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Mecillinam alone and in combination with ampicillin or moxalactam in experimental Escherichia coli meningitis
Abstract:
The activity of mecillinam, ampicillin and moxalactam alone and in combination was determined in a lapin meningitis model and a mouse meningitis model against two Escherichia coli strains isolated from infants with meningitis. Both strains were highly susceptible in vitro to the antibiotics, and responded well in systemic mouse protection tests (PD50 less than 4 mg/kg). Continuous infusion of mecillinam in the lapin model over nine hours was effective in sterilizing the CSF of three of four animals infected with one strain. This prompt bacteriologic response to mecillinam alone precluded the possibility of constant infusion administration for synergy studies. Therefore, single dose administration was used to demonstrate the synergistic potential of mecillinam with ampicillin in the lapin meningitis model against the E. coli Kl # 2 strain. The combination of moxalactam and mecillinam was synergistic against the E. coli Kl # 2 strain in the mouse meningitis model. The synergistic potential of these combinations could not be reliably predicted by in vitro tests, time kill curves or systemic mouse protection tests.
Insights
Mecillinam, ampicillin, and moxalactam showed effectiveness against infant meningitis strains. Antibiotic combinations demonstrated synergistic potential in animal models, but in vitro tests could not reliably predict these outcomes.
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Bacterial meningitis, particularly from *Escherichia coli*, remains a significant cause of infant mortality and morbidity.
- Understanding antibiotic efficacy and synergistic interactions is crucial for developing effective treatment strategies.
Purpose of the Study:
- To evaluate the activity of mecillinam, ampicillin, and moxalactam, alone and in combination, against *Escherichia coli* strains isolated from infant meningitis.
- To assess the synergistic potential of these antibiotics in preclinical meningitis models.
Main Methods:
- Antibiotic activity was determined in both a rabbit meningitis model and a mouse meningitis model.
- In vitro susceptibility testing and time-kill curves were performed.
- Systemic mouse protection tests (PD50) were utilized to assess efficacy.
Main Results:
- Both *E. coli* strains were highly susceptible in vitro and responded well in mouse protection tests.
- Continuous mecillinam infusion sterilized cerebrospinal fluid (CSF) in a rabbit model, but precluded further synergy studies with this method.
- Mecillinam and ampicillin showed synergy in the rabbit model, while moxalactam and mecillinam demonstrated synergy in the mouse model.
Conclusions:
- Antibiotic combinations, specifically mecillinam with ampicillin and moxalactam with mecillinam, exhibited synergistic effects against *E. coli* meningitis in animal models.
- In vitro methods and systemic mouse protection tests were insufficient to reliably predict the synergistic activity observed in the meningitis models.