Grepafloxacin against penicillin-resistant pneumococci in the rabbit meningitis model
C M Gerber1, L Tovar, M Cottagnoud
1Department of Internal Medicine, Zieglerspital, Berne, Switzerland.
Abstract:
Grepafloxacin, a new fluoroquinolone, produced bactericidal activity comparable to that of vancomycin and ceftriaxone in the treatment in rabbits of meningitis caused by a pneumococcal strain highly resistant to penicillin (MIC 4 mg/L) (triangle uplog(10) cfu/mL*h for grepafloxacin, -0.32 +/- 0.15; dose, 15 mg/kg iv; triangle uplog(10) cfu/mL*h for vancomycin, -0.39 +/- 0.18; dose, 2 x 20 mg/kg iv; triangle uplog(10) cfu/mL*h for ceftriaxone, -0.32 +/- 0. 12; dose, 125 mg/kg iv). Higher doses of grepafloxacin (30 mg/kg and 2 x 50 mg/kg) did not improve the killing rates. The combination of grepafloxacin with vancomycin was not significantly superior to monotherapies (P > 0.05). In vitro, grepafloxacin was bactericidal at concentrations above the MIC. Using concentrations around the MIC, addition of vancomycin to grepafloxacin showed synergic activity.
Insights
Grepafloxacin demonstrated potent bactericidal activity against penicillin-resistant pneumococcal meningitis in rabbits, performing comparably to vancomycin and ceftriaxone. Higher grepafloxacin doses did not enhance efficacy, and combinations showed no significant advantage over monotherapy.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Pneumococcal meningitis poses a significant threat, especially with increasing antibiotic resistance.
- Fluoroquinolones are a class of antibiotics with broad-spectrum activity.
- Grepafloxacin is a novel fluoroquinolone investigated for its therapeutic potential.
Purpose of the Study:
- To evaluate the in vivo efficacy of grepafloxacin against penicillin-resistant Streptococcus pneumoniae meningitis in a rabbit model.
- To compare grepafloxacin's bactericidal activity with established antibiotics like vancomycin and ceftriaxone.
- To investigate the impact of varying dosages and combination therapy on treatment outcomes.
Main Methods:
- A rabbit model of meningitis was established using a penicillin-resistant pneumococcal strain (MIC 4 mg/L).
- Animals were treated intravenously with grepafloxacin, vancomycin, or ceftriaxone at specified doses.
- Bactericidal activity was quantified by measuring the change in log10 colony-forming units per milliliter per hour (log10 cfu/mL*h).
- In vitro studies assessed the synergistic activity of grepafloxacin and vancomycin combinations.
Main Results:
- Grepafloxacin (15 mg/kg IV) exhibited bactericidal activity comparable to vancomycin and ceftriaxone (log10 cfu/mL*h: -0.32 ± 0.15, -0.39 ± 0.18, and -0.32 ± 0.12, respectively).
- Increased doses of grepafloxacin (30 mg/kg and 2 x 50 mg/kg) did not yield improved killing rates.
- Combination therapy with grepafloxacin and vancomycin was not significantly superior to monotherapy in vivo (P > 0.05).
- In vitro, synergistic activity was observed when vancomycin was added to grepafloxacin at concentrations near the minimum inhibitory concentration (MIC).
Conclusions:
- Grepafloxacin demonstrates promising in vivo bactericidal activity against penicillin-resistant pneumococcal meningitis in rabbits.
- Standard dosing of grepafloxacin appears effective, with higher doses offering no additional benefit.
- While combination therapy showed in vitro synergy, it did not translate to superior in vivo efficacy in this model.
- Grepafloxacin represents a potential therapeutic option for meningitis caused by resistant pneumococcal strains.
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