Activity of cephalosporin CXA-101 (FR264205) against Pseudomonas aeruginosa and Burkholderia cepacia group strains and isolates

David M. Livermore*, Shazad Mushtaq, Yigong Ge, Marina Warner

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)

Abstract

Twenty-five years after its introduction, ceftazidime remains the most active cephalosporin against Pseudomonas aeruginosa. Nevertheless, resistance arises by upregulation of AmpC β-lactamase, by efflux or, less often, via acquisition of additional β-lactamases. Mutational resistance is especially prevalent among cystic fibrosis (CF) isolates. We examined the activity of a novel oxyimino-aminothiazolyl cephalosporin, CXA-101 (FR264205), against P. aeruginosa strains with defined resistance mechanisms as well as against multiresistant clinical CF isolates of P. aeruginosa and Burkholderia cepacia. Minimum inhibitory concentrations (MICs) of CXA-101 were determined by the Clinical and Laboratory Standards Institute agar dilution method and were 0.25-0.5 mg/L for 'typical' P. aeruginosa strains without acquired resistance, compared with 1-2 mg/L for ceftazidime. MICs of CXA-101 were 0.5-2 mg/L and 4 mg/L, respectively, for isolates with upregulated efflux or total AmpC derepression, compared with 2-16 mg/L and 32-128 mg/L for ceftazidime. Full activity was retained against OprD mutants resistant to imipenem. Substantive resistance (MICs ≥ 32 mg/L) arose for transconjugants with PER, VEB and OXA extended-spectrum β-lactamases and for metallo-β-lactamase producers, with reduced susceptibility (MIC = 8 mg/L) for transconjugants with OXA-2, OXA-3 and NPS-1 enzymes. MICs of CXA-101 were 2- to 16-fold below those of ceftazidime for multiresistant P. aeruginosa from CF patients, but ranged up to >128 mg/L; values for B. cepacia from CF resembled those for ceftazidime.

Original languageEnglish
Pages (from-to)402-406
Number of pages5
JournalInternational Journal of Antimicrobial Agents
Volume34
Issue number5
DOIs
Publication statusPublished - Nov 2009

Bibliographical note

Funding Information:
Funding: This study was funded by Calixa Therapeutics Inc., San Diego, CA.

Keywords

  • Ceftazidime
  • Cystic fibrosis
  • Efflux
  • Pseudomonads
  • β-Lactamase

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