title: Experimental study of LY333328 (oritavancin), alone and in combination, in therapy of cephalosporin-resistant pneumococcal meningitis.
abstract: Using a rabbit model of meningitis, we sought to determine the efficacy of LY333328, a semisynthetic glycopeptide, in the treatment of cephalosporin-resistant pneumococcal meningitis. LY333328 was administered at a dose of 10 mg/kg of body weight/day, alone and in combination with ceftriaxone at 100 mg/kg/day with or without dexamethasone at 0.25 mg/kg/day. The therapeutic groups were treated with LY333328 with or without dexamethasone and LY333328-ceftriaxone with or without dexamethasone. Rabbits were inoculated with a cephalosporin-resistant pneumococcal strain (ceftriaxone MIC, 2 microg/ml; penicillin MIC, 4 microg/ml; LY333328 MIC, 0.008 microg/ml) and were treated over a 26-h period beginning 18 h after inoculation. The bacterial counts in cerebrospinal fluid (CSF), the white blood cell count, the lactic acid concentration, the CSF LY333328 concentration, and bactericidal and bacteriostatic activities were determined at different time points. In vitro, LY333328 was highly bactericidal and its use in combination with ceftriaxone at one-half the MIC was synergistic. In the rabbit model, LY333328 alone was an excellent treatment for cephalosporin-resistant pneumococcal meningitis, with a rapid decrease in colony counts and no therapeutic failures. The use of LY333328 in combination with ceftriaxone improved the activity of LY333328, but no synergistic effect was observed. The combination of LY333328 with dexamethasone was also rapidly bactericidal, but two therapeutic failures were observed. The combination of LY333328 with ceftriaxone and dexamethasone was effective, without therapeutic failures.
authors.affiliation: Experimental Infection Laboratory, Infectious Diseases Service, Ciutat Sanitària i Universitària de Bellvitge, c/Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain. ccabellos@csub.scs.es
authors.forename: Carmen
authors.initials: C
authors.lastname: Cabellos
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernàndez
authors.forename: Jose M
authors.initials: JM
authors.lastname: Maiques
authors.forename: Fe
authors.initials: F
authors.lastname: Tubau
authors.forename: Carmen
authors.initials: C
authors.lastname: Ardanuy
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Viladrich
authors.forename: Josefina
authors.initials: J
authors.lastname: Liñares
authors.forename: Francesc
authors.initials: F
authors.lastname: Gudiol
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology*; D018550:Cephalosporin Resistance; D015169:Colony Count, Microbial; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000494:pharmacology*; D005260:Female; D006020:Glycopeptides; D019344:Lactic Acid / Q000134:cerebrospinal fluid; D007958:Leukocyte Count; D000077427:Lipoglycopeptides; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D014640:Vancomycin / Q000031:analogs & derivatives
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002443:Ceftriaxone; D003907:Dexamethasone; D006020:Glycopeptides; D019344:Lactic Acid; D000077427:Lipoglycopeptides; C100708:oritavancin; D014640:Vancomycin