In Vivo Pharmacodynamics of β-Lactams/Nacubactam against Carbapenem-Resistant and/or Carbapenemase-Producing Enterobacter cloacae and Klebsiella pneumoniae in Murine Pneumonia Model

Carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) have become global threats. CRE- and CPE- derived infections have been associated with high mortality due to limited treatment options. Nacubactam is a beta-lactamase inhibitor and belongs to the new class of diazabicyclooctane. The agent has an in vitro antimicrobial activity against several classes of beta-lactamase-producing Enterobacterales. This study evaluated antimicrobial activity of combination therapies including beta-lactams (aztreonam, cefepime, and meropenem) and nacubactam against four Enterobacter cloacae and six Klebsiella pneumoniae isolates with murine pneumonia model. Based on changes in bacterial quantity, antimicrobial activities of some regimens were assessed. Combination therapies including beta-lactams (aztreonam, cefepime, and meropenem) with nacubactam showed enhanced antimicrobial activity against CRE E. cloacae (-3.70 to -2.08 & UDelta;log(10) CFU/lungs) and K. pneumoniae (-4.24 to 1.47 & UDelta;log(10) CFU/lungs) with IMP-1, IMP-6, or KPC genes, compared with aztreonam, cefepime, meropenem, and nacubactam monotherapies. Most combination therapies showed bacteriostatic (-3.0 to 0 & UDelta;log(10) CFU/lungs) to bactericidal (<-3.0 & UDelta;log(10) CFU/lungs) activities against CRE isolates. This study revealed that combination regimens with beta-lactams (aztreonam, cefepime, and meropenem) and nacubactam are preferable candidates to treat pneumonia due to CRE and CPE.

Automated summary

The study found that combination therapies with beta-lactams (aztreonam, cefepime, and meropenem) and nacubactam showed enhanced antimicrobial activity against CRE Enterobacter cloacae and Klebsiella pneumoniae. Most combination therapies exhibited bacteriostatic to bactericidal activities against CRE isolates.