The long walk to a short half-life: the discovery of augmented renal clearance and its impact on antibiotic dosing

Abstract

BACKGROUND AND OBJECTIVES: Renal function monitoring traditionally focuses on detecting impairment to prevent antibiotic toxicity. However, augmented renal clearance (ARC) represents the opposite challenge-enhanced elimination causing subtherapeutic drug concentrations. The aim of this review is to describe ARC's discovery and its impact on antibiotic therapy over two decades. METHODS: Narrative commentary examining ARC's discovery, clinical significance, diagnostic challenges and management strategies for antibiotic dosing in critically ill patients, with future research priorities. RESULTS: ARC was first noted in the late 1990s at Baragwanath Hospital, South Africa, where unexpectedly high creatinine clearance rates (>200 mL/min) were measured in ICU patients. Subsequent pharmacokinetic studies confirmed elevated antibiotic clearance with reduced systemic exposures. ARC, defined as creatinine clearance of >130 mL/min/1.73 m2, occurs in 65%-80% of critically ill patients with normal serum creatinine, particularly younger patients with sepsis, trauma or burns. The phenomenon results from increased cardiac output and renal blood flow during systemic inflammatory responses, can persist for weeks after ICU admission, and affects all renally eliminated drugs. ARC is often undiagnosed unless some form of creatine clearance is directly measured. Importantly, ARC is a major risk factor for antibiotic failure and resistance selection. CONCLUSIONS: ARC represents a significant but underrecognized challenge affecting antibiotic dosing in critically ill patients. Therapeutic drug monitoring remains the most reliable method to ensure adequate antibiotic exposure. Future research priorities include validated predictive models, simpler diagnostic methods and evidence-based dosing guidelines for high-risk populations.

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