Pharmacokinetics and pharmacodynamic target attainment of ceftriaxone in adult severely ill sub-Saharan African patients: a population pharmacokinetic modelling study

Background: In sub-Saharan Africa (SSA), the highly albumin-bound beta-lactam ceftriaxone is frequently used for the empirical treatment of severe bacterial infections. Systemic drug exposure of b-lactams can be altered in critically ill ICU patients, but pharmacokinetic and pharmacodynamic data for non-ICU SSA populations are lacking. Methods: We performed a population pharmacokinetic study in an adult hospital population in Mozambique, treated with ceftriaxone for presumptive severe bacterial infection from October 2014 to November 2015. Four blood samples per patient were collected for total ceftriaxone (CEFt) and unbound ceftriaxone (CEFu) concentration measurement. We developed a population pharmacokinetic model through non-linear mixed effect analysis and performed simulations for different patient variable, dosing and pharmacodynamic target scenarios. Results: Eighty-eight participants yielded 277 CEFt and 276 CEFu concentrations. The median BMI was 18.9 kg/m(2) and the median albumin concentration was 29 g/L. In a one-compartment model with non-linear protein binding, creatinine clearance was positively correlated with CEFu clearance. For microorganisms with an MIC of 1 mg/L, simulations demonstrated that with a 1 g twice-daily regimen and a 2 g once-daily regimen, 95.1% and 74.8% would have a CEFu concentration. MIC during half of the dosing interval (fT(>MIC) = 50%), respectively, whereas this was only 58.2% and 16.5% for the fT(>MIC) = 100% target. Conclusions: Severely ill adult non-ICU SSA patients may be at substantial risk for underexposure to CEFu during routine intermittent bolus dosing, especially when their renal function is intact.