title: Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus beta-lactamase-producing Enterobacteriaceae.
abstract: BACKGROUND
  The developmental oxyimino-cephalosporin CXA-101 (FR264205) is notable for having greater antipseudomonal activity than ceftazidime. It is active against Enterobacteriaceae too, but is compromised by extended-spectrum, AmpC and carbapenem-hydrolysing beta-lactamases. We investigated the tazobactam concentrations needed to potentiate this cephalosporin against strains with these mechanisms.
  
  
  METHODS
  MIC chequerboards were prepared between CXA-101 and tazobactam (1-32 mg/L) using CLSI agar dilution methodology and a challenge panel of 'difficult' Enterobacteriaceae isolates.
  
  
  RESULTS
  Only 20% of 59 extended-spectrum beta-lactamase (ESBL) producers were susceptible to unprotected CXA-101 at 8 mg/L (5% at 2 mg/L), but 76% were susceptible to CXA-101 + tazobactam at 8 + 4 mg/L and 93% at 8 + 8 mg/L. Among 20 AmpC-derepressed organisms, three of four Serratia spp. were susceptible to CXA-101 at 1-2 mg/L, but other species with the mechanism were more resistant; nevertheless, 70% were susceptible to CXA-101 + tazobactam at 8 + 4 mg/L and 95% at 8 + 8 mg/L. The six least-susceptible AmpC-derepressed isolates were all Enterobacter spp. The MICs of CXA-101 for Klebsiella oxytoca isolates hyperproducing K1 enzyme were 4 mg/L and were not significantly reduced by tazobactam: those for Klebsiella pneumoniae with KPC enzymes were >or=128 mg/L and, in four out of five cases, were not significantly reduced by tazobactam.
  
  
  CONCLUSIONS
  Tazobactam achieved concentration-dependent potentiation of CXA-101 versus ESBL producers and AmpC hyperproducers. If a breakpoint of 8 + 8 mg/L can be justified pharmacokinetically, CXA-101 + tazobactam should be active versus >90% of ESBL producers, AmpC hyperproducers and K1 hyperproducers. Most isolates with KPC or other carbapenemases will remain resistant.
authors.affiliation: Antibiotic Resistance Monitoring & Reference Laboratory, HPA Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Yigong
authors.initials: Y
authors.lastname: Ge
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002511:Cephalosporins / Q000494:pharmacology*; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; C519491:ceftolozane; D010397:Penicillanic Acid; D001618:beta-Lactamases; D000078142:Tazobactam