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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

Adjuvant treatment with dexamethasone plus anti-C5 antibodies reduces mortality in experimental pneumococcal meningitis. Kaplan-Meier survival curves of WT mice inoculated with 107 CFU/ml of S. pneumoniae serotype 3 and treated at 20 h after infection with ceftriaxone (100 mg/kg) in combination with adjuvant treatment. Adjuvant treatment consisted of sterile saline (n = 16; “placebo group”), dexamethasone (0.5 mg/kg, n = 15), a neutralizing antibody against C5 (C5-Ab; 1 mg/mouse; clone BB5.1, n = 31), or dexamethasone plus anti-C5 antibodies in previously mentioned doses (n = 30). a Adjuvant treatment with dexamethasone plus anti-C5 antibodies resulted in a significant reduction in mortality compared to placebo (log-rank P < .001), anti-C5 antibodies, (log-rank P = .039), and dexamethasone (log-rank P = .040). b Adjuvant dexamethasone significantly reduced mortality when all treatments with dexamethasone were compared to all treatments without dexamethasone (log-rank P = .024). c Treatments with anti-C5 antibodies significantly reduced mortality when compared to all treatments without anti-C5 antibodies (log-rank P = .006)
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Fig2: Adjuvant treatment with dexamethasone plus anti-C5 antibodies reduces mortality in experimental pneumococcal meningitis. Kaplan-Meier survival curves of WT mice inoculated with 107 CFU/ml of S. pneumoniae serotype 3 and treated at 20 h after infection with ceftriaxone (100 mg/kg) in combination with adjuvant treatment. Adjuvant treatment consisted of sterile saline (n = 16; “placebo group”), dexamethasone (0.5 mg/kg, n = 15), a neutralizing antibody against C5 (C5-Ab; 1 mg/mouse; clone BB5.1, n = 31), or dexamethasone plus anti-C5 antibodies in previously mentioned doses (n = 30). a Adjuvant treatment with dexamethasone plus anti-C5 antibodies resulted in a significant reduction in mortality compared to placebo (log-rank P < .001), anti-C5 antibodies, (log-rank P = .039), and dexamethasone (log-rank P = .040). b Adjuvant dexamethasone significantly reduced mortality when all treatments with dexamethasone were compared to all treatments without dexamethasone (log-rank P = .024). c Treatments with anti-C5 antibodies significantly reduced mortality when compared to all treatments without anti-C5 antibodies (log-rank P = .006)

Mentions: The first animals reached an endpoint at 26 h after infection, and the overall mortality rate during the 72-h observation period was 71 of 92 (77 %). The 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 (Fig. 2a; Fisher’s exact test for overall difference, P = .012). The combination of dexamethasone and anti-C5 antibodies resulted in a significant reduction in mortality compared to placebo (log-rank P < .001), anti-C5 antibodies (log-rank P = .039), and dexamethasone (log-rank P = .040). Adjuvant dexamethasone significantly reduced mortality when all treatments with dexamethasone were compared to all treatments without dexamethasone (mortality rate 67 vs. 87 %, log-rank P = .024; Fig. 2b). Treatments with anti-C5 antibodies significantly reduced mortality when compared to all treatments without anti-C5 antibodies (mortality rate 71 vs. 90 %, log-rank P = .006; Fig. 2c). Clinical severity scores for the dexamethasone plus anti-C5 antibody-treated mice increased slowly as compared to dexamethasone-treated mice (0.199 vs. 0.249 points/h, P = .012), anti-C5 antibody-treated mice (0.199 vs. 0.243 points/h, P = .009), and placebo-treated mice (0.199 vs. 0.293 points/h, P = .001). When analyzing dexamethasone vs. no dexamethasone treatment, a slower increase of the clinical score with time was observed (reduction 0.044 ± 0.018 points/h, P = .013). This effect was independent of anti-C5 antibody treatment that also caused a slower increase of the clinical score with time (reduction 0.050 ± 0.019 points/h, P = .009) compared to no anti-C5 antibody treatment. A model with inclusion of a D*C5*Time interaction did not significantly improve fitting of the data (P = .317). This indicates that the effects of dexamethasone and anti-C5 antibody treatments on clinical score are additive with no synergistic enhancement.Fig. 2


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)

Adjuvant treatment with dexamethasone plus anti-C5 antibodies reduces mortality in experimental pneumococcal meningitis. Kaplan-Meier survival curves of WT mice inoculated with 107 CFU/ml of S. pneumoniae serotype 3 and treated at 20 h after infection with ceftriaxone (100 mg/kg) in combination with adjuvant treatment. Adjuvant treatment consisted of sterile saline (n = 16; “placebo group”), dexamethasone (0.5 mg/kg, n = 15), a neutralizing antibody against C5 (C5-Ab; 1 mg/mouse; clone BB5.1, n = 31), or dexamethasone plus anti-C5 antibodies in previously mentioned doses (n = 30). a Adjuvant treatment with dexamethasone plus anti-C5 antibodies resulted in a significant reduction in mortality compared to placebo (log-rank P < .001), anti-C5 antibodies, (log-rank P = .039), and dexamethasone (log-rank P = .040). b Adjuvant dexamethasone significantly reduced mortality when all treatments with dexamethasone were compared to all treatments without dexamethasone (log-rank P = .024). c Treatments with anti-C5 antibodies significantly reduced mortality when compared to all treatments without anti-C5 antibodies (log-rank P = .006)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Adjuvant treatment with dexamethasone plus anti-C5 antibodies reduces mortality in experimental pneumococcal meningitis. Kaplan-Meier survival curves of WT mice inoculated with 107 CFU/ml of S. pneumoniae serotype 3 and treated at 20 h after infection with ceftriaxone (100 mg/kg) in combination with adjuvant treatment. Adjuvant treatment consisted of sterile saline (n = 16; “placebo group”), dexamethasone (0.5 mg/kg, n = 15), a neutralizing antibody against C5 (C5-Ab; 1 mg/mouse; clone BB5.1, n = 31), or dexamethasone plus anti-C5 antibodies in previously mentioned doses (n = 30). a Adjuvant treatment with dexamethasone plus anti-C5 antibodies resulted in a significant reduction in mortality compared to placebo (log-rank P < .001), anti-C5 antibodies, (log-rank P = .039), and dexamethasone (log-rank P = .040). b Adjuvant dexamethasone significantly reduced mortality when all treatments with dexamethasone were compared to all treatments without dexamethasone (log-rank P = .024). c Treatments with anti-C5 antibodies significantly reduced mortality when compared to all treatments without anti-C5 antibodies (log-rank P = .006)
Mentions: The first animals reached an endpoint at 26 h after infection, and the overall mortality rate during the 72-h observation period was 71 of 92 (77 %). The 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 (Fig. 2a; Fisher’s exact test for overall difference, P = .012). The combination of dexamethasone and anti-C5 antibodies resulted in a significant reduction in mortality compared to placebo (log-rank P < .001), anti-C5 antibodies (log-rank P = .039), and dexamethasone (log-rank P = .040). Adjuvant dexamethasone significantly reduced mortality when all treatments with dexamethasone were compared to all treatments without dexamethasone (mortality rate 67 vs. 87 %, log-rank P = .024; Fig. 2b). Treatments with anti-C5 antibodies significantly reduced mortality when compared to all treatments without anti-C5 antibodies (mortality rate 71 vs. 90 %, log-rank P = .006; Fig. 2c). Clinical severity scores for the dexamethasone plus anti-C5 antibody-treated mice increased slowly as compared to dexamethasone-treated mice (0.199 vs. 0.249 points/h, P = .012), anti-C5 antibody-treated mice (0.199 vs. 0.243 points/h, P = .009), and placebo-treated mice (0.199 vs. 0.293 points/h, P = .001). When analyzing dexamethasone vs. no dexamethasone treatment, a slower increase of the clinical score with time was observed (reduction 0.044 ± 0.018 points/h, P = .013). This effect was independent of anti-C5 antibody treatment that also caused a slower increase of the clinical score with time (reduction 0.050 ± 0.019 points/h, P = .009) compared to no anti-C5 antibody treatment. A model with inclusion of a D*C5*Time interaction did not significantly improve fitting of the data (P = .317). This indicates that the effects of dexamethasone and anti-C5 antibody treatments on clinical score are additive with no synergistic enhancement.Fig. 2

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