Pharmacodynamics of Imipenem in Combination with β-Lactamase Inhibitor MK7655 in a Murine Thigh Model
| Autor: | Eleftheria Mavridou, Ria J. B. Melchers, Eric Mangin, Anita C. van Mil, Mary Motyl, Johan W. Mouton |
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| Přispěvatelé: | Medical Microbiology & Infectious Diseases |
| Rok vydání: | 2015 |
| Předmět: |
Imipenem
Cmax Biology Pharmacology Microbiology Mice Pharmacokinetics In vivo medicine Animals Experimental Therapeutics Pseudomonas Infections Pharmacology (medical) Beta-Lactamase Inhibitors Dose fractionation Klebsiella Infections Disease Models Animal Klebsiella pneumoniae lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] Infectious Diseases Thigh Pharmacodynamics Pseudomonas aeruginosa Female beta-Lactamase Inhibitors Dose Frequency medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy, 59, 790-5 Antimicrobial Agents & Chemotherapy, 59(2), 790-795. American Society for Microbiology Antimicrobial Agents and Chemotherapy, 59, 2, pp. 790-5 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | MK7655 is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases. Pharmacokinetics (PK) of imipenem-cilastatin (IMP/C) and MK7655 were determined for intraperitoneal doses of 4 mg/kg to 128 mg/kg of body weight. MIC and pharmacodynamics (PD) studies of MK7655 were performed against several beta-lactamase producing Pseudomonas aeruginosa and Klebsiella pneumoniae strains to determine its effect in vitro and in vivo . Neutropenic mice were infected in each thigh 2 h before treatment with an inoculum of approximately 5 × 10 6 CFU. They were treated with IMP/C alone (every 2 hours [q2h], various doses) or in combination with MK7655 in either a dose fractionation study or q2h for 24 h and sacrificed for CFU determinations. IMP/MK7655 decreased MICs regarding IMP MIC. The PK profiles of IMP/C and MK7655 were linear over the dosing range studied and comparable with volumes of distribution ( V ) of 0.434 and 0.544 liter/kg and half-lives ( t 1/2 ) of 0.24 and 0.25 h, respectively. Protein binding of MK7655 was 20%. A sigmoidal maximum effect ( E max ) model was fit to the PK/PD index responses. The effect of the inhibitor was not related to the maximum concentration of drug in serum ( C max )/MIC, and model fits for T >MIC and area under the concentration-time curve (AUC)/MIC were comparable ( R 2 of 0.7 and 0.75), but there appeared to be no significant relationship of effect with dose frequency. Escalating doses of MK7655 and IMP/C showed that the AUC of MK7655 required for a static effect was dependent on the dose of IMP/C and the MIC of the strain, with a mean area under the concentration-time curve for the free, unbound fraction of the drug ( f AUC) of 26.0 mg · h/liter. MK7655 shows significant activity in vivo and results in efficacy of IMP/C in otherwise resistant strains. The exposure-response relationships found can serve as a basis for establishing dosing regimens in humans. |
| Databáze: | OpenAIRE |
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