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• Approximately 50% of all peripheral venous catheters (PVCs) are used to administer intravenous antibiotics. • Subsequently, 11% and 19% of PVCs lead to irritation and vessel injury, respectively. • Flucloxacillin, lincomycin and vancomycin were confirmed to increase the risk of PVC failure. • This study newly identified cefepime and ceftazidime as significant risk factors for PVC failure. • Methods to improve antibiotic delivery are necessary to improve patient care. Peripheral venous catheters (PVCs) are used to administer antimicrobials, but many fail prior to completion of therapy. While some antimicrobials are known to increase the PVC failure rate, risk profiles for many are unclear. To synthesize data from prospective PVC studies conducted between 2013 and 2019 to determine associations between common antimicrobials and PVC failure. A secondary analysis was undertaken of seven randomized controlled trials and two prospective cohort studies from three quaternary hospitals (two adult and one paediatric) in Australia between 2013 and 2019. The primary outcome was PVC failure due to vessel injury (occlusion, infiltration or extravasation) or irritation (pain or phlebitis). Associations between antimicrobial use and PVC failure were explored using multi-variable Cox regression. In total, 5252 PVCs (4478 patients) were analysed; vessel injury and irritations occurred in 19% and 11% of all PVCs, respectively. Vessel injury was significantly associated with cefepime hydrochloride [hazard ratio (HR) 2.50; 95% confidence interval (CI) 1.44–4.34], ceftazidime pentahydrate (HR 1.91, 95% CI 1.11–3.31), flucloxacillin sodium (HR 1.84, 95% CI 1.45–2.33), lincomycin hydrochloride (HR 1.67, 95% CI 1.10–2.52) and vancomycin hydrochloride (HR 1.73, 95% CI 1.25–2.40). Irritation was significantly associated with flucloxacillin sodium (HR 2.58, 95% CI 1.96–3.40). This study identified several antimicrobials associated with increased PVC failure, including some that were already known to be associated and some that had not been identified previously. Research is needed urgently to determine superior modes of delivery (e.g. dilution, infusion time, device type) that may prevent PVC failure. [ABSTRACT FROM AUTHOR]