Target attainment of benzylpenicillin in patients with infective endocarditis.

OBJECTIVES

Benzylpenicillin is commonly used to treat infective endocarditis, particularly for streptococcal infections. This study aimed to perform pharmacokinetic/pharmacodynamic analyses of benzylpenicillin to assess the probability of target attainment (PTA) across different pathogens, MIC values, pharmacokinetic/pharmacodynamic targets, and renal function levels.

METHODS

In the Partial Oral Endocarditis Treatment trial, patients with left-sided infective endocarditis were randomly assigned to either conventional intravenous or partial oral antibiotic treatment. This substudy included patients receiving intravenous benzylpenicillin (3000 mg q6h). Pharmacokinetic measurements were conducted, and a population pharmacokinetic model was developed to estimate PTAs through model-based simulations. Pharmacokinetic/pharmacodynamic targets were based on time above MIC (or 4 × MIC) of the free concentration (fT > MIC or fT > 4 × MIC).

RESULTS

A total of 75 patients were included, and 291 plasma concentrations were obtained. MIC values were available for 68 patients. Individual target attainment for 50% fT > MIC and 50% fT > 4 × MIC targets was 100% (56/56) and 94.6% (53/56) for streptococci, 100% (3/3) for staphylococci, but only 66.7% (6/9) and 33.3% (3/9) for Enterococcus faecalis. For more stringent targets of 100% fT > MIC and 100% fT > 4 × MIC, individual target attainment was 89.3% (50/56) and 75.0% (42/56) for streptococci, 100.0% (3/3) and 66.7% (2/3) for staphylococci, but 33.3% (3/9) and 11.1% (1/9) for E. faecalis. Simulations showed PTAs above 90% for MIC values ≤ 0.5 mg/L at the 50% fT > MIC target, and for MIC values ≤ 0.063 mg/L at 50% fT > 4 × MIC or 100% fT > MIC targets. Higher renal clearance was associated with substantially lower PTAs.

DISCUSSION

Intravenous benzylpenicillin achieved target levels in most patients with infective endocarditis, particularly for those infected with streptococci or susceptible staphylococci. However, low individual target attainment in patients with E. faecalis suggests limitations in treating enterococcal endocarditis, especially in patients with preserved renal function.