SUMMARY The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam–β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa. Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa. Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales. Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa. Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii. Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

Background Acinetobacter baumannii is an emerging pathogen capable of causing hospital-acquired infections (HAIs). It has the ability to survive on environmental surfaces for months, making transmission difficult to control. Our report describes the investigation and restriction of an outbreak of A.baumannii in the Neonatal Intensive Care Unit (NICU) using whole-genome sequencing (WGS) and multi-modal infection control measures. Methods A prospective surveillance of HAIs was initiated in the NICU at the Pauls Stradins Clinical University Hospital (PSCUH) in Latvia on 1/9/2012 and identified an outbreak of A.baumannii . Case definitions for A.baumannii bloodstream infection (BSI) and colonization were implemented; surveillance cultures were obtained from all admitted patients to monitor the rate of colonization; an infection prevention and control team was formed and infection control interventions implemented. Environmental sampling of the NICU and Labour ward was performed. We employed WGS to differentiate phenotypically identical multidrug-resistant A.baumannii (MDRAB) strains from simultaneous intrahospital outbreaks in the adult Intensive Care Unit and NICU. Results Between 1/9/2012 and 31/12/2017 the surveillance included 2157 neonates. A total of 17 neonates had A.baumannii BSI, with the highest rate of 30.0 cases per 1000 bed-days in November 2012. Rectal screening samples were positive for A.baumannii-complex in 182 neonates reaching 119.6 per 1000 bed-days in July 2015. All 298 environmental cultures were negative. Two phenotypically identical MDRAB isolates from the simultaneous intrahospital outbreaks were differentiated using WGS, ruling out an inter-ward transmission. Adherence to stringent infection control measures decreased BSI cases but colonization remained persistent. With several relapses, the outbreak was ongoing for four years. No new A.baumannii BSI cases were registered after total environmental decontamination in the NICU in July 2015. Colonization reappeared and persisted until in November 2016 when the ward was temporarily closed, relocated and renovated. No A.baumannii cases were registered after the renovation. Conclusion The HAI surveillance system successfully detected and facilitated the control of the A.baumannii outbreak. Whole-genome sequencing was found to be a useful method for differentiation of phenotypically identical A.baumannii strains from the intrahospital outbreak. Only multi-modal infection control program, including closure, temporary relocation, and renovation of the ward, restricted the outbreak.