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 .

Background: Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited.Methods: This was a randomized, multicenter, open-label, noninferiority trial. Inpatients with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 days (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days). The noninferiority margin was set at 10%.Results: We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in 3 centers in Israel and Italy. The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, –2.6% [95% confidence interval, –10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm.Conclusions: In patients hospitalized with gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was noninferior to 14 days. Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention.Clinical Trials Registration: NCT01737320.

In 2017 in the United States, there were an estimated 120 000 cases of Staphylococcus aureus bacteremia resulting in 20 000 deaths.¹ The mortality from S aureus bacteremia is higher for methicillin-resistant S aureus (MRSA) than for methicillin-susceptible S aureus (MSSA), typically at 20% to 25%.^1,2 Despite the heavy burden of S aureus bacteremia, there is a paucity of evidence to guide treatment. Overall, there have been fewer than 2500 patients enrolled in published randomized clinical trials for S aureus bacteremia in the past 20 years, and fewer than 450 for MRSA bacteremia.³

The polymyxin group of polypeptide antibiotics, discovered in the 1940s, were among the first antibiotics with significant activity against Gram-negative bacteria [ 1 x 1 Falagas, ME and Kasiakou, SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005; 40: 1333–1341 Crossref | PubMed | Scopus (455) | Google Scholar See all References , 2 x 2 Li, J, Turnidge, J, Milne, R, Nation, RL, and Coulthard, K. In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother. 2001; 45: 781–785 Crossref | PubMed | Scopus (131) | Google Scholar See all References ]. Polymyxin E (colistin) and polymyxin B are the main antibiotics of this group and the only polymyxins used clinically. Following reports on nephrotoxicity and neurotoxicity in the 1970s, they were largely replaced by other antibiotics [ 3 x 3 Nation, RL and Li, J. Colistin in the 21st century. Curr Opin Infect Dis. 2009; 22: 535–543 Crossref | PubMed | Scopus (88) | Google Scholar See all References , 4 x 4 Koch-Weser, J, Sidel, VW, Federman, EB, Kanarek, P, Finer, DC, and Eaton, AE. Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med. 1970; 72: 857–868 Crossref | PubMed | Google Scholar See all References ]. In the last two decades, the paucity of novel antibiotics with which to treat drug-resistant infections, especially those caused by Gram-negative pathogens, has led to their reconsideration as a therapeutic option [ 5 x 5 Boucher, HW, Talbot, GH, Bradley, JS et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009; 48: 1–12 Crossref | PubMed | Scopus (1084) | Google Scholar See all References 5 ]. The current review focuses on colistin, rather than polymyxin B, because of its wider use in current clinical practice.