Pharmacodynamics of imipenem in combination with β-lactamase inhibitor MK7655 in a murine thigh model.
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 (t1/2) of 0.24 and 0.25 h, respectively. Protein binding of MK7655 was 20%. A sigmoidal maximum effect (Emax) 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 (Cmax)/MIC, and model fits for T>MIC and area under the concentration-time curve (AUC)/MIC were comparable (R2 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 (fAUC) 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.
Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
Eleftheria
E
Mavridou
Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands.
Ria J B
RJ
Melchers
Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
Anita C H A M
AC
van Mil
Merck & Co., Inc., West Point, Pennsylvania, USA.
E
E
Mangin
Merck & Co., Inc., West Point, Pennsylvania, USA.
Mary R
MR
Motyl
Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands Canisius Wilhelmina Hospital, Nijmegen, The Netherlands Erasmus University Medical Centre, Rotterdam, The Netherlands jwmouton@gmail.com.
Johan W
http://orcid.org/0000-0001-6736-4149
JW
Mouton
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015378:Imipenem / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D007710:Klebsiella Infections / Q000188:drug therapy; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000472:pathogenicity; D051379:Mice; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity; D013848:Thigh / Q000382:microbiology*; D065093:beta-Lactamase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
D065093:beta-Lactamase Inhibitors; D015378:Imipenem