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


CONCLUSIONS
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.
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.
E Soemirien
ES
Kasanmoentalib
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. m.vallsseron@amc.nl.
Mercedes
M
Valls Seron
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales, UK. MorganBP@cardiff.ac.uk.
B Paul
BP
Morgan
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. m.c.brouwer@amc.nl.
Matthijs C
MC
Brouwer
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. d.vandebeek@amc.uva.nl.
Diederik
D
van de Beek
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003182:Complement C5 / Q000276:immunology*; D003907:Dexamethasone / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D008297:Male; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013534:Survival
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D003182:Complement C5; D003907:Dexamethasone