ATT

antitubercular drugs

1. Tuberculosis, Leprosy & Management Department of Pharmacology Late BRKM GMC Jagdalpur

2. Introduction Tuberculosis is a chronic granulomatous infectious disease. The causative organism is Mycobacterium tuberculosis , which is an acid-fast bacillus. In India, approximately 1000 people die from TB every day. In India, the control and treatment of TB is covered under a National programme called as ‘ The Revised National Tuberculosis Control Programme (RNTCP)’, in which free and full course of treatment is provided to all TB cases. RNTCP was launched in 1997, and its treatment guidelines were further revised in 2010. Government of India has declared TB to be a notifiable disease in 2012, so that any clinician, who treats a TB patient, has to notify it to the Government.

3. Epidemic and resistance India has more new tuberculosis (TB) patients annually than any other country globally, contributing to 27% of the world’s TB burden. About 2.79 million TB patients are estimated to be added annually. The Revised National Tuberculosis Control Programme (RNTCP) notified around 1.94 million TB patients in 2016. Worldwide approximately 4.1% of new TB patients and 19% of previously treated TB patients have multidrug resistant-TB (MDR-TB), i.e. TB resistant to at least two of the first-line drugs – isoniazid and rifampicin.

4. Epidemic and resistance Extensively drug- resistant TB (XDR-TB), defined as MDR-TB with additional resistance to at least one fluoroquinolone and one second line injectable drug, has been reported by 123 countries. The proportion of XDR-TB among MDR-TB patients is 6.2% worldwide. The estimated number of MDR/rifampicin resistant (RR)-TB in India is 147 000, accounting for one fourth of the global burden of MDR/RR-TB .

5. Resistance pattern MDR-TB is 6.19% (CI 5.54–6.90%) among all TB patients with 2.84% (CI 2.27–3.50%) among new and 11.60% (CI 10.21–13.15%) among previously treated TB patients. Among MDR-TB patients, additional resistance to any fluoroquinolones was 21.82% (17.33–26.87%), and 3.58% (1.8–6.32%) to any second-line injectable drugs. Among MDR-TB patients, additional resistance to at least one drug from each of the two classes, i.e. fluoroquinolone and second-line injectable drugs (XDR-TB) was 1.3% (0.36–3.30%).

6. Resistance pattern Any first- or second line drug resistance among all TB patients is 28.0% (CI 26.77– 29.29%) with 22.54% (CI 21.10–24.10%) among new and 36.82% (CI 34.64–39.04%) among previously treated TB patients. Any isoniazid resistance is 11.06% (CI 9.97–12.22%) and 25.09% (CI 23.1–-27.11%) among new and previously treated TB patients, respectively. Any pyrazinamide resistance is 6.95% (CI 6.07–7.91%) and 8.77% (7.53–10.13%) among new and previously treated TB patients, respectively.

7. Severe Symptoms Persistent cough Chest pain Coughing with bloody sputum Shortness of breath Urine discoloration Cloudy & reddish urine Fever with chills. Fatigue

8. Diagnosis Bacteriological test: Zeihl-Neelsen stain Auramine stain(fluorescence microscopy) Sputum culture test: Lowenstein –Jensen(LJ) solid medium: 4-18 weeks Liquid medium : 8-14 days Agar medium : 7 to 14 days

9. Radiography: Chest X-Ray(CXR) Nucleic acid amplification: Species identification ; several hours Low sensitivity, high cost Most useful for the rapid confirmation of tuberculosis in persons with AFB-positive sputum AFB-negative pulmonary tuberculosis Extra pulmonary tuberculosis

10. Tuberculin skin test (PPD) Injection of fluid into the skin of the lower arm. 48-72 hours later – checked for a reaction. Diagnosis is based on the size of the wheal. 1 dose = 0.1 ml contains 0.04 μ g Tuberculin PPD.

11. Interpretation of skin test

12. Preventive measures 1) Mask 2) BCG vaccine 3) Regular medical follow up 4) Isolation of Patient 5) Ventilation 6) Natural sunlight 7) UV germicidal irradiation

13. Management

14. BCG vaccine Bacille Calmette Guerin (BCG). First used in 1921. Only vaccine available today for protection against tuberculosis. It is most effective in protecting children from the disease. Given 0.1 ml intradermally. Duration of Protection 15 to 20 years Efficacy 0 to 80%. Should be given to all healthy infants as soon as possible after birth unless the child presented with symptomatic HIV infection

15. According to their clinical utility, the anti- tubercular drugs have been classified as follows: First line anti-tubercular drugs: These drugs are highly effective with low toxicity profile. These drugs are the first choice drugs and are used in routine. These drugs are always given in combinations for therapeutic purpose.

16. Second line anti-tubercular drugs: These drugs have medium anti-tubercular efficacy. The toxic effects of these drugs appear due to the longer duration of anti-tubercular therapy. These drugs are used as reserve drugs and always given in different combinations with first line drugs.

17. FIRST LINE DRUGS SECOND LINE DRUGS Rifampin (R) Isoniazid (H) Ethambutol (E) Pyrazinamide (Z) Streptomycin (S)   Rifabutin Thiacetazone Ethionamide Prothionamide Cycloserine Para- aminosalicylic acid Fluoroquinolones Moxifloxacin Ciprofloxacin Ofloxacin Levofloxacin Injectable drugs Kanamycin Amikacin Capreomycin  

18. ISONIAZID (isonicotinic acid hydrazide, H) Isoniazid (INH) is an essential component of all antitubercular regimens. It is primarily a tuberculocidal drug. It kills the fast multiplying organisms rapidly. The dormant organisms are inhibited only. It acts both on extracellular as well as intracellular TB (bacilli present within macrophages), and is equally active both in acidic and alkaline medium.

19. Mechanism of action INH acts by inhibiting the synthesis of mycolic acids in the mycobacterial cell wall. The mycobacterial cell wall is composed as fatty acid known as mycolic acids. Inhibiting mycolic acid leads to a disruption in the mycobacterial cell wall and consequently cell death. INH has good resistance preventing action also.

20. Pharmacokinetics Isoniazid is readily absorbed after oral administration. Absorption is impaired if it is taken with food, particularly high-fatty meals. The drug diffuses into all body fluids, cells, and caseous material ( necrotic tissue resembling cheese that is produced in tuberculous lesions ). The CSF concentration attained is equal to that in plasma. The metabolism occurs in liver and excretion via kidneys.

21. Adverse effects Peripheral neuritis and a variety of neurological manifestations (paresthesia, numbness, mental disturbances, rarely convulsions) are the most important dose-dependent toxic effects. Hepatitis, a major adverse effect, is common in older people, but rare in children. It is due to dose-related damage to hepatocytes and is reversible on stopping the drug. Other side effects are lethargy, rashes, fever, acne and arthralgia. Pyridoxine given prophylactically (10 mg/day) prevents the neurotoxicity. Prophylactic pyridoxine must be given to diabetics, chronic alcoholics, malnourished, pregnant, lactating and HIV infected patients. INH neurotoxicity is treated by pyridoxine 100 mg/day.

22. RIFAMYCINS (Rifampin (Rifampicin, R), Rifabutin, and Rifapentine) Rifampicin has broader antimicrobial activity than isoniazid and can be used as part of treatment for several different bacterial infections. Rifampicin is a semisynthetic derivative of Rifamycin. It has bactericidal action on Mycobacterium tuberculosis and all its subpopulations. M. leprae is also highly sensitive. It is also acts similarly against a number of gram-positive and gram-negative bacterias .

23. It acts best on the slow/intermittent dividing bacilli ( spurters ). The cidal effect of rifampicin is similar to INH. It shows bactericidal effect on both extracellular and intracellular organisms. It has good sterilizing action ( making sputum AFB negative ) and the only drug, which shows cidal effect on persisters . It has good resistance preventing action also.

24. Mechanism of Action Rifampicin blocks mycobacterial DNA-dependent RNA polymerase enzyme, which inhibits RNA transcription and leads to bacterial cell death. This action is selective to mycobacterium only and not seen in human cells.

25. Pharmacokinetics It is well absorbed orally and the bioavailability is nearly 70%. Its absorption decreases when taken with food; Hence, it should be taken empty stomach only. It is widely distributed in the body and penetrates intracellularly, enters tubercular cavities, caseous masses and placenta. It is converted to an active metabolite in liver, which is excreted mainly in bile & to lesser extend in the urine and undergoes enterohepatic circulation. It has variable plasma t½ ranging from 2–5 hrs.

26. Adverse effects Hepatitis, a major adverse effect, is dose-related and generally occurs in hepatic impaired patients. It is rarely seen with a dose less than 600 mg/day. Jaundice, if occurs, is reversible on discontinuation of the drug. Minor adverse reactions are nausea, vomiting, abdominal cramps, flu like syndrome and cutaneous syndrome in which patient presents as flushing, pruritus & rash. [Note: Urine, faeces , sweat and other secretions become orange-red in color, so patients should be informed in advance that it is harmless. Tears may even stain soft contact lenses orange-red.]

27. Other uses of Rifampicin Rifampicin is used in the treatment of Leprosy. It is used in prophylaxis of Meningococcal and H. influenzae meningitis and carrier state. Rifampicin+ Doxycycline is the first line therapy of brucellosis

28. RIFABUTIN Rifabutin is a derivative of rifampin, and is preferred for TB patients coinfected with the human immunodeficiency virus (HIV) who are receiving protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Rifabutin is a less potent inducer of cytochrome P450 enzymes as compared to rifampicin. Hence, drug interactions are less. Rifabutin has adverse effects similar to those of rifampicin but can also cause uveitis, skin hyperpigmentation, and neutropenia.

29. Rifapentine It is a rifampin congener. Used against M. tuberculosis and MAC. Rifapentine is as potent an enzyme inducer as rifampin. The only indication of rifapentine (600 mg once/twice weekly) is in the continuation phase of treatment of TB, as a substitute of daily rifampin. Once weekly rifapentine combined with INH has also been employed to treat latent TB.

30. PYRAZINAMIDE (Z) Pyrazinamide (Z) is chemically similar to INH. It is weakly tuberculocidal and more active in acidic medium. It is more lethal to intracellularly located bacilli and to those at sites showing an inflammatory response (pH is acidic at both these locations). It is highly effective during the first 2 months of therapy. By killing the residual intracellular bacilli it has good ‘sterilizing’ activity.

31. Mechanism of action It is not well established, but like INH, it is also converted inside the mycobacterial cell into an active metabolite pyrazinoic acid by an enzyme pyrazinamidase . This metabolite gets accumulated in acidic medium and probably inhibits mycolic acid synthesis.

32. Pharmacokinetics Pyrazinamide is absorbed orally and widely distributed. It has good penetration in CSF due to which it is highly useful in meningeal TB. The metabolism occurs in liver and excretion via kidneys. The plasma t½ is 6–10 hours. Adverse effects The dose related side effect is hepatotoxicity. Other adverse effects are abdominal distress, hyperuricemia, arthralgia, flushing, rashes, fever and loss of diabetes control.

33. ETHAMBUTOL (E) Ethambutol is a tuberculostatic antitubercular drug. It is more active against fast multiplying bacilli. It helps the early conversion of sputum positive patients to sputum negative ones when added to the triple drug regimen of RHZ. Primarily, it is used to prevent development of drug resistance.

34. Mechanism of action The exact mechanism of action of ethambutol is unknown. Probably, it interferes with the mycolic acid incorporation in mycobacterial cell wall. Pharmacokinetics It is absorbed orally and is widely distributed in all compartment of body. It penetrates meninges in completely and is temporarily stored in RBCs. The excretion occurs via kidneys through glomerular filtration as well as tubular secretion. The plasma t½ is nearly 4 hrs.

35. Adverse effects The most important dose and duration dependent side effect is Optic neuritis. It causes loss of visual acuity, colour vision and field defects . In colour vision defect, there is loss of ability to differentiate between red and green colour. Hyperuricemia may occur due to interference with urate excretion

36. DRUG ADVERSE EFFECTS COMMENTS Isoniazid Hepatic enzyme elevation, hepatitis, peripheral neuropathy. Take baseline hepatic enzyme measurements; repeat if abnormal or patient is at risk or symptomatic. Clinically significant interaction with phenytoin and Carbamazepine. Rifampicin Hepatitis, GI upset, rash, flu-like syndrome, significant interaction with several drugs. Take baseline hepatic enzyme measurements and CBC; Repeat if abnormal or patient is at risk or symptomatic. Warn patient that urine and tears may turn red-orange in color. Ethambutol Optic neuritis with blurred vision, red-green color blindness Establish baseline visual acuity and color vision; test monthly. Pyrazinamide Nausea, hepatitis, hyperuricemia, rash,arthralgia, gout (rare) Take baseline hepatic enzymes and uric acid measurements; repeat if abnormal or patient is at risk or symptomatic.

37. STREPTOMYCIN (S) The pharmacology of streptomycin has been already described with aminoglycosides. It was the first clinically useful antitubercular drug. The tuberculocidal effect is less as compare to INH or Rifampicin. It exerts its effect on extracellular bacilli only (because of poor penetration into cells). It penetrates tubercular cavities, but does not cross the CSF, and has poor action in acidic medium. It has lower margin of safety. Ototoxicity & nephrotoxicity are the major side effects like other aminoglycosides. Streptomycin is used in addition to other ATT in DOTs category-II for a period of two months. It is also labelled as a ‘ supplemental ’ first line drug.

38. SECOND LINE ANTI-TUBERCULAR DRUGS Second line anti-tubercular drugs are more toxic and less efficacious as compared to first line anti-TB drugs. These are used when the tubercular bacilli show a resistance to the first line antitubercular drugs or when first line anti – TBdrugs are not tolerated or contraindicated

39. Kanamycin (Km), Amikacin (Am) These are tuberculocidal aminoglycosides and very much similar to streptomycin in antitubercular activity, pharmacokinetic properties and adverse effects. Many streptomycin resistant and MDR strains of M.tuberculosisare sensitive to these drugs. During the intensive phase of MDR-TB treatment,one of these drugs is mostly included in the regimen. The RNTCP standardized regimen for MDR-TB includes kanamycindue to its lesser cost as compared to amikacin. It is administered intramuscularly in an OD dose of 0.75–1.0 g/day (10–15 mg/kg/day).

40. Capreomycin (Cm) It is chemically very different from aminoglycosides, but has similar bactericidal activity against Mycobacterium . It is administered by i.m . route. It is used only as an alternative to Streptomycin and Amikacin resistant M. tuberculos is. It is administered intramuscularly in an OD dose of 0.75–1.0 g/day.

41. Fluoroquinolones The fluoroquinolones are potent oral bactericidal drugs for TB. The preferred ones are moxifloxacin and levofloxacin. They have an important place in the treatment of multidrug-resistant tuberculosis as they penetrate cells and kill mycobacteria lodged inside the macrophages. The Antitubercular Doses are: Moxifloxacin-400mgOD, Levofloxacin-750mgOD, Ofloxacin -800 mg OD.

42. Ethionamide This is sulfur containing structural analog of isoniazid that also disrupts mycolic acid synthesis. It acts on both extracellular and intracellular bacilli. It is widely distributed in all compartment of the body, including the CSF. The metabolism occurs in liver with plasma t½ of 2-3 hrs. Adverse effects are anorexia nausea, sulfurous belching, vomiting, hepatotoxicity and peripheral neuritis. Pyridoxine (100 mg/day) can be used to treat the neurological adverse effects. Ethionamide is given in escalated dosage schedule as follows: 250 mg/day, and increased every 5–6 days to reach 750 mg daily (10–15 mg/kg/day). This is done to improve tolerance.

43. Cycloserine This is an orally effective tuberculostatic drug. It disrupts d-alanine incorporation into the bacterial cell wall. It is well distributed in all compartment of the body, including the CSF. The only 1/3 fraction in liver and the remaining part is excreted via kidneys in a unchanged form.

44. Cycloserine Commonly seen side effects are CNS disturbances like lethargy, anxiety, and suicidal tendency. Therefore, in patients with history of seizure and other mental illness, it is contraindicated. Pyridoxine (100 mg/day) can be used to treat the neurological adverse effects. It is given in escalated dosage schedule as follows::Start with 250 mg BD and increase to750 mg/day, if tolerated.

45. Para-amino salicylic acid (PAS) PAS acts by the same mechanism as sulfonamides. It is tuberculostatic and one of the least active drug. It is absorbed completely by the oral route and distributed all over body except in CSF. Some of the common side effects are anorexia, nausea, epigastric pain, rashes, fever, malaise, hypokalaemia , goiter, liver dysfunction and rarely blood dyscrasias. PAS is used only in resistant TB when one of the tuberculocidal drugs or static drugs cannot be used. PAS is given in divided doses of 10–12 gm daily.

46. TREATMENT OF TUBERCULOSIS In the previous days, the full treatment course for a tuberculosis patient used to be for nine to twelve months. The therapy of tuberculosis has undergone remarkable changes now. The ‘conventional’ treatment has been replaced by more effective and less toxic 6 months (short course) treatment. Due to shortening of duration of treatment, the treatment completion rate has increased.

47. SHORT COURSE CHEMOTHERAPY(DOTS)   After several years of trials, the WHO introduced 6–8 months multidrug ‘short course’ regimens in 1995 under DOTS programme ( D irectly O bserved T reatment, S hort course chemotherapy ). In DOTS Programme, the patients are treated in two phases. All regimens have an initial intensive phase with 4–5 drugs given for 2–3 months and a continuation phase with 2–3 drugs lasting 4–5 months.

48. The aim of intensive phase is: To kill the Mycobacterium rapidly. To bringing about rapid sputum conversion ( from sputum positive to sputum negative). To provide fast symptomatic relief. The aim of continuation phase is: To eliminate there manning bacilli so that relapse does not occur.

49. Previously, there used to be three categories of tuberculosis patients for the purpose of treatment under DOTS. These were Category I, Category II and Category III. New guidelines with revised categorization of patients were brought out in 2010. According to these guidelines, the category III was merged with category I, and patients of TB are now classified as ‘ New cases’ or category I patients , ‘Previously treated’ or category II patients, and Drug resistant MDR-TB patients .

50. New patients (Category I patients) The new smear positive TB patients who in the past have never been exposed to anti-TB drugs are called New patients or Category I patients. In these type of patients, the intensive phase treatment for two months is started with Four drugs (HRZE) which includes three bactericidal drugs. This reduces the risk of bacilli becoming resistant. After the intensive phase, the continuation phase is started which includes two highly effective mycobactericidal drugs (HR). This phase is continued for four months, which is enough for effective cure as only few bacilli are left after the intensive phase.

51. Previously treated patients (Category II patients) The smear positive TB patients who in the past had been exposed to anti-TB drugs, but did not complete the course or took inadequate/irregular medication, or relapsed after responding, or failed to respond run a higher risk of harboring drug resistant (DR) bacilli. These type of patients are included in previously treated or Category II patients. In these type of patients, the intensive phase treatment is started with Five drugs (HRZES) which includes four bactericidal drugs. The 1 st line drugs HRZES (5 drugs) are given daily for 2 months and HRZE (4 drugs) for another one month. This is followed by the continuation phase of 3 drugs (HRE) for the next 5 months.

52. Recommended doses of antitubercular drugs DRUG Daily dose maximum mg/kg dose 3 times per week dose mg/kg daily maximum Isoniazid (H) 5 (4–6) 300 mg 10 (8–12) 900 mg Rifampin (R) 10 (8–12) 600 mg 10 (8–12) 600 mg Pyrazinamide (Z) 25 (20–30) - 35 (30–40) - Ethambutol (E) 15 (15–20) - 30 (25–35) - Streptomycin (S)* 15 (12–18) - 15 (12–18) 1000 mg * Patients over 60 years age—10 mg/kg or 500–750 mg/day ( i.m .). [Adopted from Treatment of Tuberculosis: Guidelines, 4th edition (2010), WHO, Geneva]

53. Category-wise treatment regimens for tuberculosis Category Intensive phase Continuation phase Duration (months) Comment I New patient 2* HRZE daily 4* HR daily 6* Optimal 2 HRZE daily 4 HR thrice weekly 6 Acceptable if DOT ensured 2 HRZE thrice weekly   4 HR thrice weekly 6   Acceptable if DOT ensured, and no HIV coinfection or its risk II Previously treated patients pending DST result 2 HRZES daily + 1 HRZE daily 5 HRE daily 8 For patient with low/medium risk of MDR-TB (failure, default, etc.) Empirical** (Standardized) MDR-regimen Empirical (Standardized) MDR-regimen 18–24 or till DST result For patient with high risk of MDR-TB (failure, 2nd default, contact of MDR-TB. DST—Drug sensitivity testing; DOT—Directly observed therapy H, R, Z, E, S—Standard codes for isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin, respectively. *—The neumerals indicate duration of a phase/total duration in months. **—Empirical (Standardized) MDR regimen is country specific depending upon local data and situation (adopted from WHO guidelines 2010)

54. MULTIDRUG-RESISTANT (MDR) TUBERCULOSIS When the tuberculosis is due to the tubercular bacilli resistant to both INH & rifampicin and may be any number of other first line drug/drugs, it is called multidrug-resistant (MDR) tuberculosis. It has a more rapid course with worse outcomes. Its treatment requires complex multiple 2nd line drug regimens, which are more expensive, more toxic, and has to be given for longer duration.

55. GENERAL PRINCIPLES OF MDR-TB TREATMENT The regimen often includes 5–6 drugs, out of which at least 4 drugs should be certainly effective as efficacy of some drugs may be uncertain. The regimen includes drugs from group I to group IV ( alternative classification ) in a hierarchical order. Group I drugs (except H and R) can be included, add one injectable drug (group II), One FQ (group III) and one or two group IV drugs.

56. Cont … Bedaquiline fumarate, a newer anti-tubercular drug has been recently approved by US-FDA for multi-drug resistant tuberculosis. Pyridoxine 100 mg/day is given to all patients during the whole course of therapy to prevent neurotoxicity of the anti-TB drugs.

57. RNTCP regimen for MDR-TB Intensive phase (6–9 months) Continuation phase (18 months) Kanamycin (Km) Ofloxacin or Levofloxacin Ofloxacin or Levofloxacin Ethionamide Ethionamide (Eto) Cycloserine Cycloserine (Cs) Ethambutol Pyrazinamide (Z)   Ethambutol (E) + Pyridoxine 100 mg/day

58. Extensively drug-resistant tuberculosis (XDR-TB) The MDR-TB cases, which are also resistant to Fluoroquinolones, One of the injectable second line drugs and May be any number of other drugs, are called as XDR-TB patients. The bacilli are resistant to at least 4 most effective mycobactericidal drugs, viz. H, R,FQs and one of kanamycin or amikacin or capreomycin. The Extensively drug-resistant tuberculosis (XDR-TB) patients are very difficult to treat.

59. The RNTCP (2016) has recommended a treatment regimen for XDR-TB consisting of 7 drugs in the intensive phase (6-12 months) and 6 drugs in the continuation phase ( 18 months). The drugs and their adult daily doses (for 46-70 kg body weight). Drugs Doses Capreomycin 1000 mg Moxifloxacin 400 mg High dose isoniazid 900 mg Clofazimine 200 mg Linezolid 600 mg PAS 12 g Amoxicillin/clavulanate (875+125 mg tab) 2 tab morning + one tab evening. In the continuation phase, injection capreomycin is stopped and the remaining 6 drugs are continued for another 18 months.

60. Tuberculosis treatment in pregnant women The standard 6 months (2HRZE +4HR) regimen can be given to pregnant women with TB (The WHO and British Thoracic Society recommendations) . Streptomycin is contraindicated because it is ototoxic to the foetus . Treatment of TB should not be withheld or delayed because of pregnancy . All pregnant women being treated with INH should also receive pyridoxine 10–25 mg/day

61. Tuberculosis treatment in breastfeeding women All anti-TB drugs are compatible with breastfeeding. Full course of ATT should be given to the mother. The infant should receive BCG vaccination and6-months isoniazid preventive treatment after ruling out active TB. The children are given INH in a dose of 10mg/kg for 6months.

62. Chemoprophylaxis of Tuberculosis   The Aim of chemoprophylaxis is to prevent progression of latent tubercular infection to active disease. The standard drug for chemoprophylaxis of TB is Isoniazid (H) 300 mg (10 mg/kg in children) daily for 6 months. The candidates for chemoprophylaxis are as follows: Contacts of open cases that show recent Montoux conversion. Children with positive Montoux test and a TB patient in the family. Neonate of the tubercular mother. Patients of leukaemia, diabetes, silicosis, or those who are HIV positive but are not anergic, or are on corticosteroid therapy who show a positive Montoux test. Patients with old inactive disease who are assessed to have received inadequate therapy.

63. CORTICOSTEROIDS THERAPY IN TUBERCULOSIS   Corticosteroids should not be used in routine in tubercular patients. However, they are used: In miliary or severe pulmonary TB patients till the antitubercular drugs start acting When patients show sensitivity to antitubercular drugs. To reduce exudation and to prevent strictures formation in organ TB. Corticosteroids are contraindicated in intestinal tuberculosis as because perforation of intestines remains silent(painless and with poorly localized symptoms) . *Precaution: Corticosteroids should always be tapered gradually when the general condition of the patient improves.

64. TUBERCULOSIS TREATMENT IN AIDS PATIENTS   In case of M. tuberculosis infection in HIV patients, drugs used are the same as in non-HIV cases. Initial intensive phase therapy with daily HRZE for 2 months is started immediately on the diagnosis of TB. It is followed by a continuation phase of HR for 4–7 months (total 6–9 months). Thrice weekly regimen is not advised due to chances of relapse among HIV positive patients. In addition, the risk of acquiring resistance to Rifampicin is increased as compared to daily treatment.

65. Mycobacterium avium complex (MAC} infection MAC is an opportunistic pathogen which causes disseminated and multi focal disease in immunocompromised (HIV-AIDS) patients. The disease develops when cell mediated immunity is markedly depressed, i.e. when CD4 count drops to <50 cells/ μ L , HIV-RNA load is high and other opportunistic infections (P. jirovecii , etc.) are also present.

66. BEDAQUILINE Bedaquiline fumarate, a newer anti-tubercular drug has been recently approved by US-FDA for multi-drug resistant tuberculosis. It is included in the WHO list of essential drugs. Mechanism of Action It inhibits mycobacterial ATP (adenosine 5’-triphosphate) synthase, by binding to subunit c of the enzyme. This enzyme is essential for the production of energy [ATP] in M. tuberculosis.

67. Pharmacokinetics It is well absorbed orally with wide distribution in all compartments of body. The metabolism occurs in liver and excretion via faeces . The plasma t ½ is approximately 5.5 months. Indications: Pulmonary MDR TB. Dosage schedule: 400 mg once daily orally for initial two weeks then 200 mg thrice weekly upto 24 th week. The total duration of treatment is upto 24 th week only. Adverse effects Commonly seen adverse effects are, nausea, headache, arthralgia. It also leads to QT prolongation and increases liver enzyme levels. https:// tbcindia.gov.in / showfile.php?lid =3246

68. Leprosy

69. Leprosy is also known as Hansen’s disease and is caused by Mycobacterium laprae . It primarily affects skin, mucous membranes and nerves. It is more prevalent among the lowest socioeconomic population. It was considered incurable since ages. The antileprotic drugs can cure the disease but not the deformities or defects which have already in occurred. The deformities can be corrected to some extent by surgery only. In India, Multi-Drug Therapy [MDT] was introduced for the treatment of leprosy as apart of National Leprosy Eradication Programme (NLEP)in 1982.

70. Status in the Country The year 2016-17 started with 0.86 lakh leprosy cases on record as on 1st April 2016, with PR 0.66/10,000. Till then 34 States/ UTs had attained the level of leprosy elimination. 554 districts (81.23%) out of total 682 districts also achieved elimination by March 2017.

71. Sign & symptoms The first noticeable sign of leprosy is often the development of pale or pinkish patches of skin that may be insensitive to temperature or pain. This is sometimes accompanied or preceded by nerve problems including numbness or tenderness in the hands or feet.

72. Types

73. Risk factors The greatest risk factor for developing leprosy is contact with another case of leprosy. Contacts of people with leprosy are five to eight times more likely to develop leprosy than members of the general population. Leprosy also occurs more commonly among those living in poverty.

74. Diagnosis Clinically Lepromin skin test Biopsy

75. Management Drug Class Drugs Sulfone Dapsone (DDS) Phenazine derivatives Clofazimine Antitubercular drugs Rifampicin & Ethionamide Other antibiotics Ofloxacin, Minocycline, Moxifloxacin & Clarithromycin

76. DAPSONE (DDS) Dapsone is the oldest, most active and most commonly used drug. At very low concentrations, it is leprostatic and at relatively higher concentrations, it is cidal to many other sulfonamide sensitive bacteria. Dapsone is active against certain protozoa and shows some anti-inflammatory activity also.  

77. Mechanism of Action : Dapsone is chemically related to sulfonamides and has the same mechanism of action i.e. inhibition of PABA incorporation into folic acid by folate synthase

78. Pharmacokinetics It is well absorbed orally with a widely distribution in different body parts but, penetration in CSF is poor. It is concentrated in skin (especially lepromatous skin), muscles, liver and kidney. The plasma protein binding is 70%. The metabolism occurs in liver & excretion occurs in urine. The Metabolites undergo enterohepatic circulation . The plasma t½ is more than 24 hrs. Due to retention in tissues and enterohepatic circulation, the elimination may take 1–2 weeks or longer.

79. Adverse effects Dapsone is generally well tolerated. Some dose related side effects like haemolytic anaemia and gastric intolerance can occur in some patients. Patients with G-6-PD deficiency are more susceptible to haemolysis at doses > 50 mg/day. It is contraindicated in severe anaemia ( Hb < 7 g/dl), G-6-PD deficiency and in patients who are hypersensitive to dapsone.

80. Indications Multibacillary and paucibacillary leprosy. Other than leprosy: Chloroquine resistant malaria, toxoplasmosis, and P. jirovecii infection [in combination with pyrimethamine].

81. SULFONE SYNDROME This reaction develops 4–6 weeks after starting dapsone therapy. It appears with fever, malaise, lymphadenopathy, desquamation of skin, jaundice, and anaemia. This reaction has become frequent after the introduction of MDT and mostly seen in malnourished patients. Some or all of the above symptoms may occur. The treatment of this syndrome includes Stopping dapsone, Corticosteroid therapy and Supportive measures.

82. CLOFAZIMINE ( Clo )  Clofazimine is a dye with leprostatic and anti-inflammatory properties. Mechanism of action In M. leprae , it inhibits the mycobacterial growth by interfering with the template function of DNA, altering the membrane structure and disrupting the mitochondrial electron transport chain.

83. Pharmacokinetics It is absorbed orally (40–70%) and accumulates in macrophages and gets deposited in many tissues including subcutaneous fat. The CSF penetration is poor. The plasma t½ is 70 days. Dose: 50 -100 mg once daily.

84. Adverse effects clofazimine may lead to photosensitivity in which reddish-black discolouration of skin ( specially exposed parts ) occurs. Discolouration of hair, conjunctiva and body secretions cause cosmetic problems. Dryness of skin and itching can also occur. Clofazimine should be avoided during early pregnancy and in patients with poor liver or kidney functions.

85. Indications Leprosy [as a component of multidrug therapy (MDT)] Lepra reaction [due to its anti-inflammatory property]

86. RIFAMPICIN (R) It is the most potent cidal drug for M.leprae . The leprosy patients are made noncontagious within 3–7 days of starting therapy with rifampicin as 99.99% M.leprae are killed within this period. It is not given alone but has been included in the MDT of leprosy whereby it shortens the duration of treatment and prevents the development of resistance.

87. In MDT, rifampicin is given in a 600 mg monthly dose. It is effective and practically non-toxic. It should not be given during ‘ erythema nodosum leprosum ’ (ENL) and ‘ reversal reaction ’ in leprosy patients, because it can release large quantities of mycobacterial antigens by inducing rapid bacillary killing. It should be avoided in renal and hepatic compromised patients.

88. FLUOROQUINOLONES Many fluoroquinolones like ofloxacin and moxifloxacin are highly effective against Myocobacterium leprae . The most commonly used FQ in leprosy is ofloxacin. It is cidal to M. leprae . It is used only when rifampicin is intolerable. Dose: 400 mg daily.

89. MINOCYCLINE It has good antileprotic activity, but lesser than rifampicin. It penetrates the M. leprae as well. It is a part of alternative MDT regimens.

90. TREATMENT OF LEPROSY The most commonly used classification of leprosy was given by Ridley and Jopling in 1966 and leprosy was divided into: Lepromatous (LL) Borderline lepromatous (BL) Borderline (BB) Borderline tuberculoid (BT) Tuberculoid (TT) The two extreme types are Tuberculoid ( mild form ) and Lepromatous ( severe form ) types.

91. Tuberculoid leprosy (TT) Lepromatous leprosy (LL) Anaesthetic patch Diffuse skin and mucous membrane infiltration, nodules Cell mediated immunity (CMI) is normal CMI is absent Lepromin test—positive, Bacilli rarely found in biopsies Lepromin test-negative, Skin and mucous membrane lesions teeming with bacilli Prolonged remissions with periodic exacerbations Progresses to anaesthesia of distal parts, atrophy, ulceration, absorption of digits, etc.

92. For operational purposes WHO has divided leprosy into: Paucibacillary leprosy (PBL) Patient has few bacilli and is noninfectious. It includes the TT and BT types. Multibacillary leprosy (MBL) Patient has large bacillary load and is infectious. It includes the LL, BL and BB types.

93. WHO reclassified leprosy in 1998 into Single lesion paucibacillary leprosy (SLPB) : With a solitary cutaneous lesion. Paucibacillary leprosy (PB): With 2–5 skin lesions. Both SLPB and PB cases are skin smear negative for M. leprae . Multibacillary leprosy (MB): With > 6 skin lesions, as well as all smear positive cases.

94. The classification being followed by NLEP since 2009 Paucibacillary (PB) Multibacillary (MB) 1-5 skin lesions No nerve/only one nerve involvement, + 1–5 skin lesions. Skin smear negative at all sites. 6 or more skin lesions >1 nerve involved irrespective of number of skin lesions. Skin smear positive at any one site.

95. Multidrug therapy (MDT) of leprosy Drugs Multibacillary Leprosy Paucibacillary Leprosy Rifampicin 600 mg once in a month (under supervision) 600 mg once in a month (under supervision) Dapsone 100 mg daily self administered 100 mg daily self administered Clofazimine 300 mg once a month supervised and 50 mg daily self administered - Duration 12 months 6 months Doses should be reduced suitably for children.

96. ALTERNATIVE REGIMENS The alternative regimens are used only in case of rifampin-resistance or when it is not possible to employ the standard MDT regimen. Some of these regimens are : Intermittent ROM : R ifampin 600 mg + O floxacin 400 mg+ M inocycline 100 mg are given once a month for 3–6 months for PBL and for 12 or 24 months for MBL cases Single dose ROM: A single dose of rifampin + ofloxacin+ minocycline was given for single lesion PBL, but this has been discontinued now. Intermittent RMMx : Moxifloxacin 400 mg + Minocycline 200 mg + Rifampicin 600 mg is given once a month: Total six doses for PBL and 12 doses for MBL are given.

97. Reactions in leprosy Two types of reactions can occur in the patients of leprosy. The reaction occurring on start of treatment is known as Lepra reaction and that on completion of therapy is known as Reversal reaction .

98.   Lepra reaction (ENL) Reversal reaction Seen in LL TT and BL Time of Start Coincides with institution of chemotherapy and/or any intercurrent infection. Occurs suddenly even after completion of therapy. Cause Jarish Herxheimer ( Arthus ) type of reaction due to release of antigens from the killed bacilli. A manifestation of delayed hypersensitivityto M. leprae antigens. Symptoms Abrupt onset; existing lesions enlarge, become red, swollen and painful; several new lesions may appear. Malaise, fever and other constitutional symptoms generally accompany and may be marked.   Cutaneous ulceration, multiple nerve involvement with swollen, painful and tender nerves, occurs suddenly. Severity May be mild, severe or life-threatening, i.e. erythema nodosum leprosum (ENL) Moderately severe form. Treatment 1.Temporary discontinuation of dapsone. 2. Clofazimine(200 mg daily) 3. Prednisolone 40–60 mg/day 4.Thalidomide100–300 mg OD at bed time as an alternative to Prednisolone. 1. Clofazimine (200 mg daily) 2. Prednisolone 40–60 mg/day 3. Thalidomide is ineffective.  

99. Post Exposure Chemoprophylaxis Post Exposure Chemoprophylaxis is any preventive medical treatment started immediately after exposure to a pathogen, in order to prevent infection by the pathogen and the development of disease

100. Eligibility criteria for PEP Inclusion criteria A person who has been living/working/having social activities for more than three months and 20 hrs/ wk with a newly detected case of leprosy in the last 1 yr. Age ≥2 years.

101. Exclusion criteria Pregnant women (PEP can be given after delivery). People receiving rifampicin therapy for any reason in the last two years (e.g. for tuberculosis [TB] or 5 leprosy treatment, or as a contact from another index case). People with a history of liver disorders (ask for H/o jaundice, right sided abdominal pain and swelling, swelling in legs and ankles, pale coloured stool) or renal disorders (ask for H/o decreased urine output, swelling in legs and ankles, H/o high BP). People who have possible signs and/or symptoms of leprosy.

102. Cont … People who have possible signs and/or symptoms of TB (patients having any of the following symptoms should be screened for TB: cough for more than two weeks, night sweats, unexplained fever, weight loss). Person with acute febrile illness.

103. Single-dose rifampicin prophylaxis > 35 kg – 600 mg 20 – 35 kg – 450 mg < 20 kg – 10-15 mg/kg