Adjunctive daptomycin attenuates brain damage and hearing loss more efficiently than rifampin in infant rat pneumococcal meningitis.

Abstract

Exacerbation of cerebrospinal fluid (CSF) inflammation in response to bacteriolysis by beta-lactam antibiotics contributes to brain damage and neurological sequelae in bacterial meningitis. Daptomycin, a nonlytic antibiotic acting on Gram-positive bacteria, lessens inflammation and brain injury compared to ceftriaxone. With a view to a clinical application for pediatric bacterial meningitis, we investigated the effect of combining daptomycin or rifampin with ceftriaxone in an infant rat pneumococcal meningitis model. Eleven-day-old Wistar rats with pneumococcal meningitis were randomized to treatment starting at 18 h after infection with (i) ceftriaxone (100 mg/kg of body weight, subcutaneously [s.c.], twice a day [b.i.d.]), (ii) daptomycin (10 mg/kg, s.c., daily) followed 15 min later by ceftriaxone, or (iii) rifampin (20 mg/kg, intraperitoneally [i.p.], b.i.d.) followed 15 min later by ceftriaxone. CSF was sampled at 6 and 22 h after the initiation of therapy and was assessed for concentrations of defined chemokines and cytokines. Brain damage was quantified by histomorphometry at 40 h after infection and hearing loss was assessed at 3 weeks after infection. Daptomycin plus ceftriaxone versus ceftriaxone significantly (P < 0.04) lowered CSF concentrations of monocyte chemoattractant protein 1 (MCP-1), MIP-1α, and interleukin 6 (IL-6) at 6 h and MIP-1α, IL-6, and IL-10 at 22 h after initiation of therapy, led to significantly (P < 0.01) less apoptosis, and significantly (P < 0.01) improved hearing capacity. While rifampin plus ceftriaxone versus ceftriaxone also led to lower CSF inflammation (P < 0.02 for IL-6 at 6 h), it had no significant effect on apoptosis and hearing capacity. Adjuvant daptomycin could therefore offer added benefits for the treatment of pediatric pneumococcal meningitis.

• Authors: Denis Grandgirard, Melchior Burri, Philipp Agyeman, Stephen L Leib
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 8 Pg. 4289-95 (Aug 2012) ISSN: 1098-6596 [Electronic] United States
• PMID: 22644021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Chemokines
• Cytokines
• Ceftriaxone
• Daptomycin
• Rifampin

Topics

• Animals
• Anti-Bacterial Agents (therapeutic use)
• Apoptosis (drug effects)
• Brain Damage, Chronic (prevention & control)
• Ceftriaxone (therapeutic use)
• Chemokines (blood)
• Cytokines (blood)
• Daptomycin (therapeutic use)
• Drug Administration Schedule
• Drug Therapy, Combination
• Hearing Loss (prevention & control, virology)
• Inflammation (cerebrospinal fluid, drug therapy)
• Meningitis, Pneumococcal (cerebrospinal fluid, drug therapy, microbiology)
• Random Allocation
• Rats
• Rats, Wistar
• Rifampin (therapeutic use)