Treatment of experimental pneumonia in rats caused by a PER-1 extended-spectrum beta-lactamase-producing strain of Pseudomonas aeruginosa

J Antimicrob Chemother. 1999 Jul;44(1):91-7. doi: 10.1093/jac/44.1.91.

Abstract

The antibacterial activity of imipenem, cefepime and piperacillin-tazobactam alone or in combination with amikacin against a Pseudomonas aeruginosa strain producing an extended-spectrum beta-lactamase (PER-1) were compared using an experimental model of pneumonia in non-leucopenic rats. Animals were infected intratracheally with 8.0 +/- 0.4 log10 cfu of P. aeruginosa, and therapy was initiated 3 h later, by which time animal lungs showed bilateral pneumonia containing >7 log10 P. aeruginosa cfu/g of tissue. Since rats eliminate antibiotics much more rapidly than humans, renal impairment was induced in all animals to simulate the pharmacokinetic parameters of humans. MICs determined using an inoculum of 4 log10 cfu/mL were as follows: imipenem, 1 mg/L; cefepime, 8 mg/L; piperacillin-tazobactam, 32 mg/L; and amikacin, 16 mg/L. A noticeable inoculum effect was observed with the four antimicrobial agents tested, which was greatest for cefepime and piperacillin-tazobactam. In-vitro studies indicated that imipenem was the beta-lactam with the greatest bactericidal effect and that amikacin was synergic only in combination with cefepime and imipenem. Cefepime and piperacillin-tazobactam alone failed to decrease bacterial counts in the rats' lungs 60 h after therapy onset, whereas imipenem and, to a lesser extent, amikacin significantly reduced the number of viable microorganisms. Combination of amikacin with any of the three beta-lactams tested was synergic, despite a high amikacin MIC for the infecting strain. These results paralleled our in-vitro data showing a marked inoculum effect for cefepime and piperacillin-tazobactam. Based on the results of this study, the best treatment for infections caused by this type of extended-spectrum beta-lactamase-possessing strain would be imipenem plus amikacin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amikacin / pharmacology
  • Amikacin / therapeutic use
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Cefepime
  • Cephalosporins / pharmacology
  • Cephalosporins / therapeutic use
  • Colony Count, Microbial
  • Disease Models, Animal
  • Drug Synergism
  • Drug Therapy, Combination / pharmacology
  • Drug Therapy, Combination / therapeutic use*
  • Imipenem / pharmacology
  • Imipenem / therapeutic use
  • Lung / microbiology
  • Male
  • Microbial Sensitivity Tests
  • Penicillanic Acid / analogs & derivatives
  • Penicillanic Acid / pharmacology
  • Penicillanic Acid / therapeutic use
  • Piperacillin / pharmacology
  • Piperacillin / therapeutic use
  • Piperacillin, Tazobactam Drug Combination
  • Pneumonia, Bacterial / drug therapy*
  • Pneumonia, Bacterial / microbiology
  • Pseudomonas Infections / drug therapy*
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / enzymology
  • Rats
  • Rats, Wistar
  • beta-Lactamases / metabolism*

Substances

  • Anti-Bacterial Agents
  • Cephalosporins
  • Piperacillin, Tazobactam Drug Combination
  • Imipenem
  • Cefepime
  • Amikacin
  • Penicillanic Acid
  • beta-Lactamases
  • Piperacillin