The contribution of pharmacokinetic–pharmacodynamic modelling with Monte Carlo simulation to the development of susceptibility breakpoints for Neisseria meningitidis

ABSTRACTThis study used pharmacokinetic–pharmacodynamic (PK–PD) modelling and MICs of 15 antimicrobial agents, derived from testing a large international culture collection, to assist in the development of interpretative criteria, i.e., breakpoints, for Neisseria meningitidis. PK parameters, protein binding, percentage penetration into cerebrospinal fluid (CSF), and the variability of these values, were extracted from the published literature for the 15 agents. PK–PD parameters have not been developed specifically for N. meningitidis in animal or human studies. Thus, it was necessary to invoke PK–PD targets from other organisms that cause infections at similar sites. The PK–PD targets utilised were: time above the MIC for at least 50% of the dosing interval for all β-lactams, chloramphenicol, sulphafurazole and trimethoprim–sulphamethoxazole; an AUC/MIC ratio of ≥25 for the tetracyclines and macrolides; and an AUC/MIC ratio of ≥125 for the fluoroquinolones. A 10 000-subject Monte Carlo simulation was designed with the usual dosing regimens of each antimicrobial agent at MIC values of 0.03–64 mg/L in both serum and CSF. The PK–PD breakpoint was defined as the MIC at which the calculated target attainment was ≥95%. Using these assumptions, the proposed PK–PD breakpoints were: azithromycin, 0.125 mg/L; doxycycline, 0.25 mg/L; cefotaxime, ciprofloxacin and levofloxacin, 0.5 mg/L; penicillin G, meropenem, rifampicin, tetracycline and minocycline, 1 mg/L; chloramphenicol and sulphafurazole, 2 mg/L; and ampicillin, ceftriaxone and trimethoprim–sulphamethoxazole, 4 mg/L. Proposed PK–PD breakpoints applicable to CSF were: penicillin and cefotaxime, 0.06 mg/L; rifampicin, 0.125 mg/L; ceftriaxone, meropenem and trimethoprim–sulphamethoxazole, 0.25 mg/L; ampicillin, 0.5 mg/L; and chloramphenicol, 1 mg/L.