[Pharmacodynamics of antibiotics in CSF: principles and consequences (predictive factors of efficacy)].
The rational selection of antibiotics for the treatment of meningitis must take into account several criteria, among which their intrinsic activity against the causative bacteria, and their pharmacokinetic and pharmacodynamic properties. The intrinsic activity is evaluated by the Minimal Inhibitory Concentration (MIC), which, however, does not give any information on the bactericidal potency of the drug (important property for infections localized in compartments with low immune defense such as the CSF). The capacity of the antibiotic to reach the infected compartment depends on its physicochemical properties (molecular weight, lipophilicity) and its protein binding capacity, but also on the properties of the blood-CSF barrier (permeability modulated by inflammation and activity of active transporters). Pharmacodynamics correlate intrinsic activity to pharmacokinetics by determining the optimal value of the ratio between MIC and time of exposure, area under the curve, or peak concentration. On these bases, beta-lactams appear as first-line antibiotics, if used with large and repeated doses (or even as a continuous infusion), because of their time-dependent activity. The choice of the molecule is based on the susceptibility of the bacterium. Potential alternatives include chloramphenicol (limited however by its toxicity), moxifloxacin (showing high bactericidal effect, a low MIC, and appropriate penetration) but little clinically documented, linezolid and vancomycin for Methicillin-Resistant Staphylococcus aureus (MRSA), and vancomycin for penicillin non-susceptible pneumococci. Other molecules in clinical development are being evaluated for this indication.
Van Bambeke
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Unité de pharmacologie cellulaire et moléculaire, UCL7370 ,73, avenue Mounier, 1200 Bruxelles, Belgique. vanbambeke@facm.ucl.ac.be
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D000081:Acetamides / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001692:Biological Transport; D006801:Humans; D000069349:Linezolid; D016920:Meningitis, Bacterial / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D016106:Methicillin Resistance; D023303:Oxazolidinones / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D012995:Solubility; D013203:Staphylococcal Infections / Q000134:cerebrospinal fluid / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000627:therapeutic use; D047090:beta-Lactams / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D047090:beta-Lactams; D014640:Vancomycin; D000069349:Linezolid