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Pharmacodynamic modeling of carbapenems and fluoroquinolones against bacteria that produce extended-spectrum beta-lactamases.
Clin Ther. 2004 Nov; 26(11):1800-7.CT

Abstract

BACKGROUND

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.

OBJECTIVE

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

METHODS

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.

RESULTS

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 that did not produce ESBLs (85%-91%).

CONCLUSIONS

Carbapenems had superior in vitro activity against bacteria that produced ESBLs compared with fluoroquinolones. Pharmacodynamic modeling based on local ESBL-producing isolates and pharmacokinetic data from healthy humans indicated that imipenem and meropenem may have a greater likelihood of achieving pharmacodynamic targets against bacteria that produce ESBLs than ertapenem or fluoroquinolones.

Authors+Show Affiliations

College of Pharmacy, The University of Texas at Austin, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15639692

Citation

Moczygemba, Leticia R., et al. "Pharmacodynamic Modeling of Carbapenems and Fluoroquinolones Against Bacteria That Produce Extended-spectrum Beta-lactamases." Clinical Therapeutics, vol. 26, no. 11, 2004, pp. 1800-7.
Moczygemba LR, Frei CR, Burgess DS. Pharmacodynamic modeling of carbapenems and fluoroquinolones against bacteria that produce extended-spectrum beta-lactamases. Clin Ther. 2004;26(11):1800-7.
Moczygemba, L. R., Frei, C. R., & Burgess, D. S. (2004). Pharmacodynamic modeling of carbapenems and fluoroquinolones against bacteria that produce extended-spectrum beta-lactamases. Clinical Therapeutics, 26(11), 1800-7.
Moczygemba LR, Frei CR, Burgess DS. Pharmacodynamic Modeling of Carbapenems and Fluoroquinolones Against Bacteria That Produce Extended-spectrum Beta-lactamases. Clin Ther. 2004;26(11):1800-7. PubMed PMID: 15639692.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacodynamic modeling of carbapenems and fluoroquinolones against bacteria that produce extended-spectrum beta-lactamases. AU - Moczygemba,Leticia R, AU - Frei,Christopher R, AU - Burgess,David S, PY - 2004/09/20/accepted PY - 2005/1/11/pubmed PY - 2005/3/30/medline PY - 2005/1/11/entrez SP - 1800 EP - 7 JF - Clinical therapeutics JO - Clin Ther VL - 26 IS - 11 N2 - BACKGROUND: 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. OBJECTIVE: 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 METHODS: 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. RESULTS: 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 that did not produce ESBLs (85%-91%). CONCLUSIONS: Carbapenems had superior in vitro activity against bacteria that produced ESBLs compared with fluoroquinolones. Pharmacodynamic modeling based on local ESBL-producing isolates and pharmacokinetic data from healthy humans indicated that imipenem and meropenem may have a greater likelihood of achieving pharmacodynamic targets against bacteria that produce ESBLs than ertapenem or fluoroquinolones. SN - 0149-2918 UR - https://www.unboundmedicine.com/medline/citation/15639692/Pharmacodynamic_modeling_of_carbapenems_and_fluoroquinolones_against_bacteria_that_produce_extended_spectrum_beta_lactamases_ L2 - https://linkinghub.elsevier.com/retrieve/pii/0149-2918(04)80344-8 DB - PRIME DP - Unbound Medicine ER -