Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis.
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 microM 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.
Meli
Damian N
DN
Institute for Infectious Diseases, Friedbuehlstrasse 51, P.O. Box 61, 3010 Bern, Switzerland.
Coimbra
Roney S
RS
Erhart
Dominik G
DG
Loquet
Gerard
G
Bellac
Caroline L
CL
Täuber
Martin G
MG
Neumann
Ulf
U
Leib
Stephen L
SL
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000382:microbiology* / Q000473:pathology*; D002443:Ceftriaxone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003051:Cochlea / Q000382:microbiology* / Q000473:pathology*; D004318:Doxycycline / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D007279:Injections, Subcutaneous; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000401:mortality*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; D002443:Ceftriaxone; D004318:Doxycycline