Avibactam Sensitizes Carbapenem-Resistant NDM-1–Producing Klebsiella pneumoniae to Innate Immune Clearance. (29th March 2019)

• Record Type: Journal Article
• Authors: Ulloa, Erlinda R; Dillon, Nicholas; Tsunemoto, Hannah; Pogliano, Joe; Sakoulas, George; Nizet, Victor
• Is Part Of: Journal of infectious diseases. Volume 220:Number 3(2019)
• Page Start: 484
• Page End: 493
• Publication Date: 2019-03-29
• Subjects: New Delhi metallo-β-lactamase (NDM) -- Klebsiella pneumoniae -- non–β-lactam β-lactamase inhibitors -- avibactam -- innate immunity -- platelet -- neutrophil -- human serum; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiz128
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract: Infections caused by New Delhi metallo-β-lactamase (NDM)–producing strains of multidrug-resistant Klebsiella pneumoniae are a global public health threat lacking reliable therapies. NDM is impervious to all existing β-lactamase inhibitor (BLI) drugs, including the non–β-lactam BLI avibactam (AVI). Though lacking direct activity against NDMs, AVI can interact with penicillin-binding protein 2 in a manner that may influence cell wall dynamics. We found that exposure of NDM-1–producing K. pneumoniae to AVI led to striking bactericidal interactions with human cathelicidin antimicrobial peptide LL-37, a frontline component of host innate immunity. Moreover, AVI markedly sensitized NDM-1–producing K. pneumoniae to killing by freshly isolated human neutrophils, platelets, and serum when complement was active. Finally, AVI monotherapy reduced lung counts of NDM-1–producing K. pneumoniae in a murine pulmonary challenge model. AVI sensitizes NDM-1–producing K. pneumoniae to innate immune clearance in ways that are not appreciated by standard antibiotic testing and that merit further study.