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Adjuvant treatment with dexamethasone plus anti-C5 antibodies improves outcome of experimental pneumococcal meningitis: a randomized controlled trial.

Kasanmoentalib ES, Valls Seron M, Morgan BP, Brouwer MC, van de Beek D - J Neuroinflammation (2015)

Bottom Line: We compared adjunctive treatment with placebo, dexamethasone, anti-C5 antibodies, and the combination of dexamethasone plus anti-C5 antibodies in experimental pneumococcal meningitis.Modeling of severity data suggested an additive effect of dexamethasone and anti-C5 antibodies.Adjunctive treatment with dexamethasone plus anti-C5 antibodies improves survival in severe experimental meningitis caused by S. pneumoniae serotype 3, posing an important new treatment strategy for patients with pneumococcal meningitis.

View Article: PubMed Central - PubMed

Affiliation: Center for Immunity and Infection (CINIMA): Department of Neurology, Center for Immunity and Infection (CINIMA), Academic Medical Center, University of Amsterdam, PO Box 22660, 1100DD, Amsterdam, The Netherlands. e.s.kasanmoentalib@amc.nl.

ABSTRACT

Background: We compared adjunctive treatment with placebo, dexamethasone, anti-C5 antibodies, and the combination of dexamethasone plus anti-C5 antibodies in experimental pneumococcal meningitis.

Methods: In this prospective, investigator-blinded, randomized trial, 96 mice were infected intracisternally with 10(7) CFU/ml Streptococcus pneumoniae serotype 3, treated with intraperitoneal ceftriaxone at 20 h, and randomly assigned to intraperitoneal adjunctive treatment with placebo (saline), dexamethasone, anti-C5 antibodies, or dexamethasone plus anti-C5 antibodies. The primary outcome was survival during a 72-h observational period that was analyzed with the log-rank test. Secondary outcome was clinical severity, scored on a validated scale using a linear mixed model.

Results: Mortality rates were 16 of 16 mice (100%) in the placebo group, 12 of 15 mice (80%) in the dexamethasone group, 25 of 31 mice (80%) in the anti-C5 antibody group, and 18 of 30 mice (60%) in the dexamethasone plus anti-C5 antibody group (Fisher's exact test for overall difference, P = .012). Mortality of mice treated with dexamethasone plus anti-C5 antibodies was lower compared to the anti-C5 antibody-treated mice (log-rank P = .039) and dexamethasone-treated mice (log-rank P = .040). Clinical severity scores for the dexamethasone plus anti-C5 antibody-treated mice increased more slowly (0.199 points/h) as compared to the anti-C5 antibody-treated mice (0.243 points/h, P = .009) and dexamethasone-treated mice (0.249 points/h, P = .012). Modeling of severity data suggested an additive effect of dexamethasone and anti-C5 antibodies.

Conclusion: Adjunctive treatment with dexamethasone plus anti-C5 antibodies improves survival in severe experimental meningitis caused by S. pneumoniae serotype 3, posing an important new treatment strategy for patients with pneumococcal meningitis.

No MeSH data available.


Related in: MedlinePlus

C5b-9 is expressed in brain during experimental pneumococcal meningitis. C5b-9 (μg/mg) protein levels in brain of WT mice inoculated with sterile saline (n = 6) or 107 CFU/ml of S. pneumoniae serotype 3 (n = 24) and sacrificed at 6 or 24 h post inoculation. Mice with pneumococcal meningitis showed increased brain C5b-9 levels compared to saline-inoculated mice at 24 h after inoculation (median 0.78 vs. 2.53 μg/mg tissue, Mann-Whitney U test P = .001). Lines represent median values
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Fig1: C5b-9 is expressed in brain during experimental pneumococcal meningitis. C5b-9 (μg/mg) protein levels in brain of WT mice inoculated with sterile saline (n = 6) or 107 CFU/ml of S. pneumoniae serotype 3 (n = 24) and sacrificed at 6 or 24 h post inoculation. Mice with pneumococcal meningitis showed increased brain C5b-9 levels compared to saline-inoculated mice at 24 h after inoculation (median 0.78 vs. 2.53 μg/mg tissue, Mann-Whitney U test P = .001). Lines represent median values

Mentions: Bacterial meningitis was confirmed in all mice infected with S. pneumoniae serotype 3 by determination of CFU in brain homogenates, showing similar bacterial titers per time-point (data not shown). C5b-9 levels were determined in brain homogenates of these 30 mice. Mice with pneumococcal meningitis showed increased brain C5b-9 levels compared to saline-inoculated mice at 24 h after inoculation (median 0.78 vs. 2.53 μg/mg tissue, P = .001; Fig. 1).Fig. 1


Adjuvant treatment with dexamethasone plus anti-C5 antibodies improves outcome of experimental pneumococcal meningitis: a randomized controlled trial.

Kasanmoentalib ES, Valls Seron M, Morgan BP, Brouwer MC, van de Beek D - J Neuroinflammation (2015)

C5b-9 is expressed in brain during experimental pneumococcal meningitis. C5b-9 (μg/mg) protein levels in brain of WT mice inoculated with sterile saline (n = 6) or 107 CFU/ml of S. pneumoniae serotype 3 (n = 24) and sacrificed at 6 or 24 h post inoculation. Mice with pneumococcal meningitis showed increased brain C5b-9 levels compared to saline-inoculated mice at 24 h after inoculation (median 0.78 vs. 2.53 μg/mg tissue, Mann-Whitney U test P = .001). Lines represent median values
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4536776&req=5

Fig1: C5b-9 is expressed in brain during experimental pneumococcal meningitis. C5b-9 (μg/mg) protein levels in brain of WT mice inoculated with sterile saline (n = 6) or 107 CFU/ml of S. pneumoniae serotype 3 (n = 24) and sacrificed at 6 or 24 h post inoculation. Mice with pneumococcal meningitis showed increased brain C5b-9 levels compared to saline-inoculated mice at 24 h after inoculation (median 0.78 vs. 2.53 μg/mg tissue, Mann-Whitney U test P = .001). Lines represent median values
Mentions: Bacterial meningitis was confirmed in all mice infected with S. pneumoniae serotype 3 by determination of CFU in brain homogenates, showing similar bacterial titers per time-point (data not shown). C5b-9 levels were determined in brain homogenates of these 30 mice. Mice with pneumococcal meningitis showed increased brain C5b-9 levels compared to saline-inoculated mice at 24 h after inoculation (median 0.78 vs. 2.53 μg/mg tissue, P = .001; Fig. 1).Fig. 1

Bottom Line: We compared adjunctive treatment with placebo, dexamethasone, anti-C5 antibodies, and the combination of dexamethasone plus anti-C5 antibodies in experimental pneumococcal meningitis.Modeling of severity data suggested an additive effect of dexamethasone and anti-C5 antibodies.Adjunctive treatment with dexamethasone plus anti-C5 antibodies improves survival in severe experimental meningitis caused by S. pneumoniae serotype 3, posing an important new treatment strategy for patients with pneumococcal meningitis.

View Article: PubMed Central - PubMed

Affiliation: Center for Immunity and Infection (CINIMA): Department of Neurology, Center for Immunity and Infection (CINIMA), Academic Medical Center, University of Amsterdam, PO Box 22660, 1100DD, Amsterdam, The Netherlands. e.s.kasanmoentalib@amc.nl.

ABSTRACT

Background: We compared adjunctive treatment with placebo, dexamethasone, anti-C5 antibodies, and the combination of dexamethasone plus anti-C5 antibodies in experimental pneumococcal meningitis.

Methods: In this prospective, investigator-blinded, randomized trial, 96 mice were infected intracisternally with 10(7) CFU/ml Streptococcus pneumoniae serotype 3, treated with intraperitoneal ceftriaxone at 20 h, and randomly assigned to intraperitoneal adjunctive treatment with placebo (saline), dexamethasone, anti-C5 antibodies, or dexamethasone plus anti-C5 antibodies. The primary outcome was survival during a 72-h observational period that was analyzed with the log-rank test. Secondary outcome was clinical severity, scored on a validated scale using a linear mixed model.

Results: Mortality rates were 16 of 16 mice (100%) in the placebo group, 12 of 15 mice (80%) in the dexamethasone group, 25 of 31 mice (80%) in the anti-C5 antibody group, and 18 of 30 mice (60%) in the dexamethasone plus anti-C5 antibody group (Fisher's exact test for overall difference, P = .012). Mortality of mice treated with dexamethasone plus anti-C5 antibodies was lower compared to the anti-C5 antibody-treated mice (log-rank P = .039) and dexamethasone-treated mice (log-rank P = .040). Clinical severity scores for the dexamethasone plus anti-C5 antibody-treated mice increased more slowly (0.199 points/h) as compared to the anti-C5 antibody-treated mice (0.243 points/h, P = .009) and dexamethasone-treated mice (0.249 points/h, P = .012). Modeling of severity data suggested an additive effect of dexamethasone and anti-C5 antibodies.

Conclusion: Adjunctive treatment with dexamethasone plus anti-C5 antibodies improves survival in severe experimental meningitis caused by S. pneumoniae serotype 3, posing an important new treatment strategy for patients with pneumococcal meningitis.

No MeSH data available.


Related in: MedlinePlus