Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics

Abstract

Plasmid-borne colistin resistance mediated by mcr-1 may contribute to the dissemination of pan-resistant Gram-negative bacteria. Here, we show that mcr-1 confers resistance to colistin-induced lysis and bacterial cell death, but provides minimal protection from the ability of colistin to disrupt the Gram-negative outer membrane. Indeed, for colistin-resistant strains of Enterobacteriaceae expressing plasmid-borne mcr-1, clinically relevant concentrations of colistin potentiate the action of antibiotics that, by themselves, are not active against Gram-negative bacteria. The result is that several antibiotics, in combination with colistin, display growth-inhibition at levels below their corresponding clinical breakpoints. Furthermore, colistin and clarithromycin combination therapy displays efficacy against mcr-1-positive Klebsiella pneumoniae in murine thigh and bacteremia infection models at clinically relevant doses. Altogether, these data suggest that the use of colistin in combination with antibiotics that are typically active against Gram-positive bacteria poses a viable therapeutic alternative for highly drug-resistant Gram-negative pathogens expressing mcr-1.

Emerging Infectious Diseases

“…In addition, the plasmid-borne colistin resistance mediated by mcr-1 (mobilized colistin resistance) may contribute to the dissemination of pan-resistant gram-negative bacteria. 20,22…”

A macrophage-based screen identifies antibacterial compounds selective for intracellularSalmonellaTyphimurium

“…These antibiotics are known to be potentiated against Gram-negative bacteria in the presence of OM perturbing agents (e.g. colistin 27 and pentamidine 28 ), leading us to speculate that acidic (LPM) or intracellular (macrophage) environments compromise the OM of S . Tm.…”

Selection and co-selection of antibiotic resistances amongEscherichia coliby antibiotic use in primary care: an ecological analysis

“…The negative association between prescribing of tetracyclines or macrolides and ciprofloxacin resistance is harder to explain. Macrolides are typically active against Gram-positive bacteria, although they can be effective against Gram-negative bacteria when used in combination with antibiotics that do have outer-membrane disruptive activity [24]. Given the lack of selective pressure, E coli are unlikely to frequently harbor resistance mechanisms against antibiotics like macrolides, which could make such a synergistic combination therapy particularly effective against Gram-negative bacteria resistant to multiple antibiotics including ciprofloxacin [24].…”

“…Macrolides are typically active against Gram-positive bacteria, although they can be effective against Gram-negative bacteria when used in combination with antibiotics that do have outer-membrane disruptive activity [24]. Given the lack of selective pressure, E coli are unlikely to frequently harbor resistance mechanisms against antibiotics like macrolides, which could make such a synergistic combination therapy particularly effective against Gram-negative bacteria resistant to multiple antibiotics including ciprofloxacin [24]. However, this is unlikely the cause of the negative association between macrolide use and ciprofloxacin resistance, as such a combination therapy is not frequently being used or necessary in England.…”