title: Pharmacodynamics and bactericidal activity of ceftriaxone therapy in experimental cephalosporin-resistant pneumococcal meningitis.
abstract: Adequate concentrations of beta-lactam antibiotics in cerebrospinal fluid (CSF) are difficult to achieve for meningitis caused by drug-resistant Streptococcus pneumoniae. Ceftriaxone in dosages of 150 or 400 mg/kg of body weight per day, given in one or two doses, was used for the treatment of experimental highly cephalosporin-resistant (MIC and MBC, 4 microg/ml) pneumococcal meningitis. The bacterial killing rate (delta log10 CFU per milliliter per hour) and pharmacokinetic indices, including percentage of time the antibiotic concentration exceeded the MBC during a 24-h period (T>MBC), CSF peak concentration above the MBC, and area under the concentration-time curve from 0 to 24 h above MBC, were measured and correlated. By multiple stepwise regression, only T>MBC independently predicted the bacterial killing rate. There was a direct linear correlation between T>MBC in CSF and the bacterial killing rate during the first 24 h of therapy (r = 0.87; P = 0.004). Sterilization of CSF was achieved only when the T>MBC was 95 to 100%. In the first 24 h, the 200-mg/kg/12-h regimen, compared with the 400-mg/kg/24-h regimen, was associated with a greater T>MBC (87% +/- 10% versus 60% +/- 22%; P = 0.03) and greater bacterial killing rate (0.2 +/- 0.04 versus 0.13 +/- 0.07; P = 0.003), confirming that ceftriaxone exhibits time-dependent bactericidal activity. After 24 h, the T>MBC and the CSF sterilization rates were similar whether ceftriaxone was given once or twice daily.
authors.affiliation: Department of Pediatrics, Southwestern Medical Center, Dallas, Texas 75235-9063, USA.
authors.forename: I
authors.initials: I
authors.lastname: Lutsar
authors.forename: A
authors.initials: A
authors.lastname: Ahmed
authors.forename: I R
authors.initials: IR
authors.lastname: Friedland
authors.forename: M
authors.initials: M
authors.lastname: Trujillo
authors.forename: L
authors.initials: L
authors.lastname: Wubbel
authors.forename: K
authors.initials: K
authors.lastname: Olsen
authors.forename: G H
authors.initials: GH
authors.lastname: McCracken
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002443:Ceftriaxone / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002511:Cephalosporins / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004352:Drug Resistance, Microbial; D006207:Half-Life; D008297:Male; D008586:Meningitis, Pneumococcal / Q000188:drug therapy*; D011817:Rabbits; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D002511:Cephalosporins; D002443:Ceftriaxone