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

• Published in: International journal of antimicrobial agents Vol. 34; no. 5; pp. 402 - 406
• Main Authors: Livermore, David M, Mushtaq, Shazad, Ge, Yigong, Warner, Marina
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01.11.2009
• Subjects: Adolescent; Adult; Aged; Anti-Bacterial Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Burkholderia cepacia; Burkholderia cepacia - drug effects; Burkholderia cepacia - isolation & purification; Burkholderia Infections - microbiology; Cephalosporins - pharmacology; Drug Resistance, Bacterial; Errors of metabolism; Female; Humans; Infectious Disease; Medical sciences; Metabolic diseases; Microbial Sensitivity Tests; Middle Aged; Miscellaneous hereditary metabolic disorders; Pharmacology. Drug treatments; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - isolation & purification; Pseudomonas Infections - microbiology; Young Adult; Efflux; Cystic fibrosis; Pseudomonads; β-Lactamase; Ceftazidime; Pseudomonadales; Enzyme; Respiratory disease; β-Lactams; Metabolic diseases; Biological activity; Genetic disease; Strain; Antibiotic; Cephalosporin derivatives; Burkholderia cepacia; Bacteria; Hydrolases; Digestive diseases; Pseudomonadaceae; Isolate; Pseudomonas aeruginosa; Antibacterial agent; Pancreatic disease
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2009.03.021

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.