Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa

Abstract

Polymyxins are increasingly used as a last-resort class of antibiotics against extensively drug-resistant (XDR) Gram-negative bacteria. However, resistance to polymyxins can emerge with monotherapy. As nephrotoxicity is the major dose-limiting factor for polymyxin monotherapy, dose escalation to suppress the emergence of polymyxin resistance is not a viable option. Therefore, novel approaches are needed to preserve this last-line class of antibiotics. This study aimed to investigate the antimicrobial synergy of polymyxin B combined with enrofloxacin against Static time-kill studies were conducted over 24 h with polymyxin B (1 to 4 mg/liter) and enrofloxacin (1 to 4 mg/liter) alone or in combination. Additionally, one-compartment model (IVM) and hollow-fiber infection model (HFIM) experiments were performed against 12196. Polymyxin B and enrofloxacin in monotherapy were ineffective against all of the isolates examined, whereas polymyxin B-enrofloxacin in combination was synergistic against , with ≥2 to 4 log kill at 24 h in the static time-kill studies. In both IVM and HFIM, the combination was synergistic, and the bacterial counting values were below the limit of quantification on day 5 in the HFIM. A population analysis profile indicated that the combination inhibited the emergence of polymyxin resistance in 12196. The mechanism-based modeling suggests that the synergistic killing is a result of the combination of mechanistic and subpopulation synergy. Overall, this is the first preclinical study to demonstrate that the polymyxin-enrofloxacin combination is of considerable utility for the treatment of XDR infections and warrants future clinical evaluations.

Novel Polymyxin Combination with the Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-Producing Multidrug-Resistant Klebsiella pneumoniae

“…Polymyxin B (sulfate; batch number BCBD1065V; Sigma-Aldrich, Australia) solution was freshly prepared in sterile Milli-Q water before the experiments. Zidovudine (Sigma-Aldrich) was dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich) and then diluted with sterile Milli-Q water to ensure a final DMSO concentration of Յ5% (vol/vol) (14). Three isolates of NDMproducing MDR K. pneumoniae were employed in this study.…”

“…Static time-kill experiments. Static time-kill experiments were conducted to evaluate the antibacterial activity of polymyxin B and zidovudine alone and in combination against NDM-producing K. pneumoniae (3,14). All experiments were performed with an initial inoculum of ϳ10 6 CFU/ml in 20 ml CAMHB in 50-ml pyrogen-free and sterile polypropylene tubes (Thermo Fisher, Melbourne, Australia).…”

“…In vitro one-compartment PK/PD model experiment. An IVM was employed to examine the antimicrobial efficacy of polymyxin B and zidovudine alone and in combination against K. pneumoniae BM1 over 72 h (14,43). Four reservoirs were employed, namely, (i) a control reservoir without any antibiotic; (ii) polymyxin B monotherapy; (iii) zidovudine monotherapy; and (iv) polymyxin B-zidovudine combination therapy.…”

“…infections with high bacterial densities, such as pneumonia (3,11,12). Given the relatively high mutation frequency and dose-limiting nephrotoxicity of polymyxins (4), novel strategies are urgently needed to preserve their efficacy against life-threatening infections caused by NDM-producing MDR K. pneumoniae with minimal development of resistance (3,13,14).…”

In vitro Synergistic Activity of Antimicrobial Combinations Against blaKPC and blaNDM-Producing Enterobacterales With blaIMP or mcr Genes

“…A static time-kill assay was conducted for four isolates according to the previously described methodology (Lin et al, 2018). Two Klebsiella pneumoniae (bla KPC−2 , bla NDM−1 ), 1 E. coli (bla NDM−1 ), and 1 Serratia marcescens were selected to examine the bactericidal effects.…”