Evaluation of Double- and Triple-Antibiotic Combinations for VIM- and NDM-Producing Klebsiella pneumoniae by In Vitro Time-Kill Experiments

Abstract

bCombination therapy is recommended for infections with carbapenemase-producing Klebsiella pneumoniae. However, limited data exist on which antibiotic combinations are the most effective. The aim of this study was to find effective antibiotic combinations against metallo-beta-lactamase-producing K. pneumoniae (MBL-KP). Two VIM-and two NDM-producing K. pneumoniae strains, all susceptible to colistin, were exposed to antibiotics at clinically relevant static concentrations during 24-h time-kill experiments. Double-and triple-antibiotic combinations of aztreonam, ciprofloxacin, colistin, daptomycin, fosfomycin, meropenem, rifampin, telavancin, tigecycline, and vancomycin were used. Synergy was defined as a >2 log 10 decrease in CFU/ml between the combination and its most active drug after 24 h, and bactericidal effect was defined as a >3 log 10 decrease in CFU/ml after 24 h compared with the starting inoculum. Synergistic or bactericidal activity was demonstrated for aztreonam, fosfomycin, meropenem, and rifampin in double-antibiotic combinations with colistin and also for aztreonam, fosfomycin, and rifampin in triple-antibiotic combinations with meropenem and colistin. Overall, the combination of rifampin-meropenem-colistin was the most effective regimen, demonstrating synergistic and bactericidal effects against all four strains. Meropenem-colistin, meropenem-fosfomycin, and tigecycline-colistin combinations were not bactericidal against the strains used. The findings of this and other studies indicate that there is great potential of antibiotic combinations against carbapenemase-producing K. pneumoniae. However, our results deviate to some extent from those of previous studies, which might be because most studies to date have included KPC-producing rather than MBL-producing strains. More studies addressing MBL-KP are needed.

New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae

“…Administration of a polymyxin with a carbapenem and rifampin is a promising combination that was previously shown to be bactericidal (against 8/9 strains) in static time-kill experiments against carbapenemase-producing K. pneumoniae (33,34) and was further validated in the present study. In the current investigation, rifampin added to a polymyxin B burst preserved polymyxin susceptibility through 10 days (polymyxin B MIC 240 h ϭ 0.5 mg/liter) for both KPC-Kp isolates.…”

Fosfomycin

“…Against KPC-2-producing K. pneumoniae strains, synergy with meropenem primarily (65%) and colistin secondarily (12%) was reported using time-kill assays, while combination with gentamicin resulted in indifference (154). Similarly, the fosfomycin-colistin and fosfomycin-colistinmeropenem combinations showed synergy against 2 VIM-and 2 NDM-producing K. pneumoniae strains (155). However, antagonism between colistin and fosfomycin against OXA-48-producing K. pneumoniae isolates was reported (checkerboards were used) (156).…”

Clinical and laboratory considerations for the rapid detection of carbapenem-resistant Enterobacteriaceae

“…57 Many of these drugs used in combination with each other or with adjunctive agents like rifampin or minocycline, demonstrate in vitro synergy against CRE. [58][59][60][61][62] Unfortunately, several of these CRE-active agents have narrow therapeutic windows and cause adverse effects, and their efficacy is reduced by emergence of resistance. 63,64 Outbreaks of colistin-resistant CRE have been reported in many regions, [65][66][67][68] likely due to increasing use of polymyxins for treatment of CRE.…”