Combination of Daptomycin plus Ceftriaxone Is More Active than Vancomycin plus Ceftriaxone in Experimental Meningitis after Addition of Dexamethasone

Abstract

We examined the cerebrospinal fluid penetration of daptomycin after the addition of dexamethasone and its bactericidal efficacy with and without ceftriaxone in an experimental rabbit model of pneumococcal meningitis. The combination of daptomycin with ceftriaxone was the most efficacious regimen for pneumococcal meningitis. The previous addition of dexamethasone affected the antibacterial activity of daptomycin only marginally, either as monotherapy or combined with ceftriaxone, although the penetration of daptomycin into inflamed meninges was significantly reduced from 6 to 2%. Daptomycin with ceftriaxone might be a potential candidate for the empirical therapy of bacterial meningitis, although the activity of this regimen against Listeria monocytogenes remains to be demonstrated.The worldwide continuous spread of penicillin-resistant pneumococci represents one of the major challenges for clinicians and infectiologists. The epidemiological situation in Europe varies considerably with a global tendency of increasing penicillin resistance rates from 6% in 1997 to 22% in 1999 (8). In the United States and Canada, the combined rate of penicillin intermediate plus resistant strains varied between 24% and 67% as reported in the multinational SENTRY antimicrobial resistance surveillance program (5). Based on a recent study, the rates of highly resistant strains were 14.7%, 12.7%, and 15.9% for Europe, Latin America, and North America, respectively (9). In adults, pneumococci are the most frequent pathogens causing meningitis (1, 11). In meningitis due to highly resistant strains, high-dose vancomycin has been recommended, either alone or in combination with third-generation cephalosporins (1,14). In adults, the addition of steroids, now established as standard adjunctive therapy, reduces the penetration of vancomycin into the cerebrospinal fluid (CSF) by 29% (10, 12).We have previously shown that daptomycin, a cyclic lipopeptide, was very efficacious in experimental pneumococcal meningitis due to a penicillin-resistant strain and managed to sterilize the CSF samples of all rabbits at the end of the experimental period. Little is known about the effect of dexamethasone, as standard adjunctive treatment in bacterial meningitis, on the meningeal penetration and efficacy of daptomycin. The aim of this study was first to test the effect of dexamethasone on the penetration of daptomycin into inflamed meninges and second to compare the activity of the different regimens after the addition of dexamethasone in pneumococcal meningitis due to a penicillin-resistant strain. The comparator regimen was ceftriaxone combined with vancomycin, which is the standard empirical regimen. MATERIALS AND METHODSPneumococcal strain. The pneumococcal strain Streptococcus pneumoniae WB4 was isolated from a patient at the Inselspital in Bern, Switzerland, and has been routinely used in this experimental model. The MICs for this strain were as follows: 4 mg/liter for penicillin, 0.5 mg/liter for ceftriaxone, 0.12 to 0.25 mg/liter for vancomycin, a...

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

“…Treatment with daptomycin led to lower levels of inflammatory cytokines and possibly to less cortical brain damage and neuronal apoptosis than those for treatment with ceftriaxone alone (176,177). Although adjunctive treatment with dexamethasone did not result in a reduction of overall pneumococcal clearance from the CSF, daptomycin penetration into the inflamed meninges was reduced in the presence of adjunctive corticosteroid therapy (136).…”

Pharmacokinetics of Single-Dose Daptomycin in Patients with Suspected or Confirmed Neurological Infections

“…Furthermore, Gerber et al revealed that in a methicillin-susceptible S. aureus (MSSA) rabbit meningitis model the penetration of a single dose of 15 mg/kg of daptomycin was 5% into inflamed meninges versus 2% into noninflamed meninges (16). The addition of dexamethasone significantly reduced the penetration from 6% to 2% after a single 15-mg/kg dose of daptomycin into a rabbit pneumococcal meningitis model (12). Most recently, Riser et al reported on the CSF penetration of daptomycin dosed at 9 mg/kg/day in a 54-year-old patient with suspected MSSA meningitis.…”

Adjunctive Daptomycin Attenuates Brain Damage and Hearing Loss More Efficiently than Rifampin in Infant Rat Pneumococcal Meningitis

“…Meanwhile, rifampin and clindamycin reduced the release of lipoteichoic acid and had a neuroprotective effect in an experimental rabbit model of pneumococcal meningitis (9,10). Furthermore, pretreatment with rifampin 1 h prior to ceftriaxone therapy limited the extent of brain injury (59), and the combination of daptomycin with ceftriaxone was shown to be more active than vancomycin plus ceftriaxone (18) in experimental pneumococcal meningitis in rabbits.…”