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JAC Advance Access published online on September 1, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg417
© 2003 by The British Society for Antimicrobial Chemotherapy
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© 2003 The British Society for Antimicrobial Chemotherapy

Original article

Factors influencing the anti-inflammatory effect of dexamethasone therapy in experimental pneumococcal meningitis

I. Lutsar 1 *, I. R. Friedland 1 , H. S. Jafri 1 , L. Wubbel 1 , A. Ahmed 1 , M. Trujillo 1 , C. C. McCoig 1 , and G. H. McCracken Jr 1

1 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA

* Corresponding author. E-mail: irja_lutsar{at}sandwich.pfizer.com.

Received 11 January 2003 ; revised 14 July 2003 ; accepted 15 July 2003

Abstract

Dexamethasone (DXM) interferes with the production of tumour necrosis factor-{alpha} (TNF-{alpha}) and interleukin-1 (IL-1) and can thereby diminish the secondary inflammatory response that follows initiation of antibacterial therapy. A beneficial effect on the outcome of Haemophilus meningitis in children has been proven, but until recently the effect of DXM therapy in pneumococcal meningitis was uncertain. The aim of the present study was to evaluate factors that might influence the modulatory effect of DXM on the antibiotic-induced inflammatory response in a rabbit model of pneumococcal meningitis. DXM (1 mg/kg) was given intravenously 30 min before or 1 h after administration of a pneumococcal cell wall extract, or the first dose of ampicillin. In meningitis induced by cell wall extract, DXM therapy prevented the increase in cerebrospinal fluid (CSF) leucocyte and lactate concentrations, but only if given 30 min before the cell wall extract. In meningitis caused by live organisms, initiation of ampicillin therapy resulted in an increase in CSF TNF-{alpha} and lactate concentrations only in animals with initial CSF bacterial concentrations >=5.6 log10 cfu/mL. In those animals, DXM therapy prevented significant elevations in CSF TNF-{alpha} [median change -184 pg/mL, -114 pg/mL versus +683 pg/mL with DXM (30 min before or 1 h after ampicillin) versus controls (no DXM), respectively, P = 0.02] and lactate concentrations [median change -10.6 mmol/L, -1.5 mmol/L versus +14.3 mmol/L with DXM (30 min before or 1 h after ampicillin) versus controls (no DXM), respectively, P = 0.01]. These effects were independent of the timing of DXM administration. In this model of experimental pneumococcal meningitis, an antibiotic-induced secondary inflammatory response in the CSF was demonstrated only in animals with high initial CSF bacterial concentrations (>=5.6 log10 cfu/mL). These effects were modulated by DXM therapy whether it was given 30 min before or 1 h after the first dose of ampicillin.

Keywords: animal models, CSF, experimental meningitis, inflammatory response, S. pneumoniae
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