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In vitro and in vivo activities of Syn2190, a novel beta-lactamase inhibitor.

Abstract
Syn2190, a monobactam derivative containing 1,5-dihydroxy-4-pyridone as the C-3 side chain, is a potent inhibitor of group 1 beta-lactamase. The concentrations of inhibitor needed to reduce the initial rate of hydrolysis of substrate by 50% for Syn2190 against these enzymes were in the range of 0.002 to 0.01 microM. These values were 220- to 850-fold lower than those of tazobactam. Syn2190 showed in vitro synergy with ceftazidime and cefpirome. This synergy was dependent on the concentration of the inhibitor against group 1 beta-lactamase-producing strains, such as Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, and Morganella morganii. However, against beta-lactamase-derepressed mutants of P. aeruginosa, the MICs of ceftazidime plus Syn2190 were not affected by the amount of beta-lactamase, and the values were the same for the parent strains. The MICs at which 50% of isolates are inhibited (MIC(50)s) of ceftazidime plus Syn2190 were 2- to 16-fold lower than those of ceftazidime alone for ceftazidime-resistant, clinically isolated gram-negative bacteria. Similarly, the MIC(50)s of cefpirome plus Syn2190 were two- to eightfold lower for cefpirome-resistant clinical isolates. The synergies of Syn2190 plus ceftazidime or cefpirome observed in vitro were also reflected in vivo. Syn2190 improved the efficacies of both cephalosporins in both a murine systemic infection model with cephalosporin-resistant rods and urinary tract infection models with cephalosporin-resistant P. aeruginosa.
AuthorsK Nishida, C Kunugita, T Uji, F Higashitani, A Hyodo, N Unemi, S N Maiti, O A Phillips, P Spevak, K P Atchison, S M Salama, H Atwal, R G Micetich
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 43 Issue 8 Pg. 1895-900 (Aug 1999) ISSN: 0066-4804 [Print] United States
PMID10428909 (Publication Type: Journal Article)
Chemical References
  • Cephalosporins
  • Enzyme Inhibitors
  • Monobactams
  • Syn 2190
  • beta-Lactamase Inhibitors
  • Penicillanic Acid
  • Ceftazidime
  • beta-Lactamases
  • cefpirome
  • Tazobactam
Topics
  • Animals
  • Ceftazidime (pharmacology)
  • Cephalosporins (pharmacology)
  • Citrobacter freundii (drug effects, enzymology)
  • Drug Synergism
  • Enterobacter cloacae (drug effects, enzymology)
  • Enterobacteriaceae (drug effects, enzymology)
  • Enzyme Induction
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Male
  • Mice
  • Microbial Sensitivity Tests
  • Monobactams (pharmacology)
  • Penicillanic Acid (analogs & derivatives, pharmacology)
  • Pseudomonas aeruginosa (drug effects, enzymology, genetics)
  • Tazobactam
  • beta-Lactamase Inhibitors
  • beta-Lactamases (biosynthesis)

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