Systematic overdosing of oxa- and cloxacillin in severe infections treated in ICU: risk factors and side effects

BACKGROUND Oxacillin and cloxacillin are the most frequently used penicillins for the treatment of severe methicillin-susceptible Staphylococcus aureus infections in intensive care units (ICUs), especially endocarditis. International recommendations do not suggest any adaptation of the dosage in case of renal impairment. We wanted to assess the risk factors for overdosing in ICU and the related observed side effects. METHODS All patients with a therapeutic drug monitoring of oxa- or cloxacillin between 2008 and 2014 were included. The target range of trough concentration for total antibiotic activity was considered to be 20-50 mg/L. Data concerning the infection, the given treatment, the renal function, and the attributed side effects of overdosing were collected. A logistic regression model was used to compute the measured trough concentrations. RESULTS Sixty-two patients were included in this study. We found a median trough plasma concentration of 134.3 mg/L (IQR 65.3-201 mg/L). Ten patients (16.1%) reached the target concentration; all other patients (83.9%) were overdosed. Eleven patients (17.7%) experienced neurological side effects attributed to a high antibiotic concentration, i.e. persistent coma and delirium. When adjusted on the dosage used, the risk of overdosing was significantly associated with a creatinine clearance <10 mL/min (with or without hemodialysis). CONCLUSION With the suggested dose of 12 g/day for cloxacillin treatment in case of endocarditis and severe infections occurring in ICU, 83.9% of patients are largely overdosed. Considering the observed side effects, doses should be accurately monitored and reduced, particularly when renal replacement therapy is needed.