Cefalexin use in UK acute pyelonephritis practice: unaddressed challenges in dosing, breakpoints and clinical evidence

Dear Editor in Chief, Seven years after National Institute for Health and Care Excellence (NICE) endorsed cefalexin as a first-line oral agent for acute pyelonephritis, we are aware of growing divergence and uncertainty in how cefalexin is used in UK practice.1 The absence of robust clinical evidence to inform these varied approaches, coupled with evolving pharmacokinetic/pharmacodynamic (PK/PD) understanding, necessitates an urgent review of cefalexin's role in the management of upper urinary tract infections. Among patients presenting with acute pyelonephritis, appropriate antimicrobial selection and dosing are critical determinants of clinical outcomes.2 Yet identifying optimal cefalexin dosing in this context remains difficult if not impossible. Prescribers must balance the risk of inadequate drug exposure, with consequential clinical and microbiological failure, against potential toxicity (e.g. gastrointestinal disturbances) from excessive exposure, compounded by the lack of standardized dosing guidance for acute pyelonephritis treatment. While the EUCAST provides breakpoints for cefalexin, these are restricted to Enterobacterales in uncomplicated lower UTI (cystitis).3 Critically, there are no EUCAST breakpoints for cefalexin for systemic infection including acute pyelonephritis. Applying ‘susceptible’ results derived from lower UTI thresholds to pyelonephritis is not evidence-based and is explicitly discouraged by EUCAST.4 The higher tissue exposure required for effective treatment of parenchymal kidney infection, coupled with the paucity of supporting PK/PD data, renders such extrapolation inappropriate.5 The absence of a EUCAST breakpoint for cefalexin in systemic infections has significant clinical implications. Laboratory reports indicating cefalexin susceptibility for urinary isolates, predicated on criteria for cystitis, may inappropriately influence prescribing decisions for acute pyelonephritis, despite the absence of validated interpretive criteria for this indication. The potential for treatment failure due to inadequate drug exposure at the site of infection remains unquantified but concerning.