Synergistic Antimicrobial Activity of Colistin in Combination with Rifampin and Azithromycin against Escherichia coli Producing MCR-1

Abstract

The lack of available antibiotics is a global public health problem due to the emergence of antimicrobial resistance. Effective therapeutic regimens are urgently needed against strains that produce the colistin resistance gene and to inhibit the emergence of resistance. In this study, we assessed the antimicrobial activity of a series of concentrations of colistin-based combinations with rifampin and/or azithromycin against three strains of , including colistin-resistant isolate MZ1501, isolate HE1704 that produces MCR-1, and colistin-susceptible isolate MZ1509 Experiments were conducted with a medium inoculum of ∼10 CFU/ml over 48 h. Subsequently, the therapeutic effect was investigated using a neutropenic mouse thigh infection model. Almost all monotherapies showed unsatisfactory antibacterial activity against isolates producing MCR-1. In contrast, colistin in combination with rifampin or azithromycin resulted in an obvious decrease in the bacterial burden albeit with regrowth. More obviously, synergistic antimicrobial activity of colistin-based triple-combination therapy with rifampin and azithromycin was observed, resulting in a rapid and exhaustive antibacterial effect. treatments confirmed these findings, where mean decreases of 0.38 to 0.90 log CFU and 1.27 to 1.78 log CFU were noted after 24 h and 48 h of treatment, respectively, against colistin-resistant strains when 5 mg/kg of body weight of colistin was combined with rifampin and azithromycin. Colistin-based combinations with rifampin and azithromycin provide a more active therapeutic regimen than monotherapy or colistin-based double combinations against producing MCR-1.

When Combined with Colistin, an Otherwise Ineffective Rifampicin–Linezolid Combination Becomes Active in Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii

“…The use of antimicrobial agents in triple combinations has been explored in several recent studies [10,24,25]. As in our study, most of them included colistin, and the results were similar to ours.…”

“…Li et al [10] reported the synergistic activity of rifampicin-azithromycin-colistin against E. coli producing Mcr-1. This triple antimicrobial combination was tested in vitro (time kill curves) and in an animal model (neutropenic mouse thigh model).…”

“…Instead, the use of triple antimicrobial combinations has been suggested, based on encouraging in vitro data [10,11]. For example, triple antimicrobial therapies consisting of gentamicin-carbenicillin-rifampin and dicloxacillin-fusidic acid-rifampicin have been proposed for the treatment of Stenotrophomonas maltophilia and Staphylococcus aureus infections, respectively [12][13][14][15].…”

<p>Efficacy of combinations of colistin with other antimicrobials involves membrane fluidity and efflux machinery</p>

“…The authors attributed these results to the direct effect of colistin on the bacterial outer membrane. Almost simultaneously, Fang et al28 reported similar data in tests of E. coli exposed to combinations of colistin and either azithromycin or rifampin, both in vitro and in vivo. Our data provide additional, biophysical evidence supporting those observations.…”

<p>In vitro reduction of colistin susceptibility and comparative genomics reveals multiple differences between MCR-positive and MCR-negative colistin-resistant <em>Escherichia coli</em></p>

“…However, the emergence of plasmid-mediated colistin resistance via mobilized colistin resistance ( mcr ) genes has become a challenge to public health worldwide. MCR-positive Enterobacteriaceae have been isolated from various sources including humans, other animals, and food, most of which were Escherichia coli 2–5. Except for MCR, colistin resistance in Gram-negative bacteria can also be conferred by mutations in chromosomal genes associated with the biosynthesis and modification of lipopolysaccharide (LPS), and include a large array of genes and operons 6–8.…”