Is it time to move away from polymyxins?: evidence and alternatives

Eur J Clin Microbiol Infect Dis. 2021 Mar;40(3):461-475. doi: 10.1007/s10096-020-04053-w. Epub 2020 Oct 2.

Abstract

Increasing burden of carbapenem resistance and resultant difficult-to-treat infections are of particular concern due to the lack of effective and safe treatment options. More recently, several new agents with activity against certain multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative pathogens have been approved for clinical use. These include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, and cefiderocol. For the management of MBL infections, clinically used triple combination comprising ceftazidime-avibactam and aztreonam is hindered due to non-availability of antimicrobial susceptibility testing methods and lack of information on potential drug-drug interaction leading to PK changes impacting its safety and efficacy. Moreover, in several countries including Indian subcontinent and developing countries, these new agents are yet to be made available. Under these circumstances, polymyxins are the only last resort for the treatment of carbapenem-resistant infections. With the recent evidence of suboptimal PK/PD particularly in lung environment, limited efficacy and increased nephrotoxicity associated with polymyxin use, the Clinical and Laboratory Standards Institute (CLSI) has revised both colistin and polymyxin B breakpoints. Thus, polymyxins 'intermediate' breakpoint for Enterobacterales, P. aeruginosa, and Acinetobacter spp. are now set at ≤ 2 mg/L, implying limited clinical efficacy even for isolates with the MIC value 2 mg/L. This change has questioned the dependency on polymyxins in treating XDR infections. In this context, recently approved cefiderocol and phase 3 stage combination drug cefepime-zidebactam assume greater significance due to their potential to act as polymyxin-supplanting therapies.

Keywords: Carbapenem; Cefepime-zidebactam; Cefiderocol; Colistin; Polymyxin B.

Publication types

  • Review

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / standards
  • Anti-Bacterial Agents / therapeutic use*
  • Bacterial Proteins / classification
  • Bacterial Proteins / metabolism
  • Carbapenems / pharmacology
  • Carbapenems / therapeutic use
  • Developing Countries
  • Drug Resistance, Bacterial / drug effects
  • Drug Therapy, Combination
  • Gram-Negative Bacteria / classification
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacterial Infections / drug therapy
  • Gram-Negative Bacterial Infections / microbiology
  • Humans
  • Microbial Sensitivity Tests / standards
  • Polymyxins / pharmacology
  • Polymyxins / standards
  • Polymyxins / therapeutic use*
  • beta-Lactamase Inhibitors / pharmacology
  • beta-Lactamase Inhibitors / therapeutic use
  • beta-Lactamases / classification
  • beta-Lactamases / metabolism

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Carbapenems
  • Polymyxins
  • beta-Lactamase Inhibitors
  • beta-Lactamases
  • carbapenemase