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Factors influencing the therapy of experimental Proteus mirabilis meningitis in rabbits
Abstract:
The therapy of Proteus mirabilis meningitis with gentamicin alone and in combination with chloramphenicol was studied in a rabbit model. Antibiotics were administered for 8 hr. Samples of serum and cerebrospinal fluid (CSF) obtained simultaneously were assayed at 2-hr intervals for antibiotic concentration and counts of bacteria in CSF. The percentage of penetration ([concentration in CSF divided by concentration in serum] x 100%) of gentamicin ranged from 14% to 23%, but very large dosages were required to kill bacteria in the CSF. Although the minimal bactericidal concentration (MBC) of gentamicin was 1 microgram/ml, killing in vivo occurred only when concentrations in CSF were 10--30 times the MBC. The high concentration required for bactericidal activity in vivo may be explained by the reduced pH of infected CSF (mean pH, 6.98; range, 6.69--7.18). The bactericidal action of gentamicin was abolished by the simultaneous administration of chloramphenicol. Titers of bacteria in CSF were reduced 2.60 log10 (mean) with gentamicin therapy vs. 0.92 log10 (mean) with combination (P less than 0.01).
Insights
High gentamicin doses are needed for Proteus mirabilis meningitis therapy in rabbits, as low cerebrospinal fluid (CSF) penetration and pH hinder its effectiveness. Combining it with chloramphenicol proved detrimental, reducing gentamicin
Area of Science:
- Infectious Diseases
- Pharmacology
- Microbiology
Background:
- Proteus mirabilis is a common cause of bacterial meningitis.
- Gentamicin is a widely used antibiotic, but its efficacy in meningitis can be limited by penetration into the cerebrospinal fluid (CSF).
- The combination of antibiotics is often explored to enhance therapeutic outcomes.
Purpose of the Study:
- To evaluate the efficacy of gentamicin alone and in combination with chloramphenicol for treating Proteus mirabilis meningitis in a rabbit model.
- To determine gentamicin's penetration into the CSF and its bactericidal activity in vivo.
- To assess the impact of chloramphenicol on gentamicin's efficacy.
Main Methods:
- A rabbit model of Proteus mirabilis meningitis was established.
- Antibiotics (gentamicin alone or with chloramphenicol) were administered intravenously for 8 hours.
- Serum and CSF samples were collected at 2-hour intervals for antibiotic concentration and bacterial counts.
- Gentamicin penetration into CSF was calculated as a percentage of serum concentration.
- Minimal bactericidal concentration (MBC) of gentamicin was determined.
- CSF pH was measured in infected rabbits.
Main Results:
- Gentamicin penetration into CSF ranged from 14% to 23%.
- High CSF concentrations (10-30 times MBC) were required for bactericidal activity, likely due to reduced CSF pH (mean 6.98).
- Simultaneous administration of chloramphenicol abolished gentamicin's bactericidal action.
- Gentamicin monotherapy reduced bacterial titers by 2.60 log10 (mean), while combination therapy reduced them by only 0.92 log10 (mean) (P < 0.01).
Conclusions:
- Gentamicin requires high CSF concentrations for effective killing of Proteus mirabilis meningitis in rabbits, influenced by low CSF pH.
- Combination therapy with chloramphenicol antagonizes gentamicin's bactericidal activity.
- Gentamicin monotherapy is more effective than combination therapy with chloramphenicol for Proteus mirabilis meningitis in this model.