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.

Evaluation of a triple-drug combination for treatment of experimental multidrug-resistant pneumococcal meningitis

“…Since the strain used in the experiment was highly resistant to ceftriaxone, peak CSF concentrations of ceftriaxone were lower than the MBC of the strain. By pharmacodynamic analysis, sterilization of CSF by ceftriaxone could be achieved only when the time above MBC (T > MBC) was 95-100% of the dosing interval [6]. This was the basic reason for poor therapeutic efficacy of ceftriaxone alone in our study.…”

Clinical significance of cerebrospinal fluid inhibitory titers of antibiotics, based on pharmacokinetic/pharmacodynamic parameters, in the treatment of bacterial meningitis

“…In humans, an approximate indicator of the T 1/2 (CSF) is two-to threefold the T 1/2 (serum) value. 1,2 According to the package inserts of the following drugs, the T 1/2 (serum) values are as follows: ampicillin, 0.7 h; piperacillin, 0.7 h; cefotaxime, 0.8 h; panipenem/betamipron, 1.2 h; and meropenem, 1 h. If the CSF-IT is 1 : 32, the antibiotic concentration in the CSF exceeds the MIC for 24 h after q.i.d. or t.i.d.…”

“…Concentrations of antibiotics in CSF are not always parallel to concentrations in serum, because the elimination half-life (T 1/2 ) of an antibiotic in CSF is two-to threefold longer than the T 1/2 in serum, as seen in a rabbit model. 1,2 With respect to bacterial infections, the relationships between pharmacokinetic (PK) and pharmacodynamic (PD) parameters have been used to estimate the effi cacy of antimicrobial agents in several models. In general, the efficacy of antimicrobial agents such as beta-lactam antibiotics has been represented in terms of time above MIC.…”

Bactericidal activities of parenteral antibiotics and genotype of penicillin-binding protein in Streptococcus pneumoniae and Haemophilus influenzae isolated from children's blood

“…Alternatively, it is thought that the percentage of time that the cerebrospinal fluid antibiotic concentration exceeds the MBC is related to the clinical effect. 14 The MBC is a more important index than the MIC in the treatment of severe bacterial infection such as meningitis. Because measurement of the MBC is difficult in a normal laboratory examination, the antibiotics used are selected on assumptions based on the MIC results.…”