Drugs used in Meningitis Prof. M. Alhumayyd

1. Drugs used inMeningitis Prof. M. Alhumayyd

2. Objectives • At the end of the lecture , students should : • Describe briefly common types of meningitis • Describe the principles of treatment • List the name of antibiotics used for treatment of meningitis • Describe the mechanism of action & adverse effects of the individual drugs

3. Definition Meningitis is an inflammation of the protective membranes covering the brain and the spinalcord(meninges).

4. Causes Infectious • Viruses • Bacteria Non-infectious e.g,spread of cancer to meninges(malignant meningitis),etc.

5. Bacterial meningitis • Is a serious , life threatening disease. • May lead to serious long –term consequences (e.g. deafness, epilepsy, limb loss,hydrocephalus & cognitive deficits).

6. CAUSES OF BACTERIAL MENINGITIS • Neisseria meningitidis** • Streptococcus pneumoniae** • Haemophilus influenzae • Staphylococcus aureus • Pseudomonas aeruginosae • Listeria monocytogenes • Mycobacterium tuberculosis(tuberculous meningitis)

7. Route of transmission • The bacteria are carried by humans in the nose and throat and spread into the air by coughing and/or sneezing, kissing, sharing eating utensils. • The pathogens spread from the respiratory tract to the blood stream and to the nervous system and cause bacterial meningitis .

8. SYMPTOMS OF BACTRIAL MENINGITIS • High fever* • Severe headache* • Stiff neck* • Irritability • Seizures • Vomiting

9. TREATMENT PRINCIPLES • Emergency hospitalization • Antibiotics • Measures for treatment of complications

10. Treatment Principles • Antibiotic selected must penetrate adequately into the CSF. Regimen chosen must have potent activity against known or suspected pathogens & exert a bactericidal effect.(Empiric?)

11. Antibiotics for Treatment of Bacterial Meningitis1.Inhibitors of cell wall synthesis (β-Lactams)

12. PenicillinsMechanism of action • Inhibit bacterial cell wall synthesis by inhibiting the peptidoglycan layer of bacterial cell wall (bactericidal).

13. Narrow Spectrum Penicillin Penicillin G • Narrow spectrum • Destroyed by gastric acidity • Inactivated by β- lactamase • Short acting ( 4-6 hrs )

14. Extended Spectrum Penicillins • Amoxicillin • Ampicillin

15. Active against gram positive & gram negative microorganism. • Inactivated by β- lactamase enzyme, (now a days combination with B-lactamase inhibitors are available e.g Amoxicillin + Clavulanic acid and ampicillin + salbactum, are more effective against B-lactamase producing pathogens) . • Amoxicillin and ampicillin are acid stable (effective orally ) • Can also be given parenterally (I.V or I.M) • Amoxicillin is better absorbed from the gut & not affected by food.

16. Adverse effects of penicillins

17. Cephalosporins • 3rd generation Ceftriaxone • Both of them are given by intravenous infusion Ceftazidime Ceftriaxone

18. Mechanism of action • Inhibit bacterial cell wall synthesis

19. Bacterial Spectrum of 3rd Generation Cephalosporins • Highly effective against Gm –ve bacilli • Anaerobic microbes • Pseudomonas ( ceftazidime) • Highly resistant to β- lactamase

20. Adverse effects

21. Carbapenems Imipenem/cilastatin • Inhibits bacterial cell wall synthesis(bactericidal). • Has a wide spectrum of activity(aerobic & anaerobic G+ & G_ bacteria, including pseudomonads) • Resistant to most β lactamases

22. Pharmacokinetics • Not absorbed orally, taken by I.V. • Inactivated by dehydropeptidases in renal tubules, so it is given with an inhibitor cilastatin for clinical use. • Penetrates body tissues and fluids including C.S.F.

23. Adverse effects • Nausea, vomiting, diarrhea • Skin rash and reaction at the site of infusion • High doses may cause seizure in patients with renal failure • Patients allergic to penicillins may be allergic to carbapenems .

24. Other inhibitor of cell wall synthesis

25. Vancomycin • Bactericidal • Cell wall inhibitor • Poorly absorbed orally • Used orally to treat GIT infections caused by clostridium defficilee.g colitis. • Given intravenously

26. Vancomycin • Active only against Gm+ve bacteria • Used in combination with3rd generation cephalosporins for treatment of meningitis caused by penicillin resistant pneumococci. • Used against Methicillin resistant S. aureus (MRSA). • May be combined with ampicillin or ceftazidime as an initial therapy of meningitis in infant, elderly and immunocompromised patients .

27. Adverse Effects (use only when the infection is resistant to other safer drugs) • Phlebitis at site of injection • Ototoxicity • Nephrotoxicity • Histamine release (flushing of upper body) [red man ( red neck ) syndrome] and hypotension (minimized if injected slowly).

28. Fluoroquinolones • Bactericidal drugs

29. Fluoroquinolones(e.g. ciprofloxacin, i.v.) Inhibit bacterial DNA synthesis by inhibiting DNA gyrase

30. Bacterial Spectrum • Effective against :Gm-ve organisms • Limited activity :against Gm+ve organisms

31. Pharmacokinetics • Well absorbed orally • Absorption is impaired by divalent cations ; iron, zinc or those in antacids as aluminium, magnesium • Half-life 3hrs

32. Pharmacokinetics • Widely distributed in body fluids & tissues • Penetrates into CSF • Highly concentrated in bone, kidney, prostate, lung • Excreted through kidney & appear in breast milk

33. Adverse effects • GIT upset • CNS(Headache,dizziness,insomnia) • Abnormal liver function tests • Photosensitivity(avoid excessive sun light) • May damage growing cartilage (arthropathy) • Tendon damage ( tendinitis )

34. Contraindications • Growing children ( below 18 years ) • Pregnancy • Lactation

35. Prevention better than cure • Haemophilusinfluenzae type b (Hib) bacterium, a leading cause of bacterial meningitis in children. • NewHibvaccines — available as part of the routine childhood immunization schedule have greatly reduced cases of this type of meningitis.  • Pneumococcal polysaccharide vaccine (PPSV) for older children and adults • Meningococcal conjugate vaccine ,people going to Hajj.

36. Penicillins Penicillin G(narrow spectrum),i.v. & Ampicillin(broad spectrum),i.v. Mechanism of action Inhibits bacterial cell wall synthesis(bactericidal)

37. Adverse effects of penicillins . Hypersensitivity . Super infections . Diarrhea . May cause convulsions after high doses by i.v or in renal failure.

38. Vancomycin • Active only against Gm+ve bacteria • In combination with3rd generation cephalosporins for treatment of meningitis caused by penicillin resistant pneumococci. • Against Methicillin resistant S. aureus (MRSA).

39. Vancomycin Mechanism of action Inhibits bacterial cell wall synthesis Antibacterial activity Bactericidal against G+ bacteria,especially Staphylococci(including B-lactamase producing,MRSA). Not effective against G- bacteria Given by slow i.v infusion.

40. Adverse Effects of vancomycin • Phlebitis at the site of injection • Ototoxicity & Nephrotoxicity(high conc.) Rapid infusion: • Histamine release(flushing of upper body (Red man or red neck syndrome) & hypotension{minimized if injected slowly}.

41. AMINOGLYCOSIDES e.g. Gentamicin,i.v. Antibacterial Spectrum • Bactericidal ( exclusive for aerobic G- bacteria ). Mechanism of action Inhibit protein synthesis ( 30s subunit )

42. Adverse Effects of Gentamicin Ototoxicity & nephrotoxicity (directly related to serum conc.) Neuromuscular blockade ( very high dose )

43. Prevention better than cure • Haemophilusinfluenzae type b (Hib)vaccines — routine childhood immunization . (protection: 15 yrs) • Pneumococcal polysaccharide vaccine (PPSV) for older children and adults (protection: 3-5 yrs) • Meningococcal conjugate vaccine , people going to Hajj. (protection: 3-5 yrs)