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Antimicrobial Agents and Chemotherapy, June 2007, p. 2173-2178, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01014-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Prevention of Brain Injury by the Nonbacteriolytic Antibiotic Daptomycin in Experimental Pneumococcal Meningitis{triangledown}

Denis Grandgirard,1 Christian Schürch,1 Philippe Cottagnoud,2 and Stephen L. Leib1,3*

Institute for Infectious Diseases, University of Bern, Bern, Switzerland,1 Department of Internal Medicine,2 Clinic for Infectious Diseases, University Hospital, Inselspital, Bern, Switzerland3

Received 14 August 2006/ Returned for modification 27 October 2006/ Accepted 10 March 2007

Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response, which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study, antibiotic therapy with nonbacteriolytic daptomycin was compared with that of bacteriolytic ceftriaxone in experimental pneumococcal meningitis, and the treatments were evaluated for their effects on inflammation and brain injury. Eleven-day-old rats were injected intracisternally with 1.3 x 104 ± 0.5 x 104 CFU of Streptococcus pneumoniae serotype 3 and randomized to therapy with ceftriaxone (100 mg/kg of body weight subcutaneously [s.c.]; n = 55) or daptomycin (50 mg/kg s.c.; n = 56) starting at 18 h after infection. The cerebrospinal fluid (CSF) was assessed for bacterial counts, matrix metalloproteinase-9 levels, and tumor necrosis factor alpha levels at different time intervals after infection. Cortical brain damage was evaluated at 40 h after infection. Daptomycin cleared the bacteria more efficiently from the CSF than ceftriaxone within 2 h after the initiation of therapy (log10 3.6 ± 1.0 and log10 6.3 ± 1.4 CFU/ml, respectively; P < 0.02); reduced the inflammatory host reaction, as assessed by the matrix metalloproteinase-9 concentration in CSF 40 h after infection (P < 0.005); and prevented the development of cortical injury (cortical injury present in 0/30 and 7/28 animals, respectively; P < 0.004). Compared to ceftriaxone, daptomycin cleared the bacteria from the CSF more rapidly and caused less CSF inflammation. This combined effect provides an explanation for the observation that daptomycin prevented the development of cortical brain injury in experimental pneumococcal meningitis. Further research is needed to investigate whether nonbacteriolytic antibiotic therapy with daptomycin represents an advantageous alternative over current bacteriolytic antibiotic therapies for the treatment of pneumococcal meningitis.

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

{triangledown} Published ahead of print on 19 March 2007.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2173-2178, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01014-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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