title: Mutation-driven β-lactam resistance mechanisms among contemporary ceftazidime-nonsusceptible Pseudomonas aeruginosa isolates from U.S. hospitals.
abstract: OprD loss and hyperexpression of AmpC, MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM were evaluated among 120 Pseudomonas aeruginosa isolates collected during 2012 in U.S. hospitals and selected based on ceftazidime MIC values (1 to >32 μg/ml). AmpC derepression (10-fold greater than that with the control) and OprD loss (decreased/no band) were the most prevalent resistance mechanisms: 47.5 and 45.8% of the isolates were considered positive, respectively. Elevated expression of the efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM was observed in 32.5, 8.3, 0.0, and 28.4% of the isolates, respectively. A total of 21 different combinations of resistance mechanisms were noted, and the most prevalent included AmpC derepression with OprD loss with and without efflux hyperexpression (38 and 10 isolates, respectively). A total of 26 isolates had no changes in the resistance mechanisms tested and had lower MIC values for all β-lactams or β-lactam/β-lactamase inhibitor combinations analyzed. OprD loss had a strong correlation with elevated MIC results for imipenem and meropenem (median MIC values of 8 and 4 μg/ml, respectively), with all combinations displaying OprD loss also displaying elevated median MIC values for these carbapenems (4 to >8 μg/ml). AmpC expression levels were greater in isolates displaying elevated cefepime, ceftazidime, or piperacillin-tazobactam MIC values (≥4, ≥4, and ≥16 μg/ml, respectively). Isolates displaying derepressed AmpC had ceftolozane-tazobactam MIC values ranging from 1 to 16 μg/ml. No strong correlation was noticed with MIC values for this β-lactam/β-lactamase inhibitor combination and OprD loss or hyperexpression of efflux systems. Two KPC-producing isolates were detected among 16 isolates displaying ceftolozane-tazobactam MIC values of ≥8 μg/ml.
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA mariana-castanheira@jmilabs.com.
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Janet C
authors.initials: JC
authors.lastname: Mills
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Farrell
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000096:biosynthesis; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D000077723:Cefepime; D002442:Ceftazidime / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology; D003428:Cross Infection / Q000382:microbiology; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010878:Piperacillin / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D018272:Porins / Q000235:genetics; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D018440:beta-Lactam Resistance / Q000235:genetics*; D001618:beta-Lactamases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002511:Cephalosporins; D026901:Membrane Transport Proteins; D018272:Porins; C077157:OprD protein, Pseudomonas aeruginosa; D000077725:Piperacillin, Tazobactam Drug Combination; D000077723:Cefepime; D010397:Penicillanic Acid; D002442:Ceftazidime; C048795:AmpC beta-lactamases; D001618:beta-Lactamases; D010878:Piperacillin