Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) is one of the top-priority pathogens for new antibiotic development. Unlike other antibiotic-resistant threats, none of the available therapies have been shown to consistently reduce mortality or improve patient outcomes in clinical trials. Antibiotic combination therapy is routinely used in clinical practice; however, the preferred combination has not been defined. This narrative review focuses on evidence-based solutions for the treatment of invasive CRAB infections. We dissect the promise and perils of traditional agents used in combination, such as colistin, sulbactam, and the tetracyclines, and offer clinical pearls based on our interpretation of the available data. Next, we investigate the merits of newly developed β-lactam agents like cefiderocol and sulbactam-durlobactam, which have demonstrated contrasting results in recent randomized clinical trials. The review concludes with the authors’ perspective on the evolving treatment landscape for CRAB infections, which is complicated by limited clinical data, imperfect treatment options, and a need for future clinical trials. We propose that effective treatment for CRAB infections requires a personalized approach that incorporates host factors, the site of infection, pharmacokinetic-pharmacodynamic principles, local molecular epidemiology of CRAB isolates, and careful interpretation of antibiotic susceptibility testing results. In most clinical scenarios, a dose-optimized, sulbactam-based regimen is recommended with the addition of at least one other in vitro active agent. Should sulbactam-durlobactam receive regulatory approval, recommendations will need to be re-evaluated with the most recent evidence.

Twenty patients with carbapenem-resistant Enterobacteriaceae infections were treated with meropenem-vaborbactam. Thirty-day clinical success and survival rates were 65% (13/20) and 90% (18/20), respectively. Thirty-five percent of patients had microbiologic failures within 90 days. One patient developed a recurrent infection due to meropenem-vaborbactam–nonsusceptible, ompK36 porin mutant Klebsiella pneumoniae.

Cefiderocol, a newly approved cephalosporin agent with an extensive spectrum of activity against Gram-negative bacteria, binds siderophore and uses its receptors to access the bacterial periplasm. Loss of functional CirA, an iron transporter, has been associated with cefiderocol resistance.

Meropenem-vaborbactam is a new agent with the potential to treat carbapenem-resistant Enterobacteriaceae (CRE) infections. We describe the in vitro activity of meropenem-vaborbactam against representative CRE genotypes and laboratory-engineered Escherichia coli isolates harboring mutant bla _KPC genes associated with ceftazidime-avibactam resistance.

Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) present a global clinical threat, as these β-lactamases confer resistance to carbapenems and oxyimino-cephalosporins. Recent clinically identified KPC variants with substitutions at Ambler position D179, located in the Ω loop, are resistant to the β-lactam/β-lactamase inhibitor combination ceftazidime-avibactam, but susceptible to meropenem-vaborbactam.

We compared the in vitro susceptibility of multidrug-resistant Pseudomonas aeruginosa isolates collected before and after treatment-emergent resistance to ceftolozane-tazobactam. Median baseline and postexposure ceftolozane-tazobactam MICs were 2 and 64 μg/ml, respectively.