Pharmacokinetics and Pharmacodynamic Target Attainment of Benzylpenicillin in an Adult Severely ill Sub-Saharan African Patient Population

Abstract

Background

In intensive care (ICU) patients, systemic exposure of β-lactam antibiotics can be altered, and positive clinical outcome is associated with increasing fT>MIC ratios. In sub-Saharan African (SSA) hospitals, benzylpenicillin (PEN) is frequently used for the empirical treatment of severe pneumococcal infections. Pharmacokinetic data for non-ICU hospitalized populations are lacking.

Methods

We performed a population pharmacokinetic (PPK) study in an adult Mozambican hospital population treated intravenously with PEN from October 2014-November 2015. Four blood samples/patient were collected for total PEN (PEN_t) and unbound PEN (PEN_u) concentration measurement. We developed a PPK model through non-linear mixed effect analysis and performed simulations for different patient variable, dosing, and pharmacodynamic target scenarios.

Results

112 participants yielded 387 PEN_t and 53 PEN_u concentrations. The median (range) body mass index was 18.3 (10.5-31.3) and the median albumin concentration and creatinine clearance (CL_CR) were 29 (12-44) g/L and 80 (3-195) mL/min, respectively. In a one-compartment model, CL_CR was positively correlated with PEN_t CL. For infections with a microorganism with an MIC of 1 mg/L, simulations demonstrated that with 3 million IU (1.8 g) q6h, 74.1% would have a PEN_u concentration >MIC during half of the dosing interval (fT>MIC=50%), while this was 24.8% for the fT>MIC=100% target. For pathogens with an MIC of 0.06 mg/L, these percentages were 98.2% and 72.3%.

Conclusions

Severely ill adult non-ICU SSA patients may be at high risk for underexposure to PEN_u during routine intermittent bolus dosing, especially when their renal function is intact and when infected with pathogens with intermediate susceptibility.