Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla _NDM-5 : Preparation for a Postantibiotic Era

Abstract

The rapid increase of carbapenem resistance in Gram-negative bacteria has resurrected the importance of the polymyxin antibiotics. The recent discovery of plasmid-mediated polymyxin resistance (mcr-1) in carbapenem-resistant Enterobacteriaceae serves as an important indicator that the golden era of antibiotics is under serious threat. We assessed the bacterial killing of 15 different FDA-approved antibiotics alone and in combination with polymyxin B in time-killing experiments against Escherichia coli MCR1_NJ, the first reported isolate in the United States to coharbor mcr-1 and a New Delhi metallo-β-lactamase gene (blaNDM-5). The most promising regimens were advanced to the hollow-fiber infection model (HFIM), where human pharmacokinetics for polymyxin B, aztreonam, and amikacin were simulated over 240 h. Exposure to polymyxin B monotherapy was accompanied by MCR1_NJ regrowth but not resistance amplification (polymyxin B MIC from 0 to 240 h [MIC0h to MIC240h] of 4 mg/liter), whereas amikacin monotherapy caused regrowth and simultaneous resistance amplification (amikacin MIC0h of 4 mg/liter versus MIC240h of >64 mg/liter). No MCR1_NJ colonies were observed for any of the aztreonam-containing regimens after 72 h. However, HFIM cartridges for both aztreonam monotherapy and the polymyxin B-plus-aztreonam regimen were remarkably turbid, and the presence of long, filamentous MCR1_NJ cells was evident in scanning electron microscopy, suggestive of a nonreplicating persister (NRP) phenotype. In contrast, the 3-drug combination of polymyxin B, aztreonam, and amikacin provided complete eradication (>8-log10 CFU/ml reduction) with suppression of resistance and prevention of NRP formation. This is the first comprehensive pharmacokinetic/pharmacodynamic study to evaluate triple-drug combinations for polymyxin- and carbapenem-resistant E. coli coproducing MCR-1 and NDM-5 and will aid in the preparation for a so-called “postantibiotic” era.

International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti‐infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP)

“…[106][107][108][109] With the recent report of mobile colistin resistance genes, 16-18, 110, 111 the presence of heteroresistance, 19 and the association between colistin resistance and increased risk of in-hospital mortality, 106 there is mounting support for strategies to optimize polymyxins therapeutically including combination therapy. 41,[111][112][113] There is a mechanism-based rationale for using polymyxins in combination with other antimicrobials that display synergy with a membrane permeabilizer (such as the polymyxins) allowing for increased concentrations of companion antibacterial agents that have intracellular targets. 109,[114][115][116] Unfortunately, the clinical literature on combination therapy versus monotherapy is difficult to interpret due to limitations in many studies.…”

NDM Metallo-β-Lactamases and Their Bacterial Producers in Health Care Settings

“…A time-kill assay revealed that the addition of amikacin is able to restore the susceptibility of four NDM-positive and mcr-positive E. coli strains to colistin (258). However, another time-kill assay demonstrated that the combination of amikacin and polymyxin B failed to eradicate NDM-positive and mcr-positive E. coli strains but that the addition of aztreonam with amikacin and polymyxin achieved eradication (274).…”

Recent progress on elucidating the molecular mechanism of plasmid-mediated colistin resistance and drug design

“…Another method appears to be the mainstream approach involving the effective administration of colistin as well as the potential use of combination therapies with additional agents to generate synergistic associations. These agents can include antibiotics that are typically restricted for use against gram-positive bacteria, such as amikacin (Bulman et al 2017;Zhou et al 2017 (Hu et al 2019), and derivatives of tryptamine (Barker et al 2019). Alternatively, natural products acting as adjuvants can be used, some of which can interact with lipopolysaccharides to perturb the outer bacterial membrane, such as pentamidine (Stokes et al 2017) and meridianin D analogs (Huggins et al 2018).…”