1. 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- parenchimal focus (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 Inhalation of infecting particles containing 1 to 3 germs (AFB) MTB multiplication

4. Evolution of primary infection 1.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. RANKE COMPLEX 1.Inoculation (primary) focus 2.Limfangitis 3.Adenopathies (hilar or paratracheal) 1 2 3

6. primary complex adenopathy

7. TB PRIMARY COMPLEX PRIMARYFOCUS LYMPHANGITIS ADENOPATHY RANCKERANCKE

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, caseum is eliminated in a bronchus  residual cavity

10. LYMPH NODE COMPLICATED PRIMARY TB COMPLEX : caseous pneumonia caseous pneumonia COMPLICATED PRIMARY TB COMPLEX : caseous pneumonia 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. - 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. COMPLICATIONS OF PRIMARY COMPLEX (3)

14. COMPLICATED TB PRIMARY COMPLEX : periadenitis

15. COMPLICATED PRIMARY TB COMPLEX : hematogenous dissemination = miliary TB hematogenous dissemination = miliary TB COMPLICATED PRIMARY TB COMPLEX : hematogenous dissemination = miliary TB hematogenous dissemination = miliary TB LYMPHNODE

16. SCARS AFTER PRIMARY TB : PARENCHIMAL AND REGIONAL LYMPH NODE CALCIFICATIONS 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 TB Used 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. 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. INH daily Pyridoxine supplementation Breast-feeding not contraindicated PREGNANCY AND BREAST-FEEDING

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) 1.Provide safest, effective therapy in shortest time. 2.Directly observed therapy (DOT). 3.Use multiple drugs to which organisms are susceptible. 4.Never add a single drug to a failing regimen. 5.Ensure adherence to therapy. 6.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 First-Line DrugsSecond-Line Drugs Antituberculosis Drugs Cycloserine p-Aminosalicylic acid Ethionamide Amikacin or kanamycin* Capreomycin Levofloxacin* Moxifloxacin* Gatifloxacin*

34. Drug Abbreviations EthambutolEMB (E) Isoniazid INH (H) Pyrazinamide PZM (Z) Rifampin RMP (R) RifapentineRPT Streptomycin SM (S)

35. Caused byAdverse ReactionSigns and Symptoms Any drugAllergySkin rash EthambutolEye damageBlurred or changed vision Changed color vision Isoniazid, Pyrazinamide, or Rifampin HepatitisAbdominal pain Abnormal liver function test results Fatigue Lack of appetite Nausea Vomiting Yellowish skin or eyes Dark urine Common Adverse Reactions to Drug Treatment (1)

36. Common Adverse Reactions to Drug Treatment (2) Caused byAdverse ReactionSigns and Symptoms IsoniazidPeripheral neuropathy Tingling sensation in hands and feet PyrazinamideGastrointestinal intolerance Arthralgia Arthritis Upset stomach, vomiting, lack of appetite Joint aches Gout (rare) StreptomycinEar damage Kidney damage Balance problems Hearing loss Ringing in the ears Abnormal kidney function test results

37. Common Adverse Reactions to Drug Treatment (3) Caused byAdverse ReactionSigns and Symptoms Rifamycins Rifabutin Rifapentine Rifampin Thrombocytopenia Gastrointestinal intolerance Drug interactions Easy bruising Slow blood clotting Upset stomach Interferes with certain medications, such as birth control pills, birth control implants, and methadone treatment

38. ISONIAZID (INH; H) Considered the drug of choice for the chemotherapy of TB. discovered in 1945 a 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 should never 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.

51. PYRAZINAMIDE highly bactericidal drug, very effective in killing intracellular TB bacilli. It is supplied as tablets of 500 mg. Dose - daily: 25-30 mg/kg/day, maximum 2g/day, in a single dose; under 50 kg body weight, maximum 1,5g/day; - 3 days/week: 40mg/kg/day, maximum 3g/day. 51

52. Adverse Effects Hepatitis (rising of liver transaminases), rash, abdominal distress and hyperuricemia (with or without arthralgia) The facial flushing or erythematous rash with pruritus appearing in the first days of treatment are usually self-limiting. Patients with diabetes should be carefully monitored since blood glucose concentrations may become labile. Arthralgia, particularly of the shoulders, commonly occurs and is responsive to simple analgesics. Both hyperuricemia and arthralgia may be reduced by intermittent administraton of pyrazinamide. 52

53. ETHAMBUTOL Ethambutol is a bacteriostatic drug, given orally, and is used mainly to prevent selection of resistant strains of acid-fast bacilli to the main first-line TB drugs. Dose- daily: 15-25 mg/kg/day, in capsules of 250 mg or tablets of 400 mg. 15 mg/kg/day after the 8-th week of treatment (to avoid dose-related side effects) 3 days/week: 30mg/kg/day, maximum 1,5 g/day. 53

54. Side effects Retrobulbar neuritis is usually dose-related. Patients complain of blurred vision, red-green blindness (early symptoms) and, later, central scotomata. Visual acuity monitoring is strongly advised before administering ethambutol, and later if the patient reports visual symptoms. Due to difficulties of monitoring visual acuity in children, the drug should be used with caution and only after the age of 6 years. 54

55. STREPTOMYCIN The first drug used clinically for treatment of TB 1947-1952; was the only drug available at that time. is an aminoglycoside antibiotic acts by protein synthesis inhibitor and decreases the fidelity mRNA and garbles the message, leads to nonsense proteins. Streptomycin only binds to the 30s subunit.

56. Adverse Effects Affects cranial nerve 8: auditory and vestibular functions can be damaged. With its small molecule, streptomycin can pass the placental bareer and affect the fetus. It is forbidden for pregnant women and small children. Streptomycin is also nephrotoxic.

57. 2nd Line Drugs: Not as effective and have more toxicity para- Aminosalicylic Acid a structural analog of PABA (p- aminobenzoic acid) is bacteriostatic inhibits de novo folate synthesis half life = 1 hour after 4 g. dose you can give this drug up to 12 grams per day. 80% of the drug is excreted in the urine and 50% of that is as an acetylated metabolite which is insoluble. You must make sure the patient's urine is normal or alkaline.

58. Adverse effects GI irritation due to the amount of drug given (high doses) nausea, vomiting, bleeding, occurs in 30-40% of the patients. be careful with those who have peptic ulcers Hypersensitivity reactions, rash, fever, some hepatotoxicity All will disappear when the drug is stopped This drug has poor patient acceptability and compliance.

59. Capreomycin, Viomycin, Kanamycin (aminoglycosides) Adverse effects (1) 1. These drugs are nephrotoxic - will cause proteinuria, hematuria, nitrogen metabolism, and electrolyte disturbances. However effect is reversible when drug is stopped.

60. Adverse effects (2) Ototoxic will result in deafness and some loss of vestibular function, leads to cranial nerve 8 damage. The nerve damage is permanent. Capreomycin has replaced viomycin because of less toxic effects, but all three drugs have the same effects (also like streptomycin).

61. Cycloserine can cause CNS disturbances Therapeutic States Cycloserine should be used when re- treatment is necessary or when the micro- organism is resistant to the other drugs. It must be given in combination with other anti-tuberculosis drugs. Mechanism of Action: An analog of D-alanine synthetase, will block bacterial cell wall synthesis.

62. Adverse effects Most common in the CNS: headache, tremor, vertigo, confusion, nervousness, psychotic states with suicidal tendencies, paranoid reactions, catatonic and depressed reactions

63. Treatment Isoniazid, Rifampin, Pirazinamide & Ethambutol (or Streptomycin in rare situations) are given for 2 months. Isoniazid & Rifampin are given for 4 months. Prolonged bed rest is not necessary or helpful in obtaining a speedy recovery. The patient must be seen at regular and frequent intervals to follow the course of the disease and treatment. Look for toxic effects

64. 10/26/2015 Classification of Patients in Categories for Standardized Treatment Regimen CategoryType of PatientRegimenDuration months Category INew Sputum Positive Seriously ill sputum negative, Seriously ill extra pulmonary, 2 (HRZE) or 2 (HRZS) 4 (HR) 3 6 Category IISputum Positive relapse Sputum Positive failure Sputum Positive treatment after default 2 (HRZES), 1 (HRZE) 5 (HRE) 3 8 Category IIIDrug-resistant TB (MDR, XDR) Severe adverse effects Individualized treatment regimens 18-24 and more

65. Main drugs and doses (mg/kg/day); maximum dosage/day in parentheses 65 DRUG DAILY 3 TIMES / WEEK 3 TIMES / WEEK CHILDRENADULTSCHILDRENADULTS ISONIAZID (H) 10-20 (300 mg) 5 (300 mg) 20-40 (750 mg) 10 (750 mg) RIFAMPICIN (R) 10-20 (600 mg) 10 (600 mg) 10-20 (600 mg) 10 (600 mg) PYRAZINAMIDE (Z) 15-30 (2 g) 30 (2 g) 50 (3 g) 50 (3 g) ETHAMBUTOL (E) 15-25 (1,5 g) 15-25 (1,5 g) 30 (1,5 g) 30 (1,5 g) STREPTOMYCIN (S) 20 (1 g) 15 (1 g) 30 (1,5 g) 30 (1,5 g) Main drugs and doses (mg/kg/day); maximum dosage/day in parentheses

66. Infectiousness Patients no longer considered infectious if they meet all of these criteria: Are on adequate therapy Have had a significant clinical response to therapy, and Have had 3 consecutive negative sputum smear results

67. Adherence Nonadherence is a major problem in TB control Use case management and directly observed therapy (DOT) to ensure patients complete treatment

68. Directly Observed Therapy (DOT) Health care worker watches patient swallow each dose of medication Consider DOT for all patients DOT should be used with all intermittent regimens DOT can lead to reductions in relapse and acquired drug resistance Use DOT with other measures to promote adherence

69. Treatment of TB for HIV-Negative Persons Include four drugs in initial regimen - Isoniazid (INH) - Rifampin (RMP) - Pyrazinamide (PZM) - Ethambutol (EMB) or streptomycin (SM)

70. Treatment of TB for HIV-Positive Persons Management of HIV-related TB is complex Care for HIV-related TB should be provided by or in consultation with experts in management of both HIV and TB

71. Extrapulmonary TB In most cases, treat with same regimens used for pulmonary TB Bone and Joint TB, Miliary TB, or TB Meningitis in Children Treat for a minimum of 12 months

72. Multidrug-Resistant TB (MDR TB) Presents difficult treatment problems Treatment must be individualized Clinicians unfamiliar with treatment of MDR TB should seek expert consultation Always use DOT to ensure adherence