Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae

Abstract

Resistance to colistin, a polypeptide drug used as an agent of last resort for the treatment of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, including carbapenem-resistant (CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistant isolates, 15 of which were also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and the activities of those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the 4 most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in the checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative bacterial outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens.

Comparison of methods for the detection of in vitro synergy in multidrug-resistant gram-negative bacteria

“…In the present study, the agreement between the TK assay and the DA method was higher among colistin-resistant A. baumannii isolates when colistin was combined with meropenem or Fosfomycin similar to other studies [7,[9][10][11][12][13][14]. The synergistic effect of fosfomycin with carbapenem could be explained by the resistance profile of the strains evaluated-most A. baumannii isolates carried carbapenemase genes (bla OXA-23, bla OXA-143 , and fosA), which confer resistance to fosfomycin.…”

“…The treatment of infections caused by these microorganisms based on identification of resistance mechanisms and drug combinations is usually more effective than empirical treatment [1,4]. Synergy testing can also correlate to a particular resistance mechanism [8,14]. Such correlations might help predict the synergism for a particular antimicrobial combination for treatment.…”

“…Nevertheless, the in vitro synergy effect of colistin against S. marcescens is controversial [11,16]. The synergistic effect appears lower for combinations with colistin among S. marcescens isolates and species that exhibit intrinsic resistance to polymyxins [14]. In our study, we found a lower synergistic effect against S. marcescens isolates in colistin combinations consistent with Nastro [11] who evaluated colistin with rifampicin against colistinresistant A. baumannii, K. pneumoniae, and S. marcescens isolates by E-test/agar dilution and TK assays.…”

The polymyxin derivative NAB739 is synergistic with several antibiotics against polymyxin-resistant strains of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii

“…MacNair et al showed that colistin is notably synergistic in vitro with rifampin, the macrolide antibiotic clarithromycin, minocycline, and novobiocin against mcr https://doi.org/10.1016/j.peptides.2018.12.006 Received 31 October 2018; Received in revised form 20 December 2018; Accepted 21 December 2018 strains [13]. Brennan-Krohn et al described the synergism of colistin with rifampin, the macrolide antibiotic azithromycin, minocycline, fusidic acid, linezolid, and several other drugs against mcr and other PMR strains [14]. A plausible explanation for the synergism is that even though the PMR strains can grow at higher concentrations of polymyxins than the polymyxin-susceptible wild-type strains, subinhibitory concentrations of polymyxins are still able to damage the outermost permeability barrier, the outer membrane (OM) of the PMR bacteria.…”

“…A plausible explanation for the synergism is that even though the PMR strains can grow at higher concentrations of polymyxins than the polymyxin-susceptible wild-type strains, subinhibitory concentrations of polymyxins are still able to damage the outermost permeability barrier, the outer membrane (OM) of the PMR bacteria. Consequently, the damaged OM allows the entry of drugs normally excluded or partially excluded by the intact enterobacterial OM [13,14] NAB739 is a novel polymyxin derivative [15,16]. It carries only three positive groups, all in strategic positions, instead of five in PMB and colistin (Table 1).…”