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Infection and Immunity, July 2006, p. 3890-3896, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.01949-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Damian N. Meli,¹ Roney S. Coimbra,¹ Dominik G. Erhart,¹ Gerard Loquet,² Caroline L. Bellac,¹ Martin G. Täuber,¹ Ulf Neumann,³ and Stephen L. Leib^1*

Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, P.O. Box 61, CH-3010 Bern, Switzerland,¹ Department of Medicine, Unit of Physiology, University of Fribourg, Fribourg, Switzerland,² Novartis Institute for Biomedical Research, Basel, Switzerland³

Received 30 November 2005/ Returned for modification 12 January 2006/ Accepted 22 March 2006

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 µM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.

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* Corresponding author. Mailing address: Institute for Infectious Diseases, Friedbuehlstrasse 51, P.O. Box 61, 3010 Bern, Switzerland. Phone: 41 31 632 4949. Fax: 41 31 632 3550. E-mail: stephen.leib{at}ifik.unibe.ch.

Editor: F. C. Fang

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Infection and Immunity, July 2006, p. 3890-3896, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.01949-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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