Purpose of review: The spread of carbapenem-resistant Gram-negative bacteria (GNB) with changes in institutional epidemiology continues to evolve worldwide. The purpose of this review is to evaluate new data with regard to the epidemiology, mechanisms of resistance and the impact of carbapenem resistance on mortality. Recent findings: The rapid expansion of acquired carbapenem resistance is increasingly propagated by mobile genetic elements such as epidemic plasmids that transfer carbapenemase genes within and between GNB. The risk of acquisition of carbapenem-resistant Acinetobacter baumannii increases four-fold with carbapenem exposure and new meta-analyses have confirmed excess mortality associated with carbapenem-resistant Pseudomonas aeruginosa. Carbapenemase-producing Klebsiella pneumoniae, the most commonly encountered carbapenemase-producing Enterobacterales (CPE) and a major cause of high-mortality hospital-related infections, represents the most rapidly growing global threat. Carbapenem use in patients colonized with such genotypes, leads to an increase in CPE abundance in the gastrointestinal tract, which in turn increases the risk of blood-stream infections four-fold. Summary: High-resistance rates in carbapenem-resistant GNB in many countries will inevitably complicate treatment of serious infections in vulnerable patient groups and should accelerate global attempts to overcome the impediments we face with regard to effective antimicrobial stewardship and infection prevention and control programs.

A multidrug-resistant Klebsiella pneumoniae isolate exhibiting heteroresistance to colistin was investigated. The colistin-resistant subpopulation harbored a single amino acid change (Asp191Tyr) in protein PhoP, which is part of the PhoPQ two-component system that activates pmrHFIJKLM expression responsible for l -aminoarabinose synthesis and polymyxin resistance. Complementation assays with a wild-type phoP gene restored full susceptibility to colistin. Then, analysis of the colistin-susceptible subpopulation showed a partial deletion (25 bp) in the phoP gene compared to that in the colistin-resistant subpopulation. That deletion disrupted the reading frame of phoP , leading to a longer and inactive protein (255 versus 223 amino acids long). This is the first report showing the involvement of mutation(s) in PhoP in colistin resistance. Furthermore, this is the first study to decipher the mechanisms leading to colistin heteroresistance in K. pneumoniae .

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs.