Table 1.

The promise, perils, and pearls of the preferred antibiotic options for the treatment of CRAB infections

Agent	Percentages of In Vitro Activity Against CRAB Isolates [17, 19, 26, 40, 90, 141, 142]	Promise	Perils	Pearls in the Management of Invasive CRAB Infections
Polymyxins
Polymyxin B	80.3–99.3% (Defined as colistin MICs ≤2 mg/L)	Likely synergy in combination with other agents Translating data from colistin, observational reports describe success as a component of combination therapy Improved pharmacokinetics and less nephrotoxicity compared with colistin	Limited lung and urinary concentrations Limited availability of rapid and reliable susceptibility testing methods Unlike colistin, not been studied in randomized clinical trials; real-world experience is limited	Potential treatment option when used in combination with other in vitro active agents Preferred over the use of colistin Not advised as a component of combination therapy with carbapenems alone May be effective in combination with optimized doses of ampicillin-sulbactam
Tetracyclines
Minocycline	54–72.1% (Defined by the CLSI breakpoint of ≤4 mg/L)	Oral formulation available Excellent penetration for use for skin and soft tissue infections and osteoarticular infections	Limited urinary concentrations High likelihood of nausea with both oral and intravenous formulations Susceptibility breakpoint requires revision based on contemporary pharmacokinetic-pharmacodynamic studies Limited real-world clinical experience with optimized dose of 200 mg every 12 hours	Potential treatment option when used as a component of combination therapy Optimized doses are recommended Ideally used only when minocycline MICs are ≤1 mg/L
Tigecycline	No breakpoints established; MIC50 = 1–4 mg/L; MIC90 = 2–8 mg/L	Excellent penetration for use in for skin and soft tissue infections and osteoarticular infections Improved clinical efficacy demonstrated with use of higher doses (100 mg every 12 hours)	Limited serum and urinary concentrations High likelihood of nausea Susceptibility breakpoints for Acinetobacter spp. have not been established	Potential treatment option when used as a component of combination therapy Optimized doses are recommended Ideally used only when tigecycline MICs are ≤1 mg/L Not advised for the treatment of bacteremia
β-lactams
Cefiderocol	89.7–96.1% (Defined by the CLSI breakpoint of ≤4 mg/L)	Well tolerated compared with non–β-lactam treatment options Anecdotal evidence shows improved outcomes when given in combination compared to colistin-based treatment	Numerically higher likelihood of death than alternative agents in a randomized clinical trial Incidence of treatment-emergent resistance against CRAB not well defined, but limited data are concerning fT > MIC targets are higher for CRAB than other carbapenem-resistant pathogens in murine models Varying breakpoints proposed by CLSI, EUCAST, and FDA Limited availability of reliable susceptibility testing methods in clinical laboratories	Potential treatment option when used in combination Monotherapy not advised despite high rates of in vitro activity Monitor for the emergence of resistance during and following treatment
β-lactams–β-lactamase inhibitors
Ampicillin-sulbactam	3.7–24.3% (Defined by CLSI ampicillin-sulbactam breakpoint of ≤8/4 mg/L)	Well tolerated compared with non–β-lactam treatment options Daily doses ≥6 g in combination with other in vitro active agents show improved clinical outcomes when compared with other combinations	Sulbactam susceptibility breakpoints have not been developed; testing is dependent upon extrapolation from ampicillin-sulbactam results Safety of high-dose regimens has not been systematically evaluated	Preferred agent when used at optimized doses of at least 6 g/day in combination with at least 1 other in vitro active agent Automated susceptibility testing does not provide the exact sulbactam MIC Optimized doses are recommended
Sulbactam-durlobactam	96.7–96.8% (Based on FDA provisional breakpoint of ≤4 mg/L)	Well tolerated compared with non–β-lactam treatment options Improved likelihood of clinical cure compared with colistin-based treatment	Not currently approved by the FDA for clinical use	Preferred agent if FDA-approved Clinical trials have used in combination with imipenem-cilastatin Future studies are needed to determine the relative contribution, if any, of imipenem-cilastatin to efficacy

Abbreviations: CLSI, Clinical and Laboratory Standards Institute; CRAB, carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex; EUCAST, European Committee on Antimicrobial Susceptibility Testing; FDA, Food and Drug Administration; fT > MIC, time free antibiotic concentrations are above the minimum inhibitory concentration; MIC, minimum inhibitory concentration.