We compared the in vitro activities of gentamicin (GEN), tobramycin (TOB), amikacin (AMK), and plazomicin (PLZ) against 13Enterobacter isolates possessing both Klebsiella pneumoniae carbapenemase and extended-spectrum ␤-lactamase (KPC؉/ ESBL؉) with activity against 8 KPC؉/ESBL؊, 6 KPC؊/ESBL؉, and 38 KPC؊/ESBL؊ isolates. The rates of resistance to GEN and TOB were higher for KPC؉/ESBL؉ (100% for both) than for KPC؉/ESBL؊ (25% and 38%, respectively), KPC؊/ESBL؉ (50% and 17%, respectively), and KPC؊/ESBL؊ (0% and 3%, respectively) isolates. KPC؉/ESBL؉ isolates were more likely than others to possess an aminoglycoside-modifying enzyme (AME) (100% versus 38%, 67%, and 5%; P ‫؍‬ 0.007, 0.06, and <0.0001, respectively) or multiple AMEs (100% versus 13%, 33%, and 0%, respectively; P < 0.01 for all). KPC؉/ESBL؉ isolates also had a greater number of AMEs (mean of 4.6 versus 1.5, 0.9, and 0.05, respectively; P < 0.01 for all). GEN and TOB MICs were higher against isolates with >1 AME than with <1 AME. The presence of at least 2/3 of KPC, SHV, and TEM predicted the presence of AMEs. PLZ MICs against all isolates were <4 g/ml, regardless of KPC/ESBL pattern or the presence of AMEs. In conclusion, GEN and TOB are limited as treatment options against KPC؉ and ESBL؉ Enterobacter. PLZ may represent a valuable addition to the antimicrobial armamentarium. A full understanding of AMEs and other aminoglycoside resistance mechanisms will allow clinicians to incorporate PLZ rationally into treatment regimens. The development of molecular assays that accurately and rapidly predict antimicrobial responses among KPC-and ESBL-producing Enterobacter spp. should be a top research priority. Enterobacter aerogenes and Enterobacter cloacae are important nosocomial pathogens (1), which collectively constitute the 8th most common cause of health care-associated infections (2). Enterobacter spp. are well recognized for their capacity to develop acquired ␤-lactam resistance via inducible or derepressed production of AmpC ␤-lactamases (3, 4). In addition, Enterobacter isolates often manifest multiple antibiotic resistance mechanisms, including coproduction of extended-spectrum ␤-lactamases (ESBLs), upregulation of efflux pumps, and deficiency of outer membrane porins, which may confer multidrug resistance (MDR) phenotypes (5-8). More recently, carbapenem-resistant Enterobacter spp. have emerged worldwide (6, 9-15). As with other carbapenem-resistant Enterobacteriaceae (CRE), carbapenem resistance in Enterobacter spp. is most commonly conferred through production of Klebsiella pneumoniae carbapenemases (KPCs) or metallo-␤-lactamases (MBLs) (6, 16). These resistance determinants are commonly located on plasmids that carry other genes attenuating susceptibility to multiple antibiotic classes. As a result, therapeutic options against carbapenem-resistant Enterobacter infections are limited, and optimal treatment regimens are yet to be established.Aminoglycosides retain potent bactericidal activity against some, but not all, CRE (17). The most common de...