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Have you ever noticed how the indicated dosages for antimicrobials increase for CNS infections? This is because antimicrobials have a difficult time penetrating the blood brain barrier and the blood-CSF barrier, leading to difficulty of some antimicrobials to achieve therapeutic concentration levels in the CSF to properly treat a CNS infection.

(Bhaskar et al. 2010.)

Disclaimer: the penetration of antimicrobials into the CSF is much more complicated than three columns and a list of antibiotics. It’s been shown that levels of drugs differ between ventricular, cisternal, and lumbar CSF. Additionally, the treatment of CNS infections depends on more than just the CNS penetration of a certain antimicrobial, thus if any questions arise, please discuss with your ID consultants and ID pharmacists.

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For the sake of this review, we will keep it simple.

Antimicrobials can be broken down into 3 rough categories:

Excellent/Good penetration of the CSF Good penetration only in inflamed meninges Poor penetration of the CSF Fluoroquinolones Glycopeptides (vancomycin) Beta-lactams3 TMP/SMX Macrolides (azithromycin) Aminoglycosides Metronidazole Rifampin Tetracyclines (doxy, tigecycline) Chloramphenicol Ethambutol Clindamycin4 Fosfomycin1 Daptomycin Isoniazid Colistin Pyrazinamide Fusion inhibitors (enfurvitide) Zidovudine Tenofovir 5-flucytosine Amphotericin B5 Voriconazole/fluconazole Echinocandins Pyrimethamine Itraconazole/posaconazole Atovaquone?2 Albendazole >>> Praziquantel

1 only FDA-approved for UTI treatment 2 no studies have been published looking at CNS penetration; however has been used successfully in clinical CNS infections 3 overcome by increase in dosages – higher dosages of beta-lactams obtain adequate levels in the CSF and tend to be 1st line agents in bacterial meningitis due to their efficacy and bactericidal properties 4 however has been shown to effectively treat susceptible CNS infections 5 however clinical trials have shown good outcomes when used in treatment of CNS infections

*If the class of drug was not mentioned in this list, it is likely because no studies have been done to assess CNS penetration of that drug.

Why are beta-lactams recommended for empiric bacterial meningitis treatment?

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Despite the poor CSF penetration, beta-lactams have the most research documenting successful treatment of community-acquired meningitis compared to other antibiotic classes.

• When the beta-lactam dose is increased, CNS penetration increases.
• Beta-lactams are well-tolerated even at high dosages
• Ceftriaxone treats S. pneumoniae, N. meningitidis, H.influenzae, and many aerobic gram-negatives such as E.coli and K. pneumoniae.

*Vancomycin is added to empiric regimens to treat the ceftriaxone-resistant S. pneumoniae strains that have been seen in community-acquired meningitis.

(IDSA practice guidelines for Bacterial Meningitis, 2004.)

TAKE HOME POINTS:

• Not all antimicrobials penetrate the BBB. Take into account an antimicrobial’s CNS penetration properties when treating CNS infections
• Beta-lactams are still 1st line therapy for empiric meningitis treatment due to their efficacy against the most common pathogens and ability to achieve high levels with increased doses of the medication
• When treating CNS infections, deviation from the guidelines warrants involvement of the ID pharmacist and the ID consult team to ensure the best treatment regimen for the patient

References:

1. Bhaskar, S., Tian, F. et al. (2010). Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: Perspectives on tracking and neuroimaging. Particle and fibre toxicology. 7(1)3. DOI: 10.1186/1743-8977-7-3. 2. Nau, R., Sorgel, F, and Eiffert, H. (2010). Penetration of Drugs through the Blood-Cerebrospinal fluid/Blood-Brain Barrier for the treatment of central nervous system infections. Clinical Microbiology Reviews. 23(4): 858-883. DOI: 10.1128/CMR.00007-10 3. Letendre, S. (2011). Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Topics in antiviral medicine. 19(4): 137-142. 4. Marra, C. (2014). Central nervous system penetration of ARVs: Does it matter? [powerpoint]. Presented at Northwest Aids Education and Training Center on May 15th, 2014. 5. Cherubin, C.E., Eng, R.H, et al. (1989). Penetration of newer cephalosporins into cerebrospinal fluid. Review of Infectious Diseases.11(4):526-548. 6. Tunkel, A.R., Hartman, B.J, et al. (2004). Practice Guidelines for the management of bacterial meningitis. CID. 39:1267-1284.

Peer-reviewed by Jeffrey Pearson, 2nd year ID pharmacy resident

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