1176. β-lactamase Characterization of Baseline Enterobacteriaceae (ENT) from a Phase 3 Trial of ceftazidime-avibactam (CAZ-AVI) for the Treatment of Infections Caused by CAZ-nonsusceptible (NS) Pathogens
Session: Poster Abstract Session: Resistance Mechanisms
Friday, October 9, 2015
Room: Poster Hall

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.

Rodrigo E. Mendes, PhD1, Mariana Castanheira, PhD1, Leah N. Woosley, BS1, Sarah E. Costello, BS1, Gregory G. Stone, PhD2, Robert K. Flamm, PhD1 and Ronald N. Jones, MD1, (1)JMI Laboratories, Inc., North Liberty, IA, (2)AstraZeneca Pharmaceuticals LP, Waltham, MA

Disclosures:

R. E. Mendes, AstraZeneca Pharmaceuticals: Research Contractor , Research support

M. Castanheira, AstraZeneca Pharmaceuticals: Research Contractor , Research support

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

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