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The postantibiotic effect in the treatment of experimental meningitis caused by Streptococcus pneumoniae in rabbits
Abstract:
The relevance of a postantibiotic effect in the treatment of pneumococcal meningitis was evaluated in a rabbit model. After administration of a single intravenous bolus of ampicillin at various dosages, such an effect was observed in all animals. The duration of this effect in vivo (2.5-18 hr) was consistently longer than that in vitro (1-4.3 hr); however, in rabbits the postantibiotic effect was eliminated by the administration of intravenous plus intracisternal beta-lactamase. In an assessment of the potential therapeutic benefit of the postantibiotic effect, the efficacy to two regimens of treatment with different intervals between doses was compared. One group of animals received ampicillin every 4 hr and another every 12 hr. With sufficiently high doses, drug concentrations in cerebrospinal fluid exceeded the minimal bactericidal concentration for most of the 4-hr interval but for only about one-third of the 12-hr interval. The rate of cure was similar for the two regimens and approximated 100% when peak drug concentrations in cerebrospinal fluid exceeded the minimal bactericidal concentration by at least 10-fold.
Insights
The postantibiotic effect, crucial for treating pneumococcal meningitis, was observed in rabbits. Ampicillin dosing intervals did not impact cure rates, suggesting peak drug concentration is key.
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Pneumococcal meningitis remains a significant global health concern.
- Understanding antibiotic efficacy, including postantibiotic effects, is vital for treatment optimization.
- Rabbit models offer valuable insights into human disease pathophysiology.
Purpose of the Study:
- To evaluate the relevance of the postantibiotic effect in pneumococcal meningitis treatment using a rabbit model.
- To compare the therapeutic efficacy of different ampicillin dosing regimens.
- To determine the relationship between drug concentration, postantibiotic effect, and cure rates.
Main Methods:
- Induction of pneumococcal meningitis in rabbits.
- Administration of single intravenous ampicillin doses to assess postantibiotic effect (PAE) in vivo and in vitro.
- Comparison of ampicillin treatment regimens with 4-hour and 12-hour intervals.
- Measurement of ampicillin concentrations in cerebrospinal fluid (CSF).
- Assessment of cure rates and correlation with PAE and peak drug concentrations.
Main Results:
- A significant postantibiotic effect (PAE) was observed in all rabbits, with in vivo duration (2.5–18 hr) exceeding in vitro duration (1–4.3 hr).
- The PAE was eliminated by beta-lactamase administration.
- Treatment regimens with 4-hour and 12-hour intervals showed similar cure rates.
- Sufficiently high ampicillin doses in CSF exceeded the minimal bactericidal concentration (MBC) for extended periods.
- Optimal cure rates (approaching 100%) were achieved when peak CSF drug concentrations were at least 10-fold the MBC.
Conclusions:
- The postantibiotic effect plays a role in pneumococcal meningitis treatment, though its duration in vivo is influenced by factors like beta-lactamase.
- Ampicillin dosing intervals are less critical than achieving sufficiently high peak drug concentrations in CSF to exceed the MBC.
- Therapeutic strategies should focus on maximizing peak antibiotic concentrations to ensure high cure rates in pneumococcal meningitis.