Optimizing Pharmacodynamic Target Attainment Using the MYSTIC Antibiogram: Data Collected in North America in 2002

Abstract

The OPTAMA Program is intended to examine typical antimicrobial regimens used in the treatment of common nosocomial pathogens and the likelihood of these regimens attaining appropriate pharmacodynamic exposure in different parts of the world. A 5,000-subject Monte Carlo simulation was used to estimate pharmacodynamic target attainment for meropenem, imipenem, ceftazidime, cefepime, piperacillin-tazobactam, and ciprofloxacin against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Standard dosing regimens from North America were used. Pharmacokinetic parameter variability was derived from existing healthy volunteer data, and MIC data came from the 2002 MYSTIC Program. Ciprofloxacin displayed the lowest target attainment against all bacterial species (41 to 46% for A. baumannii, 53 to 59% for P. aeruginosa, and 80 to 85% for the Enterobacteriaceae). Increasing the dose to 400 mg every 8 h did not significantly increase target attainment against nonfermenters. Piperacillin-tazobactam target attainments were similar to that of ceftazidime against all pathogens. Higher doses of both compounds were needed to achieve better target attainments against P. aeruginosa. Overall, meropenem, imipenem, and cefepime attained the highest probabilities of attainment against the Enterobacteriaceae (99 to 100%). The carbapenems appear to be the most useful agents against A. baumannii (88 to 92%), and these agents, along with higher doses of any of the ␤-lactams, would be the most appropriate choices for empirical therapy for P. aeruginosa infection. Given the lack of agreement between percent susceptibility and probability of target attainment for certain antimicrobial regimens, a methodology employing stochastic pharmacodynamic analyses may be a more useful tool for differentiating the most-optimal compounds and dosing regimens in the clinical setting of initial empirical therapy.

Evaluating Ciprofloxacin Dosing for Pseudomonas aeruginosa Infection by Using Clinical Outcome-Based Monte Carlo Simulations

“…The local MIC profile including 38% of isolates with MICs of 0.5 g/ml and 7% with MICs of 1 g/ml produced PTA results of 0.44 and 0.58 for the standard and high ciprofloxacin doses, respectively. The findings were similar to those from another MCS study of ciprofloxacin against P. aeruginosa using PK data from healthy volunteers and MICs from North American susceptibility data (23). PTA using a total AUC/MIC of Ն125 was 53% with doses of 400 mg q12h compared to 59% with doses of 400 mg q8h.…”

Evaluation by Monte Carlo Simulation of the Pharmacokinetics of Two Doses of Meropenem Administered Intermittently or as a Continuous Infusion in Healthy Volunteers

“…In order to put these observations into perspective, we ob- tained meropenem MIC distributions for common gram-negative nosocomial pathogens (K. pneumoniae, Enterobacter cloacae, and P. aeruginosa) from the MYSTIC database (31,39,47). Weighted averages were calculated over the MIC distributions, and the probabilities of target attainment by dose and mode of administration and are presented in Table 3.…”

“…The low variability observed in this study with healthy volunteers may lead to confidence intervals too narrow in comparison to the clinical situation. The organism MIC distributions in the MYSTIC database represent data for a large collection of current pathogens, and the data were collected in Europe and the United States (31,39,47). Figure 5 demonstrates that K. pneumoniae and E. cloacae both have MIC distributions in which Ͼ90% of the isolates examined have meropenem MICs Յ0.25 mg/liter.…”

“…Target pathogen MIC distributions were obtained from the MYSTIC database (31,39,47). A weighted average (expectation) over the MIC distribution and the target attainment rates was taken to obtain an estimate of the population probability of target attainment for a specific pathogen for a specific mode of administration and a specific dose.…”

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

“…The probability of meeting the PK/PD target, i.e., an AUC/MIC ratio of Ն125 h for isolates with MICs of Ͼ0.3 mg/liter, was suboptimal, resulting in a target attainment rate of 53 to 59% for routinely isolated P. aeruginosa strains in 2002 (212). Therefore, an AUC/MIC target of Ͼ350 h has been set for P. aeruginosa (206,207).…”