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Absence of a postantibiotic effect in experimental Pseudomonas endocarditis treated with imipenem, with or without
M T Hessen1, P G Pitsakis, M E Levison
1Department of Medicine, Medical College of Pennsylvania, Philadelphia.
Abstract:
We found an in vitro postantibiotic effect (PAE) of 3-4 h for imipenem and of approximately 5 h for imipenem plus gentamicin against Pseudomonas aeruginosa. We therefore evaluated these antibiotics in a rat model of pseudomonas endocarditis. A rapid bactericidal effect was initially observed in vegetations from rats treated with imipenem alone or in combination with gentamicin. Bacterial counts rose rapidly, however, as soon as levels of imipenem in vegetations fell below the minimal inhibitory concentration (i.e., no PAE was demonstrated). Levels of gentamicin in vegetations were similar to those that had enhanced the bactericidal effect of imipenem and had resulted in a 5-h PAE in vitro. The presence in vitro of a PAE for imipenem, with or without gentamicin, does not necessarily predict its presence in vivo in pseudomonas endocarditis in the rat.
Insights
The in vitro postantibiotic effect (PAE) of imipenem and gentamicin against Pseudomonas aeruginosa did not predict in vivo efficacy in a rat endocarditis model. Bacterial regrowth occurred rapidly once imipenem levels dropped below the minimal inhibitory concentration.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- The postantibiotic effect (PAE) describes the delay in bacterial growth after antibiotic exposure.
- Imipenem and gentamicin are used to treat Pseudomonas aeruginosa infections.
- Understanding in vivo PAE is crucial for predicting antibiotic treatment success.
Purpose of the Study:
- To evaluate the in vivo postantibiotic effect (PAE) of imipenem, alone and with gentamicin, against Pseudomonas aeruginosa endocarditis in rats.
- To determine if in vitro PAE predicts in vivo efficacy.
Main Methods:
- In vitro testing of imipenem and imipenem plus gentamicin against Pseudomonas aeruginosa to determine PAE.
- Induction of Pseudomonas aeruginosa endocarditis in a rat model.
- Treatment of infected rats with imipenem alone or in combination with gentamicin.
- Monitoring bacterial counts and antibiotic levels in vegetations.
Main Results:
- In vitro, imipenem showed a 3-4 hour PAE, and imipenem plus gentamicin showed a 5-hour PAE.
- In vivo, rapid bactericidal effect was observed initially, but bacterial counts increased as imipenem levels fell below the minimal inhibitory concentration.
- Gentamicin levels in vegetations did not prolong the PAE observed in vitro.
Conclusions:
- The in vitro postantibiotic effect of imipenem, with or without gentamicin, does not reliably predict its presence or efficacy in a rat model of Pseudomonas aeruginosa endocarditis.
- Antibiotic efficacy in vivo is influenced by factors beyond in vitro PAE, such as drug penetration and sustained therapeutic concentrations.