Pharmacokinetics and pharmacodynamics of cephalosporins in cerebrospinal fluid

Area of Science:

• Pharmacology
• Infectious Diseases
• Neuroscience

Background:

• Cephalosporins exhibit low lipophilicity, limiting penetration into cerebrospinal fluid (CSF).
• Despite low CSF concentrations, therapeutic levels exceeding minimum bactericidal concentrations (MBCs) are often achievable for common meningeal pathogens.
• Efficacy is compromised in meningitis caused by highly penicillin-resistant Streptococcus pneumoniae.

Purpose of the Study:

• To evaluate the efficacy of cephalosporins in treating bacterial meningitis.
• To determine the pharmacokinetic/pharmacodynamic (PK/PD) targets for cephalosporin therapy in CSF.
• To identify approved cephalosporins for bacterial meningitis treatment.

Main Methods:

• Review of experimental studies on cephalosporin CSF penetration and bactericidal activity.
• Analysis of pharmacokinetic data comparing CSF and serum half-lives.
• Clinical trial efficacy data for advanced generation cephalosporins.

Main Results:

• Cephalosporin CSF concentrations are generally lower than in serum due to poor blood-brain barrier penetration.
• Therapeutic CSF concentrations above MBC are achievable with standard regimens for many pathogens.
• Maximal efficacy requires CSF drug concentrations to exceed MBC for >90% of the dosing interval (t>MBC).
• Longer CSF half-lives (2-3 fold) facilitate achieving target t>MBC values.
• Cefotaxime, ceftriaxone, and ceftazidime are approved for bacterial meningitis.

Conclusions:

• Cephalosporins can be effective in bacterial meningitis if dosing optimizes t>MBC.
• Penicillin-resistant pneumococci pose a challenge for cephalosporin therapy.
• Specific advanced-generation cephalosporins are clinically validated for meningitis treatment.