multivariable model. Conclusions For participants receiving vancomycin for S. aureus bacteraemia, use of (flu)cloxacillin and increased vancomycin area under the concentration-time curve were risk factors for acute kidney injury. These represent potentially modifiable risk factors for nephrotoxicity and highlight the importance of avoiding the use of concurrent nephrotoxins.Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Flucloxacillin worsens while imipenem–cilastatin protects against vancomycin‐induced kidney injury in a translational rat model

“…Our rat model confirms that synergistic nephrotoxicity exists, such as that observed in the CAMERA2 trial (Legg et al, 2023; due to addition of flucloxacillin to vancomycin; thus, we recommend against use of such combination in the hospital settings.…”

“…However, increasing the cilastatin dose and duration of treatment would be worth investigating. Third, the results of this study have been clinically validated in part, as it reproduces the increased clinical toxicity seen in the CAMERA2 trial (Legg et al, 2023) with combination therapy (vancomycin + flucloxacillin)…”

“…The significantly higher OPN on Day 4 could be associated with proximal tubule regeneration. Thus, this translational rat study reproduces the increased clinical toxicity seen in the CAMERA2 trial(Legg et al, 2023) with combination therapy (vancomycin + flucloxacillin), which resulted in early termination of the trial. Second, these data are in accord with preclinical models(Becerir et al, 2021;He et al, 2021;Hori et al, 2017;Humanes et al, 2015;Im et al, 2017;Kusama…”

“…Two human clinical trials, CAMERA2 and PROVIDE (PRospective Observational Evaluation of the Association Between Initial Vancomy-cIn Exposure and Failure Rates Among ADult HospitalizEd Patients With Methicillin-resistant Staphylococcus aureus Bloodstream Infections), did not generate any signal for sex-based differences (Legg et al, 2023;Lodise et al, 2020); therefore, sex as a biological variable was not incorporated in this particular study.…”

Optimal drug therapy for Staphylococcus aureus bacteraemia in adults

“…Dose adjustments are needed in patients with kidney impairment for most cephalosporins. No toxicity exposure threshold has been defined for cefazolin, and in contrast to flucloxacillin, it does not appear to increase the risk of AKI in combination with vancomycin [55,56]. Ceftaroline use for longer than 7 days has been associated with neutropenia [57].…”