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

Abstract

This 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 beta-lactams, chloramphenicol, sulphafurazole and trimethoprim-sulphamethoxazole; an AUC/MIC ratio of >or=25 for the tetracyclines and macrolides; and an AUC/MIC ratio of >or=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 >or=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.

Multicenter Study for Defining the Breakpoint for Rifampin Resistance in Neisseria meningitidis by rpoB Sequencing

“…Interestingly, our suggested breakpoint is identical to that proposed for rifampin on the basis of pharmacokinetic-pharmacodynamic (PK-PD) modeling with Monte Carlo simulation. Our biological data provide an experimental confirmation of the PK-PD assumption made for N. meningitidis (5).…”

Pharmacokinetics of doxycycline in tilapia (Oreochromis aureus × Oreochromis niloticus) after intravenous and oral administration

“…The minimum inhibitory concentration (MIC90) that inhibits 90% of Streptococcus isolated from tilapia was determined to be 0.5 μ g/mL (unpublished data). The pharmacokinetics–pharmacodynamic index accepted as a predictor of therapeutic efficacy for tetracyclines is AUC/MIC ratio (Koeth et al ., ; Prats et al ., ; Burgess et al ., ; Gutierrez et al ., ; Miller et al ., ; Embers et al ., ; Zozaya et al ., ), and for doxycycline against different bacteria, an AUC 0–24 h /MIC of ≥25 h was utilized (Koeth et al ., ; Burgess et al ., ). In the present study, the ratios of AUC 0–24 h /MIC90 were calculated for the Streptococcus isolated from tilapia, which reached up to 385.49 and 74.80 h after intravenous and oral administration, respectively.…”

Pharmacokinetics of doxycycline in sheep after intravenous and oral administration

“…Extrapolating from the MIC mentioned above and our single-dose AUC values, AUC 0-1 / MIC ratio for the oral route was 1437.6 h for C. pecorum, 89.1 h for S. pneumoniae, P. haemolytica and S. aureus, 44.6 h for H. influenzae, and 22.3 h for M. mycoides. To our knowledge, only a doxycycline AUC/MIC threshold has been established for H. influenzae (Koeth et al, 2004), and P25 for tetracyclines for Neisseria meningitidis (Burguess et al, 2007).…”