Pharmacokinetics and Pharmacodynamics of Cephalosporins in Cerebrospinal Fluid
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Largely because of their low lipophilicity, cephalosporins poorly penetrate through the blood-brain barrier, achieving relatively low cerebrospinal fluid (CSF) concentrations. However, the minimum bactericidal concentrations (MBCs) of the extended spectrum cephalosporins for common meningeal pathogens are generally low; thus, therapeutic CSF drug concentrations several-fold greater than the MBC can be achieved with currently recommended dosage regimens. However, the effectiveness of cephalosporin therapy is unreliable in patients with meningitis caused by highly penicillin-resistant pneumococci.
As in other body sites, the bactericidal activity of cephalosporins in CSF predominantly depends on the time their concentrations exceed the MBC of infecting organisms (t>mbc). Experimental studies show that, for maximal efficacy, t>mbc values greater than 90% of the dosage interval are required in meningitis. Such values are usually achieved in humans with currently recommended dosage regimens because the half-lives of cephalosporins are 2- to 3-fold longer in CSF than in serum.
Several advanced generation cephalosporins have shown equal efficacy in clinical trials, but only cefotaxime, ceftriaxone and ceftazidime are currently approved for the treatment of patients with bacterial meningitis.