Background: A Phase 3 study was conducted to evaluate CAZ-AVI and “best available therapy” in the treatment of infections caused by CAZ-NS Gram‑negative pathogens (NCT01644643). Here, the β-lactamase content of ENT recovered from patients was characterized.
Methods: Susceptibility testing was centrally performed (CLSI). MIC criteria were pre-established for selecting ENT for screening of extended-spectrum β-lactamase (ESBL), class C β-lactamase, and/or carbapenemase genes. Isolates underwent microarray-based assay, complemented by PCR/sequencing. Relative ampC transcription levels were assessed.
Results: 292 aerobic CAZ-NS ENT (MIC, ≥8 mg/ml), mostly E. coli (42.5%; 124/292) and K. pneumoniae (43.8%; 128/292) were included. Isolates were recovered from 288 mMITT patients. 4 patients had 2 species of ENT. CAZ-AVI (MIC50/MIC90, 0.5/1 mg/ml) inhibited all ENT at ≤8 mg/ml, except for 1 VIM-4 and 3 NDM-1 producers. All but 7 (117/124; 94.4%) E. coli harbored blaCTX-M. The other 7 isolates (7/124; 5.6%) had plasmid AmpC genes. 4 E. coli (4/117; 3.4%) had 2 blaCTX-M-like genes. 58.1% (68/117) blaCTX-M-harboring E. coli also had blaOXA-1/30. Meropenem-NS Klebsiella spp. (meropenem MIC, ≥2 mg/ml) produced one of: KPC (6), OXA-48 (3), VIM-4 (1) or NDM-1 (1). Other Klebsiella spp. (all ESBL) were blaCTX-M-positive (116/120; 96.7%) or SHV producers, except for 1 OXA-9. 89/120 (74.2%) of blaCTX-M-carrying Klebsiella spp. had OXA enzymes (83 OXA-1/30, 2 OXA-9 and 4 OXA-10). 5/6 (83.3%) P. mirabilis had plasmid AmpC and 2 strains also had VIM-2 and SHV-12. One P. mirabilis carried blaCTX-M-3, blaCTX-M-15, blaOXA-9, and blaSHV-5. 10/19 (52.6%) Enterobacter spp. had high expression of AmpC with (5) or without CTX-M (5), while other strains had CTX-M/OXA-1/-30 (7), NMD-1 (1) or PER-2 (1). 2 blaCTX-M–positive S. marcescens were isolated. Providencia had NDM-1 (1) or ACC-4 (1). A sole M. morganii had high expression of AmpC, while C. freundii showed overexpression of AmpC (2), CTX-M (3) or a combination of both (2). One of the latter also had DHA-4.
Conclusion: CAZ-AVI showed potent in vitro activity against CAZ-NS clinical trial ENT, excluding 4 MBL-producing isolates. This study demonstrates the complexity of β-lactamase genes carried by these CAZ-NS ENT.
R. E. Mendes,
L. N. Woosley, AstraZeneca Pharmaceuticals: Research Contractor , Research support
S. E. Costello, AstraZeneca Pharmaceuticals: Research Contractor , Research support
G. G. Stone, AstraZeneca Pharmaceuticals: Employee , Salary
R. K. Flamm, AstraZeneca Pharmaceuticals: Research Contractor , Research support
R. N. Jones, AstraZeneca Pharmaceuticals: Research Contractor , Research support