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

Antibiotics

Hideo Kato¹  Hiroyuki Suematsu¹  Daisuke Sakanashi¹  Jun Hirai¹  Yuichi Shibata¹  Hiroshige Mikamo¹  Nobuhiro Asai¹  Yuka Yamagishi¹  Mao Hagihara²  Nobuo Sato³  Hayato Okade³  Toshie Sugano³ 

[1] Department of Clinical Infectious Diseases, Aichi Medical University, Nagakute 480-1195, Japan;Department of Molecular Epidemiology and Biomedical Sciences, Aichi Medical University, Nagakute 480-1195, Japan;Meiji Seika Pharma Co., Ltd., Tokyo 104-8002, Japan;

关键词: aztreonam;    cefepime;    meropenem;    nacubactam;    carbapenemase-producing Enterobacterales;    carbapenem-resistant Enterobacterales;   

DOI  :  10.3390/antibiotics10101179

来源: DOAJ

【 摘 要 】

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 β-lactamase inhibitor and belongs to the new class of diazabicyclooctane. The agent has an in vitro antimicrobial activity against several classes of β-lactamase-producing Enterobacterales. This study evaluated antimicrobial activity of combination therapies including β-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 β-lactams (aztreonam, cefepime, and meropenem) with nacubactam showed enhanced antimicrobial activity against CRE E. cloacae (−3.70 to −2.08 Δlog₁₀ CFU/lungs) and K. pneumoniae (−4.24 to 1.47 Δlog₁₀ 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 Δlog₁₀ CFU/lungs) to bactericidal (<−3.0 Δlog₁₀ CFU/lungs) activities against CRE isolates. This study revealed that combination regimens with β-lactams (aztreonam, cefepime, and meropenem) and nacubactam are preferable candidates to treat pneumonia due to CRE and CPE.

【 授权许可】

Unknown