Abstract
Despite the relevance of carbapenemase-producing Klebsiella pneumoniae (CP-Kp) infections there are a scarce number of studies to evaluate in vivo the efficacy of combinations therapies. The bactericidal activity of colistin, rifampin, and its combination was studied (time–kill curves) against four clonally unrelated clinical isolates of CP-Kp, producing VIM-1, VIM-1 plus DHA-1(acquired AmpC β-lactamase), OXA-48 plus CTX-M-15 (extended spectrum β-lactamase) and KPC-3, respectively, with colistin MICs of 0.5, 64, 0.5, and 32 mg/L, respectively. The efficacies of antimicrobials in monotherapy and in combination were tested in a murine peritoneal sepsis model, against all the CP-Kp. Their efficacies were tested in the pneumonia model against the OXA-48 plus CTX-M-15 producers. The development of colistin-resistance was analyzed for the colistin-susceptible strains in vitro and in vivo. In vitro, colistin plus rifampin was synergistic against all the strains at 24 h. In vivo, compared to the controls, rifampin alone reduced tissue bacterial concentrations against VIM-1 and OXA-48 plus CTX-M-15 strains; CMS plus rifampin reduced tissue bacterial concentrations of these two CP-Kp and of the KPC-3 strain. Rifampin and the combination increased the survival against the KPC-3 strain; in the pneumonia model, the combination also improved the survival. No resistant mutants appeared with the combination. In conclusion, CMS plus rifampin had a low and heterogeneous efficacy in the treatment of severe peritoneal sepsis model due to CP-Kp producing different carbapenemases, increasing survival only against the KPC-3 strain. The combination showed efficacy in the less severe pneumonia model. The combination prevented in vitro and in vivo the development of colistin resistant mutants.
Highlights
Carbapenem-resistant Klebsiella pneumoniae strains are spreading worldwide, representing an urgent threat to public health, as stressed by the Center for Disease Control and Prevention (CDC) of United States, the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO)
The combination was synergistic against all the strains at 24 h, but achieving only a bacteriostatic effect against the VIM-1, VIM-1/DHA-1, and OXA-48 plus CTX-M-15 isolates; on the contrary, the combination was bactericidal against the KPC-3 isolate
Rifampin and its combination with colistimethate sodium (CMS) reduced mortality in animals infected with the KPC-3 strain to a 66.67% and a 40%, respectively, but not CMS alone
Summary
Carbapenem-resistant Klebsiella pneumoniae strains are spreading worldwide, representing an urgent threat to public health, as stressed by the Center for Disease Control and Prevention (CDC) of United States, the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO). The most important carbapenemases found in this species may belong to the Ambler classes A (mainly KPC), B (the most frequent are VIM and IMP) and D (OXA-48-like enzymes). Invasive infections by isolates producing VIM and KPC are associated with high death rates (Tzouvelekis et al, 2012). The information about infections caused by OXA-48producers is scarce, mostly because of its difficult identification (Nordmann et al, 2011; Canton et al, 2012; Tzouvelekis et al, 2012). OXA-48 is the most frequent carbapenemase produced by Enterobacteriaceae isolated in many European countries (Canton et al, 2012; Palacios-Baena et al, 2016; De Laveleye et al, 2017)
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