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

Twenty-five years after its introduction, ceftazidime remains the most active cephalosporin against Pseudomonas aeruginosa. Nevertheless, resistance arises by upregulation of AmpC Beta-lactamase, by efflux or, less often, via acquisition of additional beta-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 > or = 32 mg/L) arose for transconjugants with PER, VEB and OXA extended-spectrum beta-lactamases and for metallo-beta-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.