Mycobacteria

1. Mycobacteria

2. A. Characteristics I. Slowly growing organism; making them relatively resistant to antibiotics II. Mycobacterial cells can also be dormant and thus completely resistant to many drugs III. Lipid rich mycobacterial cell wall is impermeable to many agents IV. Substantial proportion of mycobacterial organism are intracellular, residing with macrophages and inaccessible to drugs V. Notorious for their ability to develop resistance to any single drug

3. B. Agents • Drugs used in Tuberculosis • Drugs used in Atypical mycobacteria • Drugs used in Leprosy

4. Drugs used in Tuberculosis

5. First line Anti TB Drugs

6. 1)Isoniazid • 2)Rifampin • 3)Pyrazinamide • 4)Ethambutol • 5)Streptomycin

7. Isoniazid • The most active drug for the treatment of TB • (1952), a small (MW 137) simple molecule freely soluble in water • Bactericidal; active-intracellular and extracellular organisms • Less effective in atypical mycobacteria • MOA: inhibits synthesis of mycolic acid • Availability: 50, 100, 300mg tab; 100-200mg/5ml susp.

8. Resistance - due to mutations: a. inhA b. katG c. ahpC d. kasA - if used as a single drug, 10-20% prevalence • Kinetics: readily absorbed in the GIT; serum conc. 3-5ug/ml in 1-2 hrs.; acetylation by liver N-acetyltransferase (rapid acetylators vs. slow acetylators); urine

9. Dynamics: dose: 5mgkd (child) or 300mgd (adult) daily 15mgkd or 900mg in twice weekly dosing + rifampin 600mg - add Pyridoxine 25-50mgd if (+) neuropathy - as a single agent in cases of: a. recent converters b. immunocompromised individuals c. close contacts d. abnormal CXR but activity has been R/O 300mgd or 900mg twice weekly x 6 mos.

10. Adverse effects: a. allergic reactions – fever, rashes, drug-induced SLE b. hepatitis – major toxic effect; age-dependent; 10-20% asymptomatic; if with clinical hepatitis, D/C INH; acetylhydrazide c. peripheral neuropathy – seen in 10-20% being given >5mgkd d. misc. reactions – hematologic abnormality, GI discomfort • Drug interaction: phenytoin, AlOH

11. Rifampin • A large (MW 823) complex semisynthetic derivative of Rifamycin ( Streptomyces mediterranei) • Active against gm (+), gm(-) cocci, some enteric bacteria, chlamydia • Cross resistance with Rifabutin • Bactericidal; penetrates intracellularly • MOA: binds with the β-subunit of bacterial DNA dependent RNA polymerase → inhibit RNA synthesis

12. Resistance: mutations in rpoβ • Kinetics: well absorbed; highly protein-bound (↑ in CSF in meningeal inflammation); excreted in bile, feces, urine; undergoes enterohepatic recirculation • Clinical uses: a. mycobacterial infection 600mgd (10mgkd) + INH, Ethambutol x 6 mos. atypical mycobacteria 600mgd or 2x weekly x 6 mos. leprosy 600mgd or 2x weekly x 6 mos. + sulfone

13. b. other indications: meningococcal carriage 600mgd x 2 days H. influenzae typeB contact – 20mgkd x 4 days staph. - + another agent pneumococci (meningitis) - + ceftriaxone or vancomycin • Adverse effect: a. orange color urine, sweat, tears, contact lens b. cholestatic jaundice c. flu-like syndrome – if given < 2x weekly d. hepatitis – occ. • Drug interaction: microsomal enzyme inducer (methadone, anticoagulant, protease inhibitor, some anticonvulsant, ketoconazole, contraceptive, cyclosporine, chloramphenicol)

14. Ethambutol • Synthetic, water-soluble, heat stable compound • MOA: inhibitor of mycobacterial arabinosyl transferase (involved in the polymeration of arabino- glycan, an essential component of mycobacterial cell wall barrier) by embCAB operon • Resistance: mutations within the embB structural gene or overexpression of emb gene products • Kinetics: well wbsorbed; CSF conc. –variable (4-69% in inflammed meninges); excreted 20% feces, 50% urine (reduced dose by half if with renal failure)

15. Dose: 15-25 mgkd + INH + Rifampin 50mgkg twice weekly dosing • Adverse effect: retrobulbar neuritis – most common; loss of visual acuity and red-green color blindness); dose-related (25mgkd) hyperuricemia • C/I: very young children because visual acuity assessment is difficult

16. Pyrazinamide • A relative of nicotinamide, stable, inexpensive • Inhibits intracellular organism • MOA: inhibits mycobacterial fatty acid synthase I involved in mycolic acid synthesis • Resistance: mutations in pncA • Kinetics: well absorbed; distributed widely, in inflammed meninges; t1/2 8-11 hrs. • Clinical use: a. 25mgkd + INH + Rifampin x 6 mos. or 50-70mgkg 2x-3x weekly dosing b. multi-drug resistant cases PZA + Ciprofloxacin or Ofloxacin -prevention of active disease in close contacts and recent converters

17. Adverse effects: a. hepatotoxicity (1-5%) b. nausea, vomiting c. drug fever d. hyperuricemia (gouty arthritis)

18. Streptomycin • Resistant to some non-tuberculous species • Extracellular tubercle bacilli; inflammed meninges • MOA: interfere with protein synthesis (30s subunit) • Resistance: point mutation in rpsL gene or rrs that alters the ribosomal binding site • Clinical use: a. severe, life threatening forms of TB b. drug resistance • Dose: 15mgkd IM or IV x several weeks ffed. by 1-1.5gm. 2-3x weekly x 6 mos. • Adverse reaction: ototoxicity, nephrotoxicity

23. Alternative or Second Line Drugs

24. Uses: a. resistance b. failure of clinical response to conventional tx. c. toxic effects Ethionamide • Related to INH; poorly soluble in water; liver • MOA: blocks mycolic acid synthesis • Dose: 1 gm/d – to achieve serum concentration of 20 ug/ml; CSF conc.; causes gastric irritation and neurologic symptom • Adverse effect: hepatotoxic; neurotoxicity • Dose: 250 mg OD → 500-750 mg OD • Resistance: when used as single agent

25. Capreomycin • MOA: peptide protein synthesis inhibitor from Streptomyces capreolus • Used for multidrug resistant cases (streptomycin, amikacin) • Dose: 1 gm/d IM • Resistance: rrs mutation • Adverse effect: nephrotoxic, ototoxic - reduced if 1 gm is given 2-3x weekly after initial response is observed

26. Cycloserine • MOA: inhibitor of cell wall synthesis • Dose: 0.5-1gm/d in 2 divided doses • Renal excretion (dose is reduced if creatinine clearance is <50ml/min • Adverse effect: a. peripheral neuropathy (seen in 1st 2 weeks of therapy) b. CNS dysfunction – depression, psychotic reactions (pyridoxine 150mg/d is given to ameliorate neurologic toxicity)

27. Aminosalicylic Acid (PAS) • MOA: folate synthesis antagonist • Structure – similar to PABA and sulfonamides • Widely distributed in tissues and body fluids except in CSF; excreted in urine • Adverse effect: a. anorexia, nausea, lbm, epigastric pain b. peptic ulceration, hgge c. hypersensitivity reaction – fever, jt. pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, granulocytopenia →seen 3-8 weeks of PAS

28. Kanamycin and Amikacin • MOA: inhibits 30s ribosomal subunit • For streptomycin resistant cases, multidrug resistant TB, atypical mycobacterium • Dose: 15 mgkd IV, IM + 1,2 or 3 other drugs x 2 mos. then 1-1.5 gm 2-3x weekly x 4 mos.

29. Ciprofloxacin and Levofloxacin • MOA: inhibits gyrase mediated DNA-supercoiling • M. tuberculosis: levofloxacin > ciprofloxacin • Atypical mycobacterium: levofloxacin < ciprofloxacin • Dose: ciprofloxacin – 750 mg po BID/ levofloxacin – 500 mg po OD + 2 or more active drugs • Prophylaxis: fluoroquinolone + PZA (multidrug resistant cases) • Resistance: mutations in gyrase A subunit

30. Rifabutin • Derived from rifamycin, related to rifampin • Uses: a. M. tb, M. avium intracellulare, M. foruitum b. disseminated atypical disease in AIDS pts. with CD4 count of <50/ml. c. prophylaxis: TB x 6 mos. alone or with PZA x 2 mos. • Resistance: rpo mutation • Less potent inducer – for HIV infected patients receiving other meds • Dose: 300 mg/d if with protease inhibitor – 150 mg/d if with efavirenz – 450 mg/d

31. Rifapentine • Analog of rifampin; against M. tb, M. avium • MOA: bacterial RNA polymerase inhibitor • Potent inducer of cytochrome p450 • Toxicity: • Dose: 600 mg once or 2x weekly

32. Clofazimine • Last resort for multidrug resistant TB • Effective against leprosy • MOA: unknown ( involved in DNA binding) • Adverse effect: skin discoloration, GIT intolerance • Dose: 200 mg po as single or divided doses (t1/2 2 mos.- slowly released)

33. Atypical Mycobacteria • Not communicable from person to person • Disease produced are less severe than TB • MAC – disseminated disease in late stages of AIDS; incurable - 1st line tx: azithromycin 500 mg OD or clarithromycin 500 mg BID + ethambutol 15 mgkd or Clofazimine or Ciprofloxacin 750mg BID or Amikacin - 2nd line tx: Rifabutin 300 mg OD; Rifampicin; Ethionamide; Cycloserine; Imipenem - prophylaxis in AIDS pts.: Rifabutin 300 mg OD

34. Mycobacterium marinarum - skin infections - 1st line tx: Rifampicin + Ethambutol - 2nd line tx: TMP-SMX; Clarithromycin; Amikacin; Kanamycin; Minocycline; Doxycycline

35. Mycobacterium scrofulaceum - cervical lymphadenitis - tx: surgical excision • Mycobacterium fortuitum - chronic lung disease and skin/soft tissue infection - 1st line tx: Amikacin + Doxycycline - 2nd line tx: Cefoxitin; Rifampicin; TMP-SMX; Ciprofloxacin; Ofloxacin; Imipenem; Clarithromycin

36. Mycobacterium kansasii - similar to TB but milder - 1st line tx: INH + Rifampicin + Ethambutol - 2nd line tx: Ethionamide; Cycloserine; Clarithromycin; Amikacin; Streptomycin

37. Leprosy • Caused by M. leprae • Tropical, warm temperate regions • Skin and nerve predilection • Depends upon cell-mediated immunity • Dx: biopsy; slit skin smears • Mode of transmission: nasal secretions

38. Clinical types of Leprosy: • Tuberculoid leprosy – skin macules with clear centers and well defined margins; anesthetic; no Virchow cells; (+) lepromin test • Borderline tuberculoid • Borderline disease • Borderline lepromatous • Lepromatous – impaired cell immunity; atrophy of skin, muscles; amputations; spontaneous ulcerations

39. Leprosy Dapsone (diaminodiphenylsulfone) • MOA: inhibits folate synthesis • Uses: a. leprosy b. prevent and treat P. carinii in AIDS • Mgt: dapsone + rifampin + clofazimine (100mg OD) (600mg monthly) (100mg/d po) • Adverse effect: hemolysis, GIT intolerance, erythema nodosum leprosum (steroids/thalidomide)

40. Jarisch-Herxheimer reaction: - exacerbation of lepromatous leprosy - is induced 5-6 wks. after initiation of treatment - fever, malaise, exfoliative dermatitis, jaundice with hepatic necrosis, lymphadenopathy, methemoglobinemia, anemia

41. Leprosy (cont.) • Rifampicin – 600mg OD or once a month • Clofazimine (Lamprene) MOA: inhibit the template function of DNA by binding to it -prevents the development of erythema nodosum leprosum - oral; 100mg OD - SE: discoloration of the skin, eosinophilic enteritis

42. Miscellaneous agents for leprosy • Thalidomide – treatment of erythema nodosum leprosum -dose: 100 – 300mg/day; teratogenic • Ethionamide – a substitute for clofazimine -dose: 250 -375mg/day

43. Management of Leprosy • Tuberculoid, borderline tuberculoid and indeterminate disease: Dapsone 100 mg daily + Rifampicin 600 mg daily/monthly X 6 mos. • Lepromatous, borderline lepromatous, borderline disease: Dapsone 100 mg daily + Rifampicin 60 mg daily/monthly +/- Clofazimine 100 mg daily X 1–5 yrs.

45. Leprosy-Classic Facial Appearance: Patient with chronic M Leprae infection that has led to collapse of nasal structure and subsequent development of classic "Leonine Facies.“ Skin discoloration is due to medication used to treat this infection. Patient has lost digits of hand secondary to leprosy as well.

47. Thank you Ma. Victoria M. Villarica, M.D.