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Adjuvant non-bacteriolytic and anti-inflammatory combination therapy in pneumococcal meningitis: an investigation in
1Department of Neurology, Klinikum der Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 München, Germany.
Objectives:
Therapy with antibiotics, dexamethasone, and supportive intensive care has improved the prognosis of pneumococcal meningitis, but mortality remains high. Here, we investigated an adjunctive combination therapy of the non-bacteriolytic antibiotic daptomycin plus several anti-inflammatory agents to identify the currently most promising adjunctive combination therapy for pneumococcal meningitis.
Methods:
C57BL/6 mice were infected by injection of pneumococci into the cisterna magna. Treatment was begun 21 h after infection, and consisted of ceftriaxone plus (a) dexamethasone, (b) dexamethasone plus daptomycin, (c) daptomycin, (d) daptomycin plus an anti-IL1 antibody, (e) daptomycin plus roscovitine, or (f) daptomycin plus an anti-C5 antibody. Animals were followed until 45 h after infection. Furthermore, adjunctive daptomycin plus anti-C5 antibodies were assessed in a long-term follow-up.
Results:
Adjunctive treatment with daptomycin and an anti-C5 antibody was superior to adjunctive dexamethasone and reduced disease symptoms (clinical score 1.1 ± 1.1 versus 5.0 ± 2.7, p < 0.0083), improved explorative activity (open field test 17.8 ± 8.2 versus 7.4 ± 4.3 crossed fields/2 minutes, p < 0.0083), and reduced hearing impairment (thresholds for click stimulus 96.1 ± 14.7 versus 114.8 ± 9.3 dB SPL, p < 0.0083) in the acute stage. Furthermore, explorative activity (14.4 ± 7.3 crossed fields/2 minutes versus 6.3 ± 7.2, p < 0.05) and cognitive function (t-maze test, exploration time previously unknown alley 72.4 ± 14.3 versus 48.7 ± 25.6%, p < 0.05) was improved at 2 weeks after infection. Treatment with daptomycin plus an anti-IL-1β antibody or roscovitine was not of significant benefit in comparison to adjunctive therapy with dexamethasone.
Conclusions:
An adjunctive combination of the non-lytic antibiotic daptomycin plus an anti-C5 antibody was superior to standard therapy with adjunctive dexamethasone in the treatment of pneumococcal meningitis.
Insights
A novel combination therapy using the antibiotic daptomycin and an anti-C5 antibody significantly improved outcomes for pneumococcal meningitis in mice. This approach outperformed standard dexamethasone treatment, reducing disease severity and long-term neurological deficits.
Area of Science:
- Infectious Diseases
- Neurology
- Pharmacology
Background:
- Pneumococcal meningitis remains a significant cause of mortality despite current treatments.
- Standard therapy involves antibiotics, dexamethasone, and intensive care, but prognosis is often poor.
- Investigating novel adjunctive therapies is crucial to improve patient outcomes.
Purpose of the Study:
- To evaluate the efficacy of adjunctive daptomycin combined with various anti-inflammatory agents for pneumococcal meningitis.
- To identify the most promising combination therapy for this severe infection.
- To compare novel combinations against standard adjunctive dexamethasone treatment.
Main Methods:
- C57BL/6 mice were infected with Streptococcus pneumoniae.
- Treatment regimens included ceftriaxone combined with dexamethasone, daptomycin, anti-IL1 antibody, roscovitine, or anti-C5 antibody.
- Clinical outcomes, neurological function, and hearing impairment were assessed in acute and long-term follow-ups.
Main Results:
- Adjunctive daptomycin plus anti-C5 antibody significantly reduced disease symptoms and hearing impairment compared to dexamethasone.
- This combination also improved explorative activity and cognitive function in the acute stage and at 2-week follow-up.
- Daptomycin with anti-IL-1β antibody or roscovitine showed no significant benefit over dexamethasone.
Conclusions:
- Adjunctive therapy with daptomycin and an anti-C5 antibody is superior to dexamethasone for treating pneumococcal meningitis.
- This combination therapy offers a promising new strategy to improve the prognosis of pneumococcal meningitis.
- Further research into daptomycin-based combination therapies is warranted.
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