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Trovafloxacin delays the antibiotic-induced inflammatory response in experimental pneumococcal meningitis
Abstract:
This study evaluates the ability of the new fluoroquinolone trovafloxacin to attenuate the inflammatory burst known to occur after initiation of antibiotic treatment in pneumococcal meningitis. After exposure to trovafloxacin or ceftriaxone for 3 h in vitro, Streptococcus pneumoniae was injected intracisternally (i.c.) into rabbits every 3 h over 9 h (n = 6 for each antibiotic). Ceftriaxone-treated S. pneumoniae induced consistently higher CSF leucocyte counts (median 2568/microL versus 543/microL at 6 h; P = 0.03; 4560/microL versus 2207/microL at 18 h; P = 0.03) than trovafloxacin-treated bacteria. Meningitis induced in rabbits by i.c. injection of live S. pneumoniae was treated with equal doses of trovafloxacin or ceftriaxone i.v. (ten per group). The bactericidal rates of both antibacterial agents in CSF were almost identical. In comparison with ceftriaxone, trovafloxacin resulted in lower tumour necrosis factor (TNF) and interleukin 1beta (IL-1beta) CSF levels 2 h after the initiation of treatment (TNF levels, median 26 U/mL versus 141 U/mL; P = 0.02; IL-1beta levels 455 pg/mL versus 1399 pg/mL; P = 0.02). Twelve hours after initiation of therapy, however, TNF and IL-1beta were higher in trovafloxacin-treated animals (TNF, 61 U/mL versus 7 U/mL; P = 0.001; IL-1beta, 4320 pg/mL versus 427 pg/mL; P = 0.006). The increase in CSF lactate was less during trovafloxacin therapy than with ceftriaxone (median: 2.0 mmol/L versus 4.0 mmol/L; P = 0.03). In conclusion, S. pneumoniae treated in vitro with trovafloxacin induced less CSF leucocytosis than ceftriaxone-treated S. pneumoniae. After i.c. inoculation of live S. pneumoniae, trovafloxacin therapy delayed, but did not inhibit, the release of the proinflammatory cytokines TNF and IL-1beta, probably by slowing the liberation of bacterial cell wall components into the subarachnoid space.
Insights
Trovafloxacin, an antibiotic, reduced initial inflammation in pneumococcal meningitis compared to ceftriaxone. However, it delayed, not blocked, the release of inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1beta (IL-1beta).
Area of Science:
- Pharmacology
- Infectious Diseases
- Neuroscience
Background:
- Bacterial meningitis, particularly pneumococcal meningitis, triggers a significant inflammatory response.
- Antibiotic treatment can exacerbate this inflammation, leading to increased cerebrospinal fluid (CSF) leukocytes and cytokine release.
- Understanding how different antibiotics modulate this inflammatory burst is crucial for optimizing treatment strategies.
Purpose of the Study:
- To evaluate the efficacy of trovafloxacin in attenuating the inflammatory response in pneumococcal meningitis compared to ceftriaxone.
- To investigate the impact of trovafloxacin on CSF leukocyte counts, pro-inflammatory cytokine levels (TNF and IL-1beta), and CSF lactate in a rabbit model.
Main Methods:
- In vitro exposure of Streptococcus pneumoniae to trovafloxacin or ceftriaxone.
- Intracisternal (i.c.) inoculation of rabbits with treated S. pneumoniae to induce meningitis.
- Intravenous (i.v.) treatment of meningitis with trovafloxacin or ceftriaxone.
- Measurement of CSF leukocyte counts, TNF, IL-1beta, and lactate levels at various time points.
Main Results:
- Trovafloxacin-treated bacteria induced significantly lower CSF leukocyte counts compared to ceftriaxone-treated bacteria.
- Bactericidal rates of both antibiotics in CSF were comparable.
- Trovafloxacin resulted in lower initial CSF levels of TNF and IL-1beta, but these levels increased significantly later in the treatment course.
- CSF lactate levels were lower during trovafloxacin therapy than with ceftriaxone.
Conclusions:
- Trovafloxacin demonstrates a reduced capacity to induce CSF leucocytosis compared to ceftriaxone when treating S. pneumoniae.
- Trovafloxacin therapy appears to delay, rather than inhibit, the release of pro-inflammatory cytokines TNF and IL-1beta in pneumococcal meningitis.
- This delayed cytokine release may be attributed to a slower liberation of bacterial cell wall components into the subarachnoid space.