title: In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters.
abstract: BACKGROUND
  NXL104 potentiates ceftazidime and ceftaroline against Enterobacteriaceae with extended-spectrum, AmpC, KPC and OXA β-lactamases. We examined whether similar potentiation was obtained against non-fermenters, which are less permeable than Enterobacteriaceae and have more potent efflux.
  
  
  METHODS
  MICs of ceftazidime+NXL104 (with NXL104 at 4 mg/L) and comparators were determined by CLSI agar dilution for: (i) Pseudomonas aeruginosa AmpC mutants and extended-spectrum β-lactamase (ESBL)-producing transconjugants; (ii) clinical P. aeruginosa isolates with AmpC enzymes, ESBLs or up-regulated efflux; (iii) P. aeruginosa and Burkholderia cepacia complex isolates from cystic fibrosis patients; and (iv) Acinetobacter baumannii with OXA carbapenemases, which also compromise ceftazidime.
  
  
  RESULTS
  NXL104 reversed AmpC-mediated ceftazidime resistance in P. aeruginosa, reducing MICs for fully derepressed mutants and isolates to ≤ 8 mg/L. NXL104 also reversed ceftazidime resistance caused by the ESBL PER-1, but not that due to OXA ESBLs or VEB-1 enzyme. Efflux-mediated resistance was unaffected. Resistance to ceftazidime in isolates of P. aeruginosa and the B. cepacia complex from patients with cystic fibrosis was variably overcome, generally to greater effect for B. cepacia. NXL104 had little effect on MICs of ceftazidime for A. baumannii isolates with OXA carbapenemases.
  
  
  CONCLUSIONS
  The potentiation of ceftazidime against many β-lactamase-producing P. aeruginosa and B. cepacia complex strains confirms that NXL104 penetrates these organisms. The utility of the combination against these pathogens will depend on the local prevalence of strains with β-lactamase- versus efflux-mediated resistance. The lack of potentiation against A. baumannii may reflect failure of NXL104 to penetrate these bacteria to inhibit relevant (OXA-23, -40, -51 and -58) carbapenemases.
authors.affiliation: Antibiotic Resistance Monitoring & Reference Laboratory, HPA Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000201:enzymology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D042602:Burkholderia cepacia complex / Q000187:drug effects* / Q000201:enzymology; D002442:Ceftazidime / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D001618:beta-Lactamases / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; C543519:avibactam; D002442:Ceftazidime; D001618:beta-Lactamases