Global Threat of Carbapenem-Resistant Gram-Negative Bacteria

Infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria (GNB), including carbapenem-resistant (CR) Enterobacterales (CRE; harboring mainly <i>bla</i>_KPC, <i>bla</i>_NDM, and <i>bla</i>_OXA-48-like genes), CR- or MDR/XDR-<i>Pseudomonas aeruginosa</i> (production of VIM, IMP, or NDM carbapenemases combined with porin alteration), and <i>Acinetobacter baumannii</i> complex (producing mainly OXA-23, OXA-58-like carbapenemases), have gradually worsened and become a major challenge to public health because of limited antibiotic choice and high case-fatality rates. Diverse MDR/XDR-GNB isolates have been predominantly cultured from inpatients and hospital equipment/settings, but CRE has also been identified in community settings and long-term care facilities. Several CRE outbreaks cost hospitals and healthcare institutions huge economic burdens for disinfection and containment of their disseminations. Parenteral polymyxin B/E has been observed to have a poor pharmacokinetic profile for the treatment of CR- and XDR-GNB. It has been determined that tigecycline is suitable for the treatment of bloodstream infections owing to GNB, with a minimum inhibitory concentration of ≤ 0.5 mg/L. Ceftazidime-avibactam is a last-resort antibiotic against GNB of Ambler class A/C/D enzyme-producers and a majority of CR-<i>P. aeruginosa</i> isolates. Furthermore, ceftolozane-tazobactam is shown to exhibit excellent <i>in vitro</i> activity against CR- and XDR-<i>P. aeruginosa</i> isolates. Several pharmaceuticals have devoted to exploring novel antibiotics to combat these troublesome XDR-GNBs. Nevertheless, only few antibiotics are shown to be effective <i>in vitro</i> against CR/XDR-<i>A. baumannii</i> complex isolates. In this era of antibiotic pipelines, strict implementation of antibiotic stewardship is as important as in-time isolation cohorts in limiting the spread of CR/XDR-GNB and alleviating the worsening trends of resistance.