Adjunctive daptomycin attenuates brain damage and hearing loss more efficiently than rifampin in infant rat pneumococcal meningitis.
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.
Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Switzerland.
Denis
D
Grandgirard
Melchior
M
Burri
Philipp
P
Agyeman
Stephen L
SL
Leib
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001925:Brain Damage, Chronic / Q000517:prevention & control*; D002443:Ceftriaxone / Q000627:therapeutic use*; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D017576:Daptomycin / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D034381:Hearing Loss / Q000517:prevention & control* / Q000821:virology; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000188:drug therapy; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000382:microbiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012293:Rifampin / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D018925:Chemokines; D016207:Cytokines; D002443:Ceftriaxone; D017576:Daptomycin; D012293:Rifampin