Antibiotics in Bacterial Meningitis

by Mario Wilmath, MD

Objectives

Describe the general mechanisms of antibiotic action.

Understand the antibiotics used in bacterial meningitis.

Describe the parenteral dosage forms and routes of administration of antibiotics.

Relate to case of John D.

Cell Wall Synthesis Blockade

Cephalosporins (3rd generation)Example: cefotaxime

Overview: Beta-lactam Increased activity and

distribution

MOA: Interference with cell wall

synthesis (transpeptidation) Activating autolytic enzymes

PenicillinsExample: PenG, oxacillin

Overview: Beta-lactam Resistance and allergy

MOA: Interference with final step in cell

wall synthesis (transpeptidation) Activating autolytic enzymes

http://www.itqb.unl.pt

http://www.itqb.unl.pt

Cell Wall Synthesis Blockade Example: Vancomycin

Overview: Treat beta-lactamase resistance Wide distribution

MOA: Large glycopeptide Hydrogen bonds to NAM and NAG subunits Inhibits murein synthesis and peptidoglycan cell wall

http://www.itqb.unl.pt

http://www.itqb.unl.pt

www.nlm.nih.gov

Disruption of Cell Membranes

Overview:

Selective toxicity to bacterial membrane.

MOA:

May disrupt membrane structure (sterols) or function (pores).

Examples: Polymixins

Imidazoles

http://content.answers.com

Inhibition of Protein SynthesisChlormaphenicol

Overview: Broad spectrum Used for penicillin allergy Bacteriostatic only

MOA: Binds 50S ribosomal unit Block peptidyl transferase Inhibit mitochondrial synthesis.

RifampinOverview: Wide distribution into CNS Prophylaxis for meningitis

MOA: DNA-dependent RNA polymerase

inhibition

http://wpcontent.answers.com

Inhibition of Nucleic Acid Synthesis

Example: Ciprofloxacin

Overview: » Quinolone» Poor CNS penetration » Cannot be used: Children or

pregnancy

MOA: » Inhibits bacterial DNA gyrase » Supercoiled DNA cannot relax» Transcription and replication

blocked

http://www.pharmainfo.net

www.pharmainfo.ne

Inhibition of Nucleic Acid Synthesis Example: Sulfisoxazole

Overview: » Sulfonamide: PABA-like structure » Only moderate tissue penetration

MOA: » Dihydropeteroate synthase:

Competitive inhibitor Substrate becomes nonfunctional folic acid

analogue

http://www.elmhurst.edu

Penicillin G

Powder Frozen solution IV preferred, supplement IM 250000 U/kg/d IV or IM q4-6h

x 7-14d

http://userweb.port.ac.uk/~norrismj/antimicrobial_agents/Penicillins.html

http://www.drsfostersmith.com/product/prod_display.cfm?pcatid=16196

Cefotaxime

Powder Frozen solution ADD-Vantage System IV or IM 150–225 mg/kg/d IV or IM q6-8h Case study: 250mg/kg/d IV q12h

http://www.appdrugs.com/ProductDetail.html?pfid=18&name=Cefotaxime_for_Injection_USP

Courtesy of Dr. Mobley’s lecture on parenteral delivery systems

Vancomycin

Powder Frozen solution IV Intrathecal / Intraventricular 50 – 60 mg/kg/d IV q6 – 8 h Case study: 60mg/kg/d IV

q6h

http://www.mrsapedia.com/vancomycin-and-mrsa/

Chloramphenicol

Powder IV or PO 75 – 100 mg/kg/d IV or

PO q6h

http://www.supplierlist.com/photo_images/53922/Chloramphenicol_Caps.jpg

http://www.apppharma.com/ProdJPGs/ChloramphenicolLg.jpg

Ciprofloxacin

Oral Nasal carrier state Prophylaxis 500 mg PO q12h X

5d

http://onlyhealth.wordpress.com/2009/09/16/generic-cipro-is-preeminent-antibacterial-drug/

Conclusion

The 4 mechanisms of action for antibiotics:

1. inhibit cell wall synthesis

2. membrane permeability

3. protein synthesis

4. nucleic acid synthesis

Case study received vancomycin + cefotaxime and his contacts received rifampin prophylaxis

References

Acute Bacterial Meningitis. Mace, SE. Emergency Medical Clinics of North America. Volume 26, issue 2, May 2008. Accessed Tuesday March 30, 2010 from http://www.mdconsult.com.lp.hscl.ufl.edu/das/article/body/192106220-2/jorg=journal&source=&sp=20587149&sid=0/N/638565/1.html?issn=0733-8627#tblfn3

Clinical Pharmacology. Accessed on Sunday March 28, 2010 from http://www.clinicalpharmacology-ip.com.lp.hscl.ufl.edu/default.aspx

Katzung BG and Trevor AJ.  Examination and Board Review Pharmacology, 4th edition.  Appleton & Lange.  Norwalk, Connecticut. 1995.

RX List. Accessed on Sunday March 28, 2010 from http://www.rxlist.com/bicillin-c-r-drug.htm