Experimental pneumococcus infection in mice: comparative in vitro and in vivo effect of cefuroxime, cefotaxime and ceftriaxone
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N Frimodt-Møller1, M W Bentzon, V F Thomsen
1Department of Antibiotics, Statens Seruminstitut, Copenhagen, Denmark.
Abstract:
In a mouse model using intraperitoneal inoculation of Streptococcus pneumoniae type 3, the 50% effective dose, ED50, after single doses one hour post-inoculation was considerably lower for ceftriaxone (CRO) than for cefuroxime (CXM) and cefotaxime (CTX), in spite of the same minimal inhibitory concentration, MIC, of 0.02 mcg/ml against the pneumococcus for all 3 drugs. The bactericidal activity as measured by time-kill curves was similar for the 3 drugs, as was the post-antibiotic effect in vitro. Protein binding in mouse serum was considerably higher for CRO (87%) than for both CTX (35%) and CXM (15%), respectively. Of pharmacokinetic parameters investigated on doses equal to the ED50s, the time the serum antibiotic concentration remained above the MIC (delta T(MIC)) was the factor that varied the least among 3 drugs. Therefore, the superior in vivo effect for CRO is not due to higher intrinsic activity against the pathogen but to the long serum-elimination half-life resulting in an extended delta T(MIC), probably related to the high serum protein binding.
Insights
Ceftriaxone demonstrated superior efficacy against Streptococcus pneumoniae in mice compared to cefuroxime and cefotaxime. This enhanced effectiveness is attributed to ceftriaxone's longer serum-elimination half-life and high protein binding, not increased intrinsic activity.
Area of Science:
- Pharmacology
- Microbiology
- Infectious Diseases
Background:
- Streptococcus pneumoniae is a significant bacterial pathogen.
- Cephalosporin antibiotics like ceftriaxone, cefuroxime, and cefotaxime are used to treat pneumococcal infections.
- Understanding pharmacokinetic and pharmacodynamic differences is crucial for optimizing antibiotic therapy.
Purpose of the Study:
- To compare the in vivo efficacy of ceftriaxone (CRO), cefuroxime (CXM), and cefotaxime (CTX) against Streptococcus pneumoniae in a mouse model.
- To investigate the pharmacokinetic and protein binding characteristics influencing the observed efficacy differences.
Main Methods:
- A mouse model was used with intraperitoneal inoculation of Streptococcus pneumoniae type 3.
- The 50% effective dose (ED50) was determined for single doses administered one hour post-inoculation.
- In vitro bactericidal activity (time-kill curves) and post-antibiotic effect were assessed.
- Serum protein binding and pharmacokinetic parameters, including time above minimum inhibitory concentration (delta T(MIC)), were evaluated.
Main Results:
- Ceftriaxone exhibited a significantly lower ED50 compared to cefuroxime and cefotaxime, despite having the same minimal inhibitory concentration (MIC).
- In vitro bactericidal activity and post-antibiotic effect were similar for all three drugs.
- Ceftriaxone showed substantially higher serum protein binding (87%) compared to cefotaxime (35%) and cefuroxime (15%).
- The time serum antibiotic concentration remained above the MIC (delta T(MIC)) varied least among the drugs at their respective ED50 doses.
Conclusions:
- The superior in vivo efficacy of ceftriaxone against Streptococcus pneumoniae is primarily due to its prolonged serum-elimination half-life and extended delta T(MIC).
- High serum protein binding of ceftriaxone likely contributes to its long half-life and enhanced therapeutic effect.
- Intrinsic antimicrobial activity alone does not fully explain the observed differences in efficacy among these cephalosporins.