Aminoglycosides enhance meropenem/vaborbactam activity against KPC-producing Klebsiella pneumoniae in the hollow fiber infection model

Abstract

Meropenem/vaborbactam is a preferred treatment option for KPC-producing Klebsiella pneumoniae (KPC-Kp) infections, but clinical cure rates remain suboptimal when it is used alone. This study aimed to assess the pharmacodynamic activity of meropenem/vaborbactam alone and in combination with an aminoglycoside in the hollow fiber infection model (HFIM). The HFIM was used to simulate meropenem/vaborbactam and aminoglycoside pharmacokinetic profiles that approximated antibiotic exposures in the plasma and lung epithelial lining fluid (ELF) following human doses against four meropenem/vaborbactam-susceptible KPC-Kp isolates. Two isolates had lower meropenem/vaborbactam MICs (0.125/8 to 0.25/8 mg/L; NU-CRE105 and NUCRE244), and two had higher MICs (2/8 mg/L; AR-1049 and AR-1054). Against NU-CRE105 and NU-CRE244, meropenem/vaborbactam was bactericidal and caused >5.7 log10 CFU/mL reductions by 48 h. Antibiotic exposures mimicking those in plasma and ELF yielded similar bacterial killing. Despite the robust activity of meropenem/vaborbactam alone, combinations with an aminoglycoside were synergistic, providing ≥2 log10 CFU/mL better killing of NU-CRE105 and NU-CRE244 than either monotherapy for ~40% of the experiment. Against AR-1049 and AR-1054, meropenem/vaborbactam monotherapy mimicking ELF exposures generated 2.9–5.2 log10 CFU/mL reductions at 48 h. However, meropenem/vaborbactam resistance emerged by 168 h. Combinations with an aminoglycoside displayed 4.7–7.5 log10 CFU/mL greater killing than either monotherapy at 168 h and repressed meropenem/vaborbactam resistance. Meropenem/vaborbactam remains an important agent against KPC-Kp. However, pneumonia caused by KPC-Kp isolates with MICs near the susceptibility breakpoint (≤4/8 mg/L) may reduce the pharmacodynamic activity of meropenem/vaborbactam and permit resistance to emerge. Aminoglycosides represent a promising adjunct to meropenem/vaborbactam for select KPC-Kp isolates, owing to their capacity to enhance bacterial killing and suppress resistance.