Pharmacodynamic modeling of Carbapenems and fluoroquinolones against Bacteria that produce extended-spectrum beta-lactamases

• Published in: Clinical therapeutics 2004-11, Vol.26 (11), p.1800-1807
• Main Authors: MOCZYGEMBA, Leticia R, FREI, Christopher R, BURGESS, David S
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; beta-Lactamases - biosynthesis; beta-Lactams; Biological and medical sciences; Carbapenems - pharmacokinetics; Carbapenems - pharmacology; Ciprofloxacin - pharmacology; Drug Resistance, Bacterial; Escherichia coli - drug effects; Escherichia coli - isolation & purification; Fluoroquinolones - pharmacokinetics; Fluoroquinolones - pharmacology; Humans; Imipenem - pharmacology; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - isolation & purification; Lactams - pharmacology; Levofloxacin; Medical sciences; Microbial Sensitivity Tests; Models, Biological; Monte Carlo Method; Ofloxacin - pharmacology; Pharmacology. Drug treatments; Thienamycins - pharmacology
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2004.11.009

Bacteria that produce extended-spectrum beta-lactamases (ESBLs) are resistant to penicillins,cephalosporins, and monobactams. The results of clinical studies suggest that the carbapenems imipenem and meropenem may be effective against bacteria that produce ESBLs, although it is not known whether the new once-daily carbapenem ertapenem or the fluoroquinolones are useful against infections caused by ESBL-producing bacteria. The present study compared the simulated pharmacodynamics of the carbapenems imipenem,meropenem, and ertapenem; the simulated pharmacodynamics of the fluoroquinolones levofloxacin, gatifloxacin, and ciprofloxacin with those of the carbapenems; and the simulated pharmacodynamics of levofloxacin 750 mg with those of levofloxacin 500 mg, all against gram-negative isolates that did and did not produce ESBLs Pharmacokinetic data were obtained from studies in healthy humans. Minimum inhibitory concentrationsMICs) for bacteria that did and did not produce ESBLs were determined in triplicate using broth-microdilution techniques as recommended by National Committee for Clinical Laboratory Standards guidelines. Monte Carlo simulation was used to construct pharmacodynamic models for imipenem, meropenem, ertapenem, levofloxacin, gatifloxacin, and ciprofloxacin. Pharmacodynamic measures of interest were the probability of the free concentration remaining above the MIC >-40% of the time (T>MIC > or =40%) for carbapenems and the likelihood of achieving a free AUC:MIC ratio > or =125 for fluoroquinolones. MICs were determined for 39 isolates that produced ESBLs and 45 isolates that did not Bacteria that did not produce ESBLs were > or =93% susceptible to all carbapenems and fluoroquinolones tested. Among bacteria that produced ESBLs, rates of susceptibility to the specific agents were as follows: imipenem, 100%; meropenem, 97%; ertapenem, 87%; levofloxacin, 54%; gatifloxacin, 44%; and ciprofloxacin, 36%. In the pharmacodynamic models, imipenem and meropenem had an equal likelihood of achieving a free T>MIC > or =40% against bacteria that produced ESBLs (> or =97%) and bacteria that did not produce ESBLs (> or =98%). In contrast, the likelihood of ertapenem achieving a free T>MIC > or =40% was lower against bacteria that produced ESBLs (78%) than against bacteria that did not produce ESBLs (94%). Similarly, the fluoroquinolones were less likely to achieve a free AUC:MIC ratio > or =125 against bacteria that produced ESBLs (2%-13%) than against bacteria th