Abstract
Background
ASPECT-NP, a phase 3, randomized, double-blind, multicenter trial, evaluated ceftolozane/tazobactam (C/T) 3 g q8h vs. meropenem 1 g q8h for 8–14 days in adults for treatment of ventilated nosocomial pneumonia. Baseline Gram-negative (GN) isolates from patients were tested for mechanisms of resistance.
Methods
Lower respiratory tract (LRT) isolates were sent to a central laboratory for organism identification and susceptibility. Of 664 total Enterobacteriaceae (ENT) and Pseudomonas aeruginosa (PsA) isolates, 351 (53%) were nonsusceptible to broad-spectrum cephalosporins and/or carbapenems and underwent whole-genome sequencing, quantitative RT–PCR, and western blot analysis. ENT isolates were tested for the presence of acquired β-lactamase genes and AmpC levels (selected species). PsA isolates were tested for acquired β-lactamase genes, AmpC (PDC) levels, efflux pump expression, and OprD loss.
Results
Of 262 ENT isolates, 114 (44%) were susceptible to C/T (MIC ≤2 µg/mL). An extended-spectrum β-lactamase (ESBL) gene was carried by 89 (78%) of the C/T-susceptible isolates. Of 148 C/T-nonsusceptible (C/T-NS) isolates, 87 (59%) were carbapenemase negative, and the majority 135 (91%) also carried an ESBL gene. The most common ESBL was blaCTX-M15 with blaOXA-1 and blaOXA-30. Klebsiella pneumoniae often displayed higher C/T MICs compared with other species carrying the same resistance genes. Among all C/T-NS isolates, 61 (41%) were carbapenemase positive, most commonly K. pneumoniae carrying blaOXA-48, blaNDM-1, and blaNDM-5. Of 89 PsA isolates, 58 (65%) were susceptible to C/T (MIC ≤4 µg/mL), despite elevated AmpC expression, efflux pumps, or loss of OprD; only 5 isolates had an acquired β-lactamase. Of the 31 C/T-NS PsA isolates, only 12 (39%) were carbapenemase positive and carried blaVIM or blaGES; isolates carrying blaGES had lower C/T MICs (8–32 µg/mL) compared with blaVIM (MIC > 128 µg/mL). PDC alleles were similar in isolates with high and low C/T MICs.
Conclusion
In baseline GN LRT isolates from ASPECT-NP, the most common ESBL detected in ENT was blaCTX-M15; carbapenemases were uncommon. There was no correlation of ESBL phenotype to C/T susceptibility among ENT, nor of PDC allele to C/T susceptibility among PsA.
Disclosures
All authors: No reported disclosures.
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