Too much of a good thing: a retrospective study of β-lactam concentration-toxicity relationships

Objectives: To determine the existence of concentration-toxicity relationships for common beta-lactam antibiotic adverse effects and define thresholds above which toxicity is more likely. Patients and methods: Retrospective review of consecutive patients treated with piperacillin, meropenem or flucloxacillin who underwent therapeutic drug monitoring (TDM) at St Vincent's Hospital (Sydney, Australia) between January 2013 and December 2015. Adverse events investigated included neurotoxicity, nephrotoxicity, hepatotoxicity and opportunistic Clostridium difficile infection. Toxicity was measured using observational grading criteria, clinical assessment and relevant serum biomarkers. These findings were correlated with trough TDM measurements at the time of toxicity presentation. Results: TDM results from 378 patients (piperacillin=223, meropenem=94 and flucloxacillin=61) were investigated. There was no difference in baseline patient characteristics across antibiotic groups. A statistically significant elevation in mean serum trough concentrations (C-min) was found in patients diagnosed with neurotoxicity (piperacillin, P<0.01;meropenem, P=0.04; flucloxacillin, P=0.01) and those who developed nephrotoxicity whilst being treated with piperacillin (P<0.01) ormeropenem(P<0.01). Incidence of hepatotoxicity and C. difficile was not related to C-min. Threshold concentrations for which there is 50% risk of developing a neurotoxicity event (piperacillin, C-min>361.4mg/L; meropenem, C-min>64.2mg/L; flucloxacillin, C-min>125.1mg/L) or nephrotoxicity (piperacillin, C-min>452.65mg/L; meropenem, C-min>44.45mg/L) varied across antibiotics. Conclusions: Our data reveal an association between toxic concentrations for a number of beta-lactamagents and neurotoxic/nephrotoxic effects. We have defined threshold concentrations above which these toxicities become more likely. Clinicians should balance concerns for therapeutic efficacy with potential toxicity when considering aggressive therapy.