GENERAL MANNUAL FOR TUBERCULOSIS CONTROL

Transcription

1 GENERAL MANNUAL FOR TUBERCULOSIS CONTROL National programme for Tuberculosis Control and Chest Diseases Ministry of Health Sri Lanka January 2005

2 GENERAL MANUAL FOR TUBERCULOSIS CONTROL Second Edition National Programme for Tuberculosis Control and Chest Diseases Ministry of Health Sri Lanka January 2005 i

3 NPTCCD-2005 International Consultant Dr. Shantha Devi Thottikkamath National Consultant Dr. Vessamitta R. Weeraratna First Edition 1997 ii

4 CONTENTS Foreword Preface Abbreviations and acronyms vi vii viii Introduction 1 PART I BASIC INFORMATION ON TUBERCULOSIS AND TECHNICAL GUIDELINES FOR TUBERCULOSIS CONTROL 3 1. Tuberculosis 5 2. Classification of Tuberculosis 9 3. Diagnosis of Tuberculosis Treatment of Tuberculosis Essential (First line) anti-tb drugs Monitoring of treatment Tuberculosis and HIV Pregnancy and Tuberculosis Role of BCG vaccination Prevention of Tuberculosis Multidrug-resistant TB 56 PART II OPERATIONAL GUIDELINES FOR TUBERCULOSIS CONTROL Objectives and strategy of National Tuberculosis Programme National Tuberculosis Programme Tuberculosis case finding Treatment and follow up of TB patients Recording and Reporting Supervision Evaluation Training Management of drugs and supplies 96 iii

5 10. Intersectoral co-ordination 97 PART III ADMINISTRATION OF A CHEST CLINIC District Chest Clinic Drug supplies Issue of medical certificates 106 LIST OF FLOW CHARTS Flow Chart I Treatment and follow up of new smear-positive PTB cases (CAT 1) 25 Flow Chart II Treatment and follow up of Re-treatment cases (CAT 2) 26 Flow Chart III Treatment and follow up of smear-negative PTB cases 27 Flow Chart IV Management of TB suspects at Peripheral Health Institutions 76 Flow Chart V Management of TB suspects at District Chest Clinics 79 LIST OF FIGURES Figure I Classification of Tuberculosis 12 Figure II Anti-TB drug management cycle 96 LIST OF TABLES Table 1 Case definition, Treatment Categories and Recommended Regimens 20 Table 2 WHO recommended formulations of FDC 24 Table 3 Actions in interruption of TB treatment 31 Table 4 Number of tablets of FDC used in CAT 1 and CAT 2 37 Table 5 Adverse effects of first line anti-tb drugs 38 Table 6 Symptom based management of side-effects of Anti-TB drugs 39 Table 7 Re introduction of anti-tb drugs following drug induced hepatitis after LFTs return to normal 41 Table 8 Re-introduction of anti- TB drugs following drug reaction 43 Table 9 Schedule for follow up sputum examination 45 iv

6 Table 10 How PTB differs in early and late HIV infection 48 Table 11 Dosages and mode of action of reserve anti-tuberculosis drugs 59 Table 12 Suggested treatment regimen for MDR-TB (WHO) 60 Table 13 Training schedule for operational staff of the NTP 95 ANNEXES Annex 1 Organization of the NPTCCD 111 Annex 2 Tuberculosis Treatment Card 113 Annex 3 Tuberculosis Follow up Card 115 Annex 4 District Tuberculosis Register 117 Annex 5 Tuberculosis Laboratory Register 119 Annex 6 Request for Sputum Examination form 121 Annex 7 Request for Tuberculosis Culture and Drug Susceptibility Test form 123 Annex 8 Transfer/Referral Form for Tuberculosis Patients 125 Annex 9 Quarterly Report on Case Finding 127 Annex 10 Quarterly Report on Sputum Conversion of smear-positive patients at the end of intensive phase 129 Annex 11 Quarterly Report on the Results of Treatment of patients 131 registered months earlier Annex 12 Quarterly Report on Microscopy activities and Logistics 133 Annex 13 Quarterly Report of Programme Management (District level) 135 Annex 14 Quarterly Report TB & non TB wards 143 Annex 15 Quarterly Report Chest Hospital, Welisara 147 Annex 16 Quarterly Report National TB Reference Laboratory 153 Annex 17 Register of TB suspects 157 v

7 FOREWORD Tuberculosis (TB) remains a major & growing public health problem throughout the world. Tuberculosis can affect all sections of society and all countries and communities are vulnerable to this infectious disease. In Sri Lanka about 9,000 cases are detected each year. Tuberculosis can be cured completely through directly observed treatment, short-course (DOTS) which is also the most cost-effective way of controlling the disease. Inadequate treatment of patients, in particular the sputum smear-positive cases can lead to the emergence of Multidrug-resistant tuberculosis in the country. Therefore, it is essential that all tuberculosis patients should be managed according to the national guidelines provided in this manual. This is the second edition of the manual which has been updated giving the information on HIV-related TB, Multidrug-resistant TB (MDR-TB) and the use of Fixed-dose combinations of anti-tuberculosis drugs. The manual will help all health personnel to update their knowledge on tuberculosis and its control. I request all health personnel in the country to adhere to the national guidelines provided in this manual and join hands in addressing the challenge of tuberculosis control. Dr. Athula Kahandaliyanage Director General of Health Services vi

8 PREFACE The National Programme for Tuberculosis control and Chest Diseases has prepared this second edition of General Manual for Tuberculosis Control with the aim to give practical guidance to all those who manage tuberculosis patients. In addition to updating the information already published in the first edition, the information on HIV-related TB, Multidrug-resistant TB (MDR- TB) and the Fixed-dose Combinations of anti-tuberculosis drugs has been included. The identification and cure of infectious TB cases i.e. the patients with smear-positive pulmonary TB is the only way to interrupt the transmission of the disease in the community. These guidelines cover the identification of patients in a very cost-effective manner, the treatment of patients, both adults and children, with smear-positive pulmonary TB, smear-negative pulmonary TB and extrapulmonary TB. The treatment regimens based on standardized short-course chemotherapy and proper case management ensure cure. Standardized treatment is a component of the internationally recommended strategy for TB control known as DOTS. The revised guidelines focus on this strategy. The guidelines given here closely follow the Guidelines for National Tuberculosis Programmes published by WHO. The revision and updating of the manual and the guidelines was done by Dr.(Mrs.) S. D. Thottikkamath and Dr.(Mrs.) V.R. Weeraratna in consultation with the consultant chest physicians and the medical officers of the NPTCCD. Several workshops were held to discuss different aspects of this work and to finalize the chapters. The contents have been perused by the SLMA Committee on Communicable Diseases and their comments were discussed and included. The development and the printing of the manual has been funded by the IDA assisted National HIV/AIDS Prevention Project. This edition is intended for the use by all the medical officers both in the public and private sector in the management of TB patients and I trust that they will adhere to the guidelines laid down here to diagnose the TB patients early in the disease, to ensure cure of the diagnosed patients and to prevent the emergence of Multidrug-resistant TB. I express my sincere thanks to all those who worked hard in developing the second edition. Dr. Chandra Sarukkali Director National Programme for Tubercuosis Control and Chest Diseases vii

9 ABBREVIATIONS AND ACRONYMS ABST - Antibiotic Sensitivity Test AFB - Acid Fast Bacilli AIDS - Acquired Immuno Deficiency Syndrome AMO - Assistant Medical Officer ATT - Anti-tuberculosis Therapy BCG - Bacillus Calmette Guerin BHT - Bed Head Ticket CAT 1 - Category 1 CAT 2 - Category 2 CXR - Chest X-ray CNS - Central Nervous system DDG/PHS - Deputy Director General, Public Health Services DOTS - Directly Observed Treatment Short course DTCD - Diploma in Tuberculosis and Chest Diseases DTCO - District Tuberculosis Control Officer EPI - Expanded Programme of Immunisation EPTB - Extra Pulmonary Tuberculosis FDCs - Fixed Dose Combinations FEFO - First Expired First Out HIV - Human Immuno-deficiency Virus IV - Intravenous LFT - Liver Function Test MDR-TB - Multi Drug-resistant Tuberculosis MLT - Medical Laboratory Technologist MO - Medical Officer MOH - Medical Officer of Health MRO - Medical Records Officer NGO - Non Governmental Organisation NPTCCD - National Programme for Tuberculosis and Chest Diseases NTP - National Tuberculosis Programme PHI - Public Health Inspector PTB - Pulmonary Tuberculosis RMO - Registered Medical Officer RMSD - Regional Medical Supplies Division SCC - Short Course Chemotherapy TB - Tuberculosis VCT - Voluntary Counseling and Testing WHO - World Health Organisation viii

10 INTRODUCTION Tuberculosis continues to be a major public health problem throughout the world, particularly in the developing countries. Nearly one-third of the global population (i.e. two billion people) is infected with M.tuberculosis and is at risk of developing the disease. More than eight million people develop active tuberculosis every year and about two million die of the disease. It is the leading cause of death due to a single infectious agent among adults. The highest burden of the disease is in the most economically productive age group of our society (15-54 years). The rapid increase in the incidence of tuberculosis in the developing countries and its resurgence in the developed countries led the World Health Organization (WHO) to declare Tuberculosis a Global Emergency in The aims of the fight against Tuberculosis are: For individual patients - to cure their disease, quickly restore their capacity for activities of daily living and allow them to be within the family and community and thereby maintain their socio-economic status. For the community - to decrease the spread of tuberculosis infection through early case finding and by appropriate management and cure. Much concerted efforts are needed to control the tuberculosis epidemic. The first priority of tuberculosis control is the appropriate management and cure of tuberculosis patients, especially the infectious cases who are the source of transmission of infection in the community. It is the only way to break the chain of transmission of the disease. The fight against Tuberculosis is best conducted within the setting of a National Tuberculosis Programme (NTP) integrated with the general health services of the country. For effective control of tuberculosis and to prevent emergence of drug resistance, it is important to have a uniform treatment policy for all patients. Close co-operation of all health care providers with the NTP is essential at all levels, for successful implementation of the control programme. Participation of community health workers, religious groups, political leaders, and voluntary organizations is essential to achieve success in tuberculosis control. It is important that the community is made aware of the nature and extent of the problem of tuberculosis as well as its prevention and cure. It must be 1

11 stressed that the disease is curable and preventable and there is no reason for discrimination or stigma. The key in controlling tuberculosis is to ensure that patients take their medicines regularly until they are cured. Non-compliance of patients to treatment is one of the major problems faced by all national tuberculosis programmes. To overcome this, the strategy of Directly Observed Treatment, Short-course (DOTS) has been recommended by the WHO and accepted internationally. DOTS has been recognised as the only proven costeffective method which can ensure cure. Under the DOTS strategy, a trained health worker actually watches the patient swallow his/her medicines, and ensure cure. This is the key to stopping tuberculosis at the source. Community participation will encourage people with symptoms of tuberculosis to seek medical advice for early case detection and improve patients compliance to treatment. Case finding followed by proper treatment reduces suffering, disability and death from tuberculosis and transmission of the disease in the community. 2

12 PART I BASIC INFORMATION ON TUBERCULOSIS AND TECHNICAL GUIDELINES FOR TUBERCULOSIS CONTROL 3

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14 1 TUBERCULOSIS What is tuberculosis (TB)? Tuberculosis is an infectious disease caused by the bacillus- Mycobacterium tuberculosis and occasionally by Mycobacterium bovis and Mycobacterium africanum. Tuberculosis commonly affects the lungs, but it can affect any other organ in the body. How does tuberculosis spread? The bacteria that cause tuberculosis usually spread through air. When a patient with infectious pulmonary tuberculosis coughs, sneezes or laughs, bacilli are expelled into the air in the form of tiny droplets. These droplets dry up rapidly to form droplet nuclei and may remain suspended in the air for several hours. Adequate through and through ventilation removes and dilutes these droplet nuclei, and direct sunlight quickly kills the bacilli, but they can survive in the dark for several days. When a healthy person inhales these droplet nuclei containing the tubercle bacilli, he/she may become infected. Risk of infection An individual s risk of infection depends on the extent of exposure to an infectious source and susceptibility of the individual to infection. The risk of infection is therefore high in a person who has close, prolonged exposure to a person with sputum smear positive pulmonary TB. The risk of transmission of infection from sputum smear-negative pulmonary TB is low and with extrapulmonary TB, still lower. How does TB develop? Tuberculosis develops in two stages. The first stage occurs when the tubercle bacilli from an infectious source enter the body of an individual but remain dormant without causing disease and is called tuberculous infection. The second stage is when the infected individual actually develops the disease and is called tuberculosis or tuberculous disease. 5

15 Risk of progression of infection to disease Once infected with M.tuberculosis, a person probably remains infected for life. Approximately 10% of people infected will develop active disease during their lifetime. The majority (90%) of people will not develop the disease and the only evidence of infection in these individuals, may be a positive tuberculin skin test. However the organisms may remain dormant within the body and the disease can develop at any time. The chance of developing the disease is greatest shortly after infection (within the first two years) and lessens as time goes by, but the risk probably remains for life. Any weakening of the immune system will lead to progression of infection to disease e.g. HIV infection, diabetes, malnutrition, prolonged steroid therapy, chronic alcoholism, malignancies etc. Pathogenesis Primary infection Primary infection occurs on first exposure of a person to tubercle bacilli. Once the tubercle bacilli enter the respiratory tract through inhalation, the organisms reach the alveoli of the lungs and start multiplying to form the Ghon s focus. The bacilli spread through the lymphatics to the hilar lymph nodes causing enlargement of the nodes. The Ghon s focus and the hilar lymphadenopathy form the Primary Complex. Bacilli from the primary complex may spread via the blood stream and lymphatics to other parts of the body.the immune response (delayed hypersensitivity and cellular immunity) develops about 4-6 weeks after the primary infection. In most cases the immune response is sufficient to stop the multiplication of bacilli and prevent development of disease. The primary lesion may heal by fibrosis or by calcification. A positive tuberculin skin test may be the only evidence of infection. In few cases (e.g. the newborn, malnutrition, HIV) the immune response may not be sufficient to prevent the multiplication of bacilli and the tuberculous infection may progress to tuberculous disease within a few months. 6

16 Post-primary tuberculosis Post primary tuberculosis occurs after a latent period of months or years after the primary infection. It may occur either by endogenous reactivation of the latent primary infection or by exogenous re-infection with TB bacilli. Natural history of untreated PTB Without treatment, after 5 years, 50% of pulmonary TB patients die 25% remain asymptomatic (good immune response) 25% remain ill with chronic infectious TB Who is a TB suspect? A TB suspect is a person who presents with symptoms or signs suggestive of TB, particularly cough of three weeks or more. Who is considered a Case of tuberculosis? A case of tuberculosis is a patient in whom TB has been bacteriologically confirmed or diagnosed by a clinician. Definite case of TB A definite case of TB is a patient with positive culture for the Mycobacterium tuberculosis complex. (In countries where culture is not routinely available, a patient with two sputum smears positive for acid-fast bacilli (AFB) is considered a definite case) Common symptoms of pulmonary tuberculosis Respiratory symptoms: Cough usually more than three weeks Haemoptysis (blood stained sputum) Shortness of breath Chest pain 7

17 Constitutional symptoms: Fever and night sweats Loss of appetite Loss of weight Tiredness (fatigue) Symptoms of Extrapulmonary TB The symptoms depend on the organ involved. Patients may present with constitutional features of the disease fever, night sweats, loss of weight, and loss of appetite or local symptoms related to the site of the disease. 8

18 2 CLASSIFICATION OF TUBERCULOSIS It is important to classify the cases of TB in order to determine the correct treatment regimen and the duration of treatment and for recording and reporting purposes, which will facilitate cohort analysis of treatment outcome. Classification of tuberculosis is based on: Site of TB disease Results of sputum smear History of previous TB treatment Classification by Site of disease and Result of sputum smear Pulmonary tuberculosis (PTB) Pulmonary tuberculosis refers to disease involving the lung parenchyma. Smear-positive pulmonary tuberculosis A patient with at least two sputum smears positive for AFB by direct smear microscopy OR A patient with at least one sputum smear positive for AFB by microscopy and chest X-ray abnormalities consistent with active pulmonary TB as determined by a clinician OR A patient with at least one sputum smear positive for AFB by microscopy and sputum culture positive for M. tuberculosis. Smear-negative pulmonary tuberculosis A patient with at least three sputum smears negative for AFB by microscopy and chest X-ray abnormalities consistent with active pulmonary tuberculosis and no response to a course of broad-spectrum antibiotics and a decision by a clinician to treat the patient with a full course of anti-tuberculosis therapy (Any patient given anti-tb treatment 9

19 should be recorded as a case. Incomplete trials of anti-tuberculosis treatment should not be considered a method of diagnosis). OR A patient whose initial sputum smears were negative for AFB, but whose sputum culture is positive for M. tuberculosis. This group also includes cases without smear result, which should be exceptional in adults but are relatively more frequent in children, because children rarely produce a positive sputum smear. Extrapulmonary tuberculosis (EPTB) This refers to tuberculosis of any organ of the body other than the lung parenchyma. Diagnosis should be based on one smear/culture-positive specimen, or histological or strong clinical evidence consistent with active extrapulmonary tuberculosis, followed by a decision by a clinician to treat with a full course of anti-tuberculosis chemotherapy. A patient with both pulmonary and extrapulmonary tuberculosis should be classified as a case of pulmonary TB. Cases of pleural effusion and intra-thoracic lymphadenopathy (mediastinal and hilar) without X-ray abnormalities in the lung parenchyma are also classified as extrapulmonary TB. Classification by previous treatment In order to identify those patients at increased risk of acquired drug resistance and to prescribe appropriate treatment, a case should be defined according to whether or not the patient has previously received TB treatment. The following definitions are used: New A patient who has never taken treatment for TB OR Who has taken anti-tuberculosis drugs for less than one month 10

20 Relapse A patient previously treated for TB who has been declared cured or treatment completed, and is diagnosed with bacteriologically positive (smear or culture) tuberculosis Treatment after failure A patient on treatment with category 1 who remains smear-positive at the end of 5 months or later during the course of treatment Treatment after default A patient who returns to treatment, with positive bacteriology, following interruption of treatment for two months or more Transfer in A patient already registered in one district and transferred to another district for continuation of treatment Other A patient who does not fit into anyone of the above definitions: e.g. - A patient who has been taking treatment for TB for more than four weeks without being registered with the NTP. - A patient with smear-negative pulmonary TB or extrapulmonary TB who may have relapsed (but without any bacteriological evidence) although this may be rare. Chronic Patient remaining sputum smear positive after completing a fully supervised re-treatment regimen 11

21 Figure I CLASSIFICATION OF TUBERCULOSIS BACTERIOLOGY SITE OF DISEASE PREVIOUS TREATMENT SMEAR POSITIVE PULMONARY NO NEW CASE SMEAR NEGATIVE EXTRA PULMONARY TB CASES YES RELAPSE TREATMENT AFTER FAILURE TREATMENT AFTER DEFAULT OTHERS CHRONIC 12

22 3 DIAGNOSIS OF TUBERCULOSIS The highest priority for tuberculosis control is the identification and cure of the infectious cases of tuberculosis. Therefore any person with symptoms suggestive of tuberculosis, particularly cough for more than three weeks should be investigated. Investigations Sputum Smear microscopy Sputum smear microscopy is the most reliable and cost effective method of diagnosing infectious cases of pulmonary tuberculosis cases. Whenever tuberculosis is suspected in a patient who has had a cough of three weeks or more, three sputum samples should be collected and examined by microscopy for Acid-Fast Bacilli (AFB). Collection of sputum samples A PTB suspect should submit three sputum samples for microscopy. Three early morning samples are preferable. Patient should be advised to collect sputum after coughing following a deep inspiration and it should not be saliva. Outpatients may provide sputum specimens as follows: First spot specimen - Supervised spot specimen at the first visit Early morning specimen - Patient is given a sputum container to collect early morning specimen on the following day. Second spot specimen - Second supervised spot specimen is collected when the patient returns with the early morning specimen, on the following day. Chest X-ray The chest X-ray has a limited role in confirming the diagnosis of pulmonary tuberculosis. Diagnosis of tuberculosis by means of X-ray alone is unreliable. Abnormalities seen on a chest X-ray may be mimicked by a variety of other conditions. However chest X-ray is helpful particularly in the following instances: 13

23 Diagnosis of PTB in children Diagnosis of PTB in a suspect, whose sputum smears are negative for AFB The decision to start on anti-tb treatment on patients should not be based solely on abnormal chest X-ray findings and all efforts should be made to perform sputum microscopy. Sputum Culture for AFB Culture examination of sputum for AFB is more sensitive and specific than direct smear microscopy and may be useful in detecting cases where the number of organisms are fewer than can be detected by direct smear microscopy. But this is more expensive and takes at least 6-8 weeks to get the results. Under ideal circumstances pre-treatment sputum cultures for AFB should be performed on all PTB patients. However due to limited facilities available, sputum cultures are recommended only in the following situations: - a) Pre-treatment cultures in Category 1 patients (Ref. page no. 21) who have a high risk of drug resistance like health care workers, prisoners, HIV positive patients, drug addicts and contacts of known drug resistant TB patients. b) Pre- treatment cultures in all Category 2 patients. (Ref. page no. 22) c) Pre treatment cultures in sputum smear-negative PTB patients d) patients who fail to convert at the end of two months of Category 1 treatment If there is likely to be a delay of more than 3 days in transporting the specimen, add a preservative (cetyl pyridinium chloride) to the bottle. The central laboratory will provide universal containers with CPC to the District Chest Clinics. Tuberculin Skin Test Tuberculin is a purified protein derived from tubercle bacilli. Following infection with M. tuberculosis, a person develops hypersensitivity to tuberculin. When tuberculin is injected into the skin of an infected person, a delayed local reaction occurs at the site of injection after hours. 14

24 The Tuberculin skin test is of limited value in clinical work, especially in countries with a high prevalence of TB A positive test only indicates infection and not the presence or extent of tuberculous disease. A negative test does not necessarily exclude active TB. There are several methods of doing the Tuberculin skin test- Mantoux, Heaf and Tine methods. In Sri-Lanka, the Mantoux test is the method used. Technique of Mantoux test Several preparations of Tuberculin are available. The tuberculin that is used in NTP in Sri Lanka is PPD-RT-23+ Tween 80 (2 TU). The test is done by injecting 0.1 ml of tuberculin intra-dermally to the anterior aspect of the left forearm. The transverse diameter of the induration is measured after 72 hours. The results are recorded and interpreted as follows: 0-9 mm - Negative > 10 mm - Positive > 15 mm - Strongly positive Interpretation of Tuberculin test A Positive Tuberculin skin test Only indicates past infection with Mycobacterium tuberculosis or with mycobacteria other than M. tuberculosis o May be due to previous BCG vaccination. This reaction is usually a weaker reaction less than 10 mm. A strongly positive test (>15 mm in BCG vaccinated individuals) favours a diagnosis of tuberculosis. However this should be interpreted in the context of clinical picture and other investigations. A positive tuberculin test is only one piece of evidence in favour of a diagnosis of tuberculosis A Tuberculin test has no value in diagnosis of re-activation. Repeat Mantoux testing is not recommended in the diagnosis of TB because repeat test is known to have a booster effect and may give a false positive result. 15

25 A Negative Tuberculin skin test A diameter of skin induration less than 10 mm is considered as negative. However this does not exclude a diagnosis of tuberculosis. The following conditions may suppress the tuberculin skin test HIV infection Malnutrition Severe bacterial infections including TB Viral infections e.g. measles. chickenpox, glandular fever Cancer Immuno-suppressive drugs e.g. steroids Diagnosis of Tuberculosis in children Diagnosis of TB in children is often difficult Only a small proportion of children have tuberculosis, which is sputum smear positive, and many children cannot produce sputum for examination. Since most young children swallow the sputum, gastric lavage or induced sputum may be obtained early morning and sent for culture for M. tuberculosis. However since this is very distressing to the child and the yield is low, it should be done only if it is essential e.g. when the diagnosis is particularly difficult or when the child is ill. Diagnosis of TB in children should be considered in the following situations. Respiratory symptoms more than three weeks not responding to broad-spectrum antibiotics Undiagnosed illness continuing for more than 2-4 weeks Unexplained fever History of contact with an infectious pulmonary TB case, particularly in the same household An abnormal chest X ray A positive Tuberculin test Unexplained weight loss or failure to gain weight in spite of adequate nutrition Failure to thrive in an infant Focal lesions such as enlarged lymph nodes, abdominal mass, ascites, CNS signs. 16

26 4 TREATMENT OF TUBERCULOSIS Treatment of tuberculosis is the cornerstone of any NTP. The modern treatment strategy is based on standardized short course chemotherapy regimens and proper case management to ensure completion of treatment and cure. Aims of treatment of TB are: To cure the patient of TB To prevent death from active TB or its late effects To prevent relapse of TB To decrease transmission of TB in the community To prevent the emergence of drug resistant TB Short Course Chemotherapy (SCC) is now the recommended treatment for tuberculosis and when properly applied, fulfills the above aims of anti-tb drug treatment. Requirements for adequate chemotherapy An appropriate combination of anti-tuberculosis drugs Prescribed in correct dosage Taken regularly by the patient For the prescribed period of time It is essential for the patients to receive and to adhere to the recommended course of treatment (usually 6-8 months) in order to be cured. If patients fail to take their combination of drugs regularly, the bacilli may become resistant to the drugs. The best way to ensure patient adherence to treatment is Direct Observation of Treatment (DOT). This means that the patient swallows the tablets under the direct observation of a health worker or a trained person. The strategy of DOTS has been recommended by the WHO and now internationally accepted as the standard method for TB control. 17

27 Essential (First-Line) Anti-tuberculosis Drugs The five essential anti-tb drugs are: Isoniazid (H) Rifampicin (R) Pyrazinamide (Z) Ethambutol (E) Streptomycin (S) Mode of action of anti-tb drugs A population of TB bacilli in a TB patient consists of the following groups. 1. Metabolically active, continuously growing bacilli inside cavities 2. Intra cellular dormant forms - bacilli inside macrophages 3. Extra cellular dormant forms a) Bacilli which undergo occasional spurts of metabolism (semi dormant) b) Dormant bacilli, which gradually die on their own. Different anti-tb drugs act against different groups of bacilli. Isoniazid, rifampicin, ethambutol, PAS are active against metabolically active bacilli. Rifampicin has a special action against the semi dormant forms. Pyrazinamide acts in an acid environment inside cells e.g. macrophages. So far there is no drug, which can act on dormant bacilli TB treatment regimens Treatment regimens consist of two phases: 1. Initial intensive phase 2. Continuation phase Intensive phase During the initial intensive phase, there is rapid killing of TB bacilli. Infectious patients quickly become non-infectious (within about two weeks) and symptoms improve. Most patients with sputum smear-positive pulmonary TB becomes smear negative within two months. Directly Observed Therapy (DOT) is essential in the initial phase to ensure that the patient takes every single dose. This prevents development of drug resistance. The 18

28 risk of development of drug resistance is higher during the early stages of anti-tb treatment, when there are more bacilli. Continuation Phase During the continuation phase, fewer drugs are necessary, but for a longer period. The sterilizing effect of the drugs eliminates the remaining bacilli, thus preventing subsequent relapses. Patients who have taken anti-tuberculosis drugs previously are much more likely to develop drug resistance, which may have been acquired through inadequate prior chemotherapy. Such patients require a stronger regimen consisting of more drugs and for a longer period. Therefore before starting treatment, it is essential to question all patients closely and carefully to determine whether or not they have previously taken treatment for tuberculosis, so that they can be given the proper treatment regimen. Standard code for TB treatment regimens There is a standard code for TB treatment regimens and each anti-tuberculosis drug has an abbreviation. H Isoniazid R - Rifampicin Z - Pyrazinamide E - Ethambutol S Streptomycin A TB treatment regimen consists of two phases, the intensive phase and the continuation phase. The number before a phase is the duration of that phase in months. A subscript number (e.g. 3) after a letter indicates the number of doses of that drug per week. No subscript number after a letter indicates that the treatment is daily. E.g.: 4 HR means 4 months of Isoniazid and Rifampicin daily. 5 H 3 R 3 E 3 means 5 months of Isoniazid, Rifampicin and Ethambutol three times a week. 19

29 Categories and Treatment Regimens The treatment regimen recommended depends on the treatment category for each patient. Two treatment categories and standardized regimens are used in Sri Lanka. Table 1 Case definitions, Treatment Categories and Recommended Regimens Case Definition New cases Treatment Category Intensive Phase Treatment Regimen Continuation Phase - PTB smear-positive - PTB smear-negative - Extrapulmonary TB CAT 1 2 HRZE 4 HR Re-treatment cases - Relapses -Treatment after failure -Treatment after default (smear-positive) CAT 2 2HRZES / 1 HRZE 5 HRE Category 1 (CAT 1) - (Refer Flow Chart I) This is given to all new patients: - New sputum smear-positive PTB - New sputum smear-negative PTB - New Extrapulmonary TB Recommended Treatment Regimen 2 HRZE / 4 HR Intensive Phase Isoniazid Rifampicin Pyrazinamide Ethambutol daily for two months 20

30 In patients who cannot be given Ethambutol as in the case of small children who are unable to communicate visual symptoms, Streptomycin may be given instead of Ethambutol. In pulmonary TB cases, at the end of two months of intensive phase, do the sputum smear examination. - If the smear is negative, start on the continuation phase of treatment. - If the smear is positive at the end of two months, continue the intensive phase of four drugs for another one month. Repeat the sputum smear examination at the end of the 3 rd month. If the smear is positive at the end of the 3 rd month, stop drugs for three days; send sputum for TB culture and ABST. Start on the continuation phase of treatment, regardless of the sputum result. Continuation Phase Isoniazid Rifampicin Daily for four months Do follow up sputum smear examination at the end of 5 months and end of treatment. - If sputum smear is negative at the end of the 5 th month and at the end of 6 months of treatment, chest X- ray is taken (optional) and anti-tb drugs stopped. - If the sputum is positive at the end of the 5 th month or more, re-register the patient as a Treatment Failure and start on Category 2 treatment. For patients with tuberculous meningitis, miliary TB, or spinal tuberculosis with neurological complications, continuation phase can be extended up to 7 months. Category 2 (CAT 2) - (Refer Flow Chart II) This is given to all Re-treatment cases: - Relapses - Treatment after failure 21

31 - Treatment after default (sputum smear-positive) Recommended Treatment Regimen 2 HRZES/ 1 HRZE / 5HRE Intensive phase Isoniazid Rifampicin Pyrazinamide Ethambtol Streptomycin Daily for two months Isoniazid Rifampicin Pyrazinamide Ethambutol Daily for one month Do the sputum smear examination at the end of the 3 rd month. - If the sputum smear is negative, start on the continuation phase of treatment - If the sputum is positive, the four oral drugs are continued for another month Repeat the sputum smear, at the end of the 4 th month (If found positive at the end of the 3 rd month). - If the sputum is negative, start on the continuation phase of treatment. - If the sputum is still positive, further treatment will depend on the results of pre-treatment culture and sensitivity test. - If the results are suggestive of multidrug-resistant TB, such patients should be referred to Chest Physician for further management. 22

32 Continuation Phase Isoniazid Daily for five months Rifampicin Ethambutol Do the follow up sputum smear examinations at the end of the 5 th month and end of treatment. - If the sputum is negative, do the chest X-ray (optional) and anti-tb drugs are stopped. - If the patient remains smear positive after the completion of a fully supervised re-treatment regimen, he should be referred to the Chest Physician for management. Such patients are defined as Chronic cases. Fixed-dose combination tablets (FDCs) Tablets of fixed-dose drug combinations have been recommended. There are several advantages as well as disadvantages of using fixed drug combination tablets over individual drugs. Sri Lanka has introduced FDCs for TB treatment regimens in Advantages Prescription errors are likely to be less frequent because dosage recommendations are more straightforward and adjustment of dosage according to patient weight is easier. The number of tablets to ingest is smaller and may thus encourage patient adherence to treatment. If treatment is not observed, patient cannot be selective in the choice of drugs to ingest. Disadvantages If prescription errors do occur, excess dosage (risk of toxicity) or sub-inhibitory concentrations of all drugs (favouring development of drug resistance) may result Health care workers may be tempted to evade Directly Observed Therapy, erroneously believing that adherence is automatically guaranteed. 23

33 Poor rifampicin bioavailability has been found for some FDCs, particularly in 3 or 4 drug combinations. Quality assurance is therefore essential. Using FDCs does not obviate the need for separate drugs for a minority of patients who develop drug toxicity. Table 2 WHO recommended formulations of FDC Drug Dose form Strength for daily use Strength for thrice- weekly use Isoniazid+ rifampicin Tablet 75mg +150mg 150mg+ i50mg 150mg + 300mg Tablet or pack 30mg + 60mg 60mg + 60mg of granules Isoniazid+ethambutol Tablet 150mg + 400mg -- Isoniazid+thioacetazone Tablet 100mg + 50 mg mg + 150mg Isoniazid + rifampicin + Tablet 75mg + 150mg + 400mg 150mg + 150mg+ pyrazinamide 500mg Tablet or pack 30mg+60mg+150mg -- of granules Isoniazid+rifampicin+ Tablet 75mg+150mg+400mg+ --- pyrazinamide+ethambutol 275mg 24

34 Flow chart I Treatment and follow up of new smear-positive PTB cases - (CAT 1) 2 HRZE (S) * Examine sputum (end of 2 nd month) Positive Negative Continue 1 HRZE (S)* Start continuation phase 4 HR Examine sputum (end of the 3 rd month) Examine sputum (end of the 5 th month and end of treatment) Positive Stop ATT for 3 days Send sputum for culture and ABST Negative Start continuation phase 4 HR Positive Negative Examine sputum (end of the 5 th month and end of treatment) Positive Negative Do a CXR** and stop ATT (Cured) Treatment failure Re-register and start on CAT 2 Do a CXR** and stop ATT (Cured) * Streptomycin is used where Ethambutol cannot be given as in young children ** Optional 25

35 Flow chart II Treatment and follow up of Re-treatment cases (CAT 2) (Send sputum for pre-treatment culture and ABST) 2 HRZES 1 HRZE Examine sputum (end of the 3 rd month) Positive Continue 1 HRZE Examine sputum (end of the 4 th month) Negative Start continuation phase 5 HRE Examine sputum end of the 5 th month and end of treatment) Positive Negative Further treatment determined by result Start continuation phase of pre-treatment 5 HRE Positive Negative culture & ABST Examine sputum (end of the 5 th month and end of treatment) Do a CXR** and stop ATT (Cured) Positive Negative Chronic Case Refer to a Chest Physician Do a CXR** and stop ATT (Cured) ** Optional 26

36 Flow chart III Treatment and follow up of smear-negative PTB cases Smear-negative PTB (Send sputum for pre-treatment culture) 2 HRZE(S) CXR after 1 month Examine sputum (end of the 2 nd month). Negative Positive Start Continuation Phase 4 HR Treatment Failure Examine sputum Stop ATT * Do a CXR Re-register Stop ATT Start CAT 2 (Completed Rx) * If no improvement in the abnormality found in the original CXR, refer the patient to a Chest Physician. 27

37 Directly Observed Treatment Directly Observed Treatment (DOT) is one of the important elements of the internationally recommended strategy for TB control. Directly Observed Treatment means that an observer watches the patient swallow their tablets. This ensures that a TB patient takes the right anti-tuberculosis drugs, in the right doses at the right intervals without interruption and ensures that the patient completes the full course of treatment. Why is Directly Observed Treatment necessary? Patient compliance is a key factor in treatment success. Many patients who receive selfadministered treatment often take drugs irregularly and a significant proportion of patients stop treatment before completion due to various reasons. It is impossible to predict who will or will not comply. Therefore directly observed treatment is required to ensure treatment adherence and it also helps to motivate the patient to continue treatment. It is recommended in the intensive phase of treatment at least for all sputum positive cases. A patient who misses one attendance for DOT can be traced immediately, counseled and returned to treatment. Patient compliance should be promoted through a patient centered approach by: - Facilitating easy access to treatment, by organizing directly observed treatment as close to patient s home (or the work place) as possible - Providing anti-tuberculosis drugs free of charge - Providing polite and rapid attention. 28

38 National policy for the implementation of Directly Observed Treatment (DOT) Patients who will be given DOT New Pulmonary TB (sputum positive and negative) cases Intensive phase: All new Pulmonary TB (sputum positive and negative) patients should be given directly observed treatment daily during the intensive phase. This should be arranged as far as possible community based, or hospital based wherever necessary as in the case of very ill patients or those patients who are unable to come daily for supervised treatment Continuation phase: Since the continuation phase also contains Rifampicin, every effort should be made to give each dose under observation. Wherever this is not possible patients will be advised to attend the chest clinic once a week, and the first dose will be given under direct observation and the remaining six doses will be supplied for self-administration at home. DTCO will make arrangements for supervisory visits to check drug intake (including pill counts). Extra pulmonary TB Intensive Phase: Drugs will be given under direct observation Continuation phase: Since the continuation phase also contains Rifampicin, every effort should be made to give each dose under observation. Wherever this is not possible patients will be advised to attend the chest clinic once a week and the first dose will be given under direct observation and the remaining six doses will be supplied for self-administration at home. The DTCO will make arrangements for supervisory visits to check drug intake (including pill counts). All Re-treatment cases Directly Observed treatment should be given throughout the entire period of treatment daily, both in the intensive and continuation phase of treatment. Admission to hospital is recommended whenever possible. 29

39 DOT Providers The following categories will provide Direct Observation of Treatment. Health workers at state health care facilities Field health care workers General practitioners Trained volunteers Community leaders Trained community volunteers or community leaders need regular support, motivation and supervision by the NTP staff to ensure that quality is maintained. Provision of drugs for the DOT Centres - Drugs for each patient will be delivered to the DOT centres from the District Chest Clinic by the PHI or any other staff assigned by the DTCO. Interruption of treatment (default) Directly Observed Treatment adapted to the needs of the patient is the best method of avoiding treatment interruption. However, even with directly observed treatment and during the continuation phase of treatment, which may be self-administered, there may be treatment interruption. Measures to minimize treatment interruption At the time of registration of a TB patient, the staff must educate the patient and the family regarding the duration of treatment and the importance of adherence to treatment. It is vital to record the patient s address and other relevant addresses e.g. parents or work place etc. in order to help locate the patients who interrupt treatment. As far as possible, the address should be verified at the beginning of treatment. Management of patients who interrupt treatment It is important to take action on defaulters immediately. Patients should be contacted the day after missing a dose during the intensive phase and as soon as possible during the continuation phase. It is important to find out the reason for the patient s absence in order to take appropriate action and continue treatment. 30

40 Table 3 Actions in interruption of TB treatment Interruption for less than 1 month Trace patient Solve the cause of interruption Continue treatment and prolong it to compensate for missed doses Interruption for 1-2 months Action 1 Action 2 Trace the patient Solve the cause of interruption If smears negative or EPTB Continue treatment and prolong it to compensate for missed doses Do 3 sputum smears. If one or more Treatment Continue treatment and Continue treatment smears positive received: prolong it to compensate while waiting do culture & ABST for < 5 months missed doses > 5 months Category 1: Start Cat 2 Category 2: refer for advice (may evolve to Chronic) Interruption for 2 months or more (defaulter) Action 1 Action 2 Do 3 sputum smears Solve the cause of interruption, if possible No treatment while waiting for results Negative smears or EPTB One or more Clinical decision on individual basis whether to restart or continue treatment, or no further treatment If on Category 1 Start Category 2 Send culture & ABST smears positive If on Category2 Refer for advice (may evolve to Chronic) 31

41 5 ESSENTIAL (FIRST LINE) ANTI-TB DRUGS Isoniazid (INAH) Isoniazid is highly bactericidal against replicating tubercle bacilli. It is rapidly absorbed and diffuses readily into all fluids and tissues. The plasma half-life, which is genetically determined, varies from less than one hour in fast acetylators to more than three hours in slow acetylators. It is largely excreted in the urine within 24 hours, mostly as inactive metabolites. Uses Isoniazid is a component of all TB chemotherapeutic regimens currently recommended by WHO. Isoniazid alone is occasionally used in chemoprophylaxis Administration Isoniazid is normally given orally. Dosages For treatment- Adults and children: 5mg/kg (4-6mg/kg) daily, maximum 300mg. 10 mg/kg 3 times weekly Preventive therapy: Adults: 300mg daily for at least 6 months Children: 5mg/kg daily (maximum 300mg) for at least 6 months Side-effects Isoniazid is generally well tolerated at recommended doses. Systemic or cutaneous hypersensitivity reactions occasionally occur during the first weeks of treatment. Peripheral neuropathy may occur in persons with malnutrition, chronic alcoholics, and pregnant women or in diabetics. This can be prevented or minimized by giving, supplementary pyridoxine 10 mg daily to those at risk. Other less common forms of neurological disturbances including optic neuritis, toxic psychosis, and generalized convulsions can develop in susceptible individuals, 32

42 particularly in the later stages of treatment, which occasionally may necessitate withdrawal of Isoniazid. Hepatitis is an uncommon but potentially serious reaction that can usually be averted by prompt withdrawal of the treatment. Monitoring of hepatic transaminases should be done in patients with pre-existing chronic liver disease. Isoniazid tends to raise plasma concentrations of phenytoin and carbamazapine by inhibiting their metabolism in the liver. Therefore it may be necessary to reduce the dosages of these drugs during treatment with Isoniazid. Patients on treatment with Isoniazid should be cautioned against eating Red fish such as skipjack and tuna, which contain high concentrations of histamine. Isoniazid is an inhibitor of histaminase, which is normally present in the tissues and is responsible for the inactivation of ingested histamine. As a result, the histamine level in the tissues of the patient tends to rise shortly after a meal containing these varieties of fish, and the patient may experience symptoms of histamine intoxication like erythema, severe headache, red eyes, palpitation, diarrohoea, vomiting and wheezing. Isoniazid is not teratogenic and can be used during pregnancy. Rifampicin Rifampicin has a potent bactericidal and sterilizing effect against tubercle bacilli in both cellular and extra-cellular locations. Following oral administration, it is rapidly absorbed and distributed throughout the cellular tissues and body fluids. Since resistance develops rapidly, Rifampicin must always be administered in combination with other effective anti-mycobacterial agents. Uses It is a component of all 6 months and 8 months TB chemotherapeutic regimens currently recommended by WHO. Administration and dosage: Rifampicin is administered orally and should preferably be given at least 30 minutes before meals, since absorption is reduced when it is taken with food. This however may not be clinically significant and food can reduce intolerance to the drugs. 33

43 Adults and children: 10 mg/kg (8-12 mg/kg) daily, maximum 600mg daily. 10mg/kg 3 times weekly Side-effects Rifampicin is well tolerated by most patients at currently recommended doses Side-effects include: Gastro-intestinal - nausea, anorexia, vomiting and abdominal pain Hepatitis is a major side effect although it is rare. Alcoholics and pre existing liver disease may increase the risk and it may be advisable to monitor the liver function tests in these high-risk groups. The following reactions are more likely to occur with intermittent therapy: Flu syndrome - consisting of attacks of fever, chills, malaise headache, bone pain Cutaneous reaction consisting of flushing, and pruritus with or without a rash *Thrombocytopenia and purpura *Heamolytic aneamia and acute renal failure may occur *Respiratory shock syndrome consisting of shortness of breath and rarely associated with collapse and shock. may occur * If these reactions occur Rifampicin must be stopped immediately and admitted to hospital for management. It should not be given again. Drug interactions Rifampicin induces hepatic enzymes and may accelerate clearance of drugs metabolized by the liver, and patients may need higher dosages of these drugs. These include corticosteroids, oral contraceptives, oral hypoglyceamic agents, oral anticoagualants, anticonvulsants, and cimetidine, cyclosporin and digitalis glycosides. Since Rifampicin reduces the effectiveness of oral contraceptives, women should be advised to use an alternative method of contraception. Rifampicin is excreted in urine, tears, sweat and other body fluids and may colour them red or orange. Patients should be warned of discoloration of urine and other body fluids. Rifampicin may be used safely in pregnancy. Vitamin K should be administered at birth to an infant of a mother taking Rifampicin because of the risk of postnatal haemorrhage. 34