Pharmacokinetics and pharmacodynamics of antibiotics in meningitis
1Department of Medicine, University of Wisconsin Medical School, Madison, USA. drandes@facstaff.wisc.edu
Abstract:
The penetration of antimicrobials into the CSF is dependent on lipid solubility, molecular size, capillary and choroid plexus efflux pumps, protein binding, and the degree of inflammation. Penicillins, certain cephalosporins, carbapenems, fluoroquinolones, vancomycin, and rifampin provide the highest ratios of CSF levels to the MBC for common infecting organisms. For beta-lactam antibiotics, it is the duration of time that CSF concentrations exceed the MBC that determines the rate of bactericidal activity. It appears that levels should exceed the MBC for more than 50% of the dosing interval. The peak/MBC and AUC/MBC ratios are important determinants of efficacy for aminoglycosides and fluoroquinolones. Once-daily dosing of aminoglycosides is as effective as multiple-daily dosing regimens in experimental meningitis, probably because of drug-induced prolonged persistent effects. Fluoroquinolones do not produce as prolonged persistent effects and are slightly less effective when administered once daily. Although steroid use can reduce the penetration and decrease the bactericidal activity of some antimicrobials, such as vancomycin, in experimental meningitis, the clinical impact of steroid use in human meningitis is still unclear.
Insights
Achieving adequate antimicrobial concentrations in cerebrospinal fluid (CSF) is key for treating meningitis. Optimal dosing strategies, like extended or once-daily regimens, depend on the specific antibiotic and its properties for effective bacterial killing.
Area of Science:
- Pharmacology
- Infectious Diseases
- Neuroscience
Background:
- Cerebrospinal fluid (CSF) penetration by antimicrobials is crucial for treating central nervous system infections like meningitis.
- Factors influencing antimicrobial penetration include lipid solubility, molecular size, efflux pumps, protein binding, and inflammation.
Purpose of the Study:
- To review the penetration of various antimicrobials into the CSF.
- To discuss the pharmacokinetic/pharmacodynamic (PK/PD) targets for achieving bactericidal activity.
- To evaluate the efficacy of different dosing strategies for common antimicrobial classes.
Main Methods:
- Literature review of antimicrobial penetration and efficacy in meningitis models.
- Analysis of PK/PD parameters such as CSF/MIC ratios and time above MIC.
- Comparison of once-daily versus multiple-daily dosing regimens for specific antibiotic classes.
Main Results:
- Penicillins, cephalosporins, carbapenems, fluoroquinolones, vancomycin, and rifampin show high CSF penetration relative to the minimum bactericidal concentration (MBC).
- For beta-lactams, maintaining CSF concentrations above the MBC for >50% of the dosing interval is critical.
- Once-daily aminoglycoside dosing is effective in experimental meningitis due to prolonged effects, while fluoroquinolones are less effective with this regimen.
Conclusions:
- Optimizing antimicrobial dosing in meningitis requires understanding drug-specific PK/PD properties and CSF penetration.
- Time above MBC is crucial for beta-lactams, while peak/MBC and AUC/MBC ratios are important for aminoglycosides and fluoroquinolones.
- Further research is needed to clarify the clinical impact of steroid co-administration on antimicrobial efficacy in human meningitis.
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