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Pharmacodynamics and bactericidal activity of ceftriaxone therapy in experimental cephalosporin-resistant
I Lutsar1, A Ahmed, I R Friedland
1Department of Pediatrics, Southwestern Medical Center, Dallas, Texas 75235-9063, USA.
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.
Insights
Achieving effective beta-lactam antibiotic levels in cerebrospinal fluid (CSF) is crucial for treating resistant pneumococcal meningitis. Ceftriaxone
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Meningitis caused by drug-resistant Streptococcus pneumoniae presents challenges in achieving adequate beta-lactam antibiotic concentrations in cerebrospinal fluid (CSF).
- High cephalosporin resistance in S. pneumoniae necessitates optimized antibiotic dosing strategies.
Purpose of the Study:
- To evaluate the efficacy of ceftriaxone in treating experimental pneumococcal meningitis with high cephalosporin resistance.
- To determine the pharmacokinetic-pharmacodynamic (PK-PD) targets for ceftriaxone in CSF and their correlation with bacterial killing.
Main Methods:
- Experimental model of highly cephalosporin-resistant pneumococcal meningitis.
- Administration of ceftriaxone at 150 or 400 mg/kg/day in one or two doses.
- Measurement of bacterial killing rate and PK-PD indices, including T>MBC (time above minimum bactericidal concentration).
Main Results:
- T>MBC in CSF was the sole independent predictor of the bacterial killing rate (r = 0.87; P = 0.004).
- CSF sterilization was achieved only when T>MBC reached 95-100%.
- A higher T>MBC and bacterial killing rate were observed with a 200 mg/kg/12h regimen compared to 400 mg/kg/24h in the initial 24 hours.
Conclusions:
- Ceftriaxone's bactericidal activity against resistant S. pneumoniae is time-dependent, with T>MBC being a critical PK-PD target.
- Optimizing dosing frequency to maximize T>MBC is essential for achieving CSF sterilization in pneumococcal meningitis.
- Twice-daily dosing of ceftriaxone demonstrated superior early bacterial killing compared to once-daily dosing.