Daptomycin Produces an Enhanced Bactericidal Activity Compared to Ceftriaxone, Measured by [ ³ H]Choline Release in the Cerebrospinal Fluid, in Experimental Meningitis Due to a Penicillin-Resistant Pneumococcal Strain without Lysing Its Cell Wall

Abstract

Daptomycin monotherapy was superior to ceftriaxone monotherapy and was highly efficacious in experimental pneumococcal meningitis, sterilizing the cerebrospinal fluid (CSF) of three of three rabbits after 4 to 6 h. With daptomycin therapy only a negligible release of [3H]choline as marker of cell wall lysis was detectable in the CSF, peaking around 250 cpm/min after 4 h, compared to a peak of around 2,400 cpm/min after 4 to 6 h for the ceftriaxone-treated rabbits.

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

“…For animals in the daptomycin-ceftriaxone treatment arm, a significant reduction in weight loss was noted compared to the other two treatment arms. This is likely due to a decrease in the release of cytokines and chemokines and subsequent reduction in systemic inflammation (27,60). Taken together, the present results are in accord with our previous findings that daptomycin monotherapy leads to a reduction of proinflammatory cytokines and attenuation of neuronal damage compared to ceftriaxone monotherapy in experimental pneumococcal meningitis (26).…”

“…The two most extensively studied nonbacteriolytic antibiotics in experimental meningitis are daptomycin (DAP), a cyclic lipopeptide, which disrupts cell membrane function and cell wall metabolism (6), and rifampin (RIF), which inhibits protein synthesis by inhibition of the DNA-dependent RNA polymerase (65). Both antibiotics reduce the release of bacterial cell components or toxins in vitro (15,59) and in vivo (59,60). Several experimental animal studies exploring the use of these nonlytic antibiotics in pneumococcal bacterial meningitis have demonstrated their beneficial effects.…”

“…While bacterial components are continuously released during the natural course of pneumococcal meningitis, antimicrobial therapy with expanded-spectrum cephalosporins (i.e., ceftriaxone [CRO] and cefotaxime) results in rapid bacterial cell lysis and a sudden release of large amounts of microbial components (46,60). Thus, an overshooting host-mediated inflammatory reaction, which contributes to brain damage, is elicited at the beginning of the antimicrobial therapy.…”

Attenuation of Cerebrospinal Fluid Inflammation by the Nonbacteriolytic Antibiotic Daptomycin versus That by Ceftriaxone in Experimental Pneumococcal Meningitis

“…It has also recently been shown to bind to YycG, interfering with the function of this key sensor kinase, leading to cell death without lysis (1). Accordingly, the release of [ 3 H]choline from the cell wall of labeled bacteria was diminished in daptomycin-treated rabbits in comparison to results with ceftriaxone during experimental pneumococcal meningitis (18). In the present experimental model, treatment with daptomycin compared to that with ceftriaxone led to a more rapid decrease in CSF bacterial titers and a reduction in the occurrence of cortical neuronal injury (7).…”

Treatment of Drug-resistant Pneumococcal Meningitis

“…Daptomycin is also a nonbacteriolytic agent that may be beneficial in bacterial meningitis by preventing release of proinflammatory mediators (teichoic acid and lipoteichoic acid in pneumococci) following antimicrobial-induced lysis. In a rabbit model of penicillinresistant pneumococcal meningitis, release of [ 3 H] choline, a main component of teichoic acid and lipoteichoic acid, was only mildly elevated with no morphologic changes in the pneumococcal cell wall after treatment with daptomycin, compared to drastic increases in [ 3 H] choline and cell wall morphologic changes after treatment with ceftriaxone [51]. In another study comparing ceftriaxone to daptomycin in infant rats with pneumococcal meningitis, 7 of 28 animals treated with ceftriaxone had cortical brain damage compared to none of the 30 animals treated with daptomycin [52].…”