<i>In Vivo</i> Efficacy of Relebactam (MK-7655) in Combination with Imipenem-Cilastatin in Murine Infection Models

Abstract

The World Health Organization has identified antimicrobial resistance as a global public health threat since the prevalence and spread of antibiotic resistance among bacterial pathogens worldwide are staggering. Carbapenems, such as imipenem and meropenem, have been used to treat multidrug-resistant bacteria; however, since the development of resistance to carbapenems, β-lactam antibiotics in combination with β-lactamase inhibitors (BLI) has been one of the most successful strategies to enhance the activity of β-lactam antibiotics. Relebactam (REL) is a new BLI which has been found to inhibit class A and class C β-lactamases <i>in vitro</i> REL has been reported to restore imipenem's activity against both imipenem-resistant <i>Pseudomonas aeruginosa</i> and <i>Klebsiella pneumoniae</i> Reported here are the <i>in vivo</i> efficacy studies of the imipenem-cilastatin (IMI)-REL combination in mouse models of disseminated and pulmonary infection caused by imipenem-resistant clinical isolates of <i>P. aeruginosa</i> and <i>K. pneumoniae</i> The combination was also evaluated in a <i>P. aeruginosa</i> delayed pulmonary model of infection. IMI-REL was found to be effective in the disseminated model of infection with log reduction in <i>P. aeruginosa</i> CFU of 3.73, 3.13, and 1.72 at REL doses of 40, 20, and 10 mg/kg, respectively. For <i>K. pneumoniae</i>, log reductions in CFU of 2.36, 3.06, and 2.29 were reported at REL doses of 80, 40, and 20 mg/kg, respectively. The combination was less effective in the delayed pulmonary model than in the immediate pulmonary model; however, overall REL was found to be effective against these imipenem-resistant strains.