MINISTRY OF HEALTH, MALAWI. GUIDELINES FOR THE PROGRAMMATIC MANAGEMENT OF MANAGEMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS IN MALAWI

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1 MINISTRY OF HEALTH, MALAWI. GOVERNMENT OF MALAWI GUIDELINES FOR THE PROGRAMMATIC MINISTRY OF HEALTH MANAGEMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS IN MALAWI GUIDELINES FOR THE PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS IN MALAWI National Tuberculosis Control Programme Ministry of Health P/Bag 65, Lilongwe February,2008. JUNE, 2012

2 GUIDELINES FOR THE PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT TUBERCULOSIS 1 ST EDITION (REVISED) MINISTRY OF HEALTH, MALAWI 2012 ii

3 TABLE OF CONTENTS Foreword... vi Acknowledgements... vii Abbreviations... viii Definitions... ix Section 1: BACKGROUND INFORMATION ON MDR-TB... 1 Section 2: CASE FINDING, DIAGNOSIS, CLASSIFICATION AND REPORTING FOR MDR-TB... 3 Suspecting MDR-TB Suspecting MDR-TB Target groups for culture and DST:... 3 iagnosis of MDR-TB Diagnosis of MDR-TB Classification of MDR-TB Classification according to drug use Classification according to registration group Classification according to site Category IV recording and reporting system... 5 Section 3: ORGANISATION OF TB LABORATORY SERVICES Functions of level 1 laboratory Functions of level 2 laboratory Functions of level 3 laboratory Culture and drug susceptibility testing (CDST) Infection control and bio-safety in the laboratory Quality control and quality assurance... 7 Section 4: TREATMENT FOR DRUG RESISTANT TUBERCULOSIS Treatment of patients with mono and polyresistant strains Treatment of multi-drug resistant tuberculosis Rational Classification of Anti-TB Drugs Management of rifampicin resistant cases Section 5: MANAGEMENT OF MDR- TB IN SPECIAL SITUATIONS Pregnancy Breastfeeding Contraception Children Diabetes mellitus Renal insufficiency Liver disorders Seizure disorders Psychiatric disorders Congregate settings Other conditions Section 6: MANAGEMENT SYSTEMS National MDR-TB Coordination Team iii

4 6.2 Community based management of MDR-TB patients: Responsibilities of MDR-TB management teams: Directly Observed Treatment (DOT) in MDR-TB Hospital admission of MDR-TB patients: Role of respirator masks (N95 masks) Defaulter tracing Follow up Section 7: MDR-TB MONITORING AND EVALUATION Cohort analysis Monitoring progress of treatment Section Eight: HIV INFECTION AND MDR-TB General considerations Treatment follow-up Potential drug interactions in the treatment of drug-resistant TB and HIV Potential drug toxicity in the treatment of drug-resistant TB and HIV Section 9: ADVERSE EFFECTS OF SECOND LINE ANTI-TB DRUGS Monitoring of adverse effects Management of adverse effects Section 10: MANAGEMENT OF MDR-TB CONTACTS Adult Contacts Paediatric Contacts Section 11: MDR-TB TREATMENT FAILURES Signs of MDR-TB Treatment Failure Management of MDR-TB Treatment failures Section 12: MANAGEMENT OF SECOND LINE ANTI-TB DRUGS Second line anti-tb drugs in Malawi Drug Storage, use and auditing Section 13: TB INFECTION PREVENTION AND CONTROL Reducing spread of mycobacterium tuberculosis in health care settings Workplace and administrative controls Implementation of TB infection control ANNEXES Annex 1: Functions and Information Flow at various Institutional Levels Annex 2: Category IV Forms Annex 3: Side Effect monitoring Forms iv

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6 Foreword The emergence of resistance to anti-tuberculosis drugs and particularly of multi-drug resistant TB (MDR-TB) has become a major public health problem and an obstacle to effective TB control. Drug resistance is no new phenomenon. Pathogens have almost invariably developed resistance to the drugs used to kill them. Tuberculosis is no exception: strains resistant to streptomycin were identified within months of the start of use in mid 1940 s and was the primary reason therapy for TB evolved to include treatment with more than one drug. While the exact extent of MDR-TB is unknown in most parts of Africa, the National TB Programme in Malawi has been able to pick up a few incident MDR-TB cases from the routine surveillance of previously treated smear positive TB cases. These have been confirmed by a supranational laboratory in South Africa. According to the drug-resistance survey that was conducted in Malawi (in 2010), prevalence of MDR-TB cases is 4% among previously treated patients and 0.4% among new smear positive TB patients. No cases of extremely drug resistant (XDR) TB have been diagnosed in Malawi at the moment. Use of second line anti-tb drugs in Malawi only started in the second half of 2007 using a community based approach having adapted the WHO 2006 generic guidelines for the Programmatic Management of MDR-TB. The WHO 2006 generic version has since been updated following new developments and evidence. These guidelines are a direct update of the previous guidelines on programmatic management of MDR-TB and intended for use by all medical practitioners and allied health workers in Malawi. MDR-TB is an evolving disease; therefore these guidelines will be updated as new evidence emerges. Management of MDR-TB is critical to avoid the development of XDR strains of TB. The Ministry of Health believes in a knowledgeable health workforce and in this regard every effort will be made to disseminate new information to care providers so that they are abreast with latest information on MDR-TB management. The user of these guidelines is encouraged to refer to the appropriate chapters for a specific problem and it is hoped that by using these guidelines health workers shall be effectively engaged in the fight against tuberculosis in Malawi. Rt. Hon. Khumbo Kachali, Vice President and Minister of Health vi

7 Acknowledgements Thanks to the following individuals whose efforts made the production of the very first version of these guidelines possible:- Professor F.M.L. Salaniponi, Dr. D. S. Nyangulu, Dr. M. Kagoli, Dr. D. Namarika, Mr. J. Kwanjana, Mr. I. Nyasulu, Mr. K. Mkandawire, Mr. H. Banda, Mr. I. Dambe, Mr. H. Kanyerere, Mr. A. Dimba, Mr. R. Chimzizi, Mr. C. T. Kang ombe, Mr. F. Gausi, Mr. G. Samuti, Mrs. R. Banda, Mrs. C. Chiromo, Dr. K. Kamoto, Mr. L. Donsa, Dr. T. Salimu, Dr. A. Maida, Mrs. V. Bandawe, Mr. D. Gomani, Mr. M. Chisi, Mr. N. Mphasa, Mr. A Mwale, Mr. H. Kawonga, Mr. J. Michongwe, Mr I Chelewani, Mr. A. Makwakwa Dr. Z. Mwanza, Mr. A.H.C. Kawonga and Mrs. C. Chiwaula. Thanks also to the following who contributed during revision of these Guidelines:-.Dr. J. Mpunga, Dr. D. S. Nyangulu, Mr. I. Nyasulu, Mr. H. Banda, Mr. I. Dambe, Mr. H. Kanyerere, Mr. A. Dimba, Mr. C. T. Kang ombe, Mr. G. Samuti, Mrs. R. Banda, Mr. N. Mphasa, Mr. A Mwale, Dr. R. Banda, Mr I Chelewani, L. Mlauzi and Dr. K. Mbendela. These guidelines were adopted from the WHO Guidelines for the Programmatic Management of Drug Resistant Tuberculosis. We thank WHO for allowing us to use part of their guidelines to shape these Malawi specific guidelines. The Ministry of Health would also like to thank the following organizations for their financial assistance and technical support: the World Health Organisation (WHO), Department for International Development (DFID), the Norwegian Government, the Royal Netherlands TB Association (KNCV) and United States Agency for International Development (USAID). Dr. Charles C. V. Mwansambo Principal Secretary vii

8 Abbreviations AFB AIDS ART CDST CPT CRL DFID DHO DOT DOTS DRS DST DTO EPTB FLD HCW HIV HTC IPT KNCV MDR-TB MRC M.tuberculosis NORAD NTP PTB SCC SLD TB USAID UVGI WHO XDR-TB Acid-fast staining bacillus Acquired immunodeficiency syndrome Anti-retroviral therapy Culture and drug susceptibility test Cotrimoxazole preventive therapy Central Reference Laboratory Department for International Development District Health Officer Directly Observed Treatment Directly Observed Treatment Short Course (Strategy) Drug resistance surveillance Drug Susceptibility Test District TB Officer Extra-pulmonary tuberculosis First line drug Health care worker Human immunodeficiency Virus HIV testing and counseling Isoniazid preventive therapy Royal Netherlands TB Association Multi-Drug Resistant tuberculosis Medical Research Council Mycobacterium tuberculosis Norwegian Agency for Technical Cooperation National Tuberculosis Control Programme Pulmonary Tuberculosis Short Course Chemotherapy Second line drug Tuberculosis United States Agency for International Development Ultraviolet germicidal irradiation World Health Organisation Extensively Drug Resistant TB viii

9 Definitions Drug Resistance: means loss of susceptibility to a drug. MDR-TB: resistance to at least Isoniazid and Rifampicin Mono-resistance: refers to resistance to one anti-tuberculosis drug. Poly-resistance: resistance to more than one anti-tuberculosis drug. MDR-TB is an example of poly-resistance. Extensively drug-resistant tuberculosis (XDR-TB): resistance to any fluoroquinolone, and at least one of three injectable second-line drugs (Capreomycin, Kanamycin and Amikacin), in addition to multidrug-resistance. ix

10 Section 1: BACKGROUND INFORMATION ON MDR-TB The emergence of resistance to drugs that are used to treat tuberculosis (TB), has become a significant public health problem in a number of countries and an obstacle to effective global TB control. In Malawi just like in many countries, the problem of drug resistance is emerging and the management of patients with Multi-drug Resistant Tuberculosis (MDR-TB) is inadequate. However where drug resistance has been identified, specific measures need to be taken within TB Control Programmes to address the problem through appropriate management of patients and adoption of strategies to prevent the propagation and dissemination of drug-resistant TB, including MDR-TB. The magnitude of MDR-TB in Malawi has been measured and it shows that the problem is big among patients that are receiving first line anti-tb drugs for the second time and those that show failure of the first line drugs. Since 1996, to December 2009 just over 120 MDR-TB cases have been identified through routine surveillance of smear positive re-treatment cases. Before the advent of Multi-Drug Resistant Tuberculosis (MDR-TB), Malawi has been implementing the World Health Organization (WHO) recommended basic Directly Observed Therapy- Short-course (DOTS) strategy with 5 key elements: Political commitment with sustained and increased financing Case detection through quality assured sputum microscopy Standardized short course treatment that includes observation of treatment Secure drug supply and management chain and Recording and reporting system that allows analysis of treatment results The new Stop TB Strategy continues to emphasize the basic DOTS package but includes components that tackle additional challenges. The Strategy has six components: Pursuing high quality DOTS expansion Addressing TB/HIV, MDR-TB and other challenges Contributing to Health Systems Strengthening Involving all care providers Engaging people with TB, and communities Enabling and promoting research. In the New Stop TB Strategy, the basic DOTS elements form part of the first component of pursuing High quality DOTS expansion and enhancement. 1

11 The current National Tuberculosis Control Programme (NTP) 5 Year Development Plan: has taken into consideration the additional elements including MDR-TB. In Malawi, the National Tuberculosis Control Programme (NTP) guides the programmatic management of tuberculosis. Managing drug resistant TB is one of the core activities of the NTP. Diagnostic and treatment services of MDR-TB are integrated within the general health system and these guidelines are therefore complementary to what the National TB Manual contains on management of susceptible TB cases. Factors that contribute to development of drug resistant TB include: Poorly functioning national programmes o Inadequate supervision o Interrupted drug supplies o Inadequate regimens o Inadequate record keeping o Poor quality drugs Non-adherent patients Private sector that disregards national TB guidelines Inappropriate use of anti-tb drugs 2

12 Section 2: CASE FINDING, DIAGNOSIS, CLASSIFICATION AND REPORTING FOR MDR-TB 2.1 Suspecting MDR-TB Multi-drug Resistant Tuberculosis (MDR-TB) is often suspected clinically when a patient has a persistently positive Acid-Fast staining Bacillus (AFB) smear or culture or where clinical progression of TB is evident while the patient continues to receive standard treatment. MDR-TB may also be suspected epidemiologically in contacts of known MDR-TB cases. In countries where resources are available, all patients diagnosed with TB have Drug Susceptibility Test (DST) performed at the beginning of treatment. However, a targeted approach is used in Malawi as outlined below: 2.2 Target groups for culture and DST: - Patients who fail to convert at 3 months or - Turn positive at 5 months of standard TB treatment. - Patients previously successfully treated for TB - Patients who have contact with a known MDR-TB patient - Contacts of a patient who died while on directly observed TB treatment - Health care workers in hospital/ health facility setting. - Sputum positive HIV co-infected patients. - Return after default - Patients from high risk MDR-TB countries NB: Contact tracing is done as an active approach in case finding among contacts of known MDR-TB cases. 2.3 Diagnosis of MDR-TB The only way to confirm MDR-TB is through performing DST on the patient s sputum culture and demonstrating resistance to at least Isoniazid and Rifampicin. Currently this is only done in one TB Central Reference Laboratory in Lilongwe. For proficiency testing and quality control the NTP has established links with Medical Research Council (MRC) in South Africa. 2.4 Classification of MDR-TB Classification according to drug use This classification is used mainly to assign the appropriate treatment regimen. 3

13 MDR-TB is classified as category IV type of TB. For categories I, II and III please refer to NTP manual, Classification of MDR-TB (Category IV patients) is as follows: New Category IV patients: These are Category IV patients who have never received antituberculosis treatment or who have received anti-tuberculosis treatment for less than one month. Note: Patients who had DST at the start of a WHO Category I regimen and are then switched to a Category IV regimen because of resistance are placed in this group, even if they received more than one month of Category I treatment. Previously treated with first-line drugs only: A patient who has been treated for one month or more with first-line drugs. Previously treated with second-line drugs: A patient who has been treated for one month or more with one or more second-line drugs, with or without first-line drugs Classification according to registration group This grouping allows analysis of target groups of DST, epidemiological monitoring and projection of future numbers of MDR-TB cases. Again, classification is determined by treatment history at the time of collection of sputum specimen sample that was used to confirm MDR-TB. The groups are as follows: New. (Same definition as in classification according to previous drug use). A patient who has received no or less than one month of anti-tuberculosis treatment. Relapse. A patient whose most recent treatment outcome was cured or treatment completed, and subsequently diagnosed with bacteriologically positive TB by smear or culture. Treatment after default. A patient who returns to treatment, bacteriologically positive by sputum smear or culture following interruption of treatment for two or more months. Treatment after failure of category I. A patient who has received category I treatment for TB and in whom treatment has failed. Treatment after failure of category II. A patient who has received category II treatment for TB and in whom treatment has failed. Transfer in These are Category IV patients who have been transferred from another register for treatment of drug-resistant TB to continue Category IV treatment. Their outcomes should be reported to the transferring unit so that it can report their outcomes in the cohort in which they originally started MDR-TB treatment. Other: These are Category IV patients who do not fit the above definitions. This group includes Category IV patients who were treated outside DOTS programmes Classification according to site Pulmonary MDR-TB case: This refers to TB involving the lungs Extra-pulmonary MDR-TB Case: This is TB outside the lungs 4

14 2.5 Category IV recording and reporting system A well functioning recording and reporting system is as important in MDR-TB as it is in susceptible TB for purposes of monitoring overall programme performance. The information system for management of drug-resistant TB is an extension of the basic DOTS information system. The recording and reporting tools in MDR-TB include: 1. Category IV Treatment Card (Form 01) 2. Category IV Register (Form 02) 3. Category 1V Patient identity card (Form 03) 4. Request for sputum examination form (Form 04) 5. Laboratory register for smears (Forms 05) 6. Laboratory register for culture (Form 06) 7. Quarterly report on Category IV case registration (Form 07) 8. Six-month interim outcome assessment form (Form 08) 9. Annual report of treatment outcome of Category IV regimens (Form 09) Computerized systems Initially all the forms shall be handwritten. However, in the course of implementation of MDR- TB management, electronic data entry of (Form 01) will be introduced as it facilitates better quality of information as well as data analysis. The Category IV Register and Forms can then be generated easily from the computerized register. Training The information system for drug-resistant TB requires basic knowledge of the DOTS information system, with additional training on the specifics of the forms. Regular supervisory visits at all levels to the units using the information system are fundamental to maintaining the quality of information. 5

15 Section 3: ORGANISATION OF TB LABORATORY SERVICES TB laboratory services are carried out at three levels: Level 1 - District Hospital Laboratory, (including- some CHAM laboratories, selected Health Centre Laboratories and private facilities) Level 2 - Central Hospital Laboratory Level 3 - Central Reference Laboratory 3.1 Functions of level 1 laboratory Receipt of specimens Preparation and staining of smears Direct- microscopy (mainly Ziehl-Neelsen and Fluorescent technique at district hospital laboratory) and recording of results Dispatch of results Maintenance of laboratory register Cleaning and maintenance of equipment Management of reagents and laboratory supplies Training of microscopists Preparation of reagents for microscopy. Internal and external quality control LEEL II 3.2 Functions of level 2 laboratory All the functions of Level 1 laboratory Fluorescence microscopy Quality improvement and proficiency testing of microscopy at level 1 laboratory through supportive supervision. 3.3 Functions of level 3 laboratory All the functions of Level 1 and 2 laboratories. DST of M. tuberculosis isolates Identification of mycobacteria other than M. tuberculosis Technical control of and repair services for laboratory equipment Updating and dissemination of laboratory manuals, including guidelines on diagnostic methods, on care and maintenance of equipment and on quality assurance Close collaboration with the central level of the national TB control programme Supervision of level 1 and level 2 laboratories regarding bacteriological methods and their support (particularly training and supervision) to the peripheral laboratories Quality assurance of microscopy Training of laboratory staff Organization of anti-tuberculosis drug resistance surveillance Operational and applied research relating to the laboratory network, coordinated within the requirements and needs of National TB Control Programme (NTP). 6

16 3.4 Culture and drug susceptibility testing (CDST) Currently, culture and DSTs are only done at the Central Reference Laboratory (CRL). However, there are plans to decentralize Culture to central hospital laboratories. For diagnosis of MDR-TB, at least two sputum specimens should be submitted to the CRL for AFB microscopy (smear), culture and DST. Routinely, Rifampicin, Isoniazid, Streptomycin and Ethambutol are the anti-tb drugs being tested for sensitivity in the CRL. 3.5 Infection control and bio-safety in the laboratory. All laboratory personnel are trained in laboratory bio-safety issues. Use of appropriate equipment and standard operating procedures in all laboratories is a must. Bio-safety cabinets are a must only at the CRL because that is where culture and DST is done- it is not a must to have biosafety cabinets for laboratories dealing with smear microscopy alone. 3.6 Quality control and quality assurance The NTP maintains quality control and assurance through regular supervision at all levels. Medical Research Council (MRC) - South Africa provides external quality control to the CRL. 7

17 Section 4: TREATMENT FOR DRUG RESISTANT TUBERCULOSIS 4.1 Treatment of patients with mono and polyresistant strains When a decision has been made to modify standardized SCC, the most effective regimen should be chosen from the start to maximize the likelihood of cure; effective drugs should not be withheld for later use. The recommendations for treating patients with mono and poly resistant strains are outlined in table 1 below: Table 1: Suggested regimens for mono- and poly-drug resistance (when further acquired resistance is not a factor and laboratory results are highly relevant) Pattern of drug resistance Suggested regimen Minimum duration of treatment (months) Comments H (± S) R, Z and E 6-9 A fluoroquinolone may strengthen the regimen for patients with extensive disease. H and Z H and E R R and Z (± S) H, E, Z (± S) R, E and fluoroquinolones R, Z and fluoroquinolones H, E, fluoroquinolones, plus at least 2 months of Z H, E, fluoroquinolones, plus an injectable agent for at least the first 2 3 months R, fluoroquinolones, plus an oral second-line agent, plus an injectable agent for the first 2 3 months 9 12 A longer duration of treatment should be used for patients with extensive disease 9 12 A longer duration of treatment should be used for patients with extensive disease An injectable agent may strengthen the regimen for patients with extensive disease. 18 A longer course (6 months) of the injectable agent may strengthen the regimen for patients with extensive disease. 18 A longer course (6 months) of the injectable agent may strengthen the regimen for patients with extensive disease. H = Isoniazid; R = Rifampicin; E = Ethambutol; Z = Pyrazinamide; S = Streptomycin 8

18 Treatment of polyresistance Combine the maximum possible number of available anti-tb drugs that act upon different targets in the micro-organisms. If few such drugs are available, an aminoglycoside must always be included e.g. Amicacin, or Capreomycin (though not an aminoglycoside). Duration of treatment; 18 months if H&R can not be used 12 months if H&R can be used. Or give full MDR-TB treatment (as pre-mdr-tb). NB: Pyrazinamide has low risk of resistance in the first-line regimen. All TB patients can be cured with atleast 3 drugs that have never been used by the patient or for which no drug resistance exists. Rifampicin can be substituted with Rifabutin in an HIV positive patient who needs protease inhibitor therapy. Management of Diseases caused by environmental mycobacteria other than tuberculosis (MOTT) Principle reservoir of MOTTs is water (including tap water) and ground. Increase in incidence of these diseases have increasingly been HIV related. Sensitivity tests to TB drugs is limitted with most of MOTTs resistant to TB drugs in vitro. Consult specialist for advice on their management. 4.2 Treatment of multi-drug resistant tuberculosis The selection of anti-tuberculosis agents is based upon the history of previous therapy and the results of reliable DST. Use at least 4 drugs with either certain or almost certain effectiveness. The design of individual regimens should not be based on results of DST of E, Z, or group 4 or group 5 drugs. Gatifloxacin should be considered for use with caution given the rare but dangerous adverse effects of dysglycaimia associated with the drug. Ciprofloxacin should not be used as anti-tuberculosis agent in the management of drug resistant TB because of its weak efficacy. Table below shows drugs used for the treatment of MDR-TB. Table 2: Drugs used for the treatment of MDR-TB: Am Amikacin Lfx Levofloxacin Amx/Clv Amoxicillin/Clavulanate Lzd Linezolid Mfx Moxifloxacin H Isoniazid (high dose) Cfz Clofazimine Ofx Ofloxacin Clr Clarithromycin PAS P-aminosalicylic acid Cm Capreomycin Pto Protionamide Cs Cycloserine E Ethambutol Eto Ethionamide S Streptomycin Th Thioacetazone Gfx Gatifloxacin Trd Terizidone Vi Viomycin Km Kanamycin Z Pyrazinamide In Malawi the following MDR-TB drugs are available: Capreomycin (Cm), Levofloxacin(Lfx), Streptomycin (S), Ethambutol (E), Pyrazinamide (Z), Ethionamide (Eto) and Cycloserine (Cs). The treatment for mono and poly drug resistant TB are summarized at the end of this chapter. 9

19 The recommended treatment for MDR-TB is standardized and comprises of Cm, Lfx, Z, Eto and Cs in a regimen which will be given for 26 months as follows: 8Cm-Lfx-Eto-Cs-Z/18 Lfx-Et-Cs. NB: Malawi s initial regimen included Kanamycin and Ofloxacin. These have been replaced with Capreomycin and Levofloxacin respectively because of adverse effects. There is a standard code for anti-tuberculosis regimens, and each drug has an abbreviation (shown in the list of abbreviations, above). An MDR-TB regimen consists of two phases: the first phase is the period in which the injectable agent is used and the second phase is after it has been stopped. The two phases are separated by a forward slash in the regimen format. The number shown before each phase stands for phase duration in months and is the minimum amount of time that phase should last. The subscript number after a letter is the number of drug doses per week. If there is no subscript number, treatment is daily (or six times a week). An alternative drug(s) appears as a letter(s) in parentheses. The drugs in the higher groups are written first followed in descending order of potency. The drug dosage is determined by body weight. A weight-based dosing schedule is given in the table at the end of this chapter. An injectable agent is used for a period of not less than 8 months. Treatment in the continuation phase is for a minimum duration of 18 months (beyond culture conversion). Each dose is given as DOT throughout the treatment. A treatment card is marked for each observed dose. 4.3 Rational Classification of Anti-TB Drugs Group 1: First Line Drugs, Oral (H, R, E, Z) These drugs are the most potent and best tolerated anti-tuberculosis drugs. They should be used in mono resistance TB patients only where there is laboratory evidence or clinical history to suggest their efficacy. Pyrazinamide has been chosen as an alternative second line drug because of its low risk of resistance in the first line regimen. Group 2: Injectables: Sm, Km, Ak, Cm A Group 2 injectable agent should be given to all patients in whom susceptibility is documented or suspected, according to a hierarchical order based on efficacy, adverse effects and cost. Based on this Malawi had initially settled for Kanamycin as the most suitable injectable drug for MDR- TB patients, but due to its severe adverse effects, it has been replaced with Capreomycin. The injection should be given by a well trained health worker who should be able to recognize side effects that are associated with it. Dose should be calculated according to specific body weight for each patient and not using weight bands. Group 3: Fluroquinolones: Ofx, Lfx, Mfx. Gfx A Group 3 drug should be used if the strain is susceptible. Currently, the most potent available fluoroquinolones in descending order based on in vitro activity and animal studies are: Moxifloxacin = Gatifloxacin > Levofloxacin > Ofloxacin. However, the long-term safety of the newer-generation fluoroquinolones has not yet been fully evaluated. 10

20 Group 4: Other Second Line Drugs: Eto, Pto, Cs, PAS Group 4 drugs are added on the basis of estimated susceptibility, drug history, efficacy, adverse effects profile and cost. If only one of these agents is needed, Ethionamide/Protionamide is often added because of its proven efficacy and low cost. If cost is not a constraint, PAS may be added first because the enteric-coated formulae are relatively well tolerated. If two agents are needed, Cycloserine is commonly used in conjunction with Ethionamide/Protionamide or PAS. Since the combination of Ethionamide/Protionamide and PAS has a high incidence of gastrointestinal adverse effects, these two agents are commonly used together only when all three Group 4 agents are needed. Ethionamide/Protionamide should be started at a low dose (250 mg) for a few days and then gradually increased every 3 5 days until the full dose is reached. Terizidone contains two molecules of Cycloserine and can be used instead of Cycloserine because its efficacy is assumed to be similar, although there are no direct studies comparing the two. The use of Thioacetazone is limited by the development of rashes that are more prevalent in HIV-positive individuals and can result in Stevens-Johnson syndrome and death. In addition, Thioacetazone has cross-resistance with the thionamides (Ethionamide and Protionamide) and is considered a relatively weak ant tuberculosis agent. Group 5: Reinforcement Drugs: Am/Cl, Clof, Clar, Th, H (high dose), Imipenem The Group 5 drugs are not yet recommended by WHO for routine use in MDR-TB treatment because their contribution to the efficacy of multi-drug regimens is unclear. However, they can be used in cases where adequate regimens are impossible to form with the medicines from Groups 1 4. The dosing schedule for the treatment of MDR-TB patients (according to body weight) is shown in table 3. B.1Table 3: Dosing schedules Intensive phase: 8 months Patient Weight Drug Dosage Capreomycin (Cm) mg Ethionamide (Et) 500mg <50Kg Pyrazinamide (Z) 1000mg Levofloxacin (Lfx) 750mg Cycloserine (Cs) 500mg Capreomycin 1000 mg Ethionamide 750mg 51-70Kg Pyrazinamide 1500mg Levofloxacin 750 Cycloserine 750mg Capreomycin 1000mg Ethionamide 750mg >70Kg Pyrazinamide 2000mg Levofloxacin mg Cycloserine mg Cycloserine 750mg 11

21 Continuation phase: 18 months Patient Weight Drug Dosage Ethionamide 500mg <50Kg Levofloxacin 750mg Cycloserine 500mg Ethionamide 750mg 50-70Kg Levofloxacin 750 Ethionamide mg Levofloxacin mg Cycloserine mg 4.4 Management of rifampicin resistant cases All patients diagnosed using Gen- xpert machine should be managed as follows: If rifampicin resistance is reported, a sample should be collected for culture and DST The patient should be started on second line TB treatment (as MDR-TB) after specimen is collected for confirmation When diagonosis is not confirmed, seccond line TB drugs should be discontinued and manage as indicated in Table 1 above. 12

22 Section 5: MANAGEMENT OF MDR- TB IN SPECIAL SITUATIONS This section outlines the management of drug-resistant TB in special conditions and situations as below: 5.1 Pregnancy There are currently no special multi-drug resistant TB treatment regimens for pregnant women in Malawi. The same standardized regimen shall be used, taking note of the following: Aminoglycosides can be particularly toxic to the developing fetal ear Ethionamide can increase the risk of nausea and vomiting associated with pregnancy, and teratogenic effects have been observed. All female patients of childbearing age should be tested for pregnancy and where applicable start MDR-TB treatment in second trimester since the majority of teratogenic effects occur in the first trimester, unless the condition of the patient is severe to warrant start of treatment as soon as possible. 5.2 Breastfeeding The same regimen will be used for women who are breastfeeding and have multi drug-resistant TB. The mother and her baby should not be completely separated. If the mother is sputum smearpositive, the care of the infant should be left to family members until she becomes sputum smear-negative, if this is feasible. When the mother and infant are together, this common time should be spent in well-ventilated areas or outdoors. The mother may be offered the option of using a surgical mask or an N-95 respirator until she becomes sputum smear-negative. Children who develop tuberculosis after the mother is sputum smear negative or is cured will need to be given the standard first line anti-tb treatment. However the clinician treating the child has the justification of switching to second line drugs if there is no improvement by the third month of first line treatment. 5.3 Contraception The same regimen will be used in women on oral contraceptives. Birth control is strongly recommended for all non-pregnant women receiving therapy for drugresistant TB. 5.4 Children Children clinically diagnosed with multi-drug resistant TB will receive the same regimen as adults, but the drugs will be given according to body weight as follows: 13

23 Table 4: Paediatric dosing of second-line anti-tuberculosis drugs: DRUG DAILY DOSE FREQUENCY MAXIMUM DAILY DOSE (Mg/Kg) Capreomycin Once daily 1 g Amikacin Once daily 1 g Levofloxacin once daily 750mg Ethionamide Twice daily 1 g Protionamide Twice daily 1g Cycloserine Once or twice daily 1 g Ethambutol Once daily 400 mg p-aminosalicylic acid 150 Twice or thrice daily 12 g 5.5 Diabetes mellitus All patients with diabetes mellitus will receive the same recommended regimen. However the following should be noted: Monitor blood pressure every month Patients are at risk of poor outcomes if glucose is not well controlled. There is increased risk of potentiated adverse effects of anti-tuberculosis drugs, especially renal dysfunction and peripheral neuropathy. Patients may require increased dosages of drugs for diabetes. Diabetic patients require hospitalization long enough for close monitoring of blood sugar levels. 5.6 Renal insufficiency These patients will also use the same regimen, but the following should be noted: Pyrazinamide, Levofloxacin, Cycloserine and Capreomycin should be given three times a week and not daily. See table 5 below: 14

24 Table 5: Adjustment of anti-tuberculosis medication in renal insufficiency Drug Change in frequency Recommended dosage and frequency for patients with creatinine clearance <30 ml/min or for patients receiving haemodialysis Isoniazid No change 300 mg once daily, or 900 mg three times per week Rifampicin No change 600 mg once daily, or 600 mg three times per week Pyrazinamide Yes mg/kg per dose three times per week (not daily) Ethambutol Yes mg/kg per dose three times per week (not daily) Ofloxacin Yes mg per dose three times per week (not daily) Levofloxacin Yes mg per dose three times per week (not daily) Moxifloxacin No change 400 mg once daily Cycloserine Yes 250 mg once daily, or 500 mg/dose three times per week Terizidone - Recommendations not available Protionamide No change mg per dose daily Ethionamide No change mg per dose daily p-aminosali cylic No change 4 g/dose, twice daily acidc Streptomycin Yes mg/kg per dose two or three times per week (not daily) Capreomycin Yes mg/kg per dose two or three times per week (not daily) Kanamycin Yes mg/kg per dose two or three times per week (not daily) Amikacin Yes mg/kg per dose two or three times per week (not daily) 5.7 Liver disorders The same regimen as above will be used but where there is jaundice developing, TB treatment should be stopped. Re-start TB treatment after jaundice has subsided. When there is pre-existing acute hepatitis, it is recommended to defer anti-tuberculosis treatment until the acute hepatitis has resolved. Patients with chronic liver disease should not be given Pyrazinamide, but all other drugs can be used. 5.8 Seizure disorders Use the same regimen as above but noting the following: Patients with active seizure disorders should have the anti-seizure medication adjusted upwards in order to control the seizures, especially where Cycloserine is used. Seizures that present for the first time during anti-tuberculosis therapy are likely to be the result of an adverse effect of Cycloserine. See management of adverse-effects under chapter 9. 15

25 5.9 Psychiatric disorders The same regimen will be used in these patients. The following should be noted: There is a high baseline incidence of depression and anxiety in patients with MDR-TB, often connected with the chronicity and socioeconomic stress factors related to the disease. Close monitoring is recommended since Cycloserine is used. Psychiatric emergencies include psychosis, suicidal tendencies and any situation involving the patient being a danger to oneself or others must be managed as recommended Congregate settings Patients diagnosed with MDR-TB in congregate settings e.g. prisons should be isolated until they convert to smear negative Other conditions If a health worker encounters other conditions not stated above and is not sure on how to proceed with the management of such a patient, contact any medical specialist or NTP Secretariat. 16

26 Section 6: MANAGEMENT SYSTEMS MDR-TB patients diagnosed in Malawi are managed under a community based setting. Where hospitalisation may be needed, these patients can be admitted either in a specialised MDR-TB facility or in isolation at a health facility as identified by hospital management 6.1 National MDR-TB Coordination Team At national level, MDR-TB case management is coordinated by a team led by a designated physician. The national coordination team is responsible for conducting virtual ward rounds for all patients enrolled on second line TB treatment under the direct care of local MDR-TB management teams. As far as possible arrangements are made for experts in MDR TB management to visit and advise the teams within country so that virtual ward rounds remain functional. Note: Virtual ward round is an arrangement whereby the national MDR-TB management team through the zonal MDR-TB team communicates with the local MDR-TB team to get information about the clinical condition of the patient. The national team advises the local team on how to manage the patient. 6.2 Community based management of MDR-TB patients: In all district hospitals, a District MDR-TB Management Team comprising of: the DHO, District Medical Officer, District Nursing Officer, Focal MDR-TB Clinician, Focal MDR-TB Nurse, District TB Officer, laboratory technician and Pharmacy technician is responsible for MDR-TB management. A Health centre MDR-TB management team has been established in all health centres. The health centre management team comprises of: Health Centre-in-Charge, nurse and focal TB Health Surveillance Assistant. 6.3 Responsibilities of MDR-TB management teams: District MDR-TB Management Team Intensify MDR-TB case finding- district level MDR-TB surveillance. Administer MDR-TB medications to patients Monitor management of MDR-TB patients, including hospitalised patients Recording and reporting of MDR-TB patients Timely ordering of second line anti-tb drugs for patients diagnosed Timely ordering of ancillary drugs for the management of adverse drug reactions. Monitor and manage adverse effects Conduct defaulter tracing Conduct contact tracing Training of health centre MDR-TB management teams. Supervision of health centre MDR-TB management teams Health Centre MDR-TB Management Team Administer MDR-TB medications to patients 17

27 Conduct contact tracing Monitor treatment (management) Recording and reporting at health centre level Manage MDR-TB pharmaceuticals Conduct defaulter tracing 6.4 Directly Observed Treatment (DOT) in MDR-TB. Once diagnosed all MDR-TB patients must be registered in an MDR-TB register by a District TB Officer. Patient education must be offered at the time of registration and during subsequent visits. Patient education should tackle such issues as; MDR-TB treatment duration, drugs and their adverse effects, importance of adherence to treatment, cough hygiene and prevention of disease transmission, especially to children less than six years old. Patients must be encouraged to continue treatment unless adverse effects are severe. Patients on community based management will be managed on an ambulatory basis- during both the intensive and continuation phases. A health worker will administer drugs during the intensive phase. In the continuation phase, DOT will be done by a guardian as is the current practice of managing susceptible TB patients on first line anti-tb drugs. Drug supplies during the continuation phase shall be on a monthly basis. 6.5 Hospital admission of MDR-TB patients: When hospitalization of an MDR-TB patient becomes necessary, the patient will be referred from the health centre to the hospital following normal referral procedures. At the hospital the patient must be admitted in an isolated and well ventilated room. Entry into the room should be limited to only those health workers directly managing the patient. 6.6 Role of respirator masks (N95 masks). All health care providers are required to put on respirator (N95) masks when in direct contact with the patient. Direct contact events include; Registration of patient Patient education / counseling Administration of medications- both in ambulatory and hospitalized patients. Transportation of patients. Manipulation of sputum specimens in the laboratory Note. It is recommended that MDR-TB patients must put on a surgical mask during referral or interview while the health worker must use N95 respirator mask for his/her protection MDR-TB in Specialized Hospital setting. Every effort will be made to ensure that MDR-TB treatment centres are designed to international standards for managing MDR-TB. 6.7 Defaulter tracing. An MDR-TB patient who has missed drugs should be followed up to prevent defaulting within 3 days. This should be done according to guidelines used for tracing susceptible TB patients that are on first line regimen. 18

28 6.8 Follow up MDR-TB Management Teams should regularly review MDR-TB patients within their catchment populations as recommended in Table 6. 19

29 Section 7: MDR-TB MONITORING AND EVALUATION MDR-TB treatment monitoring will include items authored in the first column of Table 6 below with their frequencies in the second column. The findings should be recorded and where necessary be, reported to the focal point for MDR-TB in the NTP. Below is a table for monitoring during treatment of drug resistant TB Table 6 Monitoring during treatment of MDR-TB MONITORING RECOMMENDED FREQUENCY EVALUATION Evaluation by clinician Screening by DOT worker Sputum smears and culture Weight Drug susceptibility Chest radiograph Serum creatinine Serum potassium Thyroid stimulating hormone (TSH) Liver serum enzymes HIV screening Pregnancy tests Haemoglobin and white blood count At baseline, then weekly in intensive phase. In continuation phase, monthly At every DOT encounter Monitor smears monthly in intensive phase then every two months. Cultures monthly in intensive phase then every two months. At baseline and then monthly At baseline to confirm MDR-TB. For patients who remain culture-positive, it is not necessary to repeat DST within 3 months of treatment At baseline, and then every 6 months At baseline, then monthly if possible while receiving an injectable drug. Every 1 3 weeks in HIV-infected patients, diabetics and other high-risk patients Monthly while receiving an injectable agent. Every 1 3 weeks in HIV-infected patients, diabetics and other high-risk patients Every 6 months if receiving Ethionamide/Protionamide hormone and/or PAS; and monitor monthly for signs/ symptoms of hypothyroidism. TSH is sufficient for screening for hypothyroidism; it is not necessary to measure hormone thyroid levels Periodic monitoring (every 1 3 months) in patients receiving Pyrazinamide for extended periods or for patients at risk for or with symptoms of hepatitis. For HIV-infected patients, do monthly monitoring At baseline, and repeat if clinically indicated At baseline for women of childbearing age, and repeat if Indicated At baseline for all patients, if on Linezolid, monitor weekly at first, then monthly or as count needed based on symptoms; there is little clinical 20

30 Lipase Lactic acidosis Serum glucose experience with prolonged use For HIV-positive patients on an ART regimen that includes AZT, monitor monthly initially and then as needed based on symptoms Indicated for work up of abdominal pain to rule out pancreatitis in patients on Linezolid, D4T, ddi, ddc. Indicated for work up of lactic acidosis in patients on Linezolid or ART If receiving Gatifloxacin, monitor glucose frequently (weekly) and educate patient on signs and symptoms of hypoglycemia and hyperglycemia End of treatment cohort analyses should be carried out at 26 months and repeated at 38 months. The analysis is done at 26 months because most of the patients would have finished treatment, allowing preliminary assessment of cure rates. Since some patients may be on treatment longer than 26 months, the cohort analysis must be repeated at 38 months. The 38-month evaluation is considered the final treatment cohort analysis result. 7.1 Cohort analysis A Category IV treatment cohort is defined as a group of patients who start Category IV treatment during a defined time period. The Category IV treatment cohort will consist of a subset of patients recorded in the Category IV Register, i.e. those who actually started Category IV treatment during the specified period of time. To allow adequate analysis of all patients who meet the criteria of diagnostic Category IV, three dates should be recorded (these dates are recorded on both Forms 01 and 02) 1. Date of initial registration as a TB case 2. Date of registration in Category IV Register 3. Date of starting Category IV treatment Registration cohort analysis focuses on the number of patients identified and the number who are placed on treatment. Treatment cohort analysis focuses on treatment outcomes among patients who actually started Category IV treatment. All patients should be assigned the first outcome they experience. Subsequent outcomes among patients followed systematically should be recorded appropriately. For example, a patient who defaults on the first Category IV treatment and then returns 14 months later to be re-registered and treated with a second Category IV treatment. This patient should receive a final outcome of defaulted in the cohort in which he or she was first registered and cured in the second cohort. Surveillance of MDR-TB The following surveillance measures are in place: 1. Routine culture and DST: Routine CDST should be performed on samples from all re-treatment cases. External quality assurance on first line and second line anti-tb drugs is done on batches of samples sent to the Supra National Reference Laboratory (SNRL). 21

31 2. New smear positive TB patients 10% of all new smear positive TB cases in a district should submit sputa samples for DST to monitor the trend of drug resistance in the country. 3. High-risk groups with TB Consideration should be given to target groups described in chapter two, 4. MDR-TB surveys Every 5 years, MDR-TB surveys will be done as part of surveillance system. This will also cater for XDR-TB surveillance. 5. Contacts of MDR-TB cases Sputum samples from all contacts of known MDR-TB cases should be sent for DST at CRL and the SNRL. 7.2 Monitoring progress of treatment Patients should be monitored closely for signs of treatment failure. Clinically, the most important way to monitor response to treatment is through regular history-taking and physical examination. The classic symptoms of TB cough, sputum production, fever and weight loss generally improve within the first few months of treatment and should be monitored frequently by healthcare providers. The recurrence of TB symptoms after sputum conversion, for example, may be the first sign of treatment failure. For children, height and weight should be measured regularly to ensure that they are growing normally. A normal growth rate should resume after a few months of successful treatment. Objective laboratory evidence of improvement often lags behind clinical improvement. The chest radiograph may be unchanged or show only slight improvement, especially in re-treatment patients with chronic pulmonary lesions. Chest radiographs should be taken at least every six months, when a surgical intervention is being considered, or whenever the patient s clinical situation has worsened. The most important objective evidence of improvement is conversion of sputum smear and culture to negative. While sputum smear is still useful clinically because of its much shorter turnaround time, sputum culture is much more sensitive and is necessary to monitor the progress of treatment. Sputum examinations are also dependent on the quality of the sputum produced, so care should be taken to obtain adequate specimens. Sputum conversion is slower in MDR-TB than in drug-susceptible TB. Paucibacillary culture results should not be automatically regarded as negative when treating MDR-TB. Acquired drug resistance and treatment failure often begin with the growth of one or two colonies on a sputum culture. DST should also be done on less than five colonies and the results (especially positive results) should be interpreted with caution. Culture conversion should not be considered to be equivalent to cure. A certain proportion of patients may initially convert and later revert to positive sputum culture. The factors associated with this reconversion and its implications are under study. Specimens for monitoring do not need to be examined in duplicate, but doing so can increase the sensitivity of the monitoring. For patients who remain smear and culture positive during treatment or who are suspects for treatment failure, DST can be repeated. It is usually not necessary to repeat DST within three months of completion of treatment. 22