Primary Tuberculosis in Children TB treatment

1. 4 • Primary Tuberculosis in Children • TB treatment

2. PATHOGENESIS • PORTAL OF ENTRY - most frequent: lungs (95%) - possibly intestine or skin • HYPERSENSITIVITY TO TUBERCULIN - 2-12 weeks • PRIMARY COMPLEX 1- parenchimalfocus (small round opacity, 3-10mm diam. subpleural in 70% cases); 2- regional lymphadenitis (hilar and paratracheal lymphnode enlargement); The primary focus often undergoes caseous necrosis and encapsulation and heals by fibrosis and calcification.

3. TB primary infection MTB multiplication Inhalation of infecting particles containing 1 to 3 germs (AFB)

4. Evolution of primary infection • Progressive reduction of micobacterial population results in: • complete elimination of AFB • persistence of dormant bacili 2. Resorbtion of inflamation areas, sometimes preceded by caseous necrosis 3. Fibrosis and eventually calcification

5. RANKECOMPLEX • Inoculation (primary) focus • Limfangitis • Adenopathies (hilar or paratracheal) 3 2 1

6. adenopathy primary complex

7. PRIMARY FOCUS ADENOPATHY LYMPHANGITIS RANCKE TB PRIMARY COMPLEX

8. In 95% of cases, the appearance of cell-mediated immunity controls TB primary infection. The primary complex occurs and undergoes fibrosis and calcification. • - There are situations of progressive primary tuberculosis with the emergence of complicated forms.

9. COMPLICATIONS OF PRIMARY COMPLEX (1) Occur in small age children , malnourished, immunedepressed - extension of caseous necrosis and evolution of the primary focus towards TB pneumonia; - the center of the primary focus liquefies, caseumis eliminated in a bronchus  residual cavity

10. LYMPH NODE COMPLICATED PRIMARY TB COMPLEX : caseous pneumonia

11. COMPLICATIONS OF PRIMARY COMPLEX (2) - focus can rupture in pleura  TB pleural effusion - enlarged hilar/mediastinal lymph nodes can compress a bronchus leading to collapse (atelectasis) of a lung segment/lobe; - caseum from a soft lymph node can brake through the bronchial wall and can block a main bronchus with caseous material  suffocation  bronchoscopy.

12. COMPLICATED PRIMARY TB COMPLEX :focal pneumonitis

13. COMPLICATIONS OF PRIMARY COMPLEX (3) - Via the bronchial tree, caseum (TB) can be spread everywhere in the lungs. - Lymph nodes in contact with the posterior part of the pericardium may rupture  TB pericarditis. - Bacilli can escape in the bloodstream  disseminate disease to liver, spleen, bones, brain, kidneys, etc.

14. COMPLICATED TB PRIMARY COMPLEX : periadenitis

15. LYMPH NODE COMPLICATED PRIMARY TB COMPLEX : hematogenous dissemination = miliary TB

16. SCARS AFTER PRIMARY TB : PARENCHIMAL AND REGIONAL LYMPH NODE CALCIFICATIONS

17. TB TRANSMISSION IN CHILDREN - From contagious adults (family, school, etc.)- Less often by underboiled milk contaminated with M. bovis- Very rare by cutaneous inoculation Between 1990 and 2000: → 15 million new cases of TB in children → 5 million deaths – mortality > in 0-4 years than the 5-15 years because of high frequency   disseminated TB in group 0-4 years → Children with primary TB are rarely contagious

18. TREATMENT OF LATENT TB INFECTION (LTBI)

19. How to reduce the risk of TB disease in infected persons • Primary: isolation and treatment of active pulmonary TB cases • Treatment of latent TB infection (LTBI) (prophylaxis) • BCG vaccination

20. Chemoprophylaxis of TBUsed only in high risk groups • Household members and other close contacts of a patient with active TB. • A positive skin test in persons less than 25 years. • A positive skin test in the immunesuppressed, persons with leukemia, and Hodgkin's Disease • HIV + patients with a positive TST test

21. Candidates for Treatment of LTBI (1) • Positive skin test result over 5 mm • HIV-positive persons • Recent contacts of a TB case • Persons with fibrotic changes on chest radiograph consistent with old TB • Patients with organ transplants and other • immunesuppressed patients

22. Candidates for Treatment of LTBI (2) • Positive skin test result over 10 mm • Recent arrivals from high-prevalence countries • Injection drug users • Residents and employees of high-risk congregate settings • Mycobacteriology laboratory personnel • Persons with clinical conditions that make them high-risk • Children < 4 years of age, or children and adolescents exposed to adults in high-risk categories

23. Treatment of LTBI with Isoniazid (INH) • ISONIAZID 5 mg/kg/day (max. 300 mg) • 6-month regimen considered optimal • 9 to 12 -months regimen in immune- depressed

24. LTBI Treatment with Rifampin • Rifampin (RMP) is recommended for people who: • cannot tolerate INH • have been exposed to INH-resistant TB • RMP should be given daily for 4 months • RMP should not be used with certain combinations of anti-retroviral (ARV) therapy • In some cases, rifabutin may be substituted when RMP cannot be used

25. PREGNANCY AND BREAST-FEEDING • INH daily • Pyridoxine supplementation • Breast-feeding not contraindicated

26. Monitoring Patients • Before treatment for LTBI is started, clinicians should: • Rule out possibility of TB disease • Determine history of treatment for LTBI or disease • Determine contraindications to treatment • Obtain information about current and previous drug therapy • Recommend HIV testing if risk factors are present

27. Monitoring Patients (2) • Establish rapport with patient and emphasize: • Benefits of treatment • Importance of adherence to treatment • Possible adverse side effects of medication • Establishment of optimal follow-up plan

28. Monitoring Patients (3) • Baseline laboratory testing • Not routinely indicated • Baseline hepatic measurements for: • - Patients whose initial evaluation suggests a • liver disorder • - Patients with HIV infection • - Pregnant women and those in immediate • postpartum period • - Patients with history of chronic liver disorder

29. Monitoring Patients (4) • At least monthly, evaluate for • Adherence to prescribed regimen • Signs and symptoms of active TB disease • Signs and symptoms of hepatitis

30. TREATMENT OF TB DISEASE

31. BASIC PRINCIPLES OF THE TB TREATMENT (1) • Provide safest, effective therapy in shortest time. • Directly observed therapy (DOT). • Use multiple drugs to which organisms are susceptible. • Never add a single drug to a failing regimen. • Ensure adherence to therapy. • Treatment regimens have 2 phases: - Initial phase: 4 or 3 drugs daily; in areas where less than 4% of cases are resistant to isoniazid, 3 drugs (H, R and Z) may be adequate for the initial regimen - Continuation phase: 2 drugs, 3 days per week.

32. BASIC PRINCIPLES OF THE TB TREATMENT (2) 7. TB drugs are administered only once a-day, in the morning (before breakfast). 8. Treatment side effects will be monitored. 9. Protection of rifampicin (rifampicine should not be used for the treatment of other diseases, in order to avoid selection of resistant germs). 10. All cases of tuberculosis will be registered. 11. TB treatment is free of charges. 12. In special situations treatment lasts longer than 6 months: - 9 months, if pyrazinamide or rifampicine are not used; - 12 months, in AIDS patients and in some extrapulmonary TB; - 18-24 months, in multidrug-resistant TB.

33. Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin And recently Rifabutin* Rifapentine Cycloserine p-Aminosalicylic acid Ethionamide Amikacin or kanamycin* Capreomycin Levofloxacin* Moxifloxacin* Gatifloxacin* Antituberculosis Drugs First-Line Drugs Second-Line Drugs

34. Ethambutol EMB (E) Isoniazid INH (H) Pyrazinamide PZM (Z) Rifampin RMP (R) Rifapentine RPT Streptomycin SM (S) Drug Abbreviations

35. Common Adverse Reactions to Drug Treatment (1)

36. Common Adverse Reactions to Drug Treatment (2)

37. Common Adverse Reactions to Drug Treatment (3)

38. ISONIAZID (INH; H) • Considered the drug of choice for the chemotherapy of TB. discovered in 1945a hydrazide of isonicotinic acid • bactericidal for growing bacilli. • Primary action seems to inhibit the biosynthesis of mycolic acids which are part of cell wall structure. • Dose - daily: 10 mg/kg/day, max.600mg/day; under 50 kg body weight:max.450mg/day - 3 days/week: 10 mg/kg/day, max.600 mg/day

39. Pharmacokinetics • Absorption: INH is rapidly absorbed either oral or parenteral route. Peak [plasma] of 3-5 micrograms/milliliter after oral administration. • Distribution: • Diffuses readily into all bodily fluids; does not bind to plasma proteins • In the CSF the conc. is about 20% of plasma, • T 1/2 =1-3 hrs.

40. Resistance to INH • Organism eventually develops resistance. • The mechanism of resistance is related to the failure of the drug to penetrate the bacterial wall or be taken up by the micro-organism (by active transport system), • Remember treatment is up to 2 years.

41. Excretion (1) • 75-95% of a dose excreted in urine in 24 hr. - Mostly as a metabolite. - The main excretory product – acetylisoniazid, is a result of enzymatic acetylation • Very important in terms of metabolism, Isoniazid is under genetic control. There are 2 groups of people: fast and slow acetylators

42. Excretion(2) • Those that have slow acetyl transferase activity are slow acetylators and may produce more of the toxic intermediate. • This is an inherited trait ==> autosomal dominant • Average t 1/2 is less than 90 minutes. In the slow acetylators, t 1/2 will be about 3 hours. • Ethnicity: Eskimo, Native American Indians, and Asians are fast aceytlators.

43. Adverse Effects • Induced hepatitis due to the buildup of toxic metabolic products of acetylisoniazid --> acetylhydrazine. This is more frequent in slow acetylators. • Hepatic reactions to Isoniazid are also age dependent: 250x increase in the incidence of hepatitis over age. • Peripheral neuropathy – higher kisk in diabetes, alcholism. Malnutrition. For prevention, co-administer pyridoxine (Vit.B6)

44. Drug Interaction • Competition between Isoniazid and Phenytoin (anticonvulsant). They both compete for drug metabolism enzymes. • Phenytoin interferes with metabolism of isoniazid by reduction in excretion or enhancement of effect of isoniazid

45. RIFAMPIN (RMP; R) • Bactericidal • Mechanism of action Rifampin inhibits DNA dependent RNA polymerase of the bacilli. • Dose- daily: 10 mg/kg/day, max. 600mg/day; under 50 kg body weight:max. 450 mg/day - 3 days/week: 10 mg/kg/day, max. 600 mg/day

46. Pharmacokinetics (1) Absorption • peak levels reached 2-4 hrs. after oral dose • rapidly eliminated in the bile and reabsorbed (enterohepatic circulation) It can be delayed with use of aminosalicylic acid. • the metabolites maintain full effect • half life is 6 hours.

47. Pharmacokinetics (2) Distribution: • Throughout the total body water • Present in effective concentrations in many organs and body fluids including CSF, • With Rifampin you must warn patients: the drug has an orange red color in body excretions; this color will be imparted to all body fluids.

48. Adverse Effects (1) • Gastro-intestinal reactions: - anorexia,nausea ,vomiting,mild abdominal pain, - hepatic reactions in children, pregnant women and alcoholics, can result in minor elevations in serum transaminase - jaundice is a serious adverse effect and needs stopping treatment

49. Adverse Effects (2) • Allergic reactions: rash, pruritus • Fever (flu-like syndrome) • Skin Eruptions • Rifampin does induce microsomal drug metabolizing enzymes. This will decrease the half-life of some other drugs. (ie. phenytoin, digitoxin, fenobarbital, oral contraceptives, anti-diabetic oral medication → patients with TB and diabetis need insulin during their treatment with rifampin)

50. WARNING! • Rifampin and Isoniazid are the most effective drugs for the treatment of TB. • But these 2 drugs shouldnever be given alone! They are always used in combination because resistance occurs to one drug alone very rapidly. • They are used in combination with each other initially as well as other drugs. Bacilli must become resistant to two drugs in order to remain viable. Statistically, the chances are very small of the bacilli becoming resistant to both.