2019

NATIONAL GUIDELINES ON Drug Resistant Tuberculosis Management

END TB

Government of Nepal Ministry of Health and Population Department of Health Services National Tuberculosis Centre Thimi, Bhakatapur

TABLE OF CONTENTS

PREFACE 3

1. INTRODUCTION 1 1.1 Background 1 1.2 Key definitions 4 1.3 Organisation of DR-TB control in Nepal 7 1.4 Roles and responsibility 7

2. DIAGNOSIS OF DR-TB 11 2.1 Identification of presumptive DR-TB 11 2.2 Management of presumptive DR-TB 11 2.3 Diagnostic tests 12 2.4 Diagnosis of extrapulmonary DR-TB in the absence of DST 20 2.5 Diagnostic pathway 20 2.6 Diagnosis of DR-TB in special groups 22

3. REGISTRATION CATEGORY OF DR-TB 24

4. TREATMENT OF DR-TB 25 4.1 Patient Education 25 4.2. Drugs used to treat DR TB and Principles of Treatment 27 4.3. RR/MDR-TB treatment regimens 32 4.4 Shorter Standardized Treatment Regimen (SSTR) 36 4.5 Treatment of INHr TB 42 4.6 Treatment of MDR-TB in special situations 44 4.7 Adjuvant therapies and interventions 57 4.8 Surgery 57

5. MANAGEMENT AND MONITORING ASPECTS OF DR-TB 58 5.1 Preparation prior to starting second-line treatment 59 5.2 Treatment administration 60 5.3 Organization of the treatment 61 5.4 Drug Intake 62 5.5 Follow-up monitoring investigations during and after completion of treatment 63 5.6 Monitoring of treatment progress 66 5.7 Follow-up after the end of treatment 67 5.8 Palliative care 67 5.9 Management of contacts of MDR-TB patients 68

6. ACTIVE DRUG SAFETY MONITORING AND MANAGEMENT (ADSM) 69 6.1 Management of AEs or ADRs 72 6.2 Causality Assessment of the Serious Adverse Event (SAEs) 90 7. INFECTION CONTROL 91 7.1 General principles of infection control 91 7.2 Infection control at TB consultation room 94 7.3 DR-TB Patient isolation room 94 7.4 Infection control at home 95 7.5 Health worker and Infection Control 95

8. MONITORING AND EVALUATION FOR TB CONTROL PROGRAM 96 8.1 Recording and reporting of DR-TB programme 96 8.2 Monitoring of DR-TB Case Detection and Treatment Activities 100

ANNEXES 103-173

NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT vii

ACKNOWLEDGEMENT

The National TB Centre director (Dr. Sagar Rajbhandari) expresses my sincere gratitude to all the authors and reviewers of this guideline particularly to the World Health Organization and all the others who contributed in coming up with this comprehensive National Tuberculosis (TB) Management Guideline 2019

1. Dr. Bhim Singh Tinkari, (Previous NTC Director) 2. Dr. Ashesh Dhungana, Chief Consultant Chest Physician, NTC 3. Dr. Sharad Kumar Sharma, Chief - SMEAR section, NTC 4. Mr. Anil Thapa, (Previous Chief - SMEAR section, NTC) 5. Dr. Naveen Prakash Shah, Consultant Chest Physician, NTC 6. Mr. Gokarna Raj Ghimire, Laboratory In-charge, NTC 7. Mr. Pushpa Raj Joshi, Statistical officer, NTC 8. Ms. Basundhara Sharma, Senior Public Health Officer, NTC 9. Ms. Meera Hada, Medical Technologist, NTC 10. Prof. Dr. Brajendra Srivastav, NAINS College of Medicine 11. Dr. Suvesh Kumar Shrestha, Technical Specialist-TB, SCI 12. Dr. Ashish Shrestha, National Consultant-TB, WHO 13. Dr. Pramod Raj Bhattarai, Damien Foundation 14. Dr. Bhawana Shrestha, Project Manager, NATA/GENETUP 15. Dr. Praveen Sanker, Laboratory Consultant, SCI-FIND 16. Mr. Rajendra Basnet, SCI/NTC 17. Mr. Ratna Bahadur Bhattarai, Monitoring and Evaluation Specialist- SCI/NTC 18. Mr. Gokul Mishra, Liaison Officer, NTC/LSTM 19. Mr. Bhagawan Maharjan, Microbiologist, GENETUP 20. Mr. Nilaramba Adhikari, SCI/NTC 21. Mr. Lok Raj Joshi, SCI/NTC 22. Mr. Naval Kishor Shrestha, SCI/NTC 23. Mr. Chitra Jung Shahi, DTLO, NTC 24. Mr. Krishna Adhikari, Lab Technician Officer, NTC 25. Ms. Kamala Devi Wagle, Public Health Nurse Officer, NTC 26. Ms. Tara Sharma, NTC 27. Ms. Anju Basnet, NTC 28. Mr. Saroj Roy, NTC 29. Mr. Brij Ranjan Yadav, NTC 30. Mr. Gopi Prasad Rupakheti, Kharidar/Supervisor, NTC 31. Dr. Mohammed Asif, Consultant, rGLC Member 32. Dr. Medea Gegia, Technical Officer Programme, WHO-HQ 33. Dr. Lungten Z. Wangchuk, Scientist- Team -Lead, CDS, WHO, Nepal

NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT ix

THE MAIN CHANGES IN THE WHO 2019 RECOMMENDATIONS

• It is recommended that any patient – child or adult – with RR-TB in whom isoniazid resistance is absent or unknown be treated with a recommended MDR-TB regimen, either a longer MDR- TB regimen to which isoniazid may be added or a standardized shorter MDR-TB regimen • Shared based decision making between doctor and patient for choice of treatment either longer or shorter regimens • A package of treatment adherence interventions may be offered to patients on TB treatment in conjunction with the selection of a suitable treatment administration option • In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, , treatment with rifampicin, ethambutol, pyrazinamide and levofloxacin is recommended for a duration of 6 months. it is not recommended to add injactables. • Regrouping of medicine (A, B & C) based on most recent available evidence and all oral longer (Inj free) regimen is recommended • All three Group A agents and at least one Group B agent should be included to ensure that treatment should start with at least four TB agents likely to be effective and that at least three effective agents are included for the rest of treatment period after the Bdq is stopped by month 6 • There is strong recommendation to use all Group A drugs(Mfx/Lfx, Bdq,Lzd) in longer regimen, until and unless there is contraindication to include in regimen. • Most patients can be treated with 18 months duration by using Longer Regimen • Kanamycin and capreomycin are no longer to be the part of treatment of RR/MDR-TB regimens. Only Amikacin or Streptomycin is to be used under certain conditions • Bedaquiline should be included in longer MDR-TB regimens for patients aged 18 years or more • Bedaquiline may also be included in longer MDR-TB regimens for patients aged 6-17 years • Delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more on longer regimens • It is strongly recommended that Clavulanic acid should not be included in the treatment of MDR/RR-TB patients on longer regimen, only in combination use with Imipenem • Intensive phase of 6-7 months will only be considered if Injectables (Am, S) are part of regimen • In MDR/RR-TB patients on longer regimens, a total treatment duration of 18-20 months is suggested for most patients • Regimens without an injectable agent are considered not to have an intensive phase • On longer regimens, a treatment duration of 15 to 17 months after culture conversion is suggested for most patients • Any modifications on standard shorter regimen should be conducted under operational research conditions • aDSM is applicable to all RR TB patients • It is desirable for sputum culture to be repeated at monthly intervals.

CHAPTER 1 INTRODUCTION

1.1 BACKGROUND National TB programme is moving forward with the vision of TB Free Nepal by 2050 in accordance with the National Health Policy 2014 and under the strategic direction of the worldwide initiative to end TB – the End TB Strategy.

The goal of National Strategic Plan 2016-21 is to decrease the TB Incidence rate by 20%, from 2015 to 2021 i.e. to identify additional 20,000 new TB cases by next 5 years.

The overall objectives of NSP 2016-21 are as follows: Objective 1: To increase case notification through improved health facility-based diagnosis; increase diagnosis among children (from 6% at baseline, to 10% of total cases by 2021); examination of household contacts and expanded diagnosis among vulnerable groups within the health service, such as PLHIV (from 179 cases at baseline to over 1,100 cases in 2020/21), and those with diabetes mellitus (DM).

Objective 2: To maintain the treatment success rate of 90% for all forms of TB (except drug resistant TB) by 2021

Objective 3: To provide DR TB diagnose services to 50% of the presumptive MDR TB patients by 2018 and 100% by 2021 and to successfully treat at least 75% of those diagnosed.

Objective 4: To expand case finding by engaging providers for TB care from the public sector (beyond MoH), medical colleges, NGO sector, and private sector through results based financing (PPM) schemes, with formal engagements (signed MoUs) to notify TB cases

Objective 5: To gradually scale up Community System Strengthening Programme (CSS) at 60% of the local administrative units by 2018 and to 100% of the administrative units by 2021. It will help in creating a patient friendly ambience in the health facilities, advocacy for TB patients regarding their rights which will, in turn, contribute to the diagnosis and management of TB cases

Objective 6: To contribute to health system strengthening through HR management and capacity development, financial management, infrastructure, procurement and supply management in TB

Objective 7: To develop comprehensive Monitoring and Evalutaion system

Objective 8: To develop plans so that NTP can function even at times of crises like natural disasters or public health emergencies. 2 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

1.1.1 Multi Drug Resistant Tuberculosis (MDRTB) in the world According to the most recent WHO Global Tuberculosis Report (2018) the total number of new (incident) TB cases worldwide in 2017 was estimated at 10.0 million. Among these, 9% were HIV+. Worldwide in 2017, 6.4 million new cases of TB were officially notified to national authorities and then reported to the WHO. The number of incident RR/MDR-TB cases in 2017 was estimated at 558 000. Globally, 160,684 cases of MDR/RR-TB were detected and notified in 2017 (a small increase from 153 119 in 2016). Of these, a total of 139,114 people (87%) were enrolled on treatment with a second-line regimen, up from 129,689 in 2016 but still only 25% of the estimated 558,000 people who developed MDR/RR-TB in 2017. China and India alone accounted for 40% of the global gap; these and eight other countries 10 accounted for 75%. Treatment success remains low, at 55% globally. Examples of high burden countries in which better treatment success rates are being achieved include Bangladesh, Ethiopia, Kazakhstan, Myanmar and Viet Nam (all of which have rates above 70%). Closing gaps in detection and treatment requires much higher coverage of drug susceptibility testing among people diagnosed with TB, reducing under diagnosis of TB, models of care that make it easier to access and continue treatment, new diagnostics, and new medicines and treatment regimens with higher efficacy and better safety.

FIGURE 1.1: DR-TB burden

1.1.2 MDR in SEAR countries Besides the high rate of relapse, the emergence of drug-resistant tuberculosis poses a major challenge to ending TB with traditional therapeutics. In SEAR, less than half the MDR-TB cases (49%) were cured. In SEAR, the estimated incidence of MDR/RR-TB was 200 000, with India alone accounting for 130 000. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 3

FIGURE 1.2: Ranking of SEAR countries by MDR-TB incidence, 2015

1.1.3 MDR-TB in Nepal In Nepal, the burden of DR TB is not as high as the regional or global burden. There are estimated around 1500 cases of DR TB annually. However, 350 to 450 MDR TB cases are notified annually. Four hundred twenty cases were notified in 2017/18. The lack of availability of and access to an early screening of presumptive TB cases with Rapid DST may still be the main reasons for this stagnation of DR TB cases in the country. The proportion of new cases with multidrug-resistant TB (MDR-TB) was 2.2% among new cases and 15.4% among retreatment cases based on DRS survey carried out in 2011/12. In 2016/17, a total of 257 RR/MDR TB, 91 Pre-XDR TB and 18 XDR TB were enrolled for treatment. Treatment Success Rate (TSR) of RR/MDR patients was 71%. However, the TSR of Pre-XDR TB is 58% and XDR TB is 61%, which were marginally lower than the RR/MDR TB cases. The routine surveillance showed a much higher proportion of drug-resistant pattern among second-line drugs used for the treatment of MDR patients in Nepal. The resistance to fluoroquinolones (FQ), SLI and both FQ and SLI were 39.3%, 3%, and 4% respectively, altogether there was 46.3% resistant to SLD among MDR patients. In other words, among all initially diagnosed as RR-MTB/MDR TB 42.3% of MDR patients may require Pre-XDR treatment similarly 4% may require XDR treatment (Source: NTP Annual Report-2018)

Five drug resistance surveys were conducted between 1996/1997 and 2011/2012:

TABLE 1.1 Findings of the drug resistance surveys conducted in Nepal between 1996 and 2011 Year MDR-TB in new TB patients MDR-TB in retreatment TB patients 1996/1997 1.1% Not available 1998/1999 3.7% 12.5% 2001/2002 1.3% 20.5% 2006/2007 2.9% 11.7% 2010/2011 2.2% 15.4% An XDR TB survey conducted by GENETUP in 2012 showed that among MDR-TB patients, 28% had Pre-XDR TB and 8% had XDR TB. 4 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Based on the findings of the last survey, the burden of MDR-TB for 2016 was calculated:

TABLE 1.2: Estimates of MDR-TB disease burden in Nepal for 2016 % of MDR-TB cases among new TB cases 2.2 (1.3–3.8) % of MDR-TB cases among retreatment TB cases 15.4 (10–23) Number of MDR-TB cases among notified new TB cases 540 (320–930) Number of MDR-TB cases among notified retreatment TB cases 620 (410–920)

This means that there are still a huge number of patients that the programme needs to find and cure. Although Nepal can be considered a low burden drug resistance country, the cases of MDR- TB are increasing every year.

1.2 KEY DEFINITIONS • Drug-susceptibility testing (DST): refers to in-vitro testing using either phenotypic methods to determine susceptibility or molecular techniques to detect resistance-conferring mutations to a medicine • Poly-resistance: resistance to more than one first-line drug (other than both isoniazid and rifampicin). • Multidrug resistance (MDR TB): resistance to at least both isoniazid and rifampicin . • Extensive drug resistance (XDR): resistance to the fluoroquinolones (at least one) and the second-line injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance. • Isoniazid-resistant TB (Hr-TB): resistance to isoniazid only and susceptibility to rifampicin has been confirmed. • Rifampicin resistance (RR-TB): resistance to rifampicin detected using phenotypic or genotypic methods, with or without resistance to other anti-TB drugs. It includes any resistance to rifampicin, in the form of mono-resistance, poly-resistance, MDR or XDR. • Pre-XDR: Resistance to either Fluroquinolone or SLD but not to both in addition to MDR • Extent or severity of disease: in patients older than 14 years, adolescents and adults usually the severity of diseases is defined by the presence of cavities or bilateral disease on chest radiography or smear-positivity and grading. While, in children <15 years, severe disease is usually defined by the presence of cavities or bilateral disease on chest radiography or extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression). In children the occurrence of advanced malnutrition (defined by syndrome or by metrics) or advanced immunosuppression or positive TB bacteriology (smear, Xpert MTB/RIF, culture) may also be considered when determining disease severity (WHO 2018) • Individualized treatment: Each regimen is designed based on the patient’s past history of TB treatment and individual DST results. NTP, Nepal has adopted combination of standardized and individualized approaches. • Longer MDR-TB regimens: are treatments for MDR/RR-TB which last minimum 18 months or NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 5

more and which may be standardized or individualized. These regimens are usually designed to include a minimum number of second-line TB medicines considered to be effective based on patient history or drug-resistance patterns. The term “conventional” was previously used to refer to such regimens but was discontinued in 2016 when WHO first issued a recommendation for the use of a shorter MDR-TB regimen (WHO 2018) • Shorter MDR-TB regimen: refers to a course of treatment for MDR/RR-TB lasting 9–12 months, which is largely standardized, and whose composition and duration follows closely the one for which there is documented evidence from different settings (WHO 2018) • Serious adverse events (SAEs): are those adverse events (AE) classified as Grade 3 (severe), Grade 4 (life-threatening or disabling) or Grade 5 (death related to AE), or which led to the medicine being stopped permanently (WHO 2018) • Definitions of Conversion & Reversion: The terms “conversion” and “reversion” of culture as used here are defined as follows: • Conversion (to negative): culture is considered to have converted to negative when two consecutive cultures, taken at least 30 days apart, are found to be negative. In such a case, the specimen collection date of the first negative culture is used as the date of conversion. • Reversion (to positive): culture is considered to have reverted to positive when, after an initial conversion, two consecutive cultures, taken at least 30 days apart, are found to be positive. • For the purpose of defining Treatment failed, reversion is considered only when it occurs in the continuation phase. • The intensive (or injectable) phase: initial part of a shorter regimen for treating multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB). During this phase, an injectable agent is used. Regimens without an injectable agent are considered not to have an intensive phase.

Drug resistance is the result of inadequate therapy M. tuberculosis resistance to anti-tuberculosis drugs is caused by spontaneous chromosomal mutations. The proportion of wild-type resistant mutants in an untreated M. tuberculosis population is usually very small. Treatment with anti-tuberculosis drugs imposes selection pressure on M. tuberculosis populations, resulting in a reduction in drug-susceptible bacilli, the advantageous reproduction of drug-resistant mutants and the emergence of drug resistance: this is acquired resistance, implying that resistance emerges during anti-tuberculosis treatment. Primary resistance refers to patients infected with M. tuberculosis that is resistant to anti- tuberculosis drugs before treatment. With a few exceptions, a mutation causes resistance to only one drug or group of drugs. Resistance to two or more drugs is caused by sequential mutations in different genes. (The UNION 2018)

A very small portion (around 1 in a million or 1/106) of the tuberculosis bacilli are spontaneously resistant to INH (these bacilli are called: drug resistant mutants). A TB patient with smear positive pulmonary TB will be infected with 108 to 109 bacilli. If a TB patient is treated with only INH, most bacilli will be killed, and the patient may improve clinically and bacteriologically, but 1 out of every million bacilli will not be killed. These resistant bacilli will continue to multiply, and soon the patient will again be infected with 108 bacilli, but this time all bacilli will be resistant to H. This phenomenon is called: selection of drug-resistant mutants. 6 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Additionally, even smaller, portion (around 1 in 100 million or 1/108) of the bacilli are spontaneously resistant to R. If a patient is treated with only R, almost all bacilli will be killed, but those few that are resistant to R will not be killed and will multiply. The result is a patient with TB that is resistant to R.

The main reason why drug resistance develops is monotherapy, giving only 1 drug a time. MDR develops as a result of sequential monotherapy: first, the bacilli become resistant to 1 drug, usually INH (this is called mono-resistance). Next, the bacilli develop additional resistance to R. This process can continue for one drug after the other. If the bacilli become resistant not only to R and H, but also to the fluoroquinolones and the injectable second-line drugs (such as kanamycin), this is called extensive drug-resistant TB or XDR-TB

TABLE 1.3: Causes of Resistance

Health care providers: Drugs: inadequate supply/ Patients: inadequate drug intake or Inappropriate treatment quality treatment response Inappropriate guidelines Poor quality Lack of information Non-adherence to Unavailability of some drugs Lack of means to adhere to treatment guidelines (stock outs) (transportation, food, etc.) Absence of guidelines Poor storage conditions Social barriers Poor training Inappropriate dosage or Adverse events (AEs) combination Lack of treatment Poor regulation of medicines Inadequate directly observed monitoring treatment (DOT) Poor management of Poor absorption of drugs adverse drug reactions Poorly organized or funded Substance abuse/dependence TB control programs

Source (Companion Handbook to the WHO Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/2014.11. Geneva, Switzerland: World Health Organization, 2014)

How to prevent drug resistance? Resistance to tuberculosis (TB) drugs is a formidable obstacle to effective TB care and prevention globally. Multidrug-resistant TB (MDR-TB) is multifactorial and fueled by improper treatment of patients, poor management of supply and quality of drugs, and airborne transmission of bacteria in public places. Case management becomes difficult and the challenge is compounded by catastrophic economic and social costs that patients incur while seeking care and on treatment.

There are five principal ways to prevent drug-resistant TB: 1. Early detection and high-quality treatment of drug-susceptible TB. 2. Early detection and high-quality treatment of drug-resistant TB. 3. Effective implementation of infection control measures. 4. Strengthening and regulation of health systems. 5. Addressing underlying risk factors and social determinants.

Source: Companion Handbook to the WHO Guidelines for the Programmematic Management of Drug Resistant Tuberculosis-2014 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 7

1.3 ORGANISATION OF DR-TB CONTROL IN NEPAL The DRTB programmeme is managed in following ways in Nepal: • Ministry of Health and Population approves the policies, strategies and allocates the budgets t0the programme • National TB Centre (NTC) approves, recommends, strategies and guidelines and manage necessary central budget for the programme • Technical Working Groups (TWG) at National TB Programmeme (NTP) provides inputs and technical advice on policies, strategies and guidelines, plans for DRTB management and provides technical inputs to the partners and stakeholders. • DR TB Treatment section at NTC, manages, monitors and evaluates of the DRTB activities and provide inputs to the DRTB programmeme • Dedicated human resources for DR TB Treatment Section will manage under NTC and support to manage the Procurement and Supplies of logistics. • Provincial Health Directorate supports to implement the DRTB activities; manage to supplies anti-TB drugs and other logistics, reporting, monitoring, supervision and evaluation of the DRTB. • Treatment and Sub-centre will provide treatment, care and support, refer for management of adverse drug reaction to the DRTB patients, record and report, manage sputum transport for culture and DST and screening of presumptive DRTB cases.

1.4 ROLES AND RESPONSIBILITY A. National Level (NTP) • Develop the policies, strategies and guideline for DRTB • Support planning, coordination, monitoring and evaluation of TB control activities with concerned stakeholders. • Support monitoring and supervision of all personnel involved in tuberculosis work. • Manage and advise on procurement and distribution of TB drugs and supplies. • Prepare forms, registers, health education and teaching materials for DRTB • Compile reports on case-finding and treatment with feedback to lower levels • Monitor and provide supportive supervision to the provincial level • Advise and carry out capacity enhancement activities at all levels on DRTB management • Coordinate with partner agencies. • Manage budget for implementation of the programme. • Promote TB/HIV Collaboration and MDR TB management. • Promote research and development in DRTB 8 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

B. Provincial Health Directorate (PHD) Office • Develop plans and strategies for DRTB programme in line with NTP • Carry out capacity enhancement activities at provincial and local levels health care workers on DRTB management • Implement, coordinate and supervise tuberculosis control activities. • Review, validate, compile and send quarterly reports on case-finding and treatment to NTP on time (end of the month following the quarter that just ended) • Coordinate with partner agencies at the province level • Request, receive, distribute and manage TB drugs, diagnostics and other supplies for the diagnosis and management of TB • Monitor and provide supportive supervision to the provincial level • Establish provincial TB, TB /HIV and PMDT committees and coordinate implementation of their respective activities in their provinces • Provide feedback to the Heatlh facilities on the quality of the reports • Conduct and ensure quality assurance for sputum microscopy services (EQA) for the facilities • Coordinate with partners and mobilise community based organisations to support implementation of DR-TB activities • Monitor, evaluate and review DR-TB activities in their respective provinces

District Level • Develop the plan at the district level • Manage, organise and facilitating TB training to health workers • Monitoring, supervision and evaluation of the programmeme • Implement the programmeme following the national policies and guideline • Manage drugs, reagents and required logistics for the programmeme • Coordinate with different stakeholders at district level • Organise awareness and education programmeme to increase knowledge on TB in the community • Update recording and reporting forms and registers and submit timely

C. Local Level (Palikas) • Manage, organise and facilitating DRTB training to health workers • Organise supportive supervision at the treatment and sub-centre to enhance the performance of the programmeme • Organise quarterly (4 monthly) workshop to review the performance of treatment and diagnostic centre • Coordinate with different stakeholders at palikas • Support to implement the programmeme following the national policies and guidelines NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 9

• Manage drugs, reagents and required logistics for the programmeme • Organise awareness and education programmeme to increase knowledge on DRTB in the community • Enhance capacity of health workers on DRTB management

D. Treatment/Sub Centre Levels • Provide directly observed Treatment (DOT) to all DRTB patients • Monitor TB treatment through follow up sputum examinations and reviews. • Trace and retrieve lost to follow up and or patients missing treatment or poor compliant patients. • Complete and update all recording and reporting forms including TB treatment cards and registers and submit quarterly reports on time • Provide health education and counseling to the patients and to the community. • Educate community on DR-TB. • Cooperate with the microscopy/diagnostic services, for examination of sputum. • Coordinate referral of DR-TB patients from hospitals to peripheral centres. • Promote and implement TB/HIV activities and referral of presumptive MDR TB • Organise contact tracing activities in the community • Manage necessary drugs, reagent and necessary logistics for the programmeme • Update patients’ records and ensure submission on time

E. DOT Providers • Provide daily DOT to the patient and maintain dublicate treatment card • Discuss the condition and the treatment being given to the patient with patients and health staff; • Recognize and managing adverse effects of medications, and make referrals when necessary • Assess the patient’s adherence to the regimen and address poor adherence when it occurs. • Complete appropriate documentations; • Collaborate with the local public health services; • Ensure that the patient accepts the proposed cared and support. • Report patient treatment status to the Treatment centre • Maintain confidentiality of the patients • If DOT provider will be absent for providing DOT due to their personal reasons, manage alternate DOT provider for that durtion. • Provide referrals for psychological, social and legal support and other services including substance abuse treatment; Priovide joint (integrated) support for DR TB patients with addictive behaviours; 10 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

F. Patient and Community Level • DRTB patients to faithfully take drugs under supervision and complete treatment • The community to supervise and support DRTB patients to ensure treatment completion • Attend regular follow ups with the health facility staff for monitoring of treatment, submit sputum, follow up on results and report side effects. • Refer DRTB presumptive persons to the health institution to check their health. • Directly observe all DR-TB patients in their communities • Mobilise patient and peer support groups, which may help also reduce stigma CHAPTER 2 DIAGNOSIS OF DR-TB

2.1 IDENTIFICATION OF PRESUMPTIVE DR-TB 2.1.1 When to think of presumptive DR-TB? All staff who are managing TB patients must be able to identify presumptive DR-TB.

The following categories of TB patients are at risk of having DR-TB and need to be screened for drug resistance:

1. Close contact of DR-TB case 2. Previously treated patients who either: - failed - relapsed - returned after loss to follow-up 3. Smear positive at 2 months or subsequent follow up during first-line treatment 4. Not getting better / getting worse during continuation phase of the first-line treatment and patients with frequent interruptions and irregular first line drugs. 5. Health care workers with presumptive TB. 6. PLHIV, DM and other immunocompromised 7. Belonging to vulnerable groups such as migrants and refugees

Most patients with presumptive DR-TB will be bacteriologically positive pulmonary cases, but clinically confirmed pulmonary or extrapulmonary TB cases may also present with presumptive DR-TB if they show a clinically unfavorable evolution.

2.2 MANAGEMENT OF PRESUMPTIVE DR-TB 2.2.1. Perform a Xpert MTB/RIF test Carry out the Xpert MTB/RIF testing for all presumptive DR TB cases as per the diagnostic algorithm. Testing can be done directly via patient going to Genexpert centers themselves or through the courier up the Genexpert sites from peripheral health facility.

2.2.2. What to do if the Xpert MTB/RIF test shows rifampicin resistance (RR)? If the result shows RR, the patient must be sent immediately to the nearest DR-TB Centre for registration and further management as per diagnostic algorithm and treatment mentioned in this guidelines. 12 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Attention! Patients with Low risk of DR TB: It is also possible that a person with presumptive TB, whose sputum is examined with Xpert MTB/RIF to confirm the diagnosis of TB, presents with an RR result. Since the test was done because of a presumption of TB and not because of a presumption of DR-TB, it is necessary to repeat the test. If the repeat Xpert MTB/RIF test also shows an RR result, the patient must be sent to the nearest DR-TB Centre without delay.

2.2.3. What needs to be done at the DR-TB Centre? • The patient must be registered in the DR-TB register (see Form DRTB 01 ) • All the baseline examinations should be done before DR-TB treatment • 2 morning sputum samples or other specimens should be collected before starting the treatment and sent to the designated laboratory without delay. Designated Laboratories perform microscopy, culture and direct line probe assay (LPA) to identify fluoroquinolones and the second-line injectables resistance • If the result of LPA from direct sample shows no result or invalid, then repeat LPA from another sample and/or second LPA will be tested from culture positive. The result of the LPA should be available at the DR-TB Centre within 2 weeks on an average, after sending the specimens. • Before LPA result is available, a shorter treatment regimen is started if no contraindication and based on LPA result, a decision is made for appropriate LR regimen.

2.3 DIAGNOSTIC TESTS 2.3.1 Direct microscopy Direct examination following proper staining of a sputum smear or other specimen by light microscopy or fluorescence microscopy is useful to detect TB but does not allow to diagnose DR- TB. Smear microscopy will be needed, however, to monitor treatment progress.

2.3.2 Xpert MTB/RIF test Xpert MTB/RIF® is a molecular test recommended by the WHO that identifies, with a very high sensitivity and specificity:

• the presence of DNA from the tubercle bacillus; • the occurrence of mutations in the DNA that cause rifampicin resistance. The test makes use of the Xpert MTB/RIF technology, a small machine that is linked to a computer. A sputum sample is transferred into a special cartridge that is inserted into the machine. The machine will analyze the sputum sample through a fully automated, closed-circuit PCR (polymerase chain reaction) and the computer will print out the findings. The whole test takes only about 2 hours.

If the presence of Mycobacterium tuberculosis (MTB) is detected, Xpert MTB/RIF will also look for evidence of rifampicin resistance. If it is present, a result of RR (rifampicin resistance) is shown. RR is not the same as MDR, because MDR requires resistance to both rifampicin and isoniazid. But from an operational point of view, RR should be treated as MDR, because 95% of rifampicin resistance is associated with concurrent resistance to isoniazid, however, monoresistance to rifampicin is found in approximately 5% of rifampicin resistant strains. Thus, detecting resistance to rifampicin can be used as a surrogate marker for MDR-TB with a high level of accuracy. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 13

Xpert MTB/RIF ultra can also be used as an alternative to Xpert MTB/RIF assay in all settings and the interpretation of results of the Xpert MTB/RIF assay for MTB detection are same as for the Xpert MTB/RIF assay, with the expection of “MTB detected trace” result. Country will transition to Xpert MTB/RIF ultra, when resource allows.

2.3.2.1 How to collect a sputum sample for Xpert MTB/RIF testing A single sputum specimen must be collected. It must be of the high quality to ensure a correct reading by Xpert MTB/RIF: - Collect one sample (early morning sample or quality spot sample also acceptable). - Before coughing up the sputum, the patient should rinse the mouth carefully; - Expectoration from deep inside the chest; - Minimum quantity 2-3 ml. * For re-treatment cases, collect two sputum specimen one for Xpert MTB/RIF and othe for LPA

Sputum samples for Xpert MTB/RIF are collected in Falcon tubes (see illustration D1). There is no need to add any reagent to the specimen. The tubes must be properly identified with a self- adhesive sticker (see illustration D2). On the sticker, the name of the patient, the registration number of the patient, the lab number and the date of specimen collection must be written with an indelible marker. The tubes must be tightly closed. They can be kept at ambient temperature, but heat and direct sunlight should be avoided.

Since the samples are collected from persons who are potentially contagious, the staff must pay extra attention to observe proper safety precautions.

D1. Falcon tube D2. Proper identification of Falcon tube

Whenever sputum is collected for Xpert MTB/RIF, it must be entered into the laboratory register and a Xpert MTB/RIF request form must be filled.

2.3.2.2 Other specimens for Xpert MTB/RIF testing in case of presumptive extrapulmonary (EP) DR-TB Xpert MTB/RIF testing on blood, urine or stool is not recommended, but testing of an appropriate specimen can be very helpful in certain types of presumptive EP DR-TB: see table 2.1. The test will not perform as well as on sputum, but it can be particularly useful when testing cerebrospinal fluid or lymph node tissue or aspirate. Xpert MTB/RIF also performs well on gastric lavage. The 14 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

test is not very sensitive on pleural fluid or other specimens such as intra-articular fluid, for which few data are available at present. Nevertheless, always do the test because some cases might be positive.

It must be borne in mind that a negative Xpert MTB/RIF result on an EP specimen is not the final answer. For every case of presumptive EP DR-TB, send a specimen for culture and DST.

TABLE 2.1: Specimens collected for Xpert MTB/RIF testing in presumptive EP DR-TB Quantity* to be Type of Type of EP TB Specimen collected container Tuberculous pleuritis Pleural Fluid 10-15 ml Tuberculous meningitis cerebrospinal fluid (CSF) Minimum 2 ml TB of the peripheral lymph adenitis Pus and/or excision biopsy Minimum 2 ml Intra-articular Fluid Musculoskeletal TB, Osteo-articular TB Minimum 2 ml Sterile Biopsy samples containers TB pericarditis Pericardial Fluid Minimum 2 ml TB peritonitis Ascitic Fluid 10-15 ml Other tissue samples e.g. TB of other organs Endometrial Biopsy

2.3.2.3 How to send the sputum (or other) sample to the Genexpert Centre In health facilities where the Xpert MTB/RIF testing is Primary receptacle present (Genexpert centers), (leakproof or siftproof) the specimen, together with Waterproof Cap the request form, will be taken Rack-type holder directly to the Genexpert (styrofoam, sponge) Absorbent centers. At health facilities packing Xpert MTB/RIF testing is not material Itemized list of contents available, samples will be (specimen record) transported to the nearest Genexpert Centers. Tripple

layer packaging must be Secondary Rigid outer made for transportation packaging ) packaging leakproof or of the samples. The tightly siftproof) Proper shipping closed Falcon tube is sealed name with paraffin tape, wrapped Package marking in absorbent paper and placed in a proper packaging To/From labels as shown in diagram and must be properly sealed. The package together with the D3. Sputum sample package Xpert MTB/RIF request form are sent to the Genxpert centre. The health facility must make sure that the specimen arrives at the Genexpert Centre within 24 -48 hours. If available, a courier service may be called upon, but any other appropriate means of transportation may be used. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 15

2.3.2.4 Xpert MTB/RIF testing results TABLE 2.2: Results of the Xpert MTB/RIF test

Label Result and Action to be taken Interpretation

MTB detected, Diagnosis of TB confirmed. Treat with first-line TB regimen. T rifampicin resistance not detected

MTB detected, If presumptive MDR- TB case: send to DR-TB Centre. RR rifampicin resistance If new TB case: consider repeat Xpert MTB/RIF test. If RR result detected is confirmed, send to DR-TB Centre.

MTB detected, Diagnosis of TB is confirmed. Start treatment with first-line TB rifampicin resistance regimen and send new sputum specimen to repeat the test. TI indeterminate Pay special attention to quality of sputum sample, conditions of storage and transportation and speed of shipment. If the result of the repeat test is RR, send to DR-TB Centre.

N MTB not detected Additional investigations required to exclude TB.

Invalid/no result/error Send new sputum specimen to repeat the test. Pay special I attention to quality of sputum sample, conditions of storage and transportation and speed of shipment

The result is written on the Xpert MTB/RIF request form and sent back to the requesting health facility.

2.3.3 Line Probe Assay (LPA) When the specimens (2 samples) arrives for LPA at designated Labs, one sample is used for culture and the other specimen for rapid molecular testing by line probe assay (LPA). This is a nucleic acid amplification test (NAAT) using the PCR (Polymerase Chain Reaction) technology. It detects the presence of mutations in certain genes of M. tuberculosis that occur in case of resistance to specific drugs:

The first-line LPA detects mutations in the rpoB gene (resistance to R) and the katG and inhA genes (resistance to H). A katG mutation signifies high level H resistance, a inhA mutation without accompanying katG mutation indicates low level H resistance. It is not necessary to perform this test if the Xpert MTB/RIF test has already detected rifampicin resistance. Whether or not additional isoniazid resistance is present in these conditions, it will not have any influence on the therapeutic decision making. In case of Xpert MBT/Rif test not detecting Rif Resistance, the result of 1st line LPA is important to make therapeutic decision.

The second-line LPA detects mutations in the gyrA and gyrB genes (resistance to the fluoroquinolones [FQ]) and the rrs and eis genes (resistance to the second-line injectable drugs [SLID] Amikacin and capreomycin). The results of the LPA should arrive at the DR-TB Centre as soon as possible (preferably within 2 week). The result of 2nd line LPA will be used to guide the therapeutic decision. If no resistance to FQ orSLID is found, the patient can continue the initially prescribed treatment regimen, either SSTR or a long-course regimen (LR1). If resistance to FQ is detected irrespective of the SLID, the patient will be put on LR2 regimen. 16 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

However, LPA needs higher bacterial load in samples than Xpert for a positive result and hence smear positive samples and cultures are preferred.

Interpretation of Second-Line (SL) LPA result:

Genotypic mutation on MTBDRsl test Level of Phenotypic result Clinical Implication resistance to FQ. gyrA Mut 1 +/- gyrA WT 2 Low/ • Levofloxacin: Mfx could be used probe Moderate/ Resistance detected. at higher dose. The High • Moxifloxacin: Low regimen should be gyrA Mut 2 +/- gyrA WT 2 Moderate/ level resistance re-evaluated based probe High detected. on phenotypic DST High level Mfx results at CB. gyrA Mut 3A +/- gyrA WT 3 Low susceptibility results probe to be reported gyrB Mut 1 +/- gyrB WT probe Moderate within 2 months. gyrB Mut 2 +/- gyrB WT probe Moderate gyrA Mut 3B +/- gyrA WT 3 Moderate/ • Levofloxacin: Mfx even at a high probe High Resistance detected dose cannot be gyrA Mut 3C +/- gyrA WT 3 sHigh Moxifloxacin: High considered as an probe level resistance effective medicine. detected. gyrA Mut 3D +/- gyrA WT 3 High probe gyrA gyrA WT 1 probe Moderate/ • Levofloxacin: Levofloxacin is not missing High Resistance detected. effective. gyrA gyrA WT 2 probe Moderate/ • Moxifloxacin: Low Mfx could be used missing High level resistance at higher dose. The detected. regimen should be gyrA gyrA WT 1 and WT Low to High High level Mfx re-evaluated based 2 probe missing susceptibility results on phenotypic DST gyrA gyrA WT 3 probe Moderate/ to be reported results at CB. missing High within 2 months. Based on “Line probe assays for drug resistant tuberculosis detection Interpretation and reporting guide for laboratory staff and clinicians”, GLI

Interpretation of Second Line (SL) LPA result for SLDs: Mutation on MTBDRsl test Level of resistance rrs Mut 1 rrs WT 1 probe missing High to Km, Am and Cm rrs Mut 2 rss WT 2 probe missing High to Km, Am and Cm rrs rss WT 1 probe missing High to Km and Cm; Sensitive to Am rrs rss WT 2 probe missing High to Km, Am and Cm eis Mut 1 eis WT 2 probe missing Low to Km; Susceptible or Low resistance eis eisWT 1 probe missing to Am and Cm eis eis WT 2 probe missing eis eis WT 3 probe missing Susceptible to Km, Am, Cm NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 17

2.3.4 Culture and drug susceptibility testing (DST) When a sample is sent for 2nd line LPA, in parallel culture is also performed for: • Identifying viability of Mycobacterium. • Carrying out phenotypic DST • Confirming the results, where direct LPA testing is not possible.

Culture tests are also used to monitor the treatment response. The frequency of follow up tests (culture and DST) is described in Table 5.3 and 5.4.

2.3.4.1 How to collect a sputum specimen for culture and DST? Two samples (good quality) are absolutely necessary in order to provide the best possible conditions for the culture to grow. If possible, both specimens should be early morning samples, collected before the patient has eaten. If morning samples are not possible to collect, then good quality sample taken at spot can also be considered.

To ensure the quality of sputum samples: • The patient should rinse the mouth carefully before coughing out the sputum • Expectoration should be from deep inside the chest; • Minimum quantity of expectorant must be 3-5 ml. • The expectorants should be mucopurulent.

Sputum samples for culture should not be collected in the usual sputum tubes, but should be collected in the sterile Falcon tubes. The tubes must be properly labelled indicating the patient’s name, TB registration no. and dates of collection. See illustrations Figure D1 to D4. Once the sputum is collected, the tubes are closed tightly and stored in the refrigerator while awaiting transportation.

In case of EP DR-TB, other specimens can be collected

TABLE 2.3 Specimens collected for culture and DST in presumptive EP DR-TB Quantity* to be Type of Type of EP TB Specimen collected container Tuberculous pleuritis Pleural Fluid 10-15 ml Tuberculous meningitis cerebrospinal fluid (CSF) Minimum 2 ml

TB of the peripheral lymph adenitis Pus and/or excision biopsy Minimum 2 ml

Musculoskeletal TB, Osteo-articular Intra-articular Fluid Sterile Minimum 2 ml TB Biopsy samples containers TB pericarditis Pericardial Fluid Minimum 2 ml TB peritonitis Ascitic Fluid 10-15 ml Genito-urinary TB Urine 100-200 ml Endometrial Biopsy 18 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

If it was not possible to collect the recommended minimum quantity, the available sample should still be sent to the laboratory. Avoid sending tissue sample/biopsy in formaldehyde. Tissue sample should be sent in normal saline.

2.3.4.2 How to send the specimens for culture DST. A Culture and DST request form must be filled in. The two tubes and the form must be sent to the designated labs without delay maintaining the cold chain. The time between sputum collection and initiation of culture should not exceed 72 hours.

Transportation of the sputum samples, which is likely to contain drug resistant TB bacilli, must be done in a safe manner. The tightly closed Falcon tubes are sealed with paraffin, wrapped in absorbent paper and placed in the container, which must be properly sealed. The container will be put inside a cold box with ice packs (see illustration D4), which must be closed tightly. D3. Sputum sample in cold box Timing and cold chain are critical because the bacilli in the sputum need to be alive when the specimen is inoculated on the culture medium.

2.3.4.3 Culture result At the culture labs, culture will be performed on both samples, which will be inoculated onto a solid culture medium (Löwenstein-Jensen) and/or MGIT. If no growth appeared till 8 weeks, the culture is considered negative. If bacilli are present in the sample, colonies start to grow on the medium after 4 to 6 weeks in Solid Culture, and nearly 2 weeks in MGIT. The colonies have a typical shape: brownish, granular and with a rough surface (see illustration D5).

For solid culture, the colony growth will be graded according to the number of colonies observed: No colonies after 8 Number of colonies Exact number 10-100 101-200 >200 weeks Result NEGATIVE 1-9 1+ 2+ 3+ If the culture is contaminated, performing culture with another sample may be considered.

Liquid Culture: Mycobacteria multiply in a nutrient-rich medium, while contaminating bacteria are inhibited by the addition of a cocktail of antibiotics. Growth of bacteria, including mycobacteria, is indicated by fluorescence, which increases proportionally as oxygen decreases in the tube. The instrument detects this fluorescence in the medium using a UV light and complex computer algorithms.

Interpretation of Liquid Culture • Positive for Mycobacterium tuberculosis complex D4.MGIT culture result • Negative for Mycobacterium tuberculosis complex NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 19

Drug Susceptibility Testing (DST): When DST is performed as per the diagnostic algorithm, the following drugs listed below are tested for susceptibility.

DST in Solid Media DST in Liquid Media Turn over time: 4 weeks Turn over time: 2 weeks 1st line drugs: 1st line drugs: - Rifampicin - Isoniazid - Isoniazid - Rifampicin - Ethambutol - Ethambutol - Pyrazinamide 2nd line Drugs: 2nd line drugs: - Levofloxacin - Levofloxacin - Moxifloxacin - Moxifloxacin - Amikacin - Bedaquiline - Streptomycin - Linezolid - Clofazimine - Amikacin - Delamanid - Streptomycin

DST for other second line drugs not listed above are not carried out because of limited reliability.

Despite the phenotypic DST results precedes over the LPA results, the patient will be managed as per the LPA results (given the prolong turnover time required for phenotypic DST). The results of phenotypic DST will be taken into consideration, if the clinical condition of the patient isn’t improving.

Xpert MTB/RIF Ultra assay Despite substantial increased sensitivity for MTB detection compared with smear microscopy, Xpert MTB/RIF sensitivity is nevertheless suboptimal, in specimens with low numbers of bacill. The Xpert® MTB/RIF Ultra assay (Ultra) has been developed as the next-generation assay to overcome this limitation.

The Ultra assay is non-inferior to the Xpert MTB/RIF assay for the detection of MTB and for the detection of rifampicin resistance. This means that the new Ultra cartridge is at least as good for the detection of MTB and rifampicin resistance as Xpert MTB/RIF. In certain populations, the Ultra assay may perform better for MTB detection, especially for individuals whose specimens are frequently paucibacillary. The Ultra cartridge showed better performance for the detection of MTB (increased sensitivity) compared to the current Xpert® MTB/RIF cartridge for the detection of Mycobacterium tuberculosis in specimens with low numbers of bacilli, especially in smear- negative, culture-positive specimens (such as those from persons with HIV co-infection), in paediatric specimens and in extra-pulmonary specimens (notably cerebrospinal fluid). The accuracy in detection of rifampicin resistance is also better. The increased sensitivity of Ultra has enabled to detect 16 bacilli per ml sputum compared to 131 per ml for Xpert® MTB/RIF. 20 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Next Generation Sequencing (NGS): NGS is a “high-throughput, massively parallel” sequencing method used to determine the nucleotide sequence of a whole genome (i.e. whole genome sequencing (WGS)) or part of a genome (i.e. targeted NGS) in a single biochemical reaction volume. NGS is performed by non-Sanger-based sequencing technologies that are capable of sequencing multiple DNA fragments in parallel, which are then pieced together and mapped to a reference genome using bioinformatics analyses. WGS can provide the near complete genome of Mycobacterium tuberculosis (MTB) in a sample, while targeted NGS can generate MTB sequence data at specific genetic loci of interest.

Since drug resistance in MTB is mainly conferred through point mutations in specific gene targets, targeted NGS offers great promise for rapid diagnosis of DR-TB. However, WGS offers higher genome coverage as required to combine genomic and epidemiological information to define transmission clusters during an outbreak, and the generated data contributes to our understanding of resistance mechanisms for both current and newer drugs as well as the identification of compensatory mutations. In this context, WGS remains invaluable for TB research and surveillance, though its clinical utility as a DR-TB diagnostic tool will require further investigation before routine WGS is more widely implemented for TB diagnosis.

2.4 DIAGNOSIS OF EXTRAPULMONARY DR-TB IN THE ABSENCE OF DST Most DR-TB will be pulmonary, but EP DR-TB is possible as well. It must be borne in mind, however, that the diagnosis of EP TB is not easy. Often, the diagnosis will be based solely on clinical criteria (see National Guidelines on DR-TB Management 2019).

While it will be difficult to obtain bacteriological confirmation of the EP TB diagnosis, it will be even more difficult to obtain bacteriological proof of drug resistance. Whenever a presumption of EP DR-TB is made, all possible efforts should be made to obtain a suitable specimen for Xpert MTB/RIF testing, culture and DST. Unfortunately, suitable specimens will not always be available. Even if a specimen is obtained, it may not be possible to arrive at a reliable test result because tests performed on other specimens are often not as sensitive as tests performed on sputum.

In the absence of culture and DST results, only a presumptive diagnosis of EP DR-TB can be made. The most likely instances when EP DR-TB will come to mind are: - an EP TB patient who is a contact of a known TB case with drug resistance - a correctly treated EP TB patient who presents a clinically unfavorable evolution

Patients with presumptive EP DR-TB should be sent to the DR-TB Centre. The diagnosis of EP DR- TB must be made in consultation with the expert team constituted under the Technical Working Group (TWG) of the NTC.

2.5 DIAGNOSTIC PATHWAY The diagnostic pathway to arrive at a proper diagnosis of DR-TB (and the subsequent prescription of the appropriate treatment) based on the procedures explained in the algorithm figure 2.1. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 21

required

Sensitive Box A - treatment H

Continue First line

MTB Detected Rif Rif MTB Detected (TI) Indeterminate first line treatment Tx Initiate Xpert MTB/Rif Test Repeat manage accordingly and (perform if required) culture - -

smear, culture, etc.) culture, smear,

Initiate First Treatment Line Initiate

Rif

, etected etected D

regimen and regimen and

LPA first line only 2, 3, 4 of for line LPA points first Not ( T ) Resistance Detected - H MTB Resistance Resistance (For Retreatment cases, consider(For Retreatment judgement clinical and if tests: additional other HrTB Initiate send for SL LPA and accordingly manage

TB patientsTB registered BUT who didn’t prior

ulmonary ulmonary ( N )

New P and ray suggestive of but TB, smear negative

- s Children < 14 years < 14 Children Contacts of Index TB and cases people living in congregate setting All presumptive cases TB with to access Xpert MTB/Rif Testing. have Xpert have MTB/Rif testing done All All PLHIV, DM and other immunocompromised Extra pulmonary patients TB (EP samples) X Health care workers

Detected Box B: groups Special for Xpert MTB/Rif testing 1. 3. 4. 7. 8. 2. Presumptive TB cases: 5. 6.

not clinical judgement judgement clinical MTB Perform additional investigation DST Culture followed by

is reported is

evaluate culture report evaluate Repeat direct SL LPA and and LPA SL direct Repeat

Indeterminate result Indeterminate ance

) Tests I

Culture followed by DST

Xpert MTB Rif Rif Xpert MTB

and manage and manage

SLI

esistant No result, error or or error result, No test ( Invalid Xpert MTB/Rif Repeat test accordingly

or R

f FQ resistance reported, switch to LR2 switch to reported, resistance f FQ Continue SSTR treatment the LR1 and or SSTR monitor Continue resist FQ response unless I FQ resistant & FQ Sensitive LR2 Initiate 1. 2.

for

for

LR1 are are (RR) # SSTR

SL LPA SL LR1 first line

LR1 &

MTB Detected Rif Rif MTB Detected Resistance Detected Detected Resistance

Initiate were who those initially on Continue already on those who FQ sensitive SLI Resistant - -

up -

converters by month 2 or subsequent -

SSTR Decision tree for the diagnosis and treatment of DR TB of DR the diagnosis and treatment for Decision tree

&

Not getting better/getting worse during the continuation phase of the treatment follow All Retreatment patients (including failure, to followloss up and relapse) Non DR TB closeDR TB contacts SSTR for those not for those

2. 3. Box Presumptive A. DR TB cases 1. 4. Continue SSTR Continue LR1 not (for those eligible for in the beginning) LR1 # For new cases with low risk of RR-TB clinician can decide to repeat in case required repeat clinician can decide to risk of RR-TB new cases with low # For TB TB and DR DS algorithms both for Treatment please follow of results, per interpretation As tools. TB/RIF should be first diagnotic Xpert Testing, Xpert to TB cases with access MTB/RIF Presumptive All Shorter MDR regimen MDR Shorter for eligible patients, and eligible for FQ sensitive SLI Sensitive - - FIGURE 2.1: 2.1: FIGURE NOTE: 1. 2. 3. 22 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

2.6 DIAGNOSIS OF DR-TB IN SPECIAL GROUPS 2.6.1 Diagnosis of DR-TB in children The term “children” incorporates a broad range as, 2-year-old child requires a different approach to a 12-year-old, and the treatment of children with MDR-TB will never be a “one size fits all” approach.

The diagnosis of TB in children is difficult, and the diagnosis of DR-TB is even more challenging. Children, particularly young ones, do not cough up sputum. Gastric aspiration using a nasogastric feeding tube should be considered. Sputum induction could be a safe and effective alternative in children of all ages. However, training and specialized equipment are required to perform this procedure properly.

Collect the specimen at optimal times (e.g. early morning fasting gastric aspirate; induced sputum after fasting 2-4 hours; expectorated sputum early morning) Always try to collect an optimal quantity of sample, which varies by specimen type; larger volumes generally provide higher bacteriological yields; neutralize stomach acid if gastric aspirate is collected.

Children often have a paucibacillary form of the disease. Direct microscopy of sputum or other specimens (such as gastric aspirates) often will be negative, and even cultures will not always show growth. Nevertheless, every effort should be made to obtain a bacteriological confirmation of diagnosis in order to avoid exposing children to toxic drugs. If a specimen can be obtained, GeneXpert testing must always be done (the test also performs well on gastric aspirates) and culture (with subsequent DST) must be attempted.

NBP: GeneXpert MTB/RIF/Ultra and culture in liquid media should be prioritized in children.

Following should always be considered for DR TB in Children to move forward with diagnosis and decision for treatment; • A high level of clinical suspicion is needed for timely diagnosis of DR-TB in children. • Confirmed DR-TB: MDR-TB is identified from the child as per the given sample • Probable MDR-TB: a. If the child under assessment has symptoms/signs/radiology of consistent with TB and has been exposed to an infectious DR-TB case In case of probable MDR TB diagnosis treatment should be based on source case. • Probable MDR TB. If a child under assessment is not improving after 2-3 months of first-line treatment and the DOT confirms appropriate drug intake and there is no other likely diagnosis OR A close contact of child who died from TB or failed TB treatment or is a TB retreatment case with unknown DST results, in all these cases, early treatment initiation is imperative. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 23

2.6.2 Diagnosis of DR-TB in PLHIV The association of TB and HIV/AIDS is well known. and MDR-TB outbreaks among PLHIV have been reported in situations where MDR-TB is common. MDR-TB in PLHIV is more difficult to treat and will have a higher mortality than in HIV-negative people. Therefore, all TB/HIV co-infected patients and all PLHIV with presumptive TB should be tested by GeneXpert.

The diagnosis of TB in PLHIV is often difficult to establish with certainty, particularly in patients in the advanced stages of HIV infection (with a very low CD4 cell count, below 200). The disease is likely to present as EP or smear negative TB. Diagnosing MDR-TB will be even more difficult because many TB/HIV co-infected patients will be paucibacillary, resulting in negative sputum smears and cultures that may not show any growth, which makes it impossible to perform DST. Even the GeneXpert test will often be negative. Nevertheless, every effort should be made to systematically perform culture and DST whenever a PLHIV is diagnosed with TB.

If the presumption of MDR-TB is present in the absence of clear clinical or bacteriological evidence and both GeneXpert and culture are negative, it is recommended that the diagnosis of MDR-TB in PLHIV be made by a team of experts at the DR-TB Centre. The team of experts can make a tentative diagnosis of MDR-TB and decide to start empirical MDR-TB treatment based on contact history or unfavorable evolution under proper first-line anti-TB treatment.

Note: G.Xpert MTB/RIF Ultra is preferred for HIV patients to diagnose TB/RR -TB but until Xpert MTB/RIF Ultra is available in Nepal, above mentioned diagnostics procedure should be followed. CHAPTER 3 REGISTRATION CATEGORY OF DR-TB

Classification based on history of previous TB treatment (patient registration group): (Reference: WHO Companion handbook for programmatic management of DR-TB- 2014)

Registration group: Patients are assigned to a registration group based on the most recent treatment history at the time of initiating DR-TB treatment

1. New. A patient who has received NO or LESS than one month of anti-TB treatment 2. Relapse. A patient who was previously treated for TB and whose most recent treatment outcome was Cured or Treatment completed, and who is subsequently diagnosed with a recurrent episode of TB (either a true relapse or a new episode of TB caused by reinfection). 3. Failure. A previously treated TB patient who has received an anti-tubercular treatment whom the treatment has failed. 3.1 After failure of first line Treatment with FLD 3.2 After failure of Re-Treatment with FLD 3.3 After failure of Treatment with Hr TB Regimen 3.4 After failure of Treatment with SLD 4. Treatment after loss to follow-up: A patient who had previously been treated for TB and was declared Lost to follow-up at the end of the most recent course of treatment. 5. Other previously treated patients. A previously treated TB patient whose outcome after the most recent course of treatment is unknown or undocumented. 6. Patients with unknown previous TB treatment history who do not fit into any of the categories listed above. CHAPTER 4 TREATMENT OF DR-TB

4.1 PATIENT EDUCATION • Patient education is an essential component of any DR-TB control program and is possible when there is trusting interpersonal communication between patients and medical personnel. • Provision of emotional & social support to DR-TB patients may increase the likelihood of adherence. • The organization of patient education should be considered equally with the other components of the DR-TB program (such as detection and diagnostics, drug supply, etc.) • The patient’s knowledge and understanding of his/her role in achieving a successful treatment outcome is an essential component for treatment selection. 26 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

The following should be covered for patient and Treatment supporter education and support:

TABLE 4.1 Components of Health education and deliverable messages S.N COMPONENT DELIVERABLE MESSAGES FOR EDUCATION OF PATIENT AND TREATMENT SUPPORTER 1 Patient knowledge What is TB and DR TB, difference between TB & DR TB, treatment for and understanding of DR TB,duration of injectables (if applicable) and treatment, monthly Disease follow ups and routine investigations, benefits of regular treatment and harms of interruption of treatment. 2 Prevention of Spread of What measures are to be taken to prevent spread of DR TB at household DR TB and community level, close contact screening, importance of regular intake of medicine 3 Information about What most common side effects patient may experience and how possible side effects to report side effects for management, appropriate ways of drug intake, like FQs should not be taken with milk or calcium, aluminum, magnesium and iron containing products. PAS should be swallowed with acidic liquid. The constituted Injecatble (if applicable) dosages should be used within 24 hrs and kept refrigerated. 4 Patients’ Rights and Explain patients’ role in treatment completion, what are patient rights Responsibilities and responsibilities during whole period of treatment. 5 Role& Responsibilities Clearly explain the role and responsibility of TS, daily supervised DOT of Treatment Supporter provision, identifying side effects, emotional support to patient and family, accompanying patient on monthly follow ups to PMDT site and on weekly basis to nearest DOTS center, support in contact tracing benefits of supervised treatment and benefits of successful treatment completion, and incentives where feasible such as communication cost for treatment supporter ) 6 Psycho-Social support Patients should be supported by the counsellors and to provide throughout Treatment counseling, support and refer where necessary to psychologists, explain that all drugs and investigations related to DR TB treatment are free of cost and delivery of social support in terms of travel allowances and food baskets where possible. 7 Maintaining The PMDT health team should explore the need of the patient to confidentiality maintain strict confidentiality regarding their disease and all aspects of ethical consideration should be applied.

Following are strongly recommended before the treatment initiation is considered: • Ahead of enrolment on DR-TB treatment, all patients should receive appropriate counseling to enable informed and participatory decision-making. • Ensure that patients are appropriately informed about their treatment options. • Ensure patient-centered approach to the delivery of care including social and psychological support. • Active TB drug safety monitoring and management (aDSM) is essential for all patients enrolled on DR-TB treatment. • Baseline and follow-up investigations are mandatory as per guideline. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 27

Key Points for RR/MDR TB Treatment It is challenging to treat and manage DR TB. Since the bacilli are resistant to the most effective first-line drugs, the treatment must include second-line drugs. These drugs are limited in number, less effective than the first-line drugs, poorly tolerated, some side effects can be very severe and difficult to recognize, and drugs are very expensive. Complicated cases with extensive drug resistance patterns are even more difficult to treat.

In Nepal, 2 types of treatment regimen are used for management of RR/MDR-TB. Both are largely standardized. F Standardized Shorter Treatment Regimen (SSTR) of 9-12 months’ duration, prescribed for uncomplicated RR/MDR-TB provided that eligibility criteria are met refer to SSTR regimen chapter) F All oral Longer Treatment Regimen (LTR) of 18-20 months’ duration for those not eligible for SSTR. There are mainly two standardized LR treatment regimens recommended by the National TB Programme (LR1, LR2) for most of the RR/MDR-TB patients. For special conditions in rare cases, there are also provision of other treatment regimen such as LR3 and LR4

4.2. DRUGS USED TO TREAT DR TB AND PRINCIPLES OF TREATMENT The probability of treatment success in RR/MDR-TB patients depends upon patients’ will and strong adherence to treatment, including severity of disease, resistance patterns and co-morbidities as well as access to health care (e.g. regimens with sufficient effective agents, medications of good quality, attention to adverse events and patient support). Longer MDR-TB regimens with sufficient effective agents are known to increase the likelihood of cure and lower the risk of death in adults and children (Ahmed et al 2018, and Harausz at al 2018)

WHO in 2018 convened the GDG (guideline development Group) meeting and assessed the individual contribution of patient outcomes of medicines used in longer MDR TB regimens using primarily the estimates of effects from 2018 individual patient data meta-analysis. Following a thorough assessment of relative benefits to harms, recommendations were made for each medicine and classified in to three groups:

Group A: Fluoroquinolones (Levofloxacin and Moxifloxacin), Bedaquiline and Linezolid were considered highly effective and strongly recommended to be included in all regimens unless contraindicated;

Group B: Clofazimine and Cycloserine or Terizidone were conditionally recommended as agents of second choice;

Group C: included all other medicines that can be used when a regimen cannot be composed with Group A and B agents.

The composition of longer regimens is guided by the selection of individual medicines considered to be effective and also by a need to combine sufficient medicines to maximize the likelihood of relapse-free cure without increasing toxicity. Regimens may be of standardized (fixed) composition or may be individualized to the patient needs. Apart from the ranking by 28 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

balance of effectiveness and harms, choice is also determined by: a preference for composition of agents; the results of drug-susceptibility testing (DST); the reliability of existing DST methods; population drug resistance levels; history of previous use of the medicine in a patient; drug tolerability; and potential drug-drug interactions.

Table below indicates the overall approaches to designing longer MDR TB regimen as oppose to the SSTR which is standardized. Based on the WHO 2019 consolidated guideline in DR TB treatment, drug grouping recommendations, the regimen is designed by adding medicines sequentially going down from group A to group C.

Grouping of Medicines recommended for the treatment of RR-TB and MDR-TB(adopted from WHO 2019, guidelines)

GROUPS STEPS MEDICINES ABBREVIATIONS

A Include all three medicines in the Levofloxacin OR Lfx /Mfx regimen, if no contraindication Moxifloxacin

Bedaquiline Bdq

Linezolid Lzd

B Clofazimine Cfz Add one or both Medicine Cycloserine OR Cs, Trd Terizidone

C Add to Complete regimen and Ethambutol E when medicines from Group A and Group B cannot be used Delamanid Dlm

Pyrazinamide Z

Imipenem-cilastatin OR Imp,Cln, Mpm Meropenem

Amikacin (OR Streptomycin) Am(S)

Ethionamide OR Eto , Pto prothionamide

P-aminosalicylic acid PAS

Important notes: 1. The recommended duration of use of Bdq is 6 months and its use beyond this duration is “off label” 2. Bdq can be used in children from 6 years and above 3. Dlm can be used in children 3 years and above 4. Bdq and Dlm can be used together to complete the regimen 5. Lzd preferably to be used for whole duration of treatment or less if not tolerated 6. If DST to Z, E shows susceptibility, can be part of regimen 7. Imipenem should be used with Amox-Clv 8. Use Am and S; if only susceptible and under close monitoring, preferably in patients who are 18 years or above NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 29

Principles of MDR TB Treatment and Regimen Construction The following general principles of DR TB should be followed for regimen designing and the objective should be with “no harm practice” keeping in view the effectiveness and safety of the regimen designed;

• At the time of enrollment, patients should be informed about available option of treatment (longer or shorter) and shared based decision should be made between Doctor and patient for choices. • RR / MDR TB diagnosed patients to be treated with a recommended MDR-TB regimen, either a longer MDR-TB regimen to which isoniazid can be added where required (if susceptible), or else a shorter MDR-TB regimen in eligible patients. • It is essential that patient’s MDR/RR-TB strain needs to be tested for susceptibility to medicines planned for inclusion in the regimen at the time of start of treatment initiation, preferably by using rapid diagnosis (LPA SL- GenoType MTBDRsl) can be used in both children and adults and as a direct and indirect test • Review patient full history of previous treatment, DST results, co-morbid conditions and concomitant drugs in use • Empirical treatment with a regimen(SSTR/LTR) likely to be effective should be started as early as possible and adjusted based on DST results once they become available and potentially life-saving treatment(SSTR/LTR) should not be withheld. • Assessment for underline cardiac disease/IHD, peripheral neuropathy, anemia should be done. Please remember that baseline anemia of some degree will be present in chronic TB/ MDR TB patients due to TB disease, mostly iron deficiency anemia, Lzd should be used with caution keeping in view anemia severity grading • For some medicine, DST results would present uncertainties (e.g. cycloserine, streptomycin, ethambutol). “Likelihood of effectiveness” is generally assessed in the programmatic setting on the basis of one or more of the following: (i) confirmed susceptibility in the individual patient; (ii) confirmed susceptibility in the presumed source case; (iii) no known resistance to another drug which has cross-resistance to the medicine; (iv) rare use of the medicine in an area (possibly supported by low drug-resistance levels from surveillance activities); (v) no previous use of the medicine in a regimen that failed to cure that same patient. • The design of the regimen has to take into account the relative benefits to harms to the individual patient, including drug-drug interactions • It is recommended by WHO that treatment should start with at least four medicines likely to be effective and that at least three agents are continued for the rest of treatment after bedaquiline is stopped. • Possibly all three Group A agents(Lfx/Mfx, Bdq,Lzd) and at least one Group B agent(Cfz or Cs) should be part of regimen and if only one or two Group A agents are used, then both Group B agents are to be included in regimen. • If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are added to complete it. 30 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

• Starting treatment with five effective agents rather than four may also be a practice and this provision is expected to apply to those with additional resistance or suspected resistance to fluoroquinolones or other medicines. • Bdq use beyond the currently recommended duration ( 6 months) and age group is considered as “off label” should be case by case keeping in view treatment response and number of effective drugs on board after Bdq is stopped • The use of three cardiotoxic drugs (Bdq, Dlm and Cfz) in combination should be with caution and with close monitoring. However, recent data shows that combined use of Bdq and Dlm is safe and QTcF interval with co administration of both drugs is clinically modest (Dooley et al, 2019) • The use of Lzd for whole duration is associated with better treatment outcomes and lower mortality, but is expected to cause toxic effects in significant number of patients. The neurological toxicity is associated with duration, while hematological toxicity/ myelosuppression is dose related. • For Lzd use in the regimen, baseline assessment by Blood picture and neuropathy screening should be done and if contraindicated, should not be part of regimen or if possible with lower dose of 300 mg daily or 600 mg alternative days • The addition of Pyrazinamide(Z) in the regimen is useful as it has synergistic effects when used in combination with strong bactericidal (FQs, Bdq, Am)and strong sterilizing drugs(Bdq,Cfz). However, if reliable DST source is confirming resistance then should not be counted effective. • Injectable, Am should only be used in regimen if there is documented susceptibility to it and appropriate monitoring for hearing loss is available. WHO also recommends to use Am in 18 years of age or above. • In cases when there is doubt about the effectiveness of a certain medicine, it may still be included in the regimen but it should not be considered clean/likely effective to the number of medicines needed in the regimen and clinical judgment is advised to decide if the benefit from its inclusion outweighs any added toxicity or pill burden, for example Mfx/Lfx, Cfz.

The basic principle of MDR TB Treatment should always be applied that never add a single drug to a failing regimen.

If the long-course regimen fails, treatment options will be very limited. The patient must be referred to the DR-TB Referral Centre.

Contraindications and Drug-Drug Interactions In line with WHO 2019 guidelines and regrouping of medicine, Bdq and Lzd will be part of standard MDR TB regimen, while Dlm from group C is an important add on drug and a good choice to replace in cases with toxicities. Therefore, it is important to thoroughly learn about these medicines and their use while constructing the regimen. However, in the best judgement of treating physician and in line with specialist advise these medicines can be used with precautions. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 31

TABLE 4.2 Contraindications and Precautions with Bdq, Dlm and Lzd ( Source: End TB 2018 DR-TB guideline) Drug Name

RELATIVE CONTRAINDICATION PRECAUTIONS Bdq, Dlm History of syncopal episodes, Use with caution if QTcF > ventricular arrhythmias or severe 450/470 ms in male/female coronary artery disease patients. Baseline ECG with QTcF > 500 ms Weekly ECG monitoring and (repeated) serum electrolyte screening should be performed if Bdq or Dlm is being used despite a cardiac contraindication. Dlm is less cardiotoxic than Bdq(new data has shown that QTC-F prolongation with combined use of Ddq and Dlm is clinically modest and safe) Bdq,Lzd,Dlm Severe renal Failure Usually no dose adjustment is required in mild to moderate renal failure With precaution in severe renal failure/impairment Bdq Severe hepatic failure Try not to use if patient has severe liver function impairment ART should be adjusted if used in HIV cases particularly efavirenz containing regimen should be avoided Lzd Pre-existing mild to moderate Special precautions when used in peripheral neuropathy (based combination with Cs, high dose on Basic Peripheral Neuropathy INH and diabetics. Screening (BPNS), subjective sensory In mild to moderate neuropathy scoring ) Myelosuppression and Anemia Severe Myelosuppression and Lzd can be used with lower Anemia, moderate neutropenia doses, 300 mg daily or 600 mg alternative days with close monitoring

Drug-Drug Interactions and Overlapping Toxicities with Bdq, Dlm and Lzd It is essential to consider the drug-drug interactions with Bdq, Dlm and Lzd as using in concomitant use of many routinely prescribed drugs may have various level impact having either decreased or increased absorption, toxicity and adverse events. It may be needed that patients should be given a card mentioning the name of drugs that should not prescribed by any GP/doctor while patient is on ambulatory care in community. Therefore, treating physicians should review all the medicines patients are taking while enrolling on MDR TB Treatment.

Drug-Drug Interactions with Bedaquiline Following drugs should be avoided to be used with Bdq; Strong/moderate inducers of cytochrome P450: These may decrease blood levels of Bdq: Efavirenz, Rifamycins, Phenytoin, Carbamazepine, Phenobarbital. 32 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Drug that may increase blood levels of Bdq: Ritonavir-boosted PIs, Oral azole antifungals (can be used up to two weeks): Itraconazole,Fluconazole, Macrolide antibiotics other than azithromycin

Drug-Drug Interactions with Delaminid Fist line Anti TB Therapy (HRZE), as these drugs appear to reduce level of Dlm Overlapping Toxicity with Bedaquiline and Delaminid

Moreover, many other drugs also have overlapping toxicity when used with Bdq and Dlm:

Antipsychotic drugs (Haloperidone, Risperidone) Many anti-nausea drugs (Ondansetrone, Granisetron, Domperidone, Chlorpromazine), Methadone, Cardiac drugs that may affect the heart rhythm(Amiodarone, Beta-blockers,Digoxin,Quinidine)

Linezolid and concomitant medicines that Increase Serotonin Levels: Serotonin re-uptake inhibitors (SSRIs): fluoxetine, paroxetine Tricyclic antidepressants: amitriptyline, nortriptyline

Serotonin 5-HT1 receptor agonists MAO inhibitors: phenelzine, isocarboxazid Other serotoninergic agents: meperidine, bupropion, or buspirone, quetiapine

For more information on drug safety and QT interval prolongation can be obtained at https:// crediblemeds.org/

4.3. RR/MDR-TB TREATMENT REGIMENS Based on the 2019 WHO consolidated guideline, the National TB programme updated the RR/ MDR TB regimens for Nepal. Step wise approach was used in constructing the standard regimens applicable for the country as Principles of MDR TB Treatment and Regimen Construction. Longer RR/MDR TB treatment regimen (LR1) should be given only in case where SSTR cannot be initiated.

TABLE 4.3 RR/MDR TB regimen construction in Line with WHO 2019 Regrouping RESISTANCE PATTERN AND REGIMEN COMMENTS BACKGROUND HISTORY LR1 Standard longer RR/MDR 1. In case of toxicity or need TB Regimen for adults and Bdq(6), 18 Lfx,Lzd,Cfz,Z to decrease or substitute Lzd children 6 yrs and above with Cs refer to aDSM relevant section 2. If Lzd is well tolerated, should Non-eligible for SSTR and be continued throughout the for those whose FQ results treatment duration unknown/ awaited/sensitive NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 33

Treatment of RR/MDR TB with additional resistance (Pre-XDR and XDR) 1. It is imperative that all diagnosed RR/MDR TB should be placed on DST regardless of choice of SSTR or Longer regimen and currently availability of rapid molecular DST(LPAs) make the results availability quicker. 2. The DST result to FQ should be known as soon as possible and regimen to be adjusted accordingly. 3. However, as implementation consideration there might be delays in result availability and treatment initiation with best empirical regimen should not be delayed. 4. Principle for designing longer regimen for DR TB patients remains same with or without additional resistance. 5. The basic principle of having at least 4 effective drugs on board in the beginning and at least 3 drugs to be continued after 6 months (or when Bdq/Dlm is stopped). It is impotant that at least one strong bactericidal drug should be on board through out. 6. The duration of treatment also applies same as minimum 18 months and can be extended based on patients response to treatment.

TABLE 4.4 Pre-XDR and XDR regimen construction in Line with WHO 2019 Regrouping LR2 RR TB with risk Bdq (12),18Lzd, 1. High dose Lfx or Mfx can be added once of FQ resistance/ Cfz, Cs,Z resistance level to FQs are known FQ resistance at 2. In cases with intolerance/toxicity to Lzd, baseline (Pre-XDR) stopping Lzd, replacing with Dlm can may be a and XDR TB suitable option. If Dlm cannot be added, then Eto. can be used instead 3. Close and careful monitoring with combination of three cardiotoxic drugs (Bdq, Cfz, Dlm) LR3 Failed by MDR TB 6 Am, Dlm, Eto, 1. DST to FLD and SLDs should guide further standard treatment PAS (Cs), Cfz modification where necessary (LR1) /Relapse or (Mfx/Lfx) – 12 2. Use Am if documented susceptibility to it, design recurrence of MDR Dlm (6), Eto, PAS regimen based on previous exposure to SLDs TB (Cs), Cfz, (Mfx/ and likely effective drugs. Lfx) 3. If susceptible to FQ, high dose Lfx or Mfx can be used, if resistance to FQ then FQ can be used in line with level of resistance reported 4. Extending use of Dlm for whole duration could be an option 5. If Cs was used as a part of LR1 then use PAS instead 6. Imp/Clv can be used when injection (Am) cannot be used, or after Am stopped by 6-8 months LR4 1.Secondary LR4.1 18 1. DST to FLD and SLDs should guide further XDR (FQ and SL Dlm(12),Cs, Imp/ modification where necessary Inj. Resistance) Clv (10), Eto,PAS, 2. Design regimen based on previous exposure to and Exposure to Cfz,Z SLDs standard MDR 3. Dlm extension through out treatment may be a regimen such as good option failure/relapse/LTFU LR 4.2 18 4. Clinical case discussion with DR experts before to LR1 Dlm(12), Imp/ initiation of LR4 (Case discussion panel) 2. Failure of LR2 Clv (10), Eto,PAS, Cfz, Z 34 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 4 ml 3 ml 1-1.5 1 tab 2 tab 4 tab 5 tab 3 tab 2 tab 1 tab 1 cap 3 cap 4 tabs 2 tabs >70kg 1.5 tabs 1gm bd 1gm 2 tab bd sachet bd 125mg bd bd bd 4 ml 1 tab 2 tab 3 tab 4 tab 3 tab 2 tab 1 tab 1 cap 3 cap 4 tabs 2 tabs 125mg 1.5 tabs 1gm bd 1gm 2.5-3 ml 1 sachet 2 tab bd 56–70kg bd 1 tab 3 tab 4 tab 3 tab 2 tab 1 tab 1 cap 2 cap 4 tabs 2 tabs 2.5 ml 3-4 ml 1.5 tabs 1gm bd 1gm 1 sachet 2 tab bd 46–55kg 1.5-2 tab 125mg bd bd 3 ml 1 tab 1 tab 2 tab 4 tab 2 tab 1 tab 1 cap 2 cap 3 tabs 2.5 ml 1.5 tab 1.5 tab 1.5 tabs 1gm bd 1gm 1 sachet 2 tab bd 36–45kg 125mg bd bd 2 ml 1 tab 1 tab 2 tab 3 tab 2 tab 1 tab 1 cap 2 cap 3 tabs 2.5 ml 1.5 tab 1.5 tabs 1gm bd 1gm 1 sachet 2 tab bd 30–35kg 1-1.5 tab 125mg bd

Daily dose 7.5-10mg/kg 15-25mg/kg/day 15mg/kg 1x/day (max 1gr) 10mg/kg 1x/day (max 750mg) 15-20mg/kg/day 100mg/day 10-15mg/kg/day 20–30mg/kg/day 15–25mg/kg/day 10mg/kg/day 150-200mg/kg/day 600mg /day 200mg/day 250mg/day 4gm/day 22 weeks for 200 mg 3 times per week by followed 2 weeks daily for 400 mg once 1 vial 3 times or 2 vials daily IV 400mg tab 400mg tab Formulation 250mg tab 500mg tab 750mg tab 500mg/2ml per vial 250mg tab 100mg cap 250mg cap 400mg tab 400mg tab 300mg tab sachet 4gm 600mg tab 50mg tab 125mg with Amoxicillin & Meropenem 500mg vial 100mg tab 1000mg vial 20 ml <60 years ≥60 years Drug Adult drug dosages in the long regimen (LR) dosages in the long regimen drug Adult 1 Moxifloxacin standard dose standard Moxifloxacin high dose Moxifloxacin 1500mg (high dose upto Levofloxacin daily) Amikacin Ethionamide Clofazimine Cycloserine Pyrazinamide Ethambutol Isoniazid high-dose PAS Linezolid Delamanid Acid Clavulanic Imipenem-cilastatin Bedaquiline acid be used with clavulanic to Meropenem TABLE 4.5 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 35

Intensive Phase and Treatment Duration: Intensive (or injectable) phase: WHO has recently in 2019 guidelines, recommended that regimens without an injectable agent are considered not to have an intensive phase. However, in Longer MDR TB treatment if Injectable (Amikacin or Streptomycin) has to be used, WHO recommends an intensive phase of 6 months for most patients and IP duration may be increased as per response to treatment.

“The recommended duration of an injectable drug during the intensive phase is guided by the culture conversion. An injectable agent should be used for a minimum of six months with at least four negative cultures and given that patient remains converted”. — Missing or contaminated results would not be counted. — Once patient is converted and if there is one positive culture followed by at least two consecutive negative cultures and patient is clinically doing well, stable and improving, this positive culture may be ignored. — If there are two positive cultures after conversion, then it should be followed by at least 4 negative cultures.

For SSTR, recommendation of Intensive phase remains same as the Injectable(Am) is used for 4 months and may be extended to 6 months case by case depending upon smear results by month 4.

Treatment Duration: As per new WHO guideines, 2019 for of longer MDR TB regimens duration following is recommended; • A total minimum duration of 18 months • A treatment duration of 16 months is recommended after culture conversion • The treatment duration may be modified as per patients response to treatment • Prolonging the treatment longer than 20 months may be considered in patients with additional resistance or late converters, extensive disease and other risk factors for failure or relapse of treatment.

Treatment Outcomes for RR-TB/MDR-TB/XDR-TB patients treated using second-line treatment

Cured: • Treatment completed as recommended by the national policy (minimum 18-months with 16 months past culture conversion) without evidence of failure AND 3(three) or more consecutive cultures taken at least 30 days apart are negative. • For the purpose of declaring cure, the patient should have three consecutive negative cultures reported by the end of treatment, ensuring that cultures are done as per national policy. • If there is one positive culture by the end of treatments, this positive culture should be followed by 3 negative cultures

Treatment completed: Treatment completed as recommended by the national policy (minimum18 months) without evidence of failure BUT no record that three consecutive cultures taken at least 30 days apart are negative. 36 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Treatment failed Treatment terminated or need for permanent regimen change of at least two anti-TB drugs because of: • lack of conversion by the end of 6 months of treatment or in case of injectable by the end of intensive phase, OR • bacteriological reversion in the continuation phase after conversion to negative, OR • evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs, OR • adverse drug reactions (ADRs) leading to permanent treatment termination

NOTE: • If an MDR TB patient has 4 positive cultures and is on month 6 of treatment, it is suggested to repeat LPA/DST to SLDs and act accordingly as per result. Please note that there may be a delayed response to treatment in XDR-TB patients. • In case of reversion after six months of treatment or after intensive phase in cases if injectable; repeat LPA/DST to SLDs, continue with treatment and decide as per result of LPA/DST.

Died: A patient who dies for any reason during the course of treatment

Lost to follow-up: A patient whose treatment was interrupted for 2 consecutive months or more. Not evaluated: A patient for whom no treatment outcome is assigned. (This includes cases “transferred out” to another treatment unit and whose treatment outcome is unknown) Treatment success: The sum of cured and treatment completed

The sum of Cured and Treatment completed is commonly used as an indicator of favorable outcome, or Treatment success. The outcome Cured is restricted to pulmonary bacteriologically confirmed TB cases only.

4.4 SHORTER STANDARDIZED TREATMENT REGIMEN (SSTR) 4.4.1 Drugs, dosages, frequency and duration of administration The SSTR consists of an intensive phase of 4 months with 7 drugs, followed by a continuation phase of 5 months with 4 drugs. The intensive phase will be extended if smear conversion is not achieved within 4 months, with a maximum of 6 months (see algorithm in figure 3):

Intensive phase 4 (+1 or 2) months Continuation phase Amikacin 5 months (fixed) Ethionamide Isoniazid high-dose Moxifloxacin high-dose Clofazimine Pyrazinamide FIXED Ethambutol

4-6 Am Mfxh Eto Hh Cfz E Z / 5 Mfxh Cfz E Z NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 37

Drugs are given daily according to the dosages in table A and B below and all drugs are to be given in a single dose.

TABLE 4.6 (A) Adult dosages of the drugs used in the SSTR Drug Dosage Weight group (Kg) 30-35 36-45 46-55 56-70 >70 Amikacin1 <60 15mg/kg 500mg 625 mg 750 mg 875mg 1000 (vial 500 mg- years (maximum 1 (2ml) (2.5ml) (3) (3.5) mg 2ml) gram) (4ml) ≥60 10mg/kg 350mg 450mg 500mg 500mg 750mg years (maximum 750 (1.5ml) (2ml) (2ml) (2ml) (3ml) mg) Ethionamide2 15-20mg/kg/d 500mg 500mg 750mg 750mg 1gm (tablet 250mg) (2 tab) (2 tab) (3 tab) (3 tab) (4 tab) Isoniazid high-dose 10mg/kg/d 300mg 450mg 600mg 600mg 600mg (tablet 300mg) (1 tab) (1.5 tab) (2 tab) (2 tab) (2 tab) Moxifloxacin high-dose 10-15mg/kg/d 600mg 600mg 600- 800mg (tablet 400mg) (1.5 Tab) (1.5 Tab) 800mg (2 Tab) 800mg (1.5-2 (2 Tab) Tab) Clofazimine 2-3mg/kg/d 100mg 100mg 100mg 100mg 100mg (capsule 100mg) (1 tab) (1 tab) (1 tab) (1 tab) (1 tab) Pyrazinamide 20-30mg/kg/d 1000mg 1200mg 1600mg 2000mg 2000mg (tablet 400mg) (2.5 tab) (3 tab) (4 tab) (5 tab) (5 tab) Ethambutol 15-25mg/kg/d 800mg 800mg 800mg 1200mg 1200mg (tablet 400mg) (2 tab) (3 tab) (3 tab) (4 tab) (4 tab) 1 Frequency of administration: 6x/week during months 1 to 4; from month 5 onwards: 3x/week. 2 250mg once daily on days 2 to 4; 2 x 250mg/day on days 5 to 7; 250mg in the morning, 500mg in the evening from day 8 onwards if patient >50kg.

TABLE 4.6 (B) Pediatric dosages of the drugs used in the SSTR Drug Dosage Weight group 10-14kg 15-19kg 20-24kg 25-29kg Amikacin1 (vial 500 mg – 2ml) 15-20mg/kg 200mg 300mg 400mg 500mg Ethionamide (tablet 250mg) 15-20mg/kg ½ tab ½ tab ½ tab 1 tab 2x/d 2x/d morning 1 2x/d tab evening Isoniazid high-dose (tablet 100mg) 10-15mg/kg 1 tab 2 tab 3 tab 4 tab Moxifloxacin high-dose (tablet 400mg) 10-15mg/kg ½ tab ½ tab 1 tab 1 tab Clofazimine (capsule 50mg) 2-3mg/kg2 1 cap 1 cap 1 cap/d 1 cap/d 4x/w 6x/w Pyrazinamide (tablet 400mg) 30-40mg/kg 1 tab 1½ tab 2 tab 2tab Ethambutol (tablet 400mg) 15-25mg/kg3 ½ tab ½ tab 1 tab 1 tab

1 Frequency of administration: 6x/week during months 1 to 4; from month 5 onwards: 3x/week. Monitor regularly through audiometry: see M5. 2 Capsules cannot be divided, as they contain a gel. Give intermittently to arrive at a correct average weekly dose. Example: child of 13 kg should receive 20-30mg/day corresponding to 182-273mg/week; give Cfz 50mg 4x/week corresponding to 200mg/week. 3 Doses closer to 15 mg/kg/day are used if the drug is used for more than 2 months 38 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

The algorithm in figure 3 shows how the drugs of the SSTR are introduced. On day 1, treatment will start with all drugs except Eto. The drugs are given together in a single daily administration. If there is no major adverse event on day 1, Eto 250 mg will be added on day 2. The dosage of Eto will be escalated to 500mg on day 5 if patient can tolerate Eto 250 mg, and further escalated to 750mg (250mg in the morning, 500mg in the evening) on day 8 if necessary depending on patients’ body weight. An antiemetic drug may be used if there is gastrointestinal disturbance.

FIGURE 3. Schematic overview of drug introduction and duration of administration in the SSTR NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 39

4.4.2. Criteria to decide when the shorter MDR-TB regimen may be offered Since 2016, the regimen has been recommended by the WHO for treatment of the MDR- TB patients who do not present resistance to the FQ or the SLID. Patients with an RR/MDR GeneXpert result are not eligible to receive the STR if all of the following conditions are fulfilled.

Is any of the following present?

• Preference by the clinician and patient for a longer MDR-TB regimen • Confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen (except isoniazid resistance) • Exposure to one or more 2nd line medicines in the shorter MDR-TB regimen for >1 month (unless susceptibility to these 2nd line medicines is confirmed) • Intolerance to medicines in the shorter MDR-TB regimen or risk of toxicity (e.g. drug-drug interactions) • Pregnancy • Disseminated, meningeal or central nervous system TB • Any extrapulmonary disease in PLHIV • One or more medicines in the shorter MDR-TB regimen not available

FAILING SHORTER REGIMEN or NON-RESPONSE, YES DRUG INTOLERANCE, EMERGENCE OF ANY OTHER NO EXCLUSION CRITERION Individualized, Standardized, shorter longer MDR-TB MDR-TB regimen may be offered regimens (conditional recommendation)

Beside above mentioned criteria if patient has severe bilateral lung damage or severe disease at baseline Longer RR/MDR regimen should be initiated.

4.4.3. When to discontinue the administration of the SSTR The SSTR will have to be discontinued in the following situations: • Severe toxicity due to Mfx: FQ is the most important drug in the regimen. If the Q-T interval is seen to increase and risks exceeding >500msec. If this has no effect and the Q-T interval continues to be elevated, the regimen must be discontinued. • In case of occurrence of ADR discontinue the SSTR in line with aDSM protocol. • Pregnancy during treatment • Sputum smears remain positive up to month 6 (dead bacilli needs to be ruled out) • Culture remains positive at end of intensive phase or reverts to positive during continuation phase: see figure 4. In practice, this amounts to: - Culture is positive at month 4 or 5 or 6, depending on the duration of the intensive phase - After negative culture at end of intensive phase, 2 consecutive cultures are positive during the continuation phase

When the SSTR has to be permanently discontinued due to AE, the patient must be sent to the DR-TB Centre, where an appropriate long-course regimen will be initiated. 40 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Treatment regimen of SSTR and Failure to SSTR (Modified LR2)

SSTR Standard Shorter 4-6 Amk,Mfxh, Cfz, Eto, INHh, E, 1.As per standard protocol (Km Treatment Z/5 Mfxh,Cfz, Z,E replaced with Am) Regimen(SSTR) 2. In case of toxicity and SSTR cannot be continued, then switch to LR1 Modified Failed by SSTR 18 Bdq(12), Dlm(6), Lzd,Cs,Cfz, DST to FLD and SLDs should LR2 PAS guide further modification where necessary Bdq can be extended to whole duration case by case as per likely effective drugs remaining in regimen after Bdq is stopped.

FIGURE 4. Monitoring treatment progress of SSTR through culture

Sputum smear result 4 months ‒ + + + 5 months ‒ + + 6 months ‒ + â â â Stop intensive phase after 4 months after 5 months after 6 months o o o culture at 4 culture at 5 culture at 6 months months months NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 41

Definition of outcome in SSTR Generally the outcome definition are similar as of Longer RR/MDR TB Regimens. However, there is slight change in failure definition.

Cured: Treatment completed without evidence of failure AND three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase.

Treatment completed: Treatment completed without evidence of failure BUT no record that three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase.

Failure: The patient may be declared failure if meets one of the following criteria; • Acquired resistance to FQ and or injectable • Sputum smear positive at month 6 along with poor clinical and radiological response or worsening by the end of intensive phase • There are two positive Cultures taken at least 30 days apart in continuation phase of SSTR treatment OR • One culture positive in the last three months of treatment and recent follow up month smears are also positive

Clinical decision in consultation with TWG has been made to permanently terminate treatment early because of poor clinical or radiological response or adverse events

NOTE: Changing or switching treatment to longer regimen due to SAEs is not failure.

Died: A patient who dies for any reason during the course of treatment.

Lost to follow-up: A patient whose treatment was interrupted for 2 consecutive months or more.

Not evaluated: A patient for whom no treatment outcome is assigned. (This includes cases “transferred out” to another treatment unit and whose treatment outcome is unknown).

Treatment success: The sum of cured and treatment completed 42 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

4.5 TREATMENT OF INH RESISTANT TB Among most potent and effective treatment of TB drugs , Isoniazid (H) plays vital role and because of its strong bactericidal activity, it is one of the most important first-line medicines for the treatment of active tuberculosis (TB) and latent TB infection (LTBI). Globally about about 8% of TB patients are estimated to have rifampicin-susceptible, isoniazid-resistant TB (Hr-TB) ranging from 5 to 11% between the WHO regions(WHO 2017), Thus emergence of TB strains resistant to isoniazid threaten to reduce the effectiveness of TB treatment (WHO 2016, 2018). While in Nepal 5.6% are with Hr monoresistance TB(DR Survey 2011, Nepal).

Treatment of mono- and poly-resistance with WHO standardized first-line anti-TB drug regimens has been shown to increase the risk of treatment failure and even worse, amplification (acquisition of additional resistance) to multidrug resistance (Jacobson KR et al 2011). Moreoevr, Diagnosis in such cases may not be known for weeks or months.

TB control programs generally focus on MDR-TB because these highly resistant strains are difficult to treat, and cause much morbidity and mortality. However, at the same time, the significant number of Hr TB who remain undiagnosed and inappropriately treated can not be ignored.

4.5.1 Following are the operational ways to treat patients; • Patients with a history of previous treatment who have pan-susceptible disease to be treated with first-line drugs • Patients with mono- or poly-resistance (other than RRTB) should be treated with appropriate regimens • Patients with RR/MDR-TB should be treated with second-line therapy

Diagnosis of Hr TB The Hr TB can be diagnosed using 1st Line LPA and phenotypic conventional DST to 1st line drugs. This has been observed that such cases are now being increasingly reported and early detection of such cases is crucial.

Following is suggested to diagnose the Hr TB: 1. Close contacts of patients who are being treated with mono/poly DR TB should be tested both by Xpert MTB/RIF and by 1st Line LPA if Xpert MTB/RIF shows no RR TB 2. DS TB retreatment patients when tested with Xpert MTB/RIF and result is T, such patient should be tested by LPA 1st Line 3. Xpert MTB/RIF with result T in DS TB non converters 4. Clinicians should request testing 1st line drugs by liquid/solid DST, where LPA not available or non-interpretable and patient response in poor to treatment

Once the mono and poly DR TB(other than RR TB) is reported, it is also imperative to request SL LPA to exclude resistance to FQs, particularly in Nepal as Pre XDR/XDR TB prevalence in high. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 43

WHO in 2017 guidelines for treatment of Hr TB has following recommendation; In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, treatment with rifampicin, ethambutol, pyrazinamide and levofloxacin is recommended for a duration of 6 months. However, if no REZ FDC is available then the suitable option is to use HREZ FDC. Intermittent or divided dosing of the 6(H)REZ-Lfx regimen is to be avoided and weight band dosing scheme for Lfx is recemmended.

The implementation to this recommendations requires that the (H)REZ-Lfx regimen is administered only in patients in whom resistance to isoniazid is confirmed and resistance to rifampicin has been excluded. Preferably, testing for resistance to fluoroquinolones possibly prior to treatment initiation . It is also important to test for resistance to pyrazinamide and later treatment adjusted, while E and S has no practical implication on treatment as DST is not usually reliable.

In line with WHO recommendations, practically following situations apply at filed level; 1. Hr-TB is confirmed before TB treatment is started: Treatment with the (H)REZ-Lfx is started immediately. If the diagnosis is strongly presumed (e.g. close contacts of a confirmed Hr-TB source case) but results of drug susceptibility testing are still pending the regimen may be introduced. Should drug susceptibility test results taken at start eventually show susceptibility to isoniazid, then levofloxacin is stopped and the patient continues treatment in order to complete a 2HREZ/4HR regimen. 2. Hr-TB is confirmed after the start of treatment with 2HREZ/4HR regimen: This includes patients who had undiagnosed isoniazid resistance at the start or who developed isoniazid resistance later while on first-line regimen treatment. In such cases, rapid molecular testing for rifampicin resistance must be done (or repeated). Once rifampicin resistance is excluded, a full 6-month course of (H)REZ-Lfx is given. The duration is driven by the need to give levofloxacin for 6 months, which usually implies that the companion first-line medicines are taken for longer than this. 3. If rifampicin resistance is detected, the patient needs to be started on a recommended MDR- TB treatment regimen.

Moreover, in cases where Lfx can not be used becuase it is hypersensitve or resistance, then WHO recommends treatment with 6(H)REZ. However, in such situations and in patients with ressitance to H+Z+E or H+Z+Lfx, the use of 6(H)RZE may not contain enough agents on board to ensure effective and relapse free treatment. Therefore, the treating physicain in line with pannel discussion has to decide best treatmnet options and drugs from Linezolid, Ethionomide and Cyclocerine may be used. However, use of Bedaquiline and delaminid other than RR TB is not recommended so far. The use of Mfx is also not recommended with rifampicin as the concentration of Mfx is decreased.

Treatment prolongation beyond 6 months: may be considered for patients with extensive cavitary disease or in patients slow to convert to negative smear/culture.

It is imperative to perform Xpert MTB/RIF in all mono and poly DR cases, before enrolling them on treatment, this excludes cases with R,RZ,RZE as such cases require full MDR TB treatment. Likewise, It is essential that always use Xpert MTB/RIF at month 0, 2, and 3 and if rifampicin resistance is found switch to full MDR-TB treatment. For monitoring purposes, it should be followed as in DS TB regimen.

* Principle of never adding single drug to failing regimen is the mainstay of treatment 44 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

4.5.2. Drug dosage for Hr-TB regimen Dosage with 4-drug FDC (RHZE) - Adults

Weight bands in adults 4-drug adult FDC Levofloxacin 250mg (15-20 mg/kg) RHZE-150/75/400/275* 30-39 kg 2 tablets 2 tablets 40-54 kg 3 tablets 3 tablets 55-70 kg 4 tablets 4 tablets More than 70 5 tablets 5 tablets

*The dose of levofloxacin should not exceed 1.5 gm per day

Dosage with 3-drug FDC (RHZ) - Children

Weight bands in 3-drug paediatric FDC Ethambutol 100mg Levofloxacin 100mg children* RHZ-75/50/150 4-7 .9 kg 1 tablet 1 tablet 1 tablet 8-11.9 kg 2 tablets 2 tablets 2 tablets 12-15.9 kg 3 tablets 3 tablets 3 tablets 16-24.9 kg 4 tablets 4 tablets 4 tablets 25 kg + Use adult doses and preparation

* In children weighing 25 kg or more, the adult schedule shown in the previous section is followed.

If levofloxacin 100mg dispersible tablet is not available, the 250mg tablet can be used with 6(H) REZ in children aged 0-14 years, based on a slightly different weight band from the above:

Weight Levofloxacin 250mg 5 - 6 kg ½ tablet / day 7 - 9 kg ¾ tablet / day 10 – 15 kg 1-1.5 tablet / day 16 – 23 kg 1.5.2 tablets / day 24 – 30 kg 2-2.5 tablets / day 31 kg + Follow adult schedule (up to 1.5g / day)

4.6 TREATMENT OF MDR-TB IN SPECIAL SITUATIONS 4.6.1 MDR-TB in women of child bearing age 4.6.1.1 Pregnancy testing and contraception Most second-line drugs are toxic for the foetus. Before starting any second-line treatment, all women of child bearing age should have a pregnancy test. If the test is negative, contraception must be recommended. The use of oral contraceptives is not contraindicated during MDR-TB treatment, but several second-line drugs may cause vomiting. Patients who vomit directly after taking an oral contraceptive can be at risk of decreased absorption of the drug and therefore of decreased efficacy. The contraceptive should be taken at a time when vomiting as a result of the anti-TB medications is least likely to occur. Patients who vomit at any time directly after, or NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 45

within the first two hours after taking the contraceptive tablet, should use a barrier method of contraception until they have been able to take the contraceptive tablets without vomiting for a full month.

4.6.2 Pregnancy and MDR-TB treatment • Pregnancy is not a contraindication for treatment of active drug-resistant TB, but poses great risk to the lives of both the mother & fetus. • All female patients of childbearing age should be tested for pregnancy upon initial evaluation. • The risks and benefits of treatment should be carefully considered, with the primary goal to protect the health of the mother and child, both before and after birth. • Most pregnant patients should be started on treatment as soon as the diagnosis is made • Treatment may be delayed until the second trimester when the patient is very stable with minimum disease as majority of taratogenic effects occur during st1 trimester. Risks and benefits should be carefully evaluated. However, it is better to start treatment with safer options • Other family members, especially the father may need to be consulted depending on the relevant family, religious, cultural and social dynamics • Treat with three or four oral second-line anti-TB drugs which are likely to be highly effective plus pyrazinamide and regimen should be reinforced with other drugs as needed immediately postpartum (WHO 2014) • Despite limited data on safety and long-term use of fluoroquinolones, cycloserine, paraaminosalicylic acid (PAS) in pregnancy, they are considered the drug of choice for MDR- TB treatment during pregnancy. Clofazimine has been used extensively in leprotic pregnant patients and also now NTPs have developing experience of using Cfz in pregnancy, therefore Clofazimine is found safer in pregnancy (thugh FDA safety class C) and can be used. Now US FDA has placed Bedaquiline in safety class B and South Africa has been using safely Bdq in pregnancy. • Therefore, the most suitable option of regimen will be Lfx, Cfz, Cs, PAS, Z or if needed Bdq may be used as best practice option • Ethionamide should be avoided as can increase the risk of nausea and vomiting associated with pregnancy, and teratogenic effects have been observed in animal studies. • The termination of pregnancy may be considered if would carry a significant risk to her life • If some of the effective drugs were withheld because of the pregnancy, they can be added back postpartum to make a more complete regimen(WHO 2014) • Please be informed of the principle of never adding single drug to failing regimen • Total duration is same as for MDR TB • The child should receive Bacillus Calmette–Guérin (BCG) vaccination at birth as per WHO policy. 46 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

FDA Safety call of SLD in pregnancy

Drugs US FDA Summary safety class Animal studies have not revealed any evidence of harm to the fetus or any effects on fertility in females, some males treated with high doses failed to procuce offspring. There are no controlled data in human Bdq B pregnancy.22 Pharmacokinetic data in rats treated with doses 1-2 times the human clinical doese have shown 6 to 12 fold higher bedaquiline concentrations in milk than the maximum concentrations observed Not yet in maternal plasma. assigned In rabbits reproductive studies, embryo-fetal toxicity was observed at Dlm an FDA maternally toxic dosages. Avoid in pregnancy; however the benefits safety in patients with no other options may outweigh the risks. class. Pharmacokinetic data in animals have shown excretion of delamanid/ metabolites into breast milk. In lactating rats, the Cmax for delamanid in breast milk was 4 fold higher than that of the blood. Lzd C Animal studies have failed to reveal evidence of teratogenicity, but embryofetal toxicity was observed at maternotoxic doses. Placental transfer of this drug and/or its metabolites was observed in rats. There are no controlled data in human pregnancy. There are no studies of clofazimine use in pregnant women. Few cases of clofazimine use during pregnancy have been reported in the Cfz C literature.

Embryofetal toxicity studies were conducted in rats, rabbits and mice. In mice, clofazimine-induced embryotoxicity and fetotoxicity was evident. Ipm/Cln C Developmental toxicity studies with imipenem and cilastatin sodium (alone or in combination) administered to monkeys, rabbits, rats, and mice revealed no evidence of teratogenicity. However, an imipenem- cilastatin dose of 40 mg/kg given to pregnant monkeys by bolus intravenous injection caused significant teratogenicity/toxicity

Treatment regimen for RR/MDR TB in pregnancy PLR1 RR/MDR TB 18Lfx, Cfz, Cs, PAS, Z 1. Cfz is relatively safe in pregnancy based on treatment in experience in human use in Leprosy patients and Pregnancy now developing experience in MDR TB. 2. FDA classifies BDQ in safety class B in pregnancy, in south Africa Bdq in pregnancy has shown safety 3. After delivery switch the back to the original applicable LR regimen NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 47

4.6.3 Breastfeeding Breastfeeding is no contra-indication for MDR-TB treatment as anti TB drugs excretion through breast milk is in very low concentration that is not harmful for neonate, but the benefit of breastfeeding has to be weighed against the risk of exposure to MDR-TB infection of the infant, as well as against the possible risks for the baby associated with the ingestion of second-line drugs with the mother milk. Infant formula can only be considered a valid alternative to breastfeeding if all required resources are available and appropriate training has been provided. If the infection prevention can be maintained through personal protection like mask to the mother and good environmental control can be achieved then breast feeding is preferred. If not option is to keep the baby away from the mother as long as she is contagious, and to collect the mother’s milk using a breast pump and bottle-feed the baby until it is safe to reunite mother and child.

4.6.4 MDR-TB in children Diagnosis of MDR-TB among children can be challenging and requires a high level of suspicion. Under field conditions, it may take several weeks from the time a child first presents with signs and symptoms of TB and the receipt of test results, during which time a child can rapidly deteriorate. Thus, it is important to consider initiating MDRTB therapy in the absence of bacteriologic confirmation in line with consultation with pediatrician expert in TB/MDR TB.

GeneXpert Ultra and culture in liquid media should be prioritized in children. All relevant and available tests should be considered; performing multiple tests on one or more samples of a variety of specimen types significantly increases the diagnostic yield. Collecting the respiratory specimen at optimal times is important to enhance the yield e.g. early morning fasting gastric aspirate, before mobilization; induced sputum after fasting 2-4 hours; expectorated sputum early morning. Of note, sputum(induced or expectorated) should be minimum 3 ml, Gastric aspirate 5 ml, gastric lavage 10 ml, or 3 ml , nasopharyngeal aspirate 2 ml.

In addition to that there are extra pulmonary samples useful to test by Xpert MTB/RIF to get diagnosis in children and can be obtained any time, e.g. CSF, and Lymph node aspirate, Urine (use of the urinary lipoarabinomannan (LAM) may be a useful test to diagnose TB in children or individuals living with HIV with low CD4 counts). Serosal fluids include pleura, pericardium, peritoneum, and synovium may also be helpful in diagnostics, but baceriolgical yield is higher in tissues than fluids.

It is important that TB should be included in the differential diagnosis list of any child with a persistent non- settling cough or fever, weight loss/failure to thrive, or focal findings that are suggestive of TB, such as lymphadenitis, spinal deformities, ascites, and joint effusions. Danger signs of possible meningitis include lethargy/sleepiness, loss of consciousness, and seizures MDR-TB in children can either be confirmed (they have clinical TB disease and a sample taken from the child shows MDR-TB) or clinically diagnosed (the child has clinical TB disease and has risk factors for drug resistance).

Clinically diagnosed TB includes probable and possible MDR-TB. 48 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Sometimes treating MDR TB in children becomes challenging as either some drugs in certain age can not be used or difficult to monitor side effects as many second-line drug formulations are not child-friendly, and preparation can be labor intensive. However, there are now child- friendly, quality assured formulations are available from the Global Drug Facility: pyrazinamide, ethambutol, levofloxacin, moxifloxacin, ethionamide, isoniazid, and cycloserine and hopefully delaminid will also be available soon.

• The principles of regimen design for adults also apply for children based on the WHO recommended regimen design as per grouping of SLDs. • As per WHO 2019 recommendation,always attempt to treat children with injectable-free regimens, especially in very young children and those with mild disease and if there is no other option and Injectable has to be added then close monitoring by audiometry is crucial. • Treatment of MDR-TB meningitis should be guided by the medicines with good penetration to CNS • Regimens should consist of at least 4 drugs to which the organism is likely to be effective and susceptible and unnecessary/additional drugs should be avoided to avoid toxicity • WHO in 2019 guidelines recommends bedaquiline for the treatment of children aged 6 years and above and the use of delamanid for the treatment of children aged 3 years and above. Moreover both the drugs are recommended for 6 months and beyond 6 months duration is off label use • In children with fluoroquinolone resistance or in whom there are limited treatment options, extension and combination of bedaquiline and/or delamanid could be considered on a patient-by-patient basis with careful monitoring • Regimens will need to be designed for each individual patient—taking into account unique resistance patterns and toxicity risks • Linezolid being group A drug with good efficacy but its use has been associated with frequent toxicity and related toxicities are duration dependent. Therefore, its use for throughout duration cannot be warranted • In children with HIV and MDR TB co morbidity, Bedaquiline and Efavirenz should be avoided in combination use as efavirenz lowers the concentrations of Bedaquiline. • Ethionamide(if no Inh A gene mutation) and PZA are also options to use if documented susceptibility, PAS can also be used if no other effective option is left. • The duration of therapy in children should depend upon the site and severity of disease; children with non-severe disease can be treated for 9 to 12 months while children with severe disease will require 12-18 months of therapy depending on their clinical progress . Of note, the 2018 WHO recommendations define severe disease as follows: “In children <15 years, severe disease is usually defined by the presence of cavities or bilateral disease on chest radiography or extrapulmonary forms of disease other than lymphadenopathy”. While Non-severe disease can be defined as TB disease that is isolated to the lymph nodes or only affects one of the lungs without cavities. However, severity of disease can also be determined by bacillary load if available. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 49

Following are the regimens for children:

0-5 yo, pediatric 18 Lfx, Lzd,Cfz,Cs,Z 1. With Lzd based regimen Standard RR/MDR TB monitor closely for related CLR1 Regimen for FQ sensitive toxicities, especially with Non-eligible for STR Cs together. and for those whose 6 Years and above FQ results unknown/ pediatric Regimen (FQ awaited/sensitive sensitive and FQ res) 0-3yo, pediatric 18 Lzd,Cfz,Cs,INHh, Z Eto follow adult LRs as Standard RR/MDR TB applicable Regimen (FQ-resistant) Treatment should be done in close consultation with pediatrician CLR2.1 1. In case of toxicity or need to decrease refer to aDSM relevant section

2. If Lzd is well tolerated, should be continued throughout the treatment duration 3-5 years pediatric 18 Lzd,Cfz,Cs,Dlm(6),Z regimen FQ resistant 3. INH high dose showed CLR2.2 good results in children as per WHO 2016 IPD analysis.

The treatment regimens for children are indicted as above. The dosages are indicated in tables 4.6. Daily dosing will be approximate: tablets may be cut into fragments and crushed, capsules may be opened and the content fractioned. Small discrepancies will even out over time. The drugs may be mixed with small amounts of liquid or soft food, particularly sweet jam. 50 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT >34 kg (>14 yrs) (>14 yrs) (>14 yrs) 20 ml 0.75 (>14 yrs) (>14 yrs) (>14 yrs) (>14 yrs) (>14 yrs) (>14 yrs) 2 bd (>14 yrs) (>14 yrs) (>14 yrs) - (>14 yrs) (>14 yrs) 31-34 kg (>14 yrs) 3 (>14 yrs) then 2 2 weeks 4 tabs OD for 22 weeks tab OD for 15 ml 0.5 2 (>14 yrs) (>14 yrs) 2 - 2 1 bd - 3 2.5 - (>14 yrs) (>14 yrs) 24-30 kg 5 2 4 14 ml 0.5 2 1 4 2 - 1-1.5 1 bd - 2.5 2 - 11 ml 2 ml 16-23 kg 3-4 1.5-2 3 then 1 2 weeks 2 tabs OD for 22 weeks tab OD for 11 ml 0.5 1 days 1 alt. 3 2 4 1 - 4-5 1.5-2 1.5 - 8-9 ml 1.2-1.5 ml 10-15 kg 2-3 1-1.5 2 - 8 ml 0.25 days 1 alt. days 1 alt. 2 - 3 - - 3 1 0.75 or 1 - 6 ml 0.8-1 ml Weight bands among patients under 15 years old under 15 years bands among patients Weight 7-9 kg 1.5 0.5 1.5 - 6 ml 0.25 days 1 alt. 1 - 2 - - 2 0.75 0.5 - 4 ml 0.6 ml 5-6 kg 1 0.5 0.8 - 4 ml 0.25 days 1 alt. 1 tab 3 times per week 1 - 1 - - 1 0.5 0.5 - 2 ml 0.4 ml Formulation 100mg dt 250mg tab 100mg dt 100mg tab 20mg/ml suspension 600mg tab 50mg cap or tab 100mg cap or tab 125mg mini cap 250mg cap 100mg dt 400mg tab 50mg tab 150mg dt 400mg tab 500mg tab vial 0.5gm vial/20ml 1gm 500mg/2 ml vial Daily dose 15-20 mg/kg 10-15 mg/kg - 15mg/kg in <16 kg 10-12mg/kg in >15 kg 2-5mg/kg 15-20mg/kg 15-25mg/kg - 30-40mg/kg - 20-40mg/kg IV every 8 hours 15-20mg/kg Pediatric dose of RR/MDT-TB longer regimen: dose of RR/MDT-TB Pediatric Medicines Lfx Mfx Bdq Lzd Cfz Cs E Dlm* Z Imipenem- cilastatin** toMeropenem be used with acidclavulanic Am TABLE 4.6 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 51 >34 kg (>14 yrs) 8gm - (>14 yrs) (>14 yrs) 31-34 kg 4 bd 8gm - 4 (>14 yrs) 24-30 kg 4 bd 6gm - 4 10 ml bd 16-23 kg 3 bd 4gm - 3 8 ml bd 10-15 kg 2 bd 3-4gm 20 ml 2 5 ml bd Weight bands among patients under 15 years old under 15 years bands among patients Weight 7-9 kg 1 bd 2-3gm 15 ml 1.5 3 ml bd 5-6 kg 1 bd 1.5gm 8-10 ml 1 2 ml bd Formulation 125mg dt sodium salt PAS 60% (9.2gm) sachet 50mg/5ml solution 100mg tab 62.5mg/5 ml suspension along with Amoxicillin Daily dose 15-20mg/kg 200-300mg/kg in 2 divided doses 15-20mg/kg - high-dose Not used in patients <15 years (use Meropenem <15 years Not used in patients Only in patients >2 years old (25 mg bd in 3-5 years; 50 mg bd I 6-11 years; 100 mg bd in 12-17 years) 50 mg bd I 6-11 years; old (25 mg bd in 3-5 years; >2 years Only in patients Medicines Eto PAS H Clavulanic acid (only tto be used with Meropenem * ** 52 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

4.6.5 DR-TB and HIV co-infection The treatment of DR-TB in PLHIV is not different from the treatment in HIV-negative people. They can receive either SSTR or a long-course regimen, based on eligable criteria. If the TB/HIV patient is already on ART, it is to be continued. If not yet on ART, it must be prescribed according to the recommendations of the National Centre for AIDS and Sexually transmitted disease Control (NCASC) and started rapidly regardless of CD4 count, as soon as the patient is seen to tolerate the MDR-TB treatment, possibly within 8 weeks. All TB/HIV patients must receive cotrimoxazole preventive therapy (CPT). All patients co-infected with HIV and MDR-TB must be managed at the DR-TB Centre.

The DR-TB therapy in PLHIV is complicated by: • cumulated drug toxicities • Drug-drug interaction • other co-infections exacerbating drug toxicity • malabsorption of drugs leading to treatment failure • paradoxical worsening of TB symptoms when ART is started (Immune Reconstitution Inflammatory Syndrome or IRIS: see national HIV/AIDS Guidelines).

The risk of adverse drug reactions in PLHIV treated with second-line TB drugs increases with the degree of immunosuppression. ART and anti-TB drugs have potential overlapping or additive toxicities and the identification of the source of adverse effects is difficult. It is often impossible to link side effects to a single drug. Using agents with shared adverse effect profiles is not the preferred option but often, the benefit of the drugs outweighs the risk. Increased monitoring of adverse effects is recommended rather than disallowing a certain combination.

The main overlapping toxicities between the second-line drugs and the anti-retroviral drugs commonly used when treating TB/HIV co-infected patients (TDF, 3TC and EFV) are shown in table 11. A full listing can be found in table 8.1 in the WHO MDR Guidelines 2014.

TABLE 4.7 Potentially overlapping adverse effects between ART drugs and second-line drugs used to treat PLHIV with MDR-TB

ART drug Second-line drug Adverse effect CNS toxicity EFV Cs (Eto, FQ, H) Depression EFV, AZT Cs, Bdq Headache Many ART drugs Z, H, Bdq (Eto, PAS, FQ) Hepatotoxicity AZT Lzd (H) Bone marrow suppression AZT, 3TC Ldz Lactic acidosis All ART drugs Eto, PAS Abdominal pain Most ART drugs Eto, PAS, Bdq, Dlm, H, E, Z Nausea, vomiting Most ART drugs Most Second-line drugs Skin rash Most ART drugs Bdq, Dlm, Mfx, Cfz Prolongation of Q-T interval NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 53

Concomitant use of bedaquiline with efavirenz (EFV) is not recommended due to possible decrease of Bdq concentration. EFV should be replaced by Dorutegravir. PIs can be used with bedaquiline but should be administered with extreme caution and close clinical monitoring. Please see more information in below table.

TABLE 4.8 Possible drug-drug interactions between antiretrovirals and the new TB drugs Drugs Instructions ARVs to avoid Efavirenz (EFV) Substitute nevirapine (NVP) or integrase with Bdq (Using EFV with Bdq inhibitor instead of EFV. Allow a 5 day will result in low levels washout of EFV if possible (substitute of Bdq NVP on day 1 and then start MDR regimen5 days later). If patient is critically ill with MDR-TB, no washout period is necessary. • When switching back to EFV after ending treatment with Bdq, this can be done immediately after Bdq is stopped Ritonavir containing If possible, use an ARV regimen with no protease inhibitors (PIs) PI. One possible solution is to substitute (Using ritonavir with the PI with an integrase inhibitors Bdq will result in high (INSTIs), e.g. dolutegravir (DTG) or levels of Bdq) raltegravir (RAL). • If a ritonavir-containing PI must be used, check ECG every two weeks. ARVs to avoid None Dlm has very little drug-drug with Dlm interactions with ARVs and no extra drug monitoring or regimen adjustment is needed.6

Patients receiving ART and MDR-TB treatment must be closely monitored. Daily DOT is obligatory, because the large pill burden and the many side effects may compromise treatment adherence. Whenever adverse effects occur, they must be treated without delay. At the same time, it is important to be alert for signs and symptoms of mal-absorption: diarrhoea, abnormal stools, poor nutritional status, evidence of vitamin deficiencies, weight loss, etc. Diarrhoea should be treated aggressively as it may lead to decreased drug absorption and impair correct treatment.

4.6.6 Patients with Extra pulmonary DR TB and DR-TB meningitis Patient with DR TB with EP TB can be initiated in SSTR except those with severe form of EP TB (TB meningitis, Bone TB, Miliary TB, Disseminated TB, TB pericarditis) and EPTB with HIV.

Patient with DR-TB meningitis should not be treated with the SSTR nor with the standard MDR long-course regimen because several of the drugs in those regimens penetrate poorly into bone and soft tissues and the CSF. Therefore, it is imperative to design appropriate regimen having sufficient drugs on board with appropriate penetration in to soft tissues and bones and who cross the blood brain barrier. 54 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Following table should be followed while designing an effective regimen to treat DR TB meningitis.

TABLE 4.9 Penetration of anti-TB drugs into the central nervous system (CNS) Medication CNS Penetration Amikacin Poor penetration except in the presence of meningeal inflammation Bedaquiline No data available; studies ongoing Clofazimine Limited data available Cycloserine CSF levels similar to serum levels Delamanid Limited human data but good CSF penetration in mice: studies ongoing Ethambutol Poor penetration Ethionamide CSF levels similar to serum levels, but higher end dosing (20mg/kg) (prothionamide) recommended in children Isoniazid 20% of serum concentrations except in the presence of meningeal inflam- mation Levofloxacin 65% of serum concentrations Linezolid Animal studies show CSF levels at 30% of serum levels: widely used in humans with excellent results Meropenem Excellent Meropenem Excellent Moxifloxacin Good penetration in animals PAS Poor penetration except in the presence of meningeal inflammation Pyrazinamide CSF levels similar to serum levels

4.6.7 Osteomyelitis and soft tissues EP MDR TB Bedaquiline and Delamind: are with limited experience about penetration in soft tissues and bones

Linezolid: Excellent bone and soft-tissue penetration; commonly used for osteomyelitis due to gram positive bacteria.

Clofazamie: Cfz has been used extensively to treat leprosy lesions in soft tissue, though it is unclear if this means that bone and soft tissue penetration is adequate

Imepeninm/Meropenim: Both drugs have been used to treat osteomyletis caused by other bacteria

Some forms of EP, when treated, may show a paradoxical worsening. This is quite common in patients co-infected with TB and HIV (Immune Reconstitution Inflammatory Syndrome or IRIS: see national HIV/AIDS Guidelines). In certain types of EP, and also if IRIS occurs, adjuvant steroid therapy may be helpful (see T5.2). NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 55

4.6.8 Patients with hepatitis Many anti-TB medications have the potential to cause hepatotoxicity, and their use must be carefully contemplated in the setting of severe liver dysfunction. Possible anti-TB drug that causes hepatotoxicity; Z, H, Cfz, PAS, Eto/Pto, Bdq, FQ, Amx/Clv. Fortunately, the most important second-line anti-tuberculosis drugs used for treatment of drug-resistant disease do not affect the liver. Among the first-line drugs, Z is the most hepatotoxic, followed by H. Among the second- line drugs, Eto and PAS can also be hepatotoxic, although less so than any of the first-line drugs. Hepatitis occurs rarely with fluoroquinolones. Lfx is less hepatotoxic than Mfx.

Hepatitis itself is not contraindication to start DR TB treatment unless liver enzymes are raised to unacceptable level i.e 5 fold increase in liver enzyme or active jaundice. Patients with history of liver disease can receive the usual anti-TB drug regimens provided there is no clinical evidence of severe chronic liver disease, hepatitis virus carriage, recent history of acute hepatitis or excessive alcohol consumption. In general, patients with chronic liver disease should not receive pyrazinamide. All other drugs can be used, but close monitoring of liver enzymes is advised. If significant aggravation of liver inflammation occurs, the drugs responsible may have to be stopped.

Treatment of drug-resistant TB in the setting of liver failure is complicated and depends on the degree of liver damage. A long-course regimen with at least 4 non-hepatotoxic drugs is required. However, as per newly WHO recomended regimen, the drugs from group A and B are safer to use and ony in severe hapetic and renal failure Bdq and Lzd may be avoided.

If a patient with acute hepatitis requires MDR-TB treatment, it may not be possible to defer the treatment until the acute episode has resolved. A similar treatment to the one outlined above may have to be given. Viral hepatitis should be treated if medically indicated and treatment can occur during drug-resistant TB treatment.

4.6.9 DR Patients with renal failure In DR-TB patients with renal insufficiency, the dosing of the second-line drugs that are cleared by the kidneys will have to be adapted if the creatinine clearance is <30ml/minute. To calculate the creatinine clearance, see Annex 4. The general strategy is to increase the interval between dosing rather than to decrease. Standard doses are given unless there is intolerance. There should be careful monitoring for evidence of neurotoxicity.

TABLE 4.10 Dosing recommendations of anti-TB drugs in adult patients with creatinine clearance <30 ml/min Drug Change in frequency? Recommended dose and frequency Isoniazid (H) No change 300 mg once daily, or 900 mg 3 times/week Rifampicin (R) No change 600 mg once daily, or 600 mg 3 times/week Pyrazinamide (Z) Yes 25– 35 mg/kg/dose 3 times/week (not daily) Ethambutol (E) Yes 15–25 mg/kg/dose 3 times/week (not daily) Levofloxacin (Lfx) Yes 750 –1000 mg/dose 3 times/week (not daily) Moxifloxacin (Mfx) No change 400 mg daily Cycloserine (Cs) Yes 500 mg/dose 3 times/week 56 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Ethionamide (Eto) No change 15–20 mg/kg/day (can be in divided doses) Para-aminosalicylate (PAS) No change 4 gm/dose twice daily Linezolid (Lzd) No change 600 mg daily Clofazimine (Cfz) No change 100mg daily Capreomycin (Cm) Yes 12–15 mg/kg/dose 2–3 times/week (not daily) Kanamycin (Km) Yes 12–15 mg/kg/dose 2–3 times/week (not daily) Bedaquiline (Bdq) no change with mild to moderate renal dysfunction but use with cau- tion in severe renal disease

4.6.10 Patients with diabetes Persons with latent TB infection and diabetes have an increased risk of progression to active TB. Also, outcomes for patients who have both TB and diabetes are poorer than for TB patients without diabetes. The role of diabetes in furthering drug resistance has remained controversial, but new evidence is accumulating that diabetes does increase the risk of drug-resistant TB. One possible mechanism for poorer outcomes and acquired drug resistance could be that blood levels of anti-TB medications may be lower and sub-therapeutic in patients with diabetes.

Diabetes must be managed closely throughout the treatment of drug-resistant TB. If the patient is on oral hypoglycaemic agents, it is recommended to switch to insulin for the duration of the MDR-TB treatment. None of the anti-TB drugs are contraindicated.

Patients with diabetes and MDR-TB may be at increased risk of adverse events since many of the anti-TB drugs have side effects that place diabetic patients at special risk. Patients with long- standing diabetes may have underlying renal impairment that can be worsened by the second- line injectable drugs. Neuropathy is a common complication of diabetes and also can be worsened by several drugs used to treat MDR-TB such as high-dose INH, cycloserine, linezolid and the fluoroquinolones. Patients with diabetes may have decreased gastric motility (gastroparesis) and may be at increased risk of nausea and vomiting with medications like ethionamide or other MDR-TB drugs.

The box summarizes the recommendations when treating patients who have MDR-TB and diabetes (from Curry MDR Guide 2016).

Recommendations when treating patients who have MDR-TB and diabetes • Follow renal function carefully and use intermittent dosing for injectable drugs if there is pre- existing or newly developing renal impairment. • Monitor creatinine and potassium levels more frequently: weekly for the first month and at least monthly thereafter in view of the renal effects of the second-line injectables if use. • Treat symptoms of gastroparesis aggressively with gastric motility agents such as metoclo- pramide. • If neuropathy develops, change the offending drug, if possible. If that cannot be done safely, consider use of agents such as tricyclic anti-depressants, gabapentin, and/or adding or in- creasing the dosage of Vitamin B-6. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 57

4.7 ADJUVANT THERAPIES AND INTERVENTIONS 4.7.1 Pyridoxine Several side effects related to the nervous system can be prevented by the daily administration of pyridoxine. Pyridoxine (vitamin B6) should be given to all TB patients who receive second-line therapy. The usual dosage is 50mg per day in children and 100mg per day in adults. If Cycloserin is part of the treatment regimen, the recommended dose is 50 mg for every 250 mg of Cs prescibed: see table 4.11.

TABLE 4.11 Daily dosing of pyridoxine according to daily administration of cycloserin Daily dose of cycloserin Daily dose of pyridoxine 250mg 50mg 500mg 100mg 750mg 150mg 1000mg 200mg

4.7.2 Steroids Steroids are useful in cases of TB meningitis and TB pericarditis, and also for children with miliary TB or obstruction of the bronchi as a result of mediastinal TB adenitis. Their use may also be considered in cases with severe respiratory insufficiency. The usual dosage is prednisone 1mg/ kg/day, to be tapered off gradually to arrive at a maintenance dose of 5mg/day. Steroids will also be given if a severe paradoxical reaction (IRIS) occurs, especially in patients with TB/HIV co- infection (see Chapter 8.4.5 in the WHO MDR Guidelines 2014).

4.8 SURGERY Surgery is an adjunct to chemotherapy. If the lung lesions are not extensive, elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB regimen. The role of pulmonary surgery is beneficial to reduce the amount of lung tissue with intractable pathology and to reduce bacterial load and thus improve prognosis.

• The surgery should be performed under infection control measures • The benefit of the surgery is when patients has no other associated factors for poor prognosis • It is considered an adjunct to chemotherapy and appears to be beneficial for improved outcome. • It is not indicated in patients with extensive bilateral disease. • Minimum two months of therapy should be given prior to resection surgery to decrease the bacterial infection in the surrounding lung tissue. • Surgery should be performed by a trained thoracic surgeon in patients with localized disease and result may reduce morbidity and mortality. Prognosis could be better when partial lung resection is performed after culture conversion and full course of treatment is given with effective regimen. CHAPTER 5 MANAGEMENT AND MONITORING ASPECTS OF DR-TB

Classification based on history of previous TB treatment (patient registration group): (Reference: WHO Companion handbook for programmatic management of DR-TB- 2014)

Registration group: Patients are assigned to a registration group based on the most recent treatment history at the time of initiating DR-TB treatment

1. New. A patient who has received NO or LESS than one month of anti-TB treatment 2. Relapse. A patient who was previously treated for TB and whose most recent treatment outcome was Cured or Treatment completed, and who is subsequently diagnosed with a recurrent episode of TB (either a true relapse or a new episode of TB caused by reinfection). 3. Failure. A previously treated TB patient who has received an anti-tubercular treatment whom the treatment has failed. 3.1 After failure of first line Treatment with FLD 3.2 After failure of Re-Treatment with FLD 3.3 After failure of Treatment with Hr TB Regimen 3.4 After failure of Treatment with SLD 4. Treatment after loss to follow-up: A patient who had previously been treated for TB and was declared Lost to follow-up at the end of the most recent course of treatment. 5. Other previously treated patients. A previously treated TB patient whose outcome after the most recent course of treatment is unknown or undocumented. 6. Patients with unknown previous TB treatment history who do not fit into any of the categories listed above. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 59

5.1 PREPARATION PRIOR TO STARTING SECOND-LINE TREATMENT Before second-line treatment can be prescribed, the patient must be thoroughly evaluated clinically, radiologically and biomedically, according to the list in table 5.1. These examinations are performed at the DR-TB Centre. The initial evaluation serves to establish a baseline (for comparison when investigations are done during treatment) and may identify patients who are at risk for adverse side effects or poor outcomes.

Prior to initiating treatment, all patients must receive albendazole. TABLE 5.1 Baseline clinical, instrumental and laboratory examination* Medical history including mental illness, drug or alcohol dependence, seizures Clinical examination including body weight and height, blood pressure, temperature Chest X-ray Calculate the Q-T interval with Fridericia’s correction (QTcF): ECG see Annex 3 needed as baseline for follow-up examinations during Sputum smear examination treatment Complete Blood Count RBC count, haemoglobin, hematocrit, WBC count, WBC differential count, platelet count Liver function tests (LFT) bilirubin, AST, ALT, albumin Thyroid function tests TSH, T3, T4 (TFT) Hepatitis B and C Determine viral load if positive for hepatitis B or C Laboratory Uric acid examinations Renal function tests serum creatinine (calculate the estimated creatinine (RFT) clearance based on the Cockcroft-Gault equation: see Annex 4), serum potassium (also magnesium and calcium if potassium is low) and sodium Serum glucose If hyperglycemia: refer Serum amylase If Lzd is used HIV test following PICT Pregnancy test (for women of child bearing age) Visual acuity Audiometry Peripheral neuropathy assessment * Diagnostic tests (Xpert MTB/RIF, culture and DST, LPA) are not included here. 60 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

5.2 TREATMENT ADMINISTRATION 5.2.1 The need for strict adherence to treatment Full adherence to DR-TB treatment is essential to prevent the amplification of resistance and increase the chances of cure. Adherence to DR-TB therapy is particularly difficult because of the lengthy treatment regimens, the high daily pill burden, the frequent and serious drug adverse reactions, and the indirect social and economic costs to patients associated with access to care. Inadequate second- line therapy would also have serious public health consequences. Therefore, all patients receiving DR-TB therapy should be on 100% DOT, preferably during the whole course of treatment. Patient centric care including community DOTS where fesibe will be prioritized, and service will be decentralized as program expands.

DOT, early and effective management of adverse effects of drugs and monitoring and follow-up of the non-adherent patients are very important to ensure maximum adherence to treatment. In addition, patient-centred care will further increase the chances of successful treatment outcome by providing:

• Counselling: health education and counselling must be provided to all patients and their family members at all levels of the health care system, from the peripheral health centre to the district hospital to the DR-TB Centre. It is started at the initial point of contact and must be continued at every visit by the patient to a health facility. The patients should receive counselling on DR-TB, the duration of treatment, the organization of the treatment (hospital/ambulatory), requirements for regular monitoring, infection control, the need for regular treatment (DOT) and the consequences of irregular treatment or pre-mature cessation of treatment. It is advisable to involve close family members during the counselling, since family support is an essential component in the management. Patients should be informed regarding the possible side effects of the drugs and advised to report if they experience any unusual problem. Female patients of child bearing age should receive special counselling on family planning because pregnancy should be avoided during second- line treatment. • Psychosocial and emotional support to strengthen self-esteem through empathy, trust, encouragement and care. Having DR-TB can result in severe emotional stress for patients and their families. The long duration of DR-TB therapy combined with the side-effects of the drugs may contribute to depression, anxiety and further difficulty with treatment adherence. A multidisciplinary approach by a support team (doctor, social worker, nurse and treatment supporter) is recommended. • Socioeconomic support can enable patients and their families to adhere to DR-TB treatment and reduce the impact that the disease and treatment have on their quality of life. Patients must have access to any socioeconomic services they may qualify for. Maximal support should be given to patients with the highest needs. There is a provision of NPR 3,000 or NPR 1000 per month for each patient (Hostel based Patient = NPR 1000/m, Clinic based Patient NPR 3000/m) to support the nutrition needs. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 61

5.3 ORGANIZATION OF THE TREATMENT 5.3.1 Hospitalization Admission for treatment is not mandatory but is may be require in some patients who are really sick. This will allow assess if the drugs are well tolerated and to gradually increase the dosage of certain drugs (Eto). Admission of DR-TB patients requires appropriate structures where proper infection control measures can be observed in order to prevent transmission to staff and other patients (see chapter 7). Patients who are not seriously ill can be accommodated in hostel-like structures where they can get proper care and monitoring until they are ready for ambulatory care. Severely ill patients need to be hospitalized in a specialized DR-TB ward.

5.3.2 Ambulatory treatment under strict DOT Ambulatory care must be practice under strict DOT. During the initial stage of treatment, while awaiting the results of the LPA, the patients must remain close to the DR-TB Centre where they will have to present themselves every day to receive their drugs. Once the LPA results have been received and the treatment regimen is finalized, treatment may be continued at the DR-TB Centre or in a DR-TB Treatment Sub-centre. All structures providing treatment to DR-TB patients should observe proper infection control measures.

If it is not possible for the patient to visit the treatment centre/subcentre on a regular daily basis, community based DOT (CBD) may be an alternative option. Community based DOT requires very close daily monitoring. The patient’s family must be well informed and motivated to collaborate, a reliable DOT provider must be appointed, and regular supervision by the (Health Co-ordinater appointed for TB Leprosy) is essential. If the patient needs to receive injections, this must be arranged either at a nearby health facility.

The DOT provider should be a person whom the patient is comfortable with. This may be a health worker trained to deliver second-line anti-TB medicines. The DOT provider should have the appropriate training, skills require to provide proper DOT and support.

Every month, patients treated in an ambulatory setting must go to the nearest DR-TB Centre or Subcentre where the monthly follow-up investigations can be performed. The DOT provider and the treatment supporter must make sure that the patient does not miss the monthly appointments.

A DR-TB patient on ambulatory treatment may be contagious, particularly during the early weeks or months of treatment. It is therefore extremely important that proper infection control measures are observed, not only in the treatment centres/subcentres but also at the patient’s home and by the patients themselves. This will require a lot of discipline by the patients, but they need to understand their responsibility and social duty to protect the community from exposure to drug resistant germs.

The following instructions should be given to the patient: • Avoid meeting other people. Do not go to markets, festivals or group meetings. Only take public transportation when absolutely necessary. If you have to go out, wear a mask at all times. • If it is possible, stay at home in a separate room. If you can have a room that is well ventilated 62 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

and has windows that let in sunlight, it is even better. Family members must stay out of the room. • Eat separately, either in the room or outside. • Whenever you meet family members or other people, wear a mask. Family members are provided with N95 masks that they must wear whenever they are together with you. • If other people come to the house, only meet them outside for a short time and stay at a safe distance.

Avoid contact with children because they are extremely vulnerable. If this is difficult, consider letting the children stay with friends or family.

5.4 DRUG INTAKE Many of the second-line drugs cause gastro-intestinal upset, which is an important cause of non-adherence to treatment, many patients refuse to take certain medications or even the full treatment. In order to improve adherence, not all drugs have to be taken together, some may be administered in split doses and some may be given together with food. The only drugs that should never be given with food are H and Cs, while other drugs (Cfz, Bdq and Dlm) have to be taken with food to improve absorption. The other drugs can be taken with or without food, but some (Eto, PAS) are better given with food to reduce gastro-intestinal upset. Table 5.2 shows a summary of how the second-line drugs are preferentially ingested.

If split doses are given, DOT is required for every intake.

The daily dose of Eto can be built up gradually: 250mg once daily on days 2 to 4; 2 x 250mg/day on days 5 to 7; 250mg in the morning, 500mg in the evening from day 8 onwards if patient >50kg.

Amikacin is given by deep intramuscular injection. The injection site must be changed every day to avoid painful reactions in the injected area: see diagram.

For every injection, a sterile syringe, a sterile needle for preparing and pulling up the solution and another sterile needle for the injection must be used. These can only be used once and must be disposed of in a safe way (contaminated waste).

Imipenum and cilastatin injection comes as powder to be mixed with liquid to be injected intravenously. When it is injected intravenously, it is usually infused over a period of 20 minutes or 1hour every 6 or 8 hours. Imipenum may cause side effects some of which can be serious (severer diarrhea, itching rash, difficulty breathing or swallowing, seizures). NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 63

TABLE 5.2 Mode of administration of the second-line drugs

With or without food Drug Number of daily doses Never with food H 1 Cs 2 or 3 Can be with or without food E 1 Z 1 Lzd 1 Possible with food but avoid drug intake within at least Lfx 1 (children <5 years: 2/ 2 hours of dairy products, coffee, antacids (especially day) aluminum-containing), vitamin supplements or mineral Mfx 1 supplements (such as iron, magnesium, calcium or zinc) or medication containing divalent cations (such as didanosine or sucralfate) Best taken with food to reduce G.I. upset Eto 2 (highest dose in the evening: e.g. 250mg in the morning, 500mg in the evening) PAS 2-3 (children: 2-4) To be taken with food to improve absorption Cfz 1 Bdq 1 Dlm 2 Amx-clv 2

5.5 FOLLOW-UP MONITORING INVESTIGATIONS DURING AND AFTER COMPLETION OF TREATMENT 5.5.1 General considerations Follow-up monitoring examinations are essential to monitor the response of the patient to the treatment and to detect side effects of the drugs early. The frequency of the examinations depends on the treatment regimen (SSTR or LR), the drugs that are administered and the treatment duration.

For patients treated in an ambulatory setting, the follow-up examinations can take place at the nearest DR-TB Centre with the required laboratory facilities. If a specialized test (e.g. TFT) cannot be performed, a sample may be sent to the nearest laboratory that can do the test. When sending a sputum specimen to the NRL for culture, the timing (within 72 hours) and the cold chain must be respected. 64 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

5.5.2 Follow-up examination during the SSTR

TABLE 5.3 Frequency of follow-up examinations during SSTR Intensive phase Continuation phase Examinations Month Month Remarks 1 2 3 4 (5) (6) 1 2 3 4 5 Clinical evaluation            including weight Single specimen, Sputum smear            preferable early examination morning sample Single specimen, Sputum culture            preferable early morning sample Chest X-ray(1)              Also on days 2, 7 and ECG(2) 14 Complete Blood If required Count(3) Liver function       In continuation phase: tests (LFT)(4) as required Thyroid function   TSH (T3, T4) tests (TFT) Uric acid      Renal function       tests (RFT)(5) Serum glucose If required       More frequent if Audiometry hearing complaints Only if eye complaints Visual acuity (For during administration optical Neuritis) of E On any cultures that are positive four SL-LPA and DST months or beyond af- ter treatment initiation

(1) To serve as a reference if later images need to be taken. (2) Calculate the Q-T interval with Fridericia’s correction (QTcF): see Annex 3 (3) RBC count, haemoglobin, haematocrit, WBC count, WBC differential count, platelet count (4) Bilirubin, AST, ALT, albumin (5) Serum creatinine (calculate the estimated creatinine clearance based on the Cockcroft-Gault equation: see Annex 4), serum potassium (also magnesium and calcium if potassium is low) and sodium

Ü Frequency of examinations may be increased as needed according to the clinical evolution of the patient and the decision of the clinicians. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 65

5.5.3 Follow-up examination during the longer treatment regimens

TABLE 5.4 Frequency of follow-up examinations during longer regimen Treatment duration Remarks Examinations Month 1 2 3 4 5 6 7 8 10 12 14 16 18 Clinical evaluation              including weight Sputum smear Single specimen, preferable              examination early morning sample Single specimen, preferable Sputum culture           early morning sample Chest X-ray    If pre-XDR or XDR regimen: on days 2, 7 and 14 and ECG(1)              monthly thereafter If MDR regimen: as required Complete Blood Monthly if Lzd.              Count(2) If no Lzd: as required For PLHIV monthly, otherwise Liver function as required         tests (LFT)(3) (mostly if ETO and/or Z is used)

Thyroid function TSH, T3, T4    tests (TFT) Only if Eto, Pto, or PAS is used

Uric acid     Only if Z is used Renal function       Only if Am is used tests (RFT)(4) Serum glucose If required Serum Amylase If required Peripheral Neuropathy              (see annex 5) Assessment Audiometry       only if Am is used Monthly if Lzd (see M5). Visual acuity (for If no Lzd: Only if eye              optic neuritis) complaints during administration of E

On any cultures that are posi- SL-LPA and DST tive four months or beyond after treatment initiation

(1) Calculate the Q-T interval with Fridericia’s correction (QTcF): see Annex 3 (2) RBC count, haemoglobin, haematocrit, WBC count, WBC differential count, platelet count (3) Bilirubin, AST, ALT, albumin (4) Serum creatinine (calculate the estimated creatinine clearance based on the Cockcroft-Gault equation: see Annex 4), serum potassium (also magnesium and calcium if potassium is low) and sodium

Ü Frequency of examinations may be increased as needed according to the clinical evolution of the patient and the decision of the clinicians. 66 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

5.5.4 Follow up after completion of the SSTR and LR After completion of the SSTR and LR it is required to follow up patients for next two years. Follow up examination should be done every 6 months which includes:

• A clinical assessment • Sputum smear examination • Any additional lab or instrumental analysis as requested by the clinicians

5.6 MONITORING OF TREATMENT PROGRESS The symptoms should improve within the first few months of treatment. If this is not the case, look for other possible causes and be alert for treatment failure.

Treatment progress of DR-TB is monitored through sputum smear examinations and culture.

In children, bacteriological follow-up of the treatment is not possible most of the time. Progress will have to be monitored clinically. The evolution of the weight of the child is of particular importance.

Bacteriological follow-up of EP DR-TB is difficult. Even if a specimen was obtained for the initial LPA, culture and DST, obtaining follow-up specimens will usually not be feasible. Progress of EP DR-TB needs to be monitored clinically.

Laboratory investigations, while useful to monitor side effects, contribute little to monitor response to treatment.

Chest X-rays are not a sensitive indicator to monitor progress. Often, the radiological image remains unchanged.

Sputum may become negative well before culture. Negative sputa are a very encouraging sign, but it is the result of the monthly cultures that will decide whether treatment is progressing well.

The sputum result at 4 and 5 months is useful to determine whether the intensive phase of the SSTR needs to be extended by an additional month. If the sputum is still positive after 6 months, the SSTR is considered to have failed and a suitable long course regimen must be initiated.

Sometimes, the sputum examination remains positive while the culture becomes negative. This is caused by the presence of dead bacilli and does not indicate treatment failure.

Monitoring of progress of the SSTR through culture is shown in table 5.3

Monitoring of progress of the long-course regimens through culture is shown in table 5.4

If the culture is positive at 4 months or reverts to positive after having been negative at 4 months, LPA and second-line DST have to be performed. Once treatment is stopped, treatment outcome must be determined (see chapter 8) NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 67

5.7 FOLLOW-UP AFTER THE END OF TREATMENT Follow-up procedures

If the patient has been fully treated and the treatment outcome has been “cured” or “treatment completed”, the patient must go to the DR-TB Centre every 6 months for 2 years, where a careful clinical control examination and a sputum examination will be performed. A chest X-ray should not be requested routinely but only if there is a clinical indication.

If the patient has not become culture negative, but a clinical decision was made to stop the treatment because of drug intolerance, the DR-TB Centre has to perform a regular clinical, radiological and bacteriological (sputum and culture) check-up every 3 months for 3 years.

All patients should receive appropriate information and education about the symptoms of a possible relapse and the need to immediately present themselves to the TB treatment centre.

5.8 PALLIATIVE CARE If a patient presents a treatment failure and an alternative treatment regimen is not possible, treatment will have to be suspended. Suspension of therapy should be carefully planned. It should start with discussions among the clinical team, including all physicians, nurses and DOT workers involved in the patient’s care. Once the clinical team decides that treatment should be suspended, a clear plan should be prepared for approaching the patient and the family. This process usually requires a number of visits and takes place over several weeks. Home visits during the process offer an excellent opportunity to talk with family members and the patient in a familiar environment. It is not recommended to suspend therapy before the patient understands and accepts the reasons to do so and agrees with the supportive care offered.

A number of supportive measures can be used once the therapy has been suspended. It is very important that medical visits continue and that the patient is not abandoned. Supportive care for MDR-TB treatment failure includes:

• Pain control and symptom relief: Codeine with paracetamol gives relief from moderate pain but also helps control cough. Other cough suppressants can be added. If possible, stronger analgesics, including morphine, should be used to keep the patient adequately comfortable. • Relief of respiratory insufficiency:Oxygen can be used to alleviate shortness of breath. Morphine also provides significant relief from respiratory insufficiency and should be offered if available. • Nutritional support: Small and frequent meals are often best for a person at the end of life. • Regular medical visits: When therapy stops, regular visits by the treating physician and support team should not be discontinued. • Continuation of ancillary medicines: All necessary ancillary medications should be continued as needed to treat symptoms such as nausea, vomiting, depression, anxiety. • Psychological support to the patient and family caregivers to assist in the planning of decisions related with the end of life and provide emotional support. 68 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

• Respect for patient’s beliefs and values: The patient and family caregivers may seek and find comfort in spiritual and religious practices. The health-care providers should respect this. • Inpatient-care or home-care: Home-based care should be offered to patients and families who want to keep the patient at home, whenever appropriate infection control practices must be followed. Institutional based end-of-life care should be available to those for whom home care is not feasible or desirable. • Preventive measures: Oral care, prevention of bedsores, bathing and prevention of muscle contractures are indicated in all patients. Regular scheduled movement of the bedridden patient is very important. • Infection control measures should be continued as the patient often remains infectious for long period of time.

5.9 MANAGEMENT OF CONTACTS OF MDR-TB PATIENTS A close contact of an MDR-TB patient is someone who has been exposed to infection with drug resistant M. tuberculosis by sharing air space with a patient who has confirmed MDR-TB. Close contacts are defined as people living in the same household or spending multiple hours a day together with the patient in the same indoor living space. They can be family members, colleagues, friends, roommates and neighbours.

All close contacts of MDR-TB cases should be identified through contact tracing and those who are symptomatic will be evaluated for active TB. Special attention needs to be paid to children. The TB screening will include a complete clinical examination, an Xpert MTB/RIF test of a sputum sample or other relevant specimen and a chest X-ray. If the Xpert MTB/RIF result is RR, the patient must be sent to the nearest MDR Unit for futher management.

Screening of contacts of MDR-TB patients should be an ongoing process. Asymptomatic contacts need to be screened at diagnosis, at the end of the intensive phase and at the end of treatment. Contacts should also receive appropriate health information and education regarding TB and MDR-TB.

Preventive therapy is not recommended for contacts of MDR-TB patients. Isoniazid or rifampicin would be useless, and there is no evidence showing that other drugs would contribute to the prevention of MDR-TB. Careful clinical follow-up of the contacts of MDR-TB patients is the strategy of choice. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 69

CHAPTER 6 ACTIVE DRUG SAFETY MONITORING AND MANAGEMENT (ADSM)

OBJECTIVES OF ADSM Overall, aDSM aims to detect, manage, and report suspected or confirmed drug toxicities in a timely fashion. The overall objectives of aDSM are to reduce risks from drug-related harms in patients on second-line (SL) treatment for DR-TB and to generate standardized aDSM data to inform future policy updates on the use of such medicines. Definitions 1. Active drug-safety monitoring and management (aDSM): active and systematic clinical and laboratory assessment of patients while on treatment. As per recent WHO 2019 recommendation, aDSM applies to all patients on RR/MDR TB treatment with (a) new anti-TB drugs, such as Bdq and Dlm; (b) new DR-TB regimens, such as the shorter (or 9-month) MDR- TB regimen; or (c) XDR-TB regimens on new/repurposed drugs, in order to detect, manage and report suspected or confirmed drug toxicities. 2. Adverse event (AE): any untoward medical occurrence that may present in a TB patient during treatment with a pharmaceutical product, but which does not necessarily have a causal relationship with this treatment. 3. Adverse drug reaction (ADR): a response to a TB medicine that is noxious and unintended, and which occurs at doses normally used in humans. 4. Causality assessment: the evaluation of the likelihood that a TB medicine was the causative agent of an observed adverse reaction. 5. Serious adverse event (SAE): an AE which either leads to death or a life-threatening experience; to hospitalization or prolongation of hospitalization; to persistent or significant disability; or to a congenital anomaly. SAEs that do not immediately result in one of these outcomes, but which require an intervention to prevent it from happening are included. SAEs may require a drastic intervention, such as termination of the drug suspected of having caused the event. 6. AE of special interest: AE documented to have occurred during clinical trials and for which the monitoring program is specifically sensitized to report regardless of its seriousness, severity or causal relationship to the TB treatment 7. AE of clinical significance: AE that is either a) serious (SAE), b) of special interest, c) leads to a discontinuation or change in the treatment, or, d) is judged as otherwise clinically significant by the clinician 8. Signal: reported information on a possible causal relationship between an adverse event and a TB medicine, the relationship being unknown or incompletely documented previously or representing a new aspect of a known association. Signal detection may not be part of practice in Nepal so far but may be a good future practice. 70 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

The second line drugs have lot of side effects. Adverse events (AEs) and Adverse drug reactions (ADRs) may occur during treatment of DR-TB with various severity grading. With the release of new WHO guidelines 2019, as new and repurposed drugs are now part of standard regimen, therefore, aDSM is applicable across the board to all RR TB patients.

Often, AEs or ADRs are the reason for treatment irregularities or inadequate therapy. Timely recognition and proper management of AEs or ADRs will help avoid these. The adverse events associated with the drugs used to treat DR-TB are described for each individual drug in the drug sheets in Annex 1. All health workers dealing with DR-TB must be able to recognize AEs and ADRs and know how to manage or refer according to their level of the health care system and record and report in a timely manner.

For Nepal, Core Package of aDSM is adopted which means only serious AEs/ADRs are reported and all DR TB/MDR-TB /Pre-XDR and XDR patients on treatment will be monitored under aDSM mechanism. When AEs and ADRs are identified, they are to be graded for seriousness and severity and SAEs reported as per national guideline.

Important Elements of aDSM There are three fundamental elements of aDSM to achieve the above objectives: 1. Active and systematic clinical and laboratory assessment during treatment to detect drug toxicity and AEs. There are ways to help health providers do this step. a. Observe and listen to patients. The detection of AEs is primarily dependent upon reporting from patients, nurses, doctors, counsellors, etc. At every DOT encounter, health workers should ask the patient and family members about clinical symptoms of common AEs including nausea, vomiting, peripheral neuropathy, skin rash, psychiatric disturbance (headache, anxiety, depression, irritability, behavior change), hearing loss, jaundice, vestibular toxicity (vertigo, ataxia, hearing loss), and symptoms of electrolyte wasting (muscle cramping, palpitations). All healthcare professionals involved must be trained on adverse event screening. b. Perform routine clinical assessments, e.g., for treatment adherence and tolerance, psychosocial support and consults with the psychiatrist, ophthalmologist, HIV specialist, etc. Clinical follow-up with the MDR-TB physician for all patients is at a minimum as per set protocols. c. Schedule regular laboratory screening, even if the patient has no specific complaints, e.g., creatinine, ECG, liver function tests, etc. Regular laboratory monitoring detects occult adverse effects. Laboratory tests and procedures related to treatment should be available and accessible to patients, free of charge. Table 5.3 & 5.4, shows the schedule of clinical and laboratory tests for patients on new and repurposed drugs and the shorter treatment regimen (SSTR) and LR. As Bdq and Dlm, Mfx, and Cfz may induce QT prolongation and ECG monitoring is essential. 2. Management of AEs in a timely manner. Early detection of signs and symptoms is key to proper management of AEs that significantly impacts patient well-being, overall treatment acceptance, and adherence. Management includes measures taken to alleviate the signs and symptoms of adverse reactions with careful individual case review, such as: a) reassurance, if AE is minor b) lowering the dose of the offending drug, c) stopping the NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 71

drug, d) drug replacement; e) providing ancillary medications and f) other interventions (surgery, transfusion, psychological support, etc.). Ancillary medicines should be available and accessible to patients, free of charge. 3. Recording and reporting: All AEs must be recorded and reported using DRTB 05 form Annex 11 to NTC either by email or through the online eTB Register (where functional). The reporting must be done in 24 to 48 hours of occurrence any serious AEs/ADRs. Management of AEs/ ADRs are equally important as monitoring and reporting of the AEs/ADRs.

Following is the pathway for aDSM reporting is followed in Nepal:

Seriousness is defined by the outcome of an adverse event. A serious adverse event (SAE) is one that leads to any of the below: 1. Death 2. Life-threatening 3. Hospitalization or prolonged hospital admission 4. Permanent disability 5. Other medically serious 6. Congenital anomaly.

Severity is defined by the impact on the patient’s ability to function. It is graded on a scale of 1 to 5, as shown below in table 6.1 72 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

TABLE 6.1 Grading of adverse events Small or transient inconvenience that does not limit normal daily activity. Grade 1 Mild No need for medical intervention or corrective treatment. Partial limitation of normal daily activity. In some, but not all cases, medical Grade 2 Moderate intervention or corrective treatment is necessary. No need to discontinue the treatment. Limitation of normal daily activity. Medical intervention and corrective treatment, often requiring hospitalization, are necessary. The responsible Grade 3 Severe drug may have to be stopped temporarily, until the symptoms have disappeared. Very severe limitation of normal daily activity. Medical intervention Life Grade 4 and corrective treatment, requiring hospitalization, are necessary. The threatening responsible drug may have to be stopped indefinitely. Grade 5 Death Death related to adverse event

6.1 MANAGEMENT OF AES OR ADRS: Management of AEs and ADRs are equally crucial as monitoring and reporting. For a number of drugs, the toxicity is dose dependent. Reducing the dosage may be an effective method of managing these adverse effects.But attention! The reduced dose must still be effective! If the serum level of the drug is too low, it will compromise the treatment regimen. This is particularly the case for Eto and Cs. Lowering the dose by more than one weight class should be avoided. In some instances, very serious adverse events will be unavoidable in order to save a life. For example, hearing loss as a result of the administration of Amikacin may have to be accepted in order to ensure the patient does not die of TB.

Particular attention needs to be paid to the side effects of linezolid, a potent but toxic drug used as a part of standard regimen. Monitoring the adverse drug reactions of Lzd requires specific investigations:

For Peripheral neuropathy, assessment, kindly refer to Annex 5 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 73 Death Grade 5 Grade Grade 4 Grade Life- threatening Incapacitating; or not narcotic to responsive analgesia 2. Same as Grade < 6.5 g/dL < 20,000 /mm³ <500/mm3 Severe Grade 3 Grade Severe discomfort; Severe analgesia or narcotic with required symptomatic and/ or improvement; BPNS subjective sensory 7-10 on score neuropathy side. any 2. Same as Grade 7.9 - 6.5 g/dL 20,000 – 49,999/mm³ 749 - 500/mm3 Grade 2 Grade Moderate Possible other causes: d4T, ddI other causes: d4T, Possible Moderate discomfort; Moderate analgesia non-narcotic and/or BPNS required; subjective sensory 4-6 on score neuropathy side. any If Cs and Lzd. Stop improve, symptoms restarting Doconsider Cs. Lzd. not reintroduce relief symptomatic Provide 9.4 - 8.0 g/dL 50,000 – 74,999 /mm³ 999 - 750/mm3 Mild Grade 1 Grade Mild discomfort; no and/ required; treatment or BPNS (Brief Peripheral Screen) Neuropathy subjective sensory 1-3 on score neuropathy side. any If Cs and Lzd. Stop improve, symptoms restartingconsider these restarting Consider drugs. dose a lower at Lzd (300mg daily or 600 mg weekly).thrice If to Cs is not essential consider the regimen suspending the drug. 10.5 - 9.5 g/dL 75,000 – 99,999/mm³ 1500 - 1000/mm3 : Lzd,Cs,H,S,Km,Cm,H,FQ,Pto/Eto,E. : Lzd,Cs,H,S,Km,Cm,H,FQ,Pto/Eto,E. Severity grading scales and suggested action for common AEs (adopted from End TB Guidelines 2019) End from AEs (adopted action scales and suggested common grading for Severity Severity grade Severity neuropathy 1. Peripheral drug causes anti-TB Possible (Burning, Paresthesia etc.) tingling, Action (anemia, thrombocytopenia, or neutropenia) 2. Myelosuppression cotrimoxazole other causes: AZT, Possible drug causes: Lzd. anti-TB Possible Anemia decreased Platelets neutrophil Absolute low count TABLE 6.2.1 74 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT Death Grade 5 Grade Grade 4 Grade arrhythmia. Life- threatening Stop Lzd immediately. immediately. Lzd Stop Consider or hemotransfusion Restart reduced at EPO. has toxicity dose once 1. Grade to decreased 501 or QTcF>= >60 ms change from baseline and one of the de Torsade following: or polymorphic pointes tachycardia ventricular of or signs/symptoms serious the suspected Stop drug(s). causative and Hospitalize as electrolytes replete necessary. as serious Severe signs/ signs/ Grade 3 Grade Stop Lzd immediately. In immediately. Lzd Stop 3 anemia, case of Grade Restart EPO. consider dose once reduced at to has decreased toxicity 1. Grade 501 ms QTcF>= without of symptoms arrhythmia. the suspected Stop drug(s). causative and Hospitalize electrolytes replete necessary. Grade 2 Grade Moderate Monitor carefully, and Monitor carefully, reduction of consider (300mg dose of Lzd daily or 600 mg thrice weekly); in case of 2 neutropenia, Grade In immediately. Lzd stop 2 anemia, case of Grade erythropoietinconsider Restart(EPO). at dose once reduced has decreased toxicity 1. Grade to interval 481 QTcF – 500 ms. closely;Monitor more least weeklyat ECG has returned QTcF until 1. less than grade to as electrolytes Replete necessary. 1. Mild Grade 1 Grade Monitor carefully, and Monitor carefully, reduction of consider (300mg dose of Lzd daily or 600 mg thrice weekly). 450 – 480 QTcF ms. closely;Monitor more least weeklyat ECG has returned QTcF until less than grade to as electrolytes Replete necessary. QTcF Prolonged QT interval QT Prolonged Severity grade Severity Action 3. drug) prolonging Mfx, Dlm, and Lfx (a mild QT drug causes: Cfz, Bdq, anti-TB Possible (all antipsychotics fluconazole, ketoconazole, quinidine, clarithromycin, erythromycin, other causes: Other e.g., drugs, Possible drugs (ondansetron/granisetron, some risk, anti-nausea and risperidone), chlorpromazine many have including haloperidol, hypothyroidism syndrome; genetic causes such as long QT and some anti-retrovirals); domperidone), methadone, Prolonged Action NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 75 Death Grade 5 Grade - - - (20/200[6/60] Grade 4 Grade Life- threatening Life-threatening con Life-threatening dialysis sequences; indicated Blindness or worse) in the affected eye immediately Lzd Stop any suspi are if there neuritis. cions of optic it. restart Do not >20.0 x ULN >20.0 x ULN all drugs, including Stop drugs; measure anti-TB weekly. LFTs may be rein Treatment is toxicity after troduced resolved. - - - be rein measure measure Severe Grade 3 Grade weekly. Limiting vision in the af eye (worse than fected 20/40[6/12] but better than 20/200[6/60]) immediately Lzd Stop any suspi are if there neuritis. cions of optic it. restart Do not >5.0 – 20.0 x ULN >5.0 – 20.0 x ULN all drugs, including Stop anti- TB drugs; LFTs may Treatment is toxicity after troduced resolved. >3 x Creatinine or >4.0mg/dL;baseline indicated hospitalization - - - - eleva (20/40[6/12] Grade 2 Grade Moderate Possible other causes: ddI causes: other Possible Limiting vision of the af eye fected or better) immediately Lzd Stop any suspi are if there neuritis. cions of optic it. restart Do not >3.0 – 5.0 x ULN >3.0 – 5.0 x ULN Continue treatment Patients regimen. should be followed (return until resolution or stabiliza baseline) to tion of AST/ALT tion. 2 - 3 x above Creatinine baseline - - - - eleva Mild Grade 1 Grade Asymptomatic; clinical clinical Asymptomatic; observa or diagnostic tions only immediately Lzd Stop any suspi are if there neuritis. cions of optic it. restart Do not 1.1 – 3.0 x upper limit of normal (ULN) 1.1 – 3.0 x ULN Continue treatment Patients regimen. should be followed (return until resolution or stabiliza baseline) to tion of AST/ALT tion. level increase Creatinine of >0.3 mg/dL; creatinine 1.5 - 2.0 x above baseline Injury kidney Hepatitis Optic nerveOptic neuritis) (optic disorder . Acute kidney. Acute injury 5. 6 Severity grade Severity 4. Lzd,E,Eto/Pto,Cfz,rifabutin,H,S. drug causes: anti-TB Possible nerveOptic disorder Action unknown causes: other Possible Z,Lzd,Cfz,Bdq. drug causes: anti-TB Possible (SGPT) ALT (SGOT) AST Action rare (TDF)- Tenofovir causes: ART S,Km,Am,Cm. Possible drug causes: anti-TB Possible Acute 76 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT Death Grade 5 Grade - - - - with life- with arrhythmia as necessary. Grade 4 Grade Life- threatening Stop injectable until injectable Stop has returned creatinine Consider baseline. to the injectable restarting (e.g. lower frequency at MWF) or substitute a non- nephrotoxic drug. < 2.0 mEq/L or abnor < 2.0 mEq/L mal potassium ileus or paresis, threatening tempo injectable Stop IV potassium Start rarily. in therapy replacement Replace oral. addition to magnesium and other electrolytes <0.30 mmol/L conse Life-threatening inter urgent quences; vention indicated drugs. all anti-TB Stop thyroxine. Start - - - with a as necessary. Severe Grade 3 Grade Stop injectable until injectable Stop has returned creatinine Consider baseline. to the injectable restarting (e.g. lower frequency at MWF) or substitute drug. non- nephrotoxic or 2.4 - 2.0 mEq/L replacement intensive or hospitaliza therapy tion required Continue injectable. IV potassium Start in therapy replacement Replace oral. addition to magnesium and other electrolytes 0.30-0.44 mmol/L limit Severe symptoms; hospi ADL* ing self-care indicated talization drugs. Continue anti-TB thyroxine. Start - - with Grade 2 Grade Moderate Stop injectable until injectable Stop has returned creatinine Consider baseline. to the injectable restarting (e.g., lower frequency at MWF) or substitute a non-nephro-toxic drug. 2.9 - 2.5 mEq/L Continue injectable. oral aggressive Start replacement potassium magne Replace therapy. sium as necessary. 0.45-0.59 mmol/L thyroid Symptomatic; indicated; replacement limiting iADL (instru of daily activities mental living) * drugs. Continue anti-TB thyroxine. Start - - - - MWF). Mild Grade 1 Grade Consider stopping inject Consider stopping has able until creatinine baseline. to returned the Consider restarting lower fre at injectable quency (e.g., 3.4 - 3.0 mEq/L Continue injectable. potassium oral Start therapy. replacement Check serum magne if sium and replace necessary. 0.60-0.70 mmol/L clinical Asymptomatic; observa or diagnostic tions only; intervention indicated not drugs. Continue anti-TB Severity grade Severity Action and hypomagnesemia 7. Hypokalemia TDF(rare) causes: ART Cm,Km,Am,S. Possible drug causes: anti-TB Possible Hypokalemia Action Hypomagnesemia 8. Hypothyroidism d4T causes: ART Possible PAS. Eto/Pto, drug causes: anti-TB Possible Hypothyroidism Action https://www.payingforseniorcare.com/longtermcare/activities-of-daily-living.html#title2 * NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 77 - - Adults: profound bilateral bilateral profound Adults: loss (Threshold> hearing and 80dBHLat2kHz above); non-service able au Pediatric: hearing for diologic indication implant and ad cochlear ditional speech-language services indicated. related - - - - - Adult enrolled in moni Adult enrolled (on a 1, program toring 2, 3, 4, 6 and8kHzaudio shift threshold gram): 3 at of >25 dB averaged frequen test contiguous one ear; least cies in at interventiontherapeutic indicated. in enrolled Adult Not program: monitoring loss with hearing hearing aid or intervention indi limiting self-care cated; ADL. (on a 1, 2, 3, 4, Pediatric 6 and 8kHz audiogram): loss sufficient hearing therapeutic indicate to intervention, including aids): Threshold hearing shift 3kHz and >20dB at one ear; least above in at additional speech-lan services related guage indicated. - Adult enrolled in Adult enrolled program monitoring (ona1,2,3,4,6and8 kHz threshold audiogram): shift of >25 dB averaged test 2 contiguous at least in at frequencies one ear. in enrolled Adult not program: monitoring loss but hear hearing ing aid or intervention limiting indicated; not ADL. instrumental Pediatric (ona1,2,3,4,6and8 kHz threshold audiogram): at 4 kHz and shift>20 dB one ear. least above in at - - 3, 6 Adults Enrolled on a Enrolled Adults Program Monitoring (ona1,2,4,3,6and8 kHz threshold audiogram): shift of 15 - 25 dB aver test 2 contiguous at aged least in at frequencies or subjective one ear in the absence change 1 Threshold of a Grade shift. (on a 1, 2, 4, Pediatric and 8 kHz audiogram): shift >20 dBat threshold one ear. 8kHzinatleast Hearing loss Hearing 8. none. causes: other Possible S,Km,Am,Cm,Clr. drug causes: anti-TB Possible loss Hearing 78 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT Over 81 dB Profound loud sounds as perceive May vibrations History should be drug allergies of previous rifampicin reaction or pyrazinamide to Flushing Hives (urticaria) drug. any can be caused by or Steven- in anaphylaxis resulted drug that Any carefully reviewed. Any known drug allergies known drug allergies Any reviewed. carefully card. on the treatment should be noted with time. is usually mild and resolves itching, Hot flashes, can be used. Antihistamines can be caused with isoniazid .Ifpalpitations that foods avoid to advise patients this occurs the reaction. precipitate the drugs one introduce the drug, identify To a desensitization In the case of hives a time. at described can be made; methods are attempt elsewhere. be reintroduced should never Johnson syndrome as a challenge not even the patient, to COMMENTS 1. 2. 3. 4. 61-80 dB Severe only hear veryMay loud speech or loud sounds in the environment, or a door truck siren such as a fire speech Most conversation slamming. is not heard. For serious allergic reactions, stop all therapy all therapy stop reactions, serious allergic For skin causes of allergic other potential Eliminate agents various reactions, minor dermatologic For pending resolution of reaction. Inpending resolution the case of emergency manage with standard anaphylaxis protocols. reaction (like scabies or other environmental agents). of the continuation be helpful and allow may They medication. include: can be tried if other measures weeks several for not helpful. are these can also cause rash use of moisturizing lotion diabetics); liberal Dry skinis recommended. and is a common with clofazimine. problem significant SUGGESTED MANAGEMENT SUGGESTED 1. 2. 3. • Antihistamines • rash localized for Hydrocortisone cream • 20 mg per day dose of 10 to in a low Prednisone • but sunscreens, to respond may Phototoxicity • Dry skin (especially in cause itching may 41-60 dB Moderate Difficulty regular speech, hearing close distance. at even SUSPECTED AGENT Any drug Any WHO Classification grading scale for hearing loss scale grading WHO Classification Adverse Events and Management Events Adverse 40dB Slight/Mild Difficulty hearing and understanding soft a distance, speech, speech from of or speech against a background noise ADVERSE EFFECT ADVERSE Rash, allergic reaction and anaphylaxis TABLE 6.3 TABLE 6.2.2 In the case of moderate hearing loss, the range for children is 31-60 dB. for children the range hearing loss, of moderate In the case NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 79 Nausea and vomiting is universal in early weeks of in early weeks is universal Nausea and vomiting should be checked and electrolytes Creatinine a responsible stop is to strategy Another Interval with QT recommended Odansetron(not particularly patients anxious about the For therapy and usually abate with time on treatment with time on treatment and usually abate therapy Some nausea and even and adjunctive therapy. least in the at be tolerated need to may vomiting should be advised about initial period and patient this side effect. replace IV fluids and Give is severe. if vomiting as needed. electrolytes and then add it days or three two medicine for the dose (advise back, increasing gradually a back to the medicine will be increased patient will be better dose in a manner that therapeutic tolerated). 5-HT3 receptor drugs) is serotonin prolonging anti- strong have to and considered antagonist WHO essential emetic properties. It is on the A number of other anti-emeticsdrug list. from antagonists 5-HT3 receptor this class of serotonin the if from even antiemetics, different Trying exist. some patients. be helpful for may same class, nausea “anticipatory nausea (and who have a small dose of an anti-anxiety and vomiting”), prior to 30 minutes medicine (5 mg of diazepam) drugs can help. the anti-TB COMMENTS 1. 2. 3. 4. 5. Once rash resolves, reintroduce remaining drugs remaining reintroduce resolves, rash Once to be drug identified any Suspend permanently including dehydration, danger signs for Assess nausea and to approach Initiate stepwise one at a time, with the most likely culprit last. a time, one at not re-introducing in the challenge any Consider be the culprit. is highly likely to drug that the cause of a serious reaction. initiate and hepatitis; disturbances electrolyte and correct any if indicated therapy rehydration If blood in the vomit, disturbances. electrolyte possible bleeding check haemoglobin and treat ulcers. vomiting. dose: overall without lowering the medications. medications. Ondansetron TB drugs and again 8 hours after. or with can either be used on its own (Ifis not available, ondansetron metoclopramide. refractory nausea can be used) For promethazine the dose can be tried. before 24 mg 30 minutes class if this can be done without one weight by Rarely is it necessary regimen. to compromising suspend the drug completely. SUGGESTED MANAGEMENT SUGGESTED 4. 5. 1. 2. • and conditions medications 1: Adjust Phase • night at the Eto/Pto Give • twice daily. or thrice or PAS Eto Give • before tea) rice, bread, snack (biscuits, a light Give • drugs 2 hours after other anti-TB PAS Give • 2: Start Phase antiemetic(s): • anti-TB before 10 mg 30 minutes Metoclopramide • the anti- before 8 mg 30 minutes Ondansetron • dose of the suspected 3: Decrease drug Phase SUSPECTED AGENT Eto, Pto, Z, Amx/ E, PAS,H, Clv,Cfz ADVERSE EFFECT ADVERSE Nausea and vomiting 80 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT Consider other causes of diarrhoea: Consider 2 years over can be used in children Loperamide History should be drug hepatitis of previous rule out other should be done to serology Viral and use should be investigated Alcohol resolves medications due to hepatitis Generally, spectrum such as the FQs is a serious antibiotics bloody Fever, condition. life-threatening and even abdominal pain and increased diarrhoea, intense of possible p s danger signs are blood cells white e u d o -memb r a n s colitis. and in the patient should be looked for the area if present. treated in a hospital not normally new foods to exposed part of their diet. old. most likely determine to analyzed carefully these drugs should be avoided agent(s); causative regimens. in future especially if available, of the hepatitis etiologies and C. A, B, to if found. addressed alcoholism of suspected drug. upon discontinuation COMMENTS 1. • broad- to related colitis Pseudo-membranous • in pathogens water-borne and common Parasites • has been especially if patient Lactose intolerance, 2. 1. 2. 3. 4. Encourage patients to tolerate some degree of some degree tolerate to patients Encourage fluid intake. Encourage diarrhoea (no blood in stool uncomplicated Treat (especially potassium) Check serum electrolytes and diarrhoea and/or blood in the stools Fever If times the upper enzymes than three more are (viral causes of hepatitis other potential Eliminate suspending most likely agent Consider loose stools and flatulence. loose stools mouth 4 mg by with loperamide and no fever) to 2 mg after each loose stool by initially followed a maximum of 10 mg per 24 hours. if diarrhea status is severe. and dehydration be secondary the diarrhoea may indicate to of effect something other than a simple adverse drugs. the anti-TB drugs and all hepatotoxic stop limit of normal, nonhepatotoxic least three with at continue non- of three (an example medications the injectable drugs are agent, hepatotoxic and fluoroquinolone cycloserine). being hepatitis and alcohol-induced hepatitis any causes) and treat most common the two identified. drugs one remaining Reintroduce ermanently. agents with the least hepatotoxic a time, at testing functionby liver while monitoring first, the enzymes and if the most every days, three not re- consider likely culprit is not essential, it. introducing SUGGESTED MANAGEMENT SUGGESTED 1. 2. 3. 4. 5. 1. 2. 3. SUSPECTED AGENT PAS, Eto/Pto PAS, Z, H, R, and Pto/Eto, FQs Bdq, PAS, A,B,C Hep, Alcohol, viral ADVERSE EFFECT ADVERSE Diarrhoea and/or flatulence Hepatitis NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 81 Symptoms of hypothyroidism include fatigue, include fatigue, of hypothyroidism Symptoms 1.5 to is above TSH Do not start unless treatment of upon discontinuation reversible Completely of ethionamide/ protionamide combination The of arthralgia diminish over generally Symptoms on in patients be elevated may Uric acid levels support to is little evidence the addition There present are and warmth redness, If swelling, acute consider hypokalaemia is present, If severe or spironolactone Amiloride 5–10 mg per day can cause potassium replacements Oral somnolence, cold intolerance, dry skin, intolerance, cold coarse somnolence, as occasional as well and constipation, hair, and inability concentrate. to depression 2.0 times upper normal limit. and/or ethionamide/protionamide. PAS with associated frequently is more with PAS than is the individual use of each hypothyroidism drug. without intervention. even time, pyrazinamide. arthralgias, although if gout is of allopurinol for it should be used. present (gout, diagnosis for aspiration consider in a joint, etc). disease, infection, autoimmune hospitalization. potassium and decrease may 25 mg per day and is useful in refractory wasting magnesium cases. magnesium Oral vomiting. nausea and significant cause diarrhea may COMMENTS 1. 2. 3. 4. 1. 2. 3. 1. 2. 3. Most adults will require 100 to 150 mcg of 100 to Most adults will require should be taken early in the morning Thyroxine every and increase TSH 2 months 1 to Monitor anti- with non-steroidal Initiate therapy dose of suspected (most commonly agent Lower if this can be done suspected agent, Discontinue Check potassium. and also check magnesium If potassium is low, Dose oral as needed. electrolytes Replace Thyroxine/levothyroxine daily. Start in the daily. Thyroxine/levothyroxine manner: following mcg daily mcg daily should start 25 mcg daily. at breakfast. before 30 minutes Adjust normalizes. TSH 12.5–25 mcg until dose by with in the elderly and patients slowly dose more conditions. cardiac inflammatory drugs daily or ibuprofen twice times a day). 400–800 mg three if this can be done without pyrazinamide), regimen. compromising regimen. without compromising magnesium, check for calcium (if unable to in all with magnesium empiric treatment consider cases of hypokalemia). apartelectrolytes FQ as they can interfere from with FQ absorption. SUGGESTED MANAGEMENT SUGGESTED 1. • adults can be started 100 healthy on 75 to Young • with 50 treatment should begin Older patients • disease cardiovascular with significant Patients 2. 1. 2. 3. 1. 2. 3. SUSPECTED AGENT Eto/Pto, PAS Eto/Pto, Z, Fluoroquinolones Km,Cm, S Am, ADVERSE EFFECT ADVERSE Hypothyroidism Arthralgias Electrolyte disturbances (hypokalaemia and hypomagnesaemia) 82 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT History disease is not a or renal of diabetes a creatine calculate to of how example An be permanent. Renal may impairment about tinnitus and monthly the patient Ask are ringing in the ears and intermittent Fullness Cs, of disequilibrium can be caused by A degree days several Some all drugs for clinicians will stop to exposure with previous Patients or permanent be reversible Hearing loss may significant tolerate choose to may Some patients contraindication to the use of the agents listed listed the use of agents to contraindication with these co-morbidities although patients here, renal developing risk for increased be at may failure. based on the serum creatinine clearance unsteadiness. toxicity. of vestibular early symptoms INH or Linezolid. Eto/Pto, FQs, these drugs. to attributed are see if symptoms to do not generally toxicity of vestibular Symptoms with withholding medications. improve baseline hearing loss. have may aminoglycosides audiometryIn be helpful at such patients, may the start of MDRTB therapy. (often permanent). of cure. a higher chance achieve hearing loss to a physician should be discussed between This Continuing and the patient. in MDR-TB trained the injectable hearing loss almost despite agent in deafness. results always COMMENTS 1. 2. 3. 1. 2. 3. 1. 2. 3. Discontinue suspected agent. Discontinue if an aminoglycoside using capreomycin Consider (NSAIDs, etiologies other contributing Consider every closely, (and electrolytes) creatinine Follow and injectable a safer changing to agent Consider the to according TB medications all Adjust appear, toxicity If of vestibular early symptoms with the If worsen tinnitus and unsteadiness with Document hearing loss and compare If then of hearing early loss are symptoms had been the prior injectable in regimen. dehydration, other medications, diabetes, heart urinarycongestive failure, obstruction, etc.) as indicated. and address 2 weeks. 1 to Dlm, Lzd drug i.e Bdq, effective clearance creatinine drug change the Inj with other safer This the injectable stop agent. adjustment, above cause reactions that adverse is one of the few and necessitate toxicity intolerable permanent of a class agents. discontinuation of baseline audiometry (Some degree if available. starting with most patients, hearing loss occurs with high-frequency loss). with the injectable and replace Discontinue agent Dlm) if this can be done other suitable drug(Bdq, the regimen. without compromising SUGGESTED MANAGEMENT SUGGESTED 1. 2. 3. 4. 5. 6. 1. 3. 1. 2. SUSPECTED AGENT S, Km, Am, Cm TDF Possible ART: S, Km, Am, Cs, Cm, H Eto, FQs, Lzd S, Km, Am, Clr Cm, ADVERSE EFFECT ADVERSE Nephrotoxicity(Renal toxicity) Vestibular Toxicity (tinnitus and dizziness) Hearing loss (also see vestibular toxicity above) NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 83 While the benefit of hearing aids is minimal to the benefit of hearing aids is minimal While Nutritional is important status BMI see as low to of disrupted be a result May associated Lzd diabetes, with co-morbid disease (e.g. Patients moderate in auditory toxicity, consider a trial use consider in auditorymoderate toxicity, with hearing loss can if a patient determine to their use. benefit from high risk of PN with use Lzd,Cs puts at functionmitochondrial in neurons. likely be more may dependence) alcohol HIV, but these neuropathy, peripheral develop to the use of to not contraindications are conditions here. listed the agents COMMENTS 4. and is dose related Myelosupression associated Lzd after start days in few of treatment occur may iron have may TB patients TB/DR chronic Many deficiencyto inflammatoryat baseline due anemia and production of hepcidin and influencing process hemostasis iron regularly Monitor full blood count 1. 2. 3. Increase pyridoxine to maximum daily dose (200 to Increase pyridoxine with linezolid associated neuropathy The mg per day). use and often after prolonged is common this For extremely painful and irreversible. if nerves damaged, permanently reason are and stopped should be immediately linezolid neuropathy when symptomatic not reintroduced additional Consider 2 or above). (grade develops the regimen. reinforce drugs to anti-TB SUGGESTED MANAGEMENT SUGGESTED Lzd associated Myelosuppression is very Myelosuppression common, associated Lzd taking 18-21% of patients linezolid approximately anemia/ Myelosuppression. experience may If has thrombocytopenia or neutropenia, the patient linezolid. be due to likely to this is more Anemai/Myelosuppression, In moderate mild to dose and consider close monitoring continue 300 mg daily or 600 to reduction of Lzd day alternative 3-4) situation(grade threatening and life In severe immediately Lzd stop Ertyhropyotein consider Transfue/hemotrnasfusion, with specialist advise severity has once Restart doses, reduced at Lzd 1) mild(grade grade to become drug. other safer and consider Lzd If necessary stop, 1. 2. SUSPECTED AGENT Lzd, Possible Possible Lzd, other causes: AZT, TB cotrimoxazole. itself, deficiencyiron , GI bleeding also causes of anemia , H, Lzd, Cs, S, Km, Cm, H, FQs, E Pto/Eto, rarely ADVERSE EFFECT ADVERSE Myelosuppression (anemia, Myelosuppression thrombocytopenia, or neutropenia) Peripheral neuropathy 84 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT Neuropathy may be irreversible but many but many be irreversible may Neuropathy with associated the neuropathy However, patients experience improvement when improvement experience patients suspended. are agents offending use and after prolonged is common linezolid suspension this reason often (for permanent when should be considered of this agent develops). neuropathy COMMENTS 4. Consider whether the dose of cycloserineConsider can Initiate medical therapy: or 100 night Gabapentine: 100-300 mg daily at but only be discontinued, may medication Rarely, be reduced without compromising the regimen. the regimen. without compromising be reduced the dose of likely culprits can also be (Lowering ethionamide). isoniazid, done – linezolid, symptoms. amitriptyline (start bedtime; the with 25 mg at a maximum of 150 mg). to be increased dose may tricyclic drugs. prolonging Do not use with QT reuptake with selective serotonin antidepressants Avoid, drugs. (SSRIs) antidepressant inhibitors and Amitriptyline because of riskLzd together syndrome. serotonergic is a Carbamazepine mg twice daily can be tried. and should not be used of CYP3A4 inducer strong with bedaquiline or delamanid PN and many treat to is a good therapy TID, mg support its use Trials clinical and the regimen drug is available if an alternative is not compromised. SUGGESTED MANAGEMENT SUGGESTED 3. 4. • help alleviate may NSAIDs or acetaminophen • such as with tricyclic antidepressants Therapy • 100–400 at an anticonvulsant, Carbamazepine, 5. 6. SUSPECTED AGENT ADVERSE EFFECT ADVERSE NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 85 Socioeconomic conditions and chronic illness and chronic Socioeconomic conditions fluctuate during may symptoms Depressive History is not a depression of previous suicidal ideation regarding Question the patient risk of in the hospital until Keep the patient after holding occurs If no improvement should not be underestimated as contributing as contributing should not be underestimated factors depression. to as illness is successfully improve and may therapy treated. listed the use of agents to contraindication the likelihood of depression increase but may If significant during treatment. developing the start at is present of treatment, depression with cycloserine if possible. a regimen avoid be more is judged to time the depression any than mild. suicide has passed. hold H and/or Eto/Pto. cycloserine, COMMENTS 1. 2. 3. 4. 1. 2. Assess and address underlying socioeconomic underlying socioeconomic and address Assess co-existing for abuse patients substance Assess (or group Initiate individual counselling initiate significant, is more depression When dose of suspected if this can be done agent Lower suspected if this can be done agent Discontinue and put under 24- hour the patient Hospitalize cycloserine. Discontinue consultation. Request psychiatric therapy. Initiate antidepressant 500 mg daily until to the dose of Eto/Pto Lower issues. if appropriate. treatment to and refer and culture- is smear- if the patient counselling negative). (amitryptiline, therapy fluoxetine antidepressant and SSRIs antidepressants Tricyclic or similar). and should not be together should not be given with QT avoid Also on linezolid. patients to given drugs. prolonging (Reducing the regimen. without compromising the dose of cycloserine 500 and ethionamide to is lessened a see if the depression mg daily to strategy). common regimen. without compromising surveillance. is stable. the patient

SUGGESTED MANAGEMENT SUGGESTED 1. 2. 3. 4. 5. 6. 1. 2. 3. 4. 5. SUSPECTED AGENT Socioeconomic circumstances, chronic disease, fluoroquinolones, Cs, H, Eto/Pto CS, H, Eto/ Pto ADVERSE EFFECT ADVERSE Depression Suicidal ideation 86 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT Some patients will need to continue antipsychotic antipsychotic continue will need to Some patients history disease is not a of psychiatric Previous cycloserine with an will tolerate Some patients reversible generally are symptoms Psychotic with new- in patients check creatinine Always MDR- until continued is generally Anticonvulsant is not a History disorder seizure of previous may with history seizures of previous Patients treatment throughout MDRTB therapy (and MDRTB therapy throughout treatment therapy). of MDR-TB upon completion iscontinue but the use of cycloserine, to contraindication the likelihood of psychotic increase its use may during treatment. developing symptoms but this should be done in drug, antipsychotic as these patients with a psychiatrist consultation will need special observation and this should only is no other alternative. be done when there or treatment of MDR-TB upon completion agent. of the offending cessation function in renal can A decrease onset psychosis. which of cycloserine, in high blood levels result can cause psychosis. or suspected agent is completed TB treatment discontinued. if here listed the use of agents to contraindication and/or the controlled well are seizures a patient’s (Do therapy. anticonvulsant is receiving patient drug is not include cycloserine if an alternative available). of seizures development risk for increased be at therapy. during MDR-TB COMMENTS 1. 2. 3. 4. 5. 1. 2. 3. Stop suspected agent for a short suspected for agent Stop period of time antipsychotic initiate severe, to If moderate expertise with psychiatric if in a ward Hospitalize maximum daily dose (200 to Increase pyridoxine dose of suspected (most commonly agent Lower suspected if this can be done agent Discontinue is off and patient resolve all symptoms Once FQs and isoniazid pending Hold cycloserine, (carbamazepine, therapy Initiate anticonvulsant maximum daily dose (200 to Increase pyridoxine including potassium Check serum electrolytes (1–4 weeks) while psychotic symptoms are are symptoms while psychotic (1–4 weeks) most likely drug is The under control. brought high-dose by isoniazid. cycloserine followed (haloperidol). therapy himself/herself or others. risk to is at patient mg per day). if this can be done cycloserine 500 mg a day) to regimen. without compromising regimen. without compromising can be therapy anti-psychotic cycloserine, If a lower cycloserine at tapered. is continued be need to may therapy anti-psychotic dose, tapering should at attempts and any continued in the adverse trained be done with a psychiatrist drugs. anti-TB effects of second-line of seizures. resolution most commonly acid are or valproic phenytoin, used). mg per day). calcium (HCO3−), (K+), sodium (Na+), bicarbonate (Mg2+), chloride (Cl−). magnesium (Ca2+), SUGGESTED MANAGEMENT SUGGESTED 1. 2. 3. 4. 5. 6. 7. 1. 2. 3. 4. SUSPECTED AGENT Cs, H, FQs Cs, H, Cs, fluoroquinolones ADVERSE EFFECT ADVERSE Psychotic symptoms Seizures NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 87 Always check creatinine in patients with new- in patients check creatinine Always of ethambutol, with cessation reverses Usually in diabetic patients diabetic control Improve is stopped. when treatment returns Normal taste is stopped afterResolution treatment occurs onset seizures. A decrease in renal function in renal A decrease onset seizures. of cycloserine, in high blood levels can result the dose of Adjusting which can cause seizures. may creatinine of low cycloserine in the presence the seizures. control is needed to be all that also cause ON and may Lzd ethambutol. the risk. enhances of E and Lzd combination LZD COMMENTS Comments 5. is drug responsible most common The 1. 2. 3. 1. 1. When seizures have resolved, restart medications resolved, have seizures When this side effect. tolerate to the patient Encourage Sucking candy or chewing gum can be hard side- can be a troublesome enlargement Breast this side effect tolerate to patients Encourage one at a time. Cycloserine should not be restarted Cycloserine a time. one at If the regimen. to essential unless it is absolutely start cycloserine a dose one weight is reinitiated, band lower. helpful. for male especially therapy, Eto/Pto effect of Galactorrhoeapatients. has also been reported. SUGGESTED MANAGEMENT SUGGESTED Suggested Management Suggested 5. Do not restart. ethambutol. 1. Stop an ophthalmologist. to patient 2. Refer 1. 2. 1. 2. SUSPECTED AGENT Suspected Agent Eto/Pto, E, Cfz, Lzd, H, S Clr, Eto/Pto, FQs Eto/Pto ADVERSE EFFECT ADVERSE Adverse Effect Adverse Optic neuritis Metallic Taste Gynecomastia 88 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

6.2.1 Adverse Event Causality Assessment Flowchart:

For all SAEs, the first level Causality Assessment can be done at the DR-TB treatments centers by the treating doctor using the below Adverse Event Causality Assessment definitions and Flowchart:

Unknown 1. Did AE start after medicine was started? No Not drug-related YES UNASSESSED or 2. Is timing of AE consistent with drug related effect? No UNLIKELY UNASSESSABLE* YES

Unknown 3. Have other possible causes of the AE been excluded? No YES

4. Were any of the medicines stopped? No POSSIBLE YES

5. Did patient recover from AE after stopping the medicine? No YES

6. Was the medicine restarted? No

YES PROBABLE

7. Did the AE occur again after restarting the medicine? No YES

8. Is the AE a well-defined, objective event? YES CERTAIN

Causality Assessment Flow Chart based on WHO-UMC system standardized case causality assessment available at: http://www.who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf

Notes:

1. Check the start date of each of the medicines and the onset date of the AE. If the AE started before the medicines was started, there is no causal relationship between the medicines and the AE. (Note: is a pre-existing condition got worse after starting medicine it may be a drug- related effect, in which case select ‘yes’ and go to step 2)

* Select UNASSESSED if unknown but awaiting further information. Select UNASSESSABLE if unknown and no further information can be obtained (eg, information not recorded at health facility) 2. Is the time-to-onset of the adverse event consistent with a drug-related effect? Consider NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 89

known actions and pharmacokinetics (absorption, distribution, metabolism and elimination) of the medicines and the pathology of the adverse event (how long would it take for condition to develop?) 3. Are there other factors that could account for AE, such as: • Condition for which medicines were prescribed? • Other illnesses? • Other medicines (including traditional/herbal medicines)? ** If other factors provide a more likely explanation for the AE, the casual association between the medicine and the AE is assesses as UNLIKELY 4. DECHALLENGE 5. Did the patient recover from the AE or show objective signs of improvement after the medicine was stopped? Is it biologically plausible that the response observed after stopping the medicine was due to the medicine being stopped? 6. RECHALLENGE 7. Was the re-challenge at the same dose or a lower dose? If the re-challenge was negative at a lower dose, consider whether the AE may have been a dose-related effect 8. The causal association can only be assessed as CEARTAIN if the AE is a well-defined, objective event. (Vague, non-specific symptoms do not meet the criteria for CEARTAIN)

When required, second level of Causality Assessment will be done by the national level by a Causality Assessment team from the National Tuberculosis Centre (NTC) using the same Adverse Event Causality Assessment Flowchart. This will enable the findings from the first level causality assessment to be verified. 90 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

6.2 CAUSALITY ASSESSMENT OF THE SERIOUS ADVERSE EVENT (SAES):

TABLE 6.4 The WHO-UMC Classification System for causality assessment Causality term Definition Assessment criteria* 1. Certain Clearly caused by the exposure • Event or laboratory test abnormality, with There is clear evidence to plausible time relationship to drug intake suggest a causal relationship • Cannot be explained by disease or other and other possible contributing drugs factors can be ruled out. • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Re-challenge satisfactory, if necessary 2. Probable/ Likely to be related to the • Event or laboratory test abnormality, with Likely exposure reasonable time relationship to drug intake There is evidence to suggest a • Unlikely to be attributed to disease or other likely causal relationship and drugs the influence of other factors is • Response to withdrawal clinically reasonable unlikely. • Re-challenge not required 3. Possible May be related to the exposure • Event or laboratory test abnormality, with There is some evidence to reasonable time relationship to drug intake suggest a causal relationship • Could also be explained by disease or other (e.g. because the event occurs drugs within a reasonable time • Information on drug withdrawal may be after administration of the lacking or unclear trial medication). However, the influence of other factors may have contributed to the event (e.g. the patient’s clinical condition, other concomitant treatments). 4. Unlikely Doubtfully related to the • Event or laboratory test abnormality, with a exposure time to drug intake that makes a relationship There is little evidence to improbable (but not impossible) suggest there is a causal • Disease or other drugs provide plausible relationship (e.g. the event did explanations not occur within a reasonable time after administration of the study regimen). There is another reasonable explanation for the event (e.g. the patient’s clinical condition, other concomitant treatment). 5. Conditional There is insufficient information • Event or laboratory test abnormality or Unclassified about the ADRs to allow for an • More data for proper assessment needed, or assessment of causality. • Additional data under examination 6. Unassessable There is insufficient information • Report suggesting an adverse reaction or about the ADRs to allow for an • Cannot be judged because information is Unclassifiable assessment of causality and NO insufficient or contradictory MORE is expected. • Data cannot be supplemented or verified

*All points should be reasonably complied for assessment CHAPTER 7 INFECTION CONTROL

TB infection control is a combination of measures aimed at minimizing the risk of TB transmission within populations. The foundation of infection control is early and rapid diagnosis, and proper treatment of TB patients.

7.1 GENERAL PRINCIPLES OF INFECTION CONTROL There are three levels of infection control measures, operating at different points in the transmission process, and all are interdependent:

7.1.1 Administrative (managerial) controls Administrative controls should be implemented as a first priority because they have been shown to reduce transmission of TB in health-care facilities. Such controls are a vital part of sound infection control practices, which require people with TB symptoms to be promptly identified, separated and treated. Administrative control includes:

• Develop and implement written policies and protocols to ensure: o Rapid identification of TB cases (e.g., improving the turn-around time for obtaining sputum results) o Isolation of patients with PTB o Rapid diagnostic evaluation o Rapid initiation treatment • Educate, train, and counsel HCWs about TB 92 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

• To the extent possible, avoid mixing TB patients and HIV patients in the hospital or clinic setting • Find cases Actively, Separate temporarily and Treat effectively (FAST) is intensified, refocused administrative approach to TB transmission control in healthcare facilities. Active case finding with cough screening followed by rapid molecular diagnostics, which enables prompt treatment of unsuspected drug-sensitive and drug-resistant TB, thereby decreasing TB transmission. The basis principle for FAST are as follows: o TB is spread in institutions predominantly by coughing patients with unsuspected TB or unsuspected drug resistance o Most potentially infectious patients can be identified by cough surveillance o Coughing TB patients most likely to be infectious can be diagnosed using rapid molecular sputum tests o By dramatically reducing the duration of institutional exposure through effective treatment, transmission among patients and to health care workers will be reduced proportionately Note: For detail please consult FAST Guideline

7.1.2 Environmental controls include methods to reduce the concentration of infectious respiratory aerosols (i.e. droplet nuclei) in the air, and methods to control the direction of infectious air.

Such measures include: • Use of ventilation systems. • Use upper-room germicidal ultraviolet irradiation (GUV) fixtures, at least when adequate ventilation cannot be achieved

7.1.2.1 Use of ventilation systems Adequate ventilation in health-care facilities is essential for preventing transmission of airborne infections, and is strongly recommended for controlling spread of TB. The choice of ventilation system will be based on assessment of the facility and informed by local programmatic, climatic and socioeconomic conditions. Any ventilation system must be monitored and maintained on a regular schedule.

Kind of ventilation systems: • Natural • Mechanical

Natural Ventilation Created by the use of external airflows generated by natural forces such as: • Wind • Differences in temperature Naturally ventilated rooms can achieve very high ventilation rates (ACH) under ideal conditions but natural ventilation is unpredictable. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 93

Maximize Natural Ventilation • Openings on opposite walls (cross ventilation) • Openings are unrestricted (stay open) • 10% of floor space should be openable- window-area on each wall • Upper levels of the building • Building and openings are oriented to use the prevailing wind, without obstruction by other nearby buildings

Mechanical ventilation Well-designed, maintained and operated fans (mixed-mode ventilation) can help to obtain adequate dilution when natural ventilation alone cannot provide sufficient ventilation rates. In some settings, mechanical ventilation (with or without climate control) will be needed. This may be the case, for example, where natural or mixed-mode ventilation systems cannot be implemented effectively, or where such systems are inadequate given local conditions (e.g. building structure, climate, regulations, culture, cost and outdoor air quality).

7.1.2.2 Use of upper room or shielded germicidal ultraviolet irradiation fixtures Priority should be given to achieving adequate ACH using ventilation systems. However, in some settings it is not possible to achieve adequate ventilation; for example, because of climatic changes (e.g. in winter or during the night) or building structure, or because transmission of TB would pose a high risk of morbidity and mortality (e.g. in MDR-TB wards). In such cases, a complementary option is to use upper room or shielded germicidal ultraviolet irradiation (GUV) devices. This environmental control does not provide fresh air or directional airflow.

7.1.3 Personal respiratory protection aims to protect the health workers in areas where the concentration of droplet nuclei cannot be adequately reduced by administrative and environmental controls. Health workers should use high filtration masks (N95) or “respirators” to protect them against the inhalation of airborne infectious droplets. The patients should wear a surgical mask to reduce the spread of droplets.

Respirator Vs Surgical Mask

RESPIRATORS SURGICAL MASKS • Designed to filter out droplet nuclei from • Designed to stop droplet nuclei from being being inhaled by the health-care worker and spread (exhaled) by the patient. other individuals. • Should NOT be worn by the health-care • Should properly fit different face sizes and worker features. • Should NOT be worn by the patient

Personal respiratory protection by themselves are insufficient to prevent TB transmission. They will not be worn continuously and are likely not to be in use when unsuspected TB cases are encountered. Administrative and environmental controls are more important. 94 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

7.2 INFECTION CONTROL AT TB CONSULTATION ROOM The rooms for TB consultation, counselling and health education should be arranged according to sound infection control principles:

v Both windows and door should be open all the time. v Direct sunlight gets into the room easily v A stand fan ensures an airflow direction toward the opened window v Patient and health staff sit in front of each other across the airflow v Exhaust fan to extract the air v One patient at a time should be received in the room v The patient should wear a surgical mask v Staff and family should wear N95 mask v Appropriate cough hygiene must be observed by the patient 1. The ventilation flow:

Wind Wind Wind Wind

Patient HCW Patient HCW

Good!!! Bad!!!

HCW

Wind Wind Patient

Good compromise

7.3 DR-TB PATIENT ISOLATION ROOM The DR-TB isolation room should have large open windows allowing direct sunlight into the room, a closing door, a stand fan to establish an air flow direction toward the window, and preferably a UV light installation with a shield to protect the eyes from direct exposure to it. The UV light should be turned on for 15 to 20 minutes every 12 hours (in the morning and evening), preferably with the patients not being in the room. An exhaust fan may help to extract the air from the room. The DR-TB room should be isolated from the other departments, especially the out-patient clinic, the HIV ward, the pediatric ward and other high risk group departments.

DR-TB infectious patients in the isolation room must wear a surgical mask at all times. If no masks are available, the patients should use a handkerchief or a piece of cloth to cover their mouth when talking, coughing, sneezing or speaking. The patients should refrain from spitting on the floor, but should spit in a sputum cup that will be later burned.

Health workers must wear high filtration (N95) masks, fitted correctly, every time they meet DR- TB patients or enter the DR-TB ward.

Instructions on how to wear masks should be posted at all entries of the DR-TB area for staff, patients and visitors NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 95

DR-TB patients should not receive many visitors and avoid contact with small children until sputum smear or culture conversion. Good infection control measures for visitors and small children include: - Meeting in a room with good ventilation or outside - Patient wearing surgical mask and visitor wearing high filtration (N95) mask

Room disinfected by appropriate use of UV light

7.4 INFECTION CONTROL AT HOME Contagious or potentially contagious patient may have to be isolated at home. The following infection control measures can be taken: • If feasible, the patient should stay and sleep in a specific room separated from the other family members. • If possible, the isolation room should have good ventilation with a large opened window, direct exposure to sunlight, and preferably with good air flow direction (natural or with fan). • Other people should not enter the room unless necessary. If they do so, patient must a surgical mask. • At all stages the patient should be encouraged to stay outside. • The patient should eat separately, outside or in the room. • The patient should wear a surgical mask all the time when in contact with other people. • Strict coughing hygiene must be observed by the patient, inside as well as outside the house. • If other people come to see the patient, they should meet outside. They need to keep a safe distance and duration of contact should be kept as short as possible. • The patient should avoid contact with children or other high-risk groups and restrict close contacts with other people during the contagious period.

Role of TB patient in infection control: • Patient should maintain a well-balanced diet to keep the immune system strong • Patient should TB patient to stop smoking and minimize intake of alcohol • Patient should wear mask and hold a cloth or handkerchief over mouth when coughing • Patient should not spit on the floor but in a container (preferably disposable) and dispose of properly

7.5 HEALTH WORKER AND INFECTION CONTROL Always follow recommended infection control procedures in your work in the health facility. Be aware of possible signs and symptoms of TB in yourself. If one or more of these develop, report promptly for assessment and care. If you are diagnosed with TB, start treatment promptly and adhere to treatment until it is completed.

Health workers should decrease their risk factors for TB disease to the extent possible eg. Living healthy live-styles, stress free, stop smoking, or following treatment for diabetes, knowing their HIV status or getting retested periodically etc. If a health worker is HIV-infected, he/she may decrease his/her risk of developing TB by taking CPT, ART and IPT as appropriate. Health workers who have positive HIV status should be given alternate choice of work area by the employers. CHAPTER 8 MONITORING AND EVALUATION FOR TB CONTROL PROGRAM

8.1 RECORDING AND REPORTING OF DR-TB PROGRAMME In Nepal, The National DRTB program has endorsed 16 DRTB Recording and Reporting tools. Out of the 20 forms (and the subset of forms) are common for DS and there are 8 forms are specific to DR-TB (Highlighted in Bold) below.

Forms, Records and Registers The following recording and reporting are used for DR-TB:

S.N TB NUMBER TOOLS 1 TB 01 Presumptive TB register 2 TB 02a Laboratory Request Form 3 TB 02b Laboratory Report Form (LPA and Culture DST) 4 TB 03a Laboratory Register (Microscopy) 5 TB 03b Laboratory Register (GeneXpert) 6 TB 03c Laboratory Register (Culture DST) 7 TB 03d Laboratory Register (LPA) 8 TB 03e Culture / DST Reporting Forms 9 DRTB 01 DR-TB Register 10 DRTB 02 DR-TB Treatment Card 11 DRTB 03 DR-TB Patient Identity Card 12 TB 07 Contact Investigation form 13 TB 08 Contact and TBPT Register 14 TB 10 Referral / Transfer Slip 15 TB 11 Referral Form (Community, Private, Contact) 16 DRTB 04 Commitment Form 17 DRTB 05 aDSM Recording and Reporting Form 18 DRTB 06 DR-TB Drug Order Form 19 DRTB 07 DR-TB Reporting Form (for cohort reporting) 20 DRTB 08 Six-monthly Report on Detection and Enrolment of DR-TB NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 97

1. Presumptive TB register (TB 01). Once a patient is suspected of having TB in the OPDs/Clinics, then they are registered in the Presumptive TB Register at the OPDs by the treating physicians/health care workers. Presumptive TB Register contains sociodemographic information of TB patients, history of TB, where the patient is referred to for diagnosis, diagnosis result details, TB management suggested and details where the patient is referred for management (DOT centers). The new serial number will be assigned at the beginning of each month while using this register. The register is the same for both DS and DR-TB.

2. Laboratory Request Form (TB 02a) These forms are filled by OPDs / clinics for diagnosis of TB/DRTB and or from DR TB Treatment Centers for follow up purpose. There is only one Laboratory Request Form that will be used for both DS and DR TB diagnosis as well as follow up. Once the tests are done, the lab reports back the test results of Smear Microscopy and Xpert MTB/RIF testing using the same Form. Results of LPA and Culture DST are given in separate form using Laboratory Report Form(LPA and Culture DST) (TB 02b).

The Form is divided broadly into 2 parts.

Part 1 is for Laboratory Test request, which has sub-sections for different requesting different types of tests (for diagnosis of TB with smear and Xpert MTB/RIF testing Part A, For LPA for HrTB diagnosis part B, for retreatment cases requiring further confirmation with culture DST part C, for DRTB baseline and followup test part D, and HIV testing part E).

Part 2 is for reporting the results of smear and Xpert MTB/RIF testing.

3. Laboratory Report Form(LPA and Culture DST) (TB 02b) The results of LPA and Culture DST are reported by Lab using this form. This is also the same for DS and DR-TB for initial diagnosis or follow up purpose.

4. Laboratory Register and Form (TB 03) These registers are present in the Laboratories where the bacteriological test for TB are carried out. The registers are separate for different types for laboratory process even within the same Laboratory. a. Sputum Smear Microscopy Register (TB 03a) b. GeneXpert Register (TB 03b) c. LPA Register (TB 03c) d. Culture DST Register (TB 03d)

Once the results are obtained, it is then sent back to the treatment center requesting for the tests (via patient or their accompany, courier or other means as available)

e. Culture/DST Reporting Form (TB 03e) There is also a separate Culture/DST Reporting Form (TB 03e), which is filled by the Culture Laboratories which contains compiled information of all Culture/DST tests performed by the respective laboratory in that given time frame. This is submitted to NTP on a monthly/ 98 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

quarterly basis. Compiled information of other tests; smear, GeneXpert, and LPA are captured through HMIS 9.3 reporting template, but as detail information regarding culture is required to NTP, the information is captured and reported separately using this format.

5. DRTB Register (DRTB 01) This register is present at DRTB Treatment centers where the patients are registered for treatment. This register also contains the details of patients’ particulars, diagnosis details, registration category details and treatment details, sputum conversion and outcome details with other additional details on contact investigation, smoking habits. This register will be the basis for filling out the DRTB 07 Reporting Format will be used for cohort reporting of DRTB on monthly basis and analyzed 4 monthly by the NTP.

6. DRTB Treatment Card (DRTB 02) Once on the DR TB register, a DRTB Treatment card is also issued to the patient. This card contains all the information of patients that is in the DR TB register including the section for monitoring daily drug adherence. Three duplicate copies are made of the card. One copy is kept in the DRTB Treatment center; one is sent to the DR TB treatment Sub-centers and one copy is given to the treatment supporter if the patient is managed under CBDOT program.

The details of the patient’s smoking habit along with ABC provided are recorded at the attached Smoking Cessatithe on the card at 0 months and for 3 more visits (in equal intervals).

7. DRTB Patient Identity Card (DRTB 03) Once the treatment card is issued, the Patient’s identity card is also issued to be kept by the patient, which basically has all the information from the treatment card and is also updated every day.

8. Contact Investigation Form (TB 07) Though the patient is registered in the DR TB center, the DOT center which referred the patient to the DR TB Treatment center is responsible for carrying out the contact investigation and also inform the DRTB treatment center of the finding. Volunteers are given out these Contact Investigation Forms with details of DR TB index cases, which they use while carrying out contact investigation in the community. If there are presumptive DRTB among contacts identified during screening, a separate Referral Form (TB 11) is filled out and issued by the volunteers and referred for further diagnosis. All the information are then recorded for all contacts screened in this form and are submitted back to the DOT centers. The same form will be used to access contacts of drug-sensitive and/or drug-resistant TB.

9. Contact and TBPT Register (TB 08) Once Household contacts are referred from the community, then they are then registered in the Contacts and TB Preventive Therapy (TBPT) Register at the DOT center. This register contains details of the contact, their TB/DRTB status. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 99

10. Referral / Transfer Form (TB 10) These forms are filled when a patient needs to be referred or transferred out from one center to the next. This contains the information of the patient’s particular, diagnostic details, treatment category and regimen details along with details from where and the reason for referral/transfer out. It also has acknowledgement slip which need to be filled and sent back by the receiving centre.

11. Community Referral Form (TB 11) These forms are present in the treatment centers and are provided to the community health volunteers (esp. FCHVs). These are used while referring presumptive TB cases from the community (during contact tracing) to the health facilities for further diagnosis or can also be used for referring a TB patient if they have side effects or requiring other tests and follow up, which they identify in the community.

12. Commitment Form (DRTB 04) These forms are maintained in the DR TB treatment centers. These forms are filled taking consent from the patient regarding their willingness and commitment to be enrolled into daily DOT DR TB management as well as commitment from service provider to provide the treatment as required to the DR TB patients.

13. aDSM Recording and Reporting Form (DRTB 05) These forms are maintained in the DR TB treatment center level where the adverse events are recorded, managed, and reported. The reporting forms are sent to NTC aDSM unit every monthly/quarterly basis for minor adverse event but immidiately for severe adverse events.

14. DRTB Drug Order form (DR TB 06) Drug order forms are present in the treatment centers where DOT is provided. They are filled in a regular basis and used for ordering drugs for TB program.

15. DRTB Cohort reporting Form (DRTB 07) DRTB Cohort reporting format is present at the DR-TB treatment centers, where the DRTB register is being maintained. The cohort reporting is done on a monthly/quarterly basis.

16. Six-monthly Report on Detection and Enrolment of DR-TB (DRTB 08) These forms are filled and reported by treament centre and sent to the National TB program for analysis and feedback from the NTC will be given to the treatment centre. 100 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

8.2 MONITORING OF DR-TB CASE DETECTION AND TREATMENT ACTIVITIES Monitoring DR-TB control activities are important to assess progress and identify areas that need improvement. The National TB Program monitors the following indicators

1. TB case detection indicators A. Monitoring is done by NTP level i. The proportion of DR-TB cases detected ( all forms) among presumptive TB cases and enrolled under treatment at different levels (national, provincial and local level). The monitoring is done for all forms of TB. ii. The proportion of detected DR-TB cases enrolled under treatment. iii. The Cohort analysis (sputum conversion and Treatment outcome) of the registered DR-TB cases.

B. Monitoring is done at the DR TB treatment center level i. Daily treatment adherence of DR -TB cases registered in their center. ii. Carrying out regular follow up activities of each DR TB cases. iii. The proportion of adverse events of DR-TB cases and management of adverse events. iv. Regular (monthly) follow up of DR-TB cases (for daily adherence and follow up tests) managed by Treatment Sub-centres. v. Regular (monthly) follow up of DR-TB cases (for daily adherence and follow up tests) managed under CBDOT program. iv. The cohort analysis (sputum conversion and Treatment outcome) of each registered DR- TB cases. vi. Contact investigation of index DR-TB cases and the proportion of contacts tested for TB, diagnosed with TB, managed with TB and for <5 year or PLHIV who do not have TB are put on TBPT.

C. Monitoring is done at the DR TB treatment sub-center level i. Daily treatment adherence of DR TB cases managed from their center. ii. Assurance of follow up test is done by the registered DR-TB cases. iii. Supervision of DR TB cases being managed under CBDOT assigned under their center.

2. TB Treatment Outcome indicators i. Sputum Conversion Rate This indicator refers to the conversion of sputum during follow up, which was initially bacteriologically positive (sputum or culture) at the time of diagnosis. Conversion is seen usually at each month with smear and culture. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 101

For programmatic analysis: • For a patient under an SSTR - the sputum smear conversion is checked at 4 months, for which the cohort analysis is done at 8 months of the start of treatment. • For Longer Regimen, the conversion of culture is checked at 6 months, for which the cohort analysis is done at 12 months of the start of treatment. ii. TB Treatment Outcome This indicator refers to treatment outcomes for all registered DR TB cases. Treatment Outcome indicators are measured with the following treatment outcomes. Conversion of sputum and cohort analysis is done at: For SSTR - after 16 months of initiation of treatment. For LR 1,2,3,4 - after 24 months of initiation of treatment.

1. Cured 2. Treatment Completed 3. Treatment Failed 4. Died 5. Lost to follow up 6. Not evaluated

*Treatment Success Rate (proportion of cured plus completed)

The most important treatment outcome is the cure rate for bacteriologically confirmed patients. The desired cure rate for DR-TB in Nepal is more than 70%. 102 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 103

ANNEXURES

1. Drug information sheets

2. Grading of the severity of Adverse Drug Events

3. Calculating the QT interval

4. Calculating the creatinine clearance

5. Peripheral Neuropathy Diagnostics

6. Forms, records and registers

7. Gastric aspirate Job aid

8. Monitoring and Evaluation Checklist (Programmatic & Clinical) for DR-TB Treatment Site

9. Modified Shorter Regimen and Future SSTR Options

10. Forms, Records and Registers 104 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Annex 1. Drug information sheets

The drug information are a summary of the most relevant information in the medication fact sheets in Companion handbook to the WHO guidelines for the PMDT, 2014, part 3, p 252-296 and Curry MDR Guide 2016, part 5, p 99-148. For the complete details as well as the drugs not included in Annex 1, please consult the reference. The drugs are described in alphabetical order: A1.1. Bedaquiline A1.2. Capreomycin A1.3. Clofazimine A1.4. Cycloserine A1.5. Delamanid A1.6. Ethambutol A1.7. Ethionamide A1.8. Isoniazid A1.9. Kanamycin A1.10. Levofloxacin A1.11. Linezolid A1.12.a Meropenem A1.12.b Amoxicillin-clavulanic acid A1.13. Moxifloxacin A1.14. Para-aminosalicylic acid A1.15. Pyrazinamide NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 105

A1.1. BEDAQUILINE (BDQ) Activity against Bactericidal; has strong anti-TB activity with in vitro activity against both TB replicating and nonreplicating bacilli. Cross-resistance Cross-resistance with clofazimine has been demonstrated Dose Adults: 400 mg daily for 14 days, followed by 200 mg 3 times weekly for 22 weeks. Has not been studied past 24 weeks of administration. Missed doses: After the first 2 weeks of treatment, the dose changes to the 200 mg three times per week, even if doses were missed during the first 2 weeks. Patients should not make up for missed doses during the first 2 weeks of treatment. Concomitant medications: co- administration of rifamycins (e.g., rifampin, rifapentine and rifabutin) or other strong CYP3A4 inducers may require dose adjustment. Children: Has not been studied in children. Based strictly on weight, converting from the adult doses in a 70 kg patient, estimated pediatric doses would be 6 mg/kg daily for 14 days, followed by 3 mg/kg 3times weekly for 22 weeks. However, these doses are not supported by clinical experience. Renal failure/dialysis: No dose adjustment needed for mild to moderate renal insufficiency, but should be used with caution in patients requiring renal dialysis. Route of Oral. administration Preparation 100 mg tablets. Storage Store at room temperature. Tablets removed from the original packaging should be stored in a tight, light-resistant container and labeled with an expiration date not to exceed 3 months. Oral absorption Good oral absorption. Should be given with a meal to increase bioavailability. CSF penetration No data available. Also, there are no data on the treatment of extra- pulmonary TB (e.g., central nervous system) with bedaquiline. Special Use in pregnancy/breastfeeding: Pregnancy category B. No fetal harm circumstances found in animal studies. The drug is concentrated in breast milk and avoiding nursing should be considered. Use in renal disease: No dose adjustment needed for mild to moderate renal insufficiency. Use in hepatic disease: No dose adjustment is necessary for bedaquiline in patients with mild or moderate hepatic impairment. Use with caution in patients with severe hepatic impairment, and only when the benefits outweigh the risks. Adverse QTc prolongation, hepatitis, nausea, joint pain, headache, elevated amylase, reactions coughing up blood, chest pain, loss of appetite, and/or rash. Contra- None, but use with caution if other QTc prolonging agents, such as indications clofazimine or fluoroquinolones, are being given. 106 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Monitoring EKG at baseline, 2, 12 and 24 weeks of treatment. Stop bedaquiline if QTc > 500 and monitor EKGs frequently until QTc returns to normal. Baseline potassium, calcium and magnesium, repeat if QTc prolongation occurs, and monthly if on injectable drug. Baseline and monthly liver function tests. Warning Only use bedaquiline when an effective treatment regimen cannot otherwise be provided. QTc prolongation can occur with bedaquiline. Use with drugs that prolong the QTc interval may cause additive QTc prolongation. Patient Avoid alcohol. Take medication with food instructions Call your doctor and stop the medicine right away if you have: • serious heart rhythm changes (QTc prolongation). Tell your healthcare provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you faint. • liver problems (hepatotoxicity). Call your healthcare provider right away if you have unexplained symptoms such as nausea or vomiting, stomach pain, fever, weakness, itching, unusual tiredness, loss of appetite, light- colored bowel movements, dark-colored urine, yellowing of your skin or the white of your eyes. Refer to Annex 4.1 (p 341-368) of WHO MDR Guidelines 2014 for detailed description of Bdq use.

A1.2. CAPREOMYCIN (CM) Activity against Bactericidal; has strong anti-TB activity; TB Cross-resistance Amikacin and kanamycin. Variable frequency of cross-resistance has been reported. Dose (all once Adults: 15 mg/kg/day in a single daily dose, 5–7 days per week daily) 15 mg/kg/dose, 2–3 times per week after initial period of daily administration > 59 yrs of age: use a lower starting dose of 10 mg/kg/dose (max 750 mg) 5–7 times per week or 2–3 times per week after initial period. Children: 15–30 mg/kg/day (max 1 gram) 5–7 days per week. 15–30 mg/kg/day (max 1 gram) 2–3 days per week after initial period daily. In STR, 15-20 mg/kg/day is given. Renal failure/dialysis: 12–15 mg/kg/dose 2–3 times weekly (not daily). Markedly obese individuals: dose must be adjusted downwards. Route of IV or IM. administration Preparation Capreomycin is available in vials of 1 gram for either IM or IV administration. The contents of the vial should be reconstituted with 2 ml or more of Normal Saline or sterile water. Storage Package insert indicates that reconstituted capreomycin can be stored in the refrigerator up to 24 hours prior to use. Other data suggest that it may be held for 14 days in the refrigerator or 2 days at room temperature. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 107

Oral absorption There is no significant oral absorption. Intramuscular absorption might be delayed if the same site is used consistently. CSF penetration There is a paucity of data regarding capreomycin’s penetration of the meninges. Use in pregnancy/breastfeeding: Generally avoided in pregnancy due to congenital deafness. There are case reports of its safe use in pregnancy Special (unaffected newborns). Can be used while breastfeeding. circumstances Use in renal disease: Use with caution. Interval adjustment is recommended for patients with impaired renal function. Use in hepatic disease: Drug concentrations not affected by hepatic disease . Presumed to be safe in severe liver disease; however, use with caution—some patients with severe liver disease may progress rapidly to hepato-renal syndrome. Adverse Similar to the aminoglycosides. reactions Nephrotoxicity: occurs in 20%–25%. Proteinuria, reduced creatinine clearance, and depletion of potassium and magnesium. Ototoxicity (hearing loss): Occurs more often in elderly persons or those with pre- existing renal impairment; vestibular toxicity. Local pain with IM injections. Electrolyte abnormalities, including hypokalemia, hypocalcemia, and hypomagnesemia. Liver function test abnormalities when used with other TB drugs. Contra- Hypersensitivity to capreomycin. Some experts would not use indications capreomycin if vestibular side effects resulted from aminoglycoside use. Generally avoided in pregnancy due to congenital deafness. Monitoring Monitor renal function by documenting creatinine at least monthly (more frequently if renal or hepatic impairment); Document creatinine clearance if there is baseline renal impairment or any concerns; Follow monthly electrolytes, magnesium, and calcium. Document baseline and monthly audiology exam; Question patient regularly about vestibular complaints and perform serial vestibular exams. Patient Call your doctor right away if you have: instructions Rash / Fever or chills / Bleeding or bruising / Problems with hearing, dizziness, or balance / Bleeding or a lump where the shot is given / Decreased urination / Trouble breathing / Muscle weakness 108 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

A1.3. CLOFAZIMINE (CFZ) Activity against In vitro activity against M. tuberculosis without much in vivo data. TB Cross-resistance Bedaquiline. Dose (all once Adults: 100 mg/day. (200 mg daily have been used. A regimen of 200 mg daily) daily for 2 months, followed by 100 mg daily has been used.) Children: Limited data. Suggested dose 2-3 mg/kg/day Renal failure/dialysis: No adjustment required. Route of Oral; not available parenterally. administration Preparation 50 and 100 mg capsules. Storage Room temperature. Oral absorption 70% absorption after an oral dose. CSF penetration Limited data are available regarding CNS penetration. Special Use in pregnancy/breastfeeding: Not recommended due to limited data. circumstances Avoided with breastfeeding due to pigmentation of the infant. Use in renal disease: No dosage adjustment required. Use in hepatic disease: Partially metabolized by the liver; use caution and/ or adjust the dose for severe hepatic insufficiency. Adverse Pink or red discoloration of skin, conjunctiva, cornea, and body fluids. reactions Gastrointestinal intolerance. Photosensitivity. Other side effects include retinopathy, dry skin, pruritus, rash, ichthyosis, xerosis, and severe abdominal symptoms, bleeding, and bowel obstruction. Contra- Allergy to clofazimine. indications Monitoring Symptomatic monitoring. Patient Take with food to avoid stomach upset and improve absorption. instructions This medicine may discolor your skin and body secretions pink, red, or brownish-black. This should go away after stopping the medicine, but may take a long time. Avoid the sun and use strong sunscreens. Call your doctor right away if you have: • Bloody or black stools or diarrhea • Yellowing of your skin or eyes • Severe nausea, vomiting, abdominal pain, cramps, or burning • Depression or thoughts of hurting yourself NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 109

A1.4. CYCLOSERINE (CS) Activity against Bacteriostatic; inhibits cell wall synthesis. TB Cross-resistance None reported Dose Adults: 10–15 mg/kg/day. Usually 250 mg twice a day or 500 mg in a single dose; can increase to 250 mg 3 times a day or 250 mg in the morning and 500 mg in the evening. concentrations are kept below 35 mcg/ml. Some patients may require only alternate day 250 mg and 500 mg dosing to achieve desired blood levels. Children: 10– 20 mg/kg/day divided every 12 hours (daily maximum 1 gram). Vitamin B6: MDR-TB experts recommend that all patients should receive vitamin B6 while taking cycloserine. Adults need 100 mg or more (or 50 mg per 250 mg of cycloserine) and children should receive a dose proportionate to their weight. Renal failure/dialysis: 250 mg once daily or 500 mg 3 times per week; Route of Oral; not available parenterally. administration Preparation 250 mg capsule. Storage Room temperature in airtight containers. Oral absorption Modestly decreased by food (best to take on an empty stomach); not significantly affected by antacids or orange juice. CSF penetration Concentrations approach those in serum. Special Use in pregnancy/breastfeeding: Not well studied, but no teratogenicity circumstances documented. Use if there are not better choices. Can be used while breastfeeding (dose the infant with vitamin B6 if breastfed). Use in renal disease: Cycloserine is cleared by the kidney and requires dose adjustment for renal failure. Use with caution. Use in hepatic disease: Not associated with hepatotoxicity. Adverse CNS toxicity, including inability to concentrate and lethargy. reactions More serious CNS side effects, including seizure, depression, psychosis, and suicidal ideation, usually occur with high dosing, but may be seen in the normal therapeutic range. Other side effects include peripheral neuropathy and skin changes. Skin problems include lichenoid eruptions and Stevens-Johnson syndrome. Contra- Significant CNS disease, including seizure disorder, psychotic disease, or indications alcohol abuse. Monitoring Baseline and monthly monitoring for depression should be done. Patient Best taken on an empty stomach, with juice or antacids. If food is taken, instructions avoid a large fatty meal. Avoid alcohol. You must also take a high-dose vitamin B6 supplement while on this drug. Call your doctor right away if you have: • Seizures • Shakiness or trouble talking • Depression or thoughts of hurting yourself • Anxiety, confusion, or loss of memory • Personality changes, such as aggressive behavior • Rash or hives • Headache 110 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

A1.5. DELAMANID (DLM) Activity against Bactericidal; has strong anti-TB activity. Inhibits mycolic acid biosynthesis. TB Cross-resistance Cross-resistance with investigational drug PA-824, also a Nitroimidazole Dose Adults: 100 mg twice daily with food for 24 weeks. Administration for more than 6 consecutive months has not been studied. Children: The safety and efficacy in children under 18 years has not been published. Based strictly on weight, converting from the adult doses in a 70 kg patient, estimated pediatric doses would be 1.5 mg/kg twice daily for 24 weeks. Studies are testing delamanid at 50 mg twice daily for ages 6-11 and 100 mg twice daily for ages 12-17. Renal failure/dialysis: No dose adjustment needed for mild to moderate renal insufficiency but there are no data regarding use in patients with severe renal impairment. Therefore, delamanid is not recommended for patients with severe renal impairment. Route of Oral. administration Preparation 50 mg film coated tablets. Storage Store at room temperature and in original package in order to protect from moisture. Oral absorption 25- 47% of the delamanid dose is absorbed following oral administration with food. CSF penetration No data are available. Also, there are no data on the treatment of extrapulmonary TB (e.g., central nervous system, bone) with delamanid. Special Use in pregnancy/breastfeeding: Delamanid may cause harm to a fetus. circumstances It is usually not recommended for use during pregnancy. It is not known if delamanid passes into breast milk in humans. Breastfeeding is not recommended during treatment with delamanid. Use in renal disease: No dose adjustment needed for mild to moderate renal insufficiency, but not recommended for patients with severe renal impairment. Use in hepatic disease: No dose adjustment necessary in patients with mild hepatic impairment, but not recommended in patients with moderate to severe hepatic impairment. Contraindicated in patients with serum albumin levels <2.8 g/ml. Use in cardiac disease: Patients with various cardiac risk factors, including QTc interval prolongation, should not receive delamanid unless the potential benefits of treatment are expected to outweigh the possible risks. Take ECG prior to starting delamanid, and then monthly throughout treatment. Patients with serum albumin levels <3.4 g/ml (but at least 2.8 g/ml), or with cardiac risk factors, should receive more frequent ECG monitoring. Serum electrolytes should be checked and corrected as needed. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 111

Adverse The most frequent adverse drug reactions noted in controlled trials were reactions nausea, vomiting, dizziness, insomnia, and upper abdominal pain. QTc prolongation occurred in about 10% of patients receiving 100 mg twice daily. However, no episodes were accompanied by clinical symptoms such as arrhythmias or syncope. Contra- Hypersensitivity to delamanid indications Serum albumin < 2.8 g/ml because of an increased risk of QTc prolongation Taking other medications that are strong inducers of CYP3A (e.g. carbamazepine, rifamycins) Monitoring ECG at baseline and monthly during treatment. Baseline electrolytes, repeat if QTc prolongation occurs.

A1.6. Ethambutol Activity against Bacteriostatic inhibitor of cell wall synthesis; bactericidal only at the high TB end of the dosing range. At doses used over long periods of time, ethambutol protects against further development of resistance. Cross-resistance None reported Dose Adults: 15–25 mg/kg/day. Higher doses should be used only during the ini- tial months of therapy. For prolonged therapy, the dose should be closer to 15 mg/kg/day to avoid toxicity. Intermittent dosing at 50 mg/kg thrice or twice weekly can be used. Children: 15–25 mg/kg/day; doses closer to 15 mg/kg/day should be used if the drug is used for more than 2 months Renal failure/dialysis: 15–25 mg/kg/dose 3 times weekly (not daily). Route of Oral; not available parenterally administration Preparation 400 mg tablets Storage Room temperature Oral absorption 80% bioavailability independent of food CSF penetration Ethambutol penetrates meninges poorly Special Use in pregnancy/breastfeeding: Safe in pregnancy; can be used while circumstances breastfeeding. Use in renal disease: Use with caution—cleared by the kidneys; dose adjustment required for renal failure. Increased risk of toxicity with renal failure. Use in hepatic disease: Safe in liver disease. Adverse eactions Retrobulbar neuritis (dose-related—exacerbated during renal failure). Contra- Pre-existing optic neuritis; visual changes on ethambutol indications Monitoring Patients should be counseled to report any changes in vision. Baseline and monthly visual acuity and color discrimination monitoring should be performed (particular attention should be given to individuals on higher doses or with renal impairment). 112 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Patient Can be taken with food or on an empty stomach. instructions Call your doctor right away if you have: • Any problems with your eyes: vision changes, blurring, color blind- ness, trouble seeing, or eye pain • Swelling of face • Rash, hives, or trouble breathing • Numbness, pain, or tingling in hands or feet • Joint pain • Fever or chills • Nausea, vomiting, poor appetite, or abdominal pain • Headache or dizziness

A1.7. Ethionamide Activity against Weakly bactericidal; blocks mycolic acid synthesis. TB Cross-resistance Cross-resistance to isoniazid may occur when there is low-level resistance to isoniazid due to mutation in inhA or the promoter region. Dose Adults: 15–20 mg/kg/day (max dose 1 gram per day); usually 500–750 mg per day in 2 divided doses or a single daily dose. Most patients will experience GI intolerance with doses greater than 1 gram daily. Children: 15– 20 mg/kg/day usually divided into 2–3 doses. A single daily dose can sometimes be given at bedtime or with the main meal. Many indi- viduals require gradual ramping up of the dose and treatment for GI upset. Renal failure/dialysis: No change Vitamin B6: Although there is little supporting data, most MDR-TB experts rec- ommend that all patients should receive vitamin B6 while taking thionamide. Adults need 100 mg and children should receive a dose proportionate to their weight. Route of Oral administration Preparation 250 mg tablet Storage Store at room temperature Oral absorption Erratic absorption, possibly due to GI disturbances associated with the medication CSF penetration Concentrations approach those in serum; one pediatric study evaluating drug concentrations in the CSF suggests that ethionamide should be dosed on the high end of the range for patients with meningitis. Special Use in pregnancy/breastfeeding: Generally avoided during pregnancy due circumstances to reports of teratogenicity; little data about use during breastfeeding (dose the infant with vitamin B6 if breastfed). Use in renal disease: No precautions are required for renal impairment Use in hepatic disease: Can cause hepatotoxicity similar to that of INH— use with caution in liver disease NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 113

Adverse Gastrointestinal upset and anorexia: Sometimes intolerable (symptoms are reactions moderated by food or taking at bedtime). Premedication with an antiemetic like ondansetron is often helpful. Metallic taste. Hepatotoxicity. Endocrine effects: Gynecomastia, hair loss, acne, impotence, menstrual irregu- larity, and reversible hypothyroidism—treat with thyroid replacement. Neurotoxicity (patients taking ethionamide should take high doses of vitamin B6). Side effects may be exaggerated in patients also taking cycloserine. Contra- Sensitivity to ethionamide. indications Monitoring Monitor TSH for evidence of hypothyroidism requiring replacement. Monitor liver function tests. Patient Take this medicine with food. instructions You must also take a high-dose vitamin B6 supplement while on this drug. Call your doctor right away if you have: • Any problems with your eyes: eye pain, blurred vision, color blindness, or trouble seeing • Numbness, tingling, or pain in your hands or feet • Unusual bruising or bleeding • Personality changes such as depression, confusion, or aggression • Yellowing of your skin or eyes • Dark-colored urine • Nausea and vomiting • Dizziness • Swollen breasts (in men 114 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

A1.8. Isoniazid Activity against Bactericidal, especially for rapidly dividing cells. Affects mycolic acid (cell TB wall) synthesis. Inclusion of INH in the regimen of patients with strain W MDR- TB and other strains with low-level INH resistance were also associated with improved outcomes. Cross-resistance Cross-resistance to ethionamide may occur when there is low-level resistance to isoniazid due to a mutation in inhA or the promotor region Dose Adults: high dose 10 mg/kg/day (maximum 600 mg) Children: 10–15 mg/kg/day up to 300 mg Renal failure/dialysis: 300 mg once daily or 900 mg thrice weekly. Vitamin B6 should be used when high-dose INH employed and in patients with diabetes, uremia, HIV infection, alcohol abuse, malnutrition, or peripheral neuropathy. Additionally, pregnant and post-partum women and exclusively breastfeeding infants should receive vitamin B6 while taking INH. Route of Oral administration Preparation 100 mg, and 300 mg tablets Storage Suspension must be kept at room temperature Oral absorption Well absorbed orally or intramuscularly; best absorbed on an empty stomach; up to 50% reduction in peak concentration with a fatty meal. CSF penetration Concentration equivalent to plasma in inflamed meninges. 20% of concentrations in plasma in non-inflamed meninges. Special Use in pregnancy/breastfeeding: Safe during pregnancy; safe during circumstances breastfeeding (both baby and mother should receive pyridoxine supple- mentation). Up to 20% of the infant therapeutic dose will be passed to the baby in the breast milk. Use in renal disease: No dose adjustment for renal failure, but pyridoxine supplementation should be used. Use in hepatic disease: May exacerbate liver failure. Use with caution Drug Interactions: INH may increase the concentrations of phenytoin and carbamazepine. Adverse Hepatitis (age-related). reactions Peripheral neuropathy. Hypersensitivity reactions. Other reactions, including optic neuritis, arthralgias, CNS changes, drug- induced lupus, diarrhea, and cramping with liquid product. Contra- Patients with high-level INH resistance who have failed an INH-containing indications regimen should not receive INH. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 115

Monitoring Clinical monitoring of all patients on INH is essential. Routine laboratory monitoring is not recommended for patients receiving INH monotherapy. For patients receiving multiple TB drugs or other hepatotoxic drugs, or with underlying liver disease (including viral hepatitis), baseline liver function testing is recommended. Follow-up liver function testing is determined by baseline concerns and symptoms of hepatotoxicity. Patient Do not take this medication with a large fatty meal. If you have an upset instructions stomach, take the medicine with a snack. Avoid alcohol while taking this medicine. If you need an antacid, don’t take it within an hour of this medicine. Call your doctor right away if you have any of these side effects: • Loss of appetite for a few days that is not going away • Tiredness, weakness • Moderate stomach pain, nausea, or vomiting • Numbness or tingling of your fingers or toes • Blurred vision, eye pain • Yellow skin or eyes or dark-colored urine

A 1.9. Kanamycin Activity against Bactericidal; has strong anti-TB activity. Inhibits protein synthesis. TB Cross-resistance High likelihood of cross-resistance between kanamycin and amikacin because it is associated with the same mutation (rrs). However, there are some kanamycin mutations (eis) that do not cause amikacin resistance. Some data suggests amikacin cross-resistance with capreomycin. Dose Adults: 15 mg/kg/day in a single daily dose, 5–7 days per week. 15 mg/kg/dose, 2–3 times per week after culture conversion is documented following initial period of daily administration > 59 yrs of age: Many experienced clinicians prefer to use a lower starting dose of 10 mg/kg 5–7 times per week or 2–3 times per week after initial period. Children: 5–30 mg/kg/day (max 1 gram) 5–7 days per week. 15–30 mg/kg/day (max 1 gram) 3 days per week after initial daily period In STR: 15-20 mg/kg/day Renal failure/dialysis: 12–15 mg/kg/dose 2–3 times weekly (not daily). Markedly obese individuals should have an adjusted dose due to the de- creased distribution of extracellular fluids in adipose tissues. Dosing based on actual weight will give supratherapeutic concentrations. Route of Intravenous or intramuscular; not absorbed orally. administration Preparation Clear colorless solution stable at room temperature; 250 mg/ml in vials of 1 gram. Can be mixed with D5W or normal saline for intravenous infusion. Adult doses should be mixed in at least 100 ml of fluid, and pediatric doses should be mixed to a concentration of at least 5 mg/ml. 116 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Storage Kanamycin supplied by the Global Drug Facility does not need storage in in the refrigerator. Oral absorption Not absorbed orally; 40–80% of the dose is absorbed intramuscularly. Intramuscular absorption might be delayed if the same site is used consistently. CSF penetration Minimal and variable CSF penetration—slightly better with inflamed meninges. Special Use in pregnancy/breastfeeding: Generally avoided in pregnan- circumstances cy due to documented congenital deafness. Can be used while breastfeeding. Use in renal disease: Use with caution. Concentrations should be monitored for patients with impaired renal function. Interval adjustment is recommended in case of renal impairment. Use in hepatic disease: Drug concentrations not affected by hepatic disease. Presumed to be safe in severe liver disease; however, use with cau- tion—some patients with severe liver disease may progress rapidly to hepato- renal syndrome. Diuretic use: Coadministration of loop diuretics and aminoglycoside antibiotics carries an increased risk of ototoxicity Adverse Nephrotoxicity. reactions Ototoxicity (hearing loss) and vestibular toxicity: Increased with advanced age and prolonged use; Local pain with IM injections. Electrolyte abnormalities, including hypokalemia, hypocalcemia, and hypomagnesemia Contra- Pregnancy (congenital deafness seen with kanamycin use in pregnancy); indications Hypersensitivity to aminoglycosides; Caution with renal, vestibular, or auditory impairment; Patients with intestinal obstructions. Monitoring Monitor renal function by documenting creatinine at least monthly (more frequently if renal or hepatic impairment); Document creatinine clearance if there is baseline renal impairment or any concerns; Document baseline and monthly audiology exam. Question patient regularly about vestibular complaints and perform serial vestibular exams. Patient Call your doctor right away if you have: instructions • Problems with hearing, dizziness, or balance • Rash or swelling of your face • Trouble breathing • Decreased urination • Watery or bloody diarrhea • Swelling, pain, or redness at your IV site • Muscle twitching or weakness NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 117

A1.10. Levofloxacin Activity against Bactericidal; has strong anti-TB activity. Data suggests greater activity than TB ciprofloxacin or ofloxacin. Inhibits DNA gyrase. Cross-resistance In general, there is a complete class effect cross-resistance among fluoroquinolones in vitro. Dose Adults: 15-25 mg/kg/ day (maximum 1000 mg). Children: 15-20 mg/kg/day once daily if ≥5 years; 2 divided doses if <5 years Renal failure/dialysis: 750–1000 mg/dose 3 times weekly (not daily) for creatinine clearance < 30 ml/min. Route of Oral administration Preparation tablets 500 mg Storage Oral forms, undiluted solution, and pre-mixed solutions are stored at room temperature. Oral absorption Excellent oral absorption. Should not be administered within 2 hours of ingestion of milk-based products, antacids, or other medications containing divalent cations (iron, magnesium, calcium, zinc, vitamins, didanosine, sucralfate). CSF penetration Concentrations are 65% of that in the serum. Special Use in pregnancy/breastfeeding: Fluoroquinolones are generally circumstances avoided in pregnancy and breastfeeding due to observation of ar- thropathy in puppy models. However, there are a few case reports of fluoroquinolones being used safely in pregnancy. Use in renal disease: Dosage adjustment is recommended if creatinine clearance is < 50 ml/min. Use in hepatic disease: Drug concentrations not affected by hepatic disease. Presumed to be safe in severe liver disease. Adverse Nausea and bloating. reactions Headache, dizziness, insomnia, or tremulousness. Rare tendon rupture, arthralgias (can usually be treated symptomatically). QTc prolongation, hypoglycemia. Contra- Fluoroquinolone intolerance, prolonged QTc, pregnancy (relative indications contraindication) Monitoring Side effect monitoring, but no specific laboratory monitoring required. 118 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Patient Avoid caffeinated foods and beverages while taking this medicine; you can instructions take levofloxacin with food. Drink plenty of beverages. Do not take milk- based products, antacids (especially aluminum-containing), mineral supple- ments such as iron or magnesium, or multivitamins within 2 hours of this medication. This medicine may cause sun sensitivity; use sunscreens. Do not undertake new strenuous activities. Call your doctor and stop the medicine right away if you have: • Pain, swelling or tearing of a tendon (such as the back of your ankle, elbow, etc.), or muscle or joint pain • Rashes, hives, bruising or blistering, trouble breathing, or tightness in your chest • Diarrhea • Yellow skin or eyes • Anxiety, confusion, or dizziness

A1.11. Linezolid Activity against Has in vitro bactericidal activity; inhibits protein synthesis. TB Cross-resistance None reported Dose Adults: 600 mg once daily. Children: If ≥12 years: 10 mg/kg/day single dose; if <12 years: 10 mg/kg every 12 hours Renal failure/dialysis: No dose adjustment required. Vitamin B6: All patients should receive vitamin B6 while receiving linezolid Route of Oral administration Preparation tablets 600 mg; Storage Store at room temperature. Oral absorption Nearly complete oral absorption CSF penetration CSF concentrations are about 1/3 of those in serum in animal models, and linezolid has been used to treat meningitis in humans. Special Use in pregnancy/breastfeeding: Not recommended during circumstances pregnancy or breastfeeding due to limited data. Use in renal disease: No dose adjustment is recommended, Use in hepatic disease: Rarely associated with increased transaminases Adverse Myelosuppression. Diarrhea and nausea. reactions Optic and peripheral neuropathy – may be irreversible. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 119

Contra- Hypersensitivity to oxazolidinones. indications Symptoms of neuropathy (pain, numbness, tingling or weakness in the extremities). Drug Interactions: Linezolid should generally not be administered to pa- tients taking antidepressants such as monoamine oxidase inhibitors or selective serotonin reuptake inhibitors due to the potential for serious CNS reactions, such as serotonin syndrome or neuroleptic malignant syndrome-like reactions Monitoring Monitor for peripheral neuropathy and optic neuritis. Monitor CBC weekly during the initial period, then monthly, and then as needed based on symptoms; there is little clinical experience with prolonged use. Patient This medicine may be taken with or without food. Try taking it with food instructions if it bothers your stomach. Make sure your doctor knows if you’re taking medicines for colds, congestion, or depression. Call your doctor right away if you have any of these side effects: • Pain, numbness, tingling or weakness in the extremities • Black, tarry stools or severe diarrhea • Unusual bleeding or bruising • Unusual tiredness or weakness • Headache, nausea, or vomiting • Changes in vision

A1.12.a. Meropenem Activity against In vitro activity—very limited clinical experience TB Cross-resistance Imipenem Dose Adults: 1000 mg every 8 or 12 hours. Must be given with clavulanate (avail- able as amoxicillin / clavulanate ) 125 mg every 8 –12 hours Children: Not established for TB. Suggested dose 20-40mg/kg IV every 8 hours. Renal failure/dialysis: Adjustment in dose and interval based on severity of renal failure and body weight—for example, 750 mg every 12 hours for creatinine clearance 20–40 ml/min, 500 mg every 12 hours for creatinine clearance < 20 ml/min. Route of IV only administration Preparation Vial 1 gram Storage Store at room temperature. Oral absorption No CSF penetration Adequate 120 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Special Use in pregnancy/breastfeeding: Little information known circumstances Use in renal disease: Dose adjustment required, Use in hepatic disease: Liver disease does not alter the pharmacodynamics of meropenem Adverse Diarrhea, nausea, or vomiting. reactions Seizure (noted with CNS infection), but rare Rarely elevated LFTs, hematologic toxicity, hypersensitivity. Contra- Carbapenem intolerance indications Monitoring Symptomatic Patient Make sure your doctor knows if you are also taking valproic acid or have instructions allergy to penicillins or cephalosporins Call your doctor right away if you have any of these side effects: • Severe diarrhea (watery or bloody) • Skin rash, hives, or itching • Swelling in the face, throat, or lips • Wheezing or trouble breathing

A1.12.b. Amoxicillin – clavulanic acid Activity against Only to be used because of the Clv component in combination with TB meropenem Cross-resistance None Dose Adults: 250mg/day of Clv in 2 divided doses Children: 5 mg/kg/day of Clv in 2 divided doses Renal failure/dialysis: For creatinine clearance 10 – 30 ml/min dose 1000 mg as amoxicillin twice daily; for creatinine clearance < 10 ml/min dose 1000 mg as amoxicillin once daily. Route of Oral administration Preparation Various combinations of amoxicillin and clavulanate. Storage Store at room temperature. Oral absorption Good oral absorption, best tolerated and well absorbed when taken at the start of a standard meal. CSF penetration Poor Special Use in pregnancy/breastfeeding: No known risk circumstances Use in renal disease: Dose adjustment required, Use in hepatic disease: Clavulanate is cleared by the liver, so care should be used when using in patients with liver failure. Adverse Diarrhea and abdominal discomfort are most reactions common. Hypersensitivity. Nausea, vomiting, and rash are also common. Rare side effects have been reported in all other organ systems NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 121

Contra- Penicillin allergy; use with caution with cephalosporin allergies indications Monitoring No specific monitoring is required Patient Take at the beginning of a meal. instructions Store tablets at room temperature Call your doctor right away if you have any of these side effects: • Rash or swelling • Trouble breathing • Severe diarrhea

A1.13. Moxifloxacin Activity against Bactericidal; inhibits DNA gyrase; may be more active than other TB fluoroquinolones based on in vitro data. Cross-resistance In general, there is a complete class effect cross-resistance among fluoroquinolones in vitro. However, data suggest that moxifloxacin may continue to demonstrate some activity despite in vitro resistance to ofloxacin. Dose Adults: standard dose 400 mg daily; high dose in STR 10-15mg/kg/day Children: No established dose. Suggested standard dose 7,5-10mg/kg/day; high dose in STR 10-15mg/kg/day Renal failure/dialysis: No dose adjustment required Route of Oral or IV. administration Preparation Tablets 400 mg Storage Store oral and IV products at room temperature (do not refrigerate). Oral absorption Good oral absorption (90% bioavailable). Should not be administered within 2 hours of ingestion of milk-based products, antacids, or other medications containing divalent cations (iron, magnesium, calcium, zinc, vitamins, didanosine, sucralfate). CSF penetration Good penetration in animal model studies. Special Use in pregnancy/breastfeeding: Fluoroquinolones are generally avoided circumstances in pregnancy and breastfeeding due to observation of arthropathy in puppy models. However, there are a few case reports of fluoroquinolones being used safely in pregnancy. Use in renal disease: Excretion unchanged in the face of renal failure; Use in hepatic disease: Rarely associated with hepatotoxicity; use with caution. No dose adjustment required for mild or moderate liver disease. Adverse Nausea and diarrhea. reactions Headache and dizziness. Rare tendon rupture; arthralgias. Rare hepatotoxicity. QTc prolongation, hypo/hyperglycemia. Contra- Fluoroquinolone intolerance, prolonged QTc, pregnancy (relative contrain- indications dication). Monitoring Symptomatic monitoring. 122 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Patient Keep moxifloxacin at room temperature. Moxifloxacin can be taken with food, instructions but do not take milk-based products, antacids (especially aluminum-coating), vitamin supplements, or sucralfate within 2 hours of this medication. Do not undertake new strenuous activities. Call your doctor and stop the medicine right away if you have: • Pain, swelling or tearing of a tendon (such as the back of your ankle, elbow, etc.), or muscle or joint pain • Rashes, hives, bruising or blistering, trouble breathing, or tightness in your chest • Diarrhea • Yellow skin or eyes • Anxiety, confusion, or dizziness

A1.14. Para-aminosalicylic acid Activity against Bacteriostatic. TB Cross-resistance None reported Dose Adults: 150-200mg/kg/day in 2-3 divided doses per day. Maximum 12 grams daily. Children: 200 –300 mg/kg/day divided 2–4 times per day Renal failure/dialysis: No change. Route of Oral; should be given sprinkled on or stirred into yogurt or similar food. Do not administration chew the granules; they should be swallowed whole. Preparation 4 grams per sachet. Storage Sachets should be kept in the refrigerator or freezer. Oral absorption Incomplete absorption—sometimes requires increased doses to achieve therapeutic concentrations. CSF penetration Poorly penetrates the meninges (somewhat better with inflammation). Special Use in pregnancy/breastfeeding: Not studied, but no teratogenicity circumstances known. There is little data regarding use during breastfeeding Use in renal disease: Inactive metabolite is cleared by the kidneys. The package insert says to avoid with severe renal failure. Other authorities believe it can be used with caution (no toxicity of metabolite known). Use in hepatic disease: Use with caution; 0.5% incidence of hepatotoxicity Adverse Gastrointestinal distress reactions Rare hepatotoxicity and coagulopathy. Reversible hypothyroidism (increased risk with concomitant use of ethionamide)—treat with thyroid replacement. Contra- Pregnancy (relative) indications Monitoring Monitor TSH, electrolytes, blood counts, and liver function tests. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 123

Patient Keep the product in the refrigerator or freezer. instructions Sprinkle granules over applesauce or yogurt or swirl in acidic juices (tomato, grape, grapefruit, cranberry, apple, or orange). Do not chew the granules. Take with food if desired. Do not use the packet if expanded or if the granules are discolored. Gastrointestinal discomfort and diarrhea usually improve over time. The shells of the granules may be seen in the stool— this is normal. Call your doctor right away if you have any of these side effects: • Skin rash, severe itching, or hives • Severe abdominal pain, nausea, or vomiting • Unusual tiredness or loss of appetite • Black stools or bleeding

A1.15. Pyrazinamide Activity against Bactericidal for semi-dormant M. tuberculosis. Mechanism unclear. TB Cross-resistance None reported. Dose Adults: 20-30 mg/kg/day. Children: 30–40 mg/kg/day. Route of Oral; administration Preparation 500 mg tablet. Storage Store the tablets at room temperature. Oral absorption Well absorbed from the GI tract. CSF penetration Concentrations equivalent to serum. Special Use in pregnancy/breastfeeding: no known teratogenicity but lack of data circumstances regarding teratogenicity. Can be used while breastfeeding. Use in renal disease: Cleared by the kidneys; dose 3 times a week Use in hepatic disease: Use with caution; pyrazinamide is associated with hepatotoxicity in about 1% of patients. It can be quite severe and worsen off treatment. Adverse Gout (hyperuricemia) and arthralgias. reactions Hepatotoxicity. Rash. Photosensitivity. Gastrointestinal upset. Contra- Allergy to pyrazinamide; severe gout. indications Monitoring Monitor transaminases and uric acid. 124 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Patient May be taken with or without food. instructions This medicine may cause a rash after sun exposure: limit your sun exposure.

Call your doctor right away if you have any of these side effects: • Skin rash, severe itching, or hives • Pain or swelling in the joints • Yellowing of the skin or eyes or dark urine • Nausea or vomiting • Unusual tiredness or loss of appetite NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 125 - Grade 4 Grade Life threatening Life < 6,50 < 1 000 < 500 < 20 000 or diffuse petechiae > 10,00 x N > 10,00 x N > 10,00 x N > 10,00 x N > 10,00 x N > 6,00 x N or dialysis required or hyperosmolarity Acidoketosis (>27,8 mmol/l without acidosis) < 2,5 < 1,50 > 10 x N liquids; to limited intake Food required hospitalisation hypovolemic for Hospitalisation shock deficiency: > 90 dB hearing Extreme be cannot loss; speach of hearing all at heard signs (venticu > 500ms with clinical lar arrythmia, de torsade syncope, pointe) Severe Grade 3 Grade 6,5 – 6,99 1 000 – 999 500 – 749 20 000 – 49 999 > 5,00 – 10,00 x N > 5,00 – 10,00 x N > 5,00 – 10,00 x N > 5,00 – 10,00 x N > 5,00 – 10,00 x N > 3,00 – 6,00 x N > 16,5 without ketosis 2,5 – 2,7 1,50 – 1,74 5,1 – 10 x N more for compromised intake Food than 3 days 24 hours; Solid/liquid vomiting for perfusion hypotension; orthostatic required 90 deficiency: 70 to Severe hearing is heard loss; speach dB of hearing the ear loudly close to only if spoken > 500ms - Grade 2 Grade Moderate 7,0 – 7,99 2 000 – 999 750 – 999 50 000 – 74 999 > 2,50 – 5,00 x N > 2,50 – 5,00 x N > 2,50 – 5,00 x N > 2,50 – 5,00 x N > 2,50 – 5,00 x N > 1,50 – 3,00 x N > 7,0 – 16,5 2,8 – 3,1 1,75 – 1,94 2,6 – 5,0 x N less for compromised intake Food than 3 days or 4 – 5 episodes/day Repeated; > 1 week duration 70 deficiency: 40 to hearing Moderate is heard loss; speach dB of hearing or only under but poorly understood lip reading through stood Male: 450< <500 ms 470< <500 ms Female: Mild Grade 1 Grade 8,0 – 9,40 3 000 – 900 1 000 – 500 75 000 – 99 1,25 – 2,50 x N 1,25 – 2,50 x N 1,25 – 2,50 x N 1,25 – 2,50 x N 1,25 – 2,50 x N 1,00 – 1,50 x N 6,1 – 7,0 3,2 – 3,4 1,95 – 2,10 1,25 – 2,5 x N intake normal food Transient; 2 – 3 episodes/ day or Transient; ≤ 1 week duration 40 deficiency: 20 to Mild hearing to hear loss; difficulty dB of hearing complex intensity, sounds of weak voices noises and low or distant N.A. N = normal value; N.A. = not applicable N.A. = not N = normal value; Hemoglobine (g/dl) (/mm3) Leucocytes (/mm) Neutrophiles (/mm3) Plateletss Serum bilirubine (μmol/l) (IU/l) SGOT (IU/l) SGPT (IU/l) phosphatase Alkaline (IU/l) Gamma GT (μmol/l) Serum creatinine (mmol/l) fasting glycemia, (mEq/l) Serum potassium (mmol/l) Serum calcium Uric acid (TU/l) Nausea Vomiting problems Hearing of the QT Lengthening interval Annex 2. Grading of the severity of Adverse Drug Events Adverse of the severity of 2. Grading Annex 126 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT Grade 4 Grade Life threatening Life Myxoedematous coma Myxoedematous of skin or Any bullous condition or Stevens- (type Lyell mucosa Johnson); diffuse erythema with or without other with fever, of the hypersensitivity signs; necrosis excision surgical skin, reuiring shock Anaphylactic psychosis with suicidal Acure manic state tendencies, and hallucinatory delirium; required hospitalisation N.A. Blindness dependency total stand, Inability to Severe Grade 3 Grade Severe hypothyroidism with multiple Severe hypothyroidism urgently; be treated signs; to clinical may be required hospitalisation or oozing papular-vesicular Extended purpura palpable eruptions; oedema Quincke’s Giant urticaria; depression or manifest Major anxiety treatment requiring arthritis with or without Manifest joint effusion or presenting loss functional important 3m at fingers count Cannot of upper or lower limbs Ataxia on impact abnormal movements; daily activity Grade 2 Grade Moderate Manifest hypothyroidism without hypothyroidism Manifest required treatment complications; eruptions maculopapular Extended with or without itching urticaria localised Acute or treatment requiring Anxiety depression moderate with or without joint Joint pain moderate effusion or presenting loss functional at 3m but not at fingers Can count 6m or dyskinesia dysmetria tremors on impact or dysarthria; moderate daily activity Mild Grade 1 Grade Infraclinical erythema and itching Moderate N.A. Minor anxiety Joint pain count can complaints; Subjective 6m at fingers clumsiness; mild Occational problems coordination N = normal value; N.A. = not applicable N.A. = not N = normal value; Hypothyroidism mucous and/or Cutaneous eruptions with hypersensitivity, Acute or without dermatological signs Psychosis Arthritis of vision Loss movements Uncontrolled Annex 2. Grading of the severity of Adverse Drug Events Adverse of the severity of 2. Grading Annex NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 127

Annex 3. Calculating the QT interval

Note: The information below is about QTcF measurement and for management please see the relevant information in aDSM chapter

What is QT Interval and measuring QTc (Ref: E. Burns 2017) • QT Interval is the time measurement from the start of Q wave to the end of T wave • It tells us the time taken for ventricular depolarization and ventricular repolarisation-means ventricular contraction to relaxation • QT interval is inversely proportional to Heart Rate-----,QT shortens at faster heart rate and QT lengthens at slower heart rate • Abnormally prolonged QT wave is associated with sudden arrhythmias and leading to Torsade de pointes(Tdp)

Measuring QTc: Standardization • The QT interval should be measured in Long lead II, V5, V6 • Several successive beats should be measured with the maximum interval taken • Large U waves(more than 1 mm) that are fuse to the T wave should be included in measurement • Small U waves and those which are separate from T should be excluded • The maximum slope intercept method is used to define the end of T wave 128 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Corrected QT– is called QTc • With Irregular Rhythms (such as Atrial Fibrillation) always note the general(average) ventricular rate (QRS’s per 6-sec. strip ✕ 10)

Rule of Thumb: Always remember 1. Use triplets method quickly to estimate heart rate, one larger square is 300, 2 LSs = 150, 3LSs=100,4 LSs=75,5LSs =60 all per minute 2. The normal QT interval is between 7-11 small squares 3. The normal QT is less than half of the preceding RR interval NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 129

QTcF Nomogram How to use the QTcF Nomogram 1. Identify the patient’s HR or RR interval on the top of the table. 2. Identify the measured QT (uncorrected) interval on the left of the table. 3. Find the corresponding calculated QTcF in the cell below the HR (or RR) and to the right of the QT interval.

The Framingham Formula Calculation of QTcFra QTFra(s)= QT +0.154 [1-RR(s)] QT: distance between start of QRS complex and end of T wave, in seconds (number of small squares x 0.04) RR: distance between two R waves: R et R’ in seconds (number of small squares x 0.04) QTcFra(sec) x 1000= QTcFra(ms) 130 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Annex 4. Calculating the creatinine clearance

The estimated creatinine clearance is calculated based on the Cockcroft-Gault equation and is expressed in ml/minute.

140 – age Weight Creatinine clearance (CreatClear) = constant * ( ) * ( ) Serum creatinine 72

The constant is dependent on the sex: male = 1; female = 0.85

The serum creatinine should be expressed in mg/dl. If the laboratory gives the result in µmol/l, it can be converted into mg/dl by dividing the µmol/l by 88.4.

Example: 212µmol/l = 212/88.4 = 2.398 mg/l.

A calculator to convert a serum creatinine result expressed in µmol/L to mg/dL can be found on the internet: http://www.endmemo.com/medical/unitconvert/Creatinine.php

Example: a female patient (age = 46 years, weight = 50 kg) has serum creatinine = 212 µmol/l. 140-46 50 94 50 CreatClear = 0.85 * ( ) * ( ) = 0.85 * ( ) * ( ) = 0.85*39.2*0.694 = 23.1ml/min 2.398 72 2.398 72

A calculator to calculate the estimated creatinine clearance based on the Cockcroft-Gault equation can be found on the internet: http://reference.medscape.com/calculator/creatinine-clearance- cockcroft-gault.

Normal values for creatinine clearance are:

Men: 97 to 137 ml/min Women: 88 to 128 ml/min NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 131

Annex 5: Peripheral Neuropathy Diagnostics

Note: Please use this with relevant chapter of aDSM to follow gradings and management

It is characterized by a decline and damage of nerve function leading to loss of sensation, ulceration and subsequent amputation.

There is a common misconception that diabetic neuropathy is a phenomenon limited largely to the lower limbs, which is not really true. About 40% of patients with neuropathy have upper limb involvement in addition and the associated symptoms could be positive with that of pain, paresthesias and dysesthesias, typically glove and stocking distribution.

There is probability that in some TB, HIV, Diabetic patients there is some level of pre-existing peripheral neuropathy and use of toxic drugs may further exacerbate the situation leading to grade 1 or grade 2 of PN, which limits the use of such toxic drugs(for example Lzd, Cs, high dose INH)

Table; Distal symmetrical Polyneuropathy, small fiber and large fiber neuropathy (Source: A Practical guide to DM,7th edition, © 2016, Jaypee Brothers Medical Publishers

Small fiber neuropathy Large fiber neuropathy Fiber C-fiber type Delta type (Aδ) Sensory loss 0 to + (Warm thermal perception) 0 to +++ (touch, vibration perception)– Pinprick hypoesthesia checked with biothesiometer and tuning Light touch sensation ↓↓ fork (128 Hz) Monofilament testing–1 and 50 g) ↓ position sense and muscle strength ↓ sharp-dull and two-point discrimination. Prominent Hyperalgesia-superficial pain (+ to +++) Deep-seated, dull aching pain (+ to +++) symptoms Constant burning Sensory ataxia → falls → minor trauma/ Allodynia– ↓ sweating → dryness fractures → ulcers/amputation Severe hyperesthesia Shock-like sensations Hypoalgesia–late

ACTG Brief Peripheral Neuropathy Screening Tool(Source: NIAID Adult AIDS Clinical Trials Group)

Following are the step wise approaches to detect peripheral neuropathy in patients. Please remember that this assessment is subjective and may lead to wrong scoring if not properly carried out. Therefore, it is imperative that doctors/nurses/health care workers should be appropriately trained to carry out below assessments.

1: Elicit Subjective Symptoms

Ask the subject to rate the severity of each symptom listed in Question 1 on a scale of 01 (mild) to 10 (most severe) for right and left feet and legs. Enter the score for each symptom in the columns marked R (right lower limb) and L (left lower limb). If a symptom has been present in the past, but not since the last visit, enter "00 - Currently Absent." If the symptom has never been present, enter "11 - Always Been Normal." 132 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Always Been Normal Currently Absent Mild Severe 11 00 01 02 03 04 05 06 07 08 09 10

Symptoms R L a. Pain, aching or burning in feet, legs b. “pins and needles” in feet, legs c. Numbness (lack of feeling) in feet, legs

2. Grade Subjective Symptoms

Use the single highest severity score from Question 1 above to obtain a subjective sensory neuropathy score. If all severity scores are "00" or "11," the subjective sensory neuropathy score will equal "0."

Subjective Sensory Neuropathy Score (based on highest severity rating)

01- 03 = grade of 1 04- 06 = grade of 2 07- 10 = grade of 3 11 or 00 = grade of 0

R L

3. Evaluate Perception of Vibration

Compress the ends of a 128-Hz tuning fork just hard enough that the sides touch. Place the vibrating tuning fork on a bony prominence on the subject's wrist or hand to be sure that he/she can recognize the vibration or "buzzing" quality of the tuning fork. Again, compress the ends of the tuning fork just hard enough that the sides touch. Immediately place the vibrating tuning fork gently but firmly on the top of the distal interphalangeal (DIP) joint of one great toe and begin counting the seconds. Instruct the subject to tell you when the "buzzing" stops. Repeat for the other great toe.

Vibration perception

a. Great toe DIP joint perception of vibration in seconds b. Vibration perception score 0 = felt >10 seconds (normal) 1 = felt 6-10 seconds (mild loss) 2 = felt <5 seconds (moderate loss) 3 = not felt (severe loss) 8 = unable to or did not assess

R L NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 133

Picture: Adopted from , End TB Guidelines 2018

Vlbration perception Result Score Felt > 10 seconds Normal 0 Felt 6-10 seconds Mild loss 1 Felt

4. Evaluate Deep Tendon Reflexes

With the subject seated, the examiner uses one hand to press upward on the ball of the foot, dorsiflexing the subject's ankle to 90 degrees. Using a reflex hammer, the examiner then strikes the Achilles tendon. The tendon reflex is felt by the examiner's hand as a plantar flexion of the foot, appearing after a slight delay from the time the Achilles tendon is struck. Use reinforcement by having the subject clench his/her fist before classifying the reflex as absent.

Ankle Reflexes Score

0 = absent 1 = hypoactive 2 = normal deep tendon reflexes 3 = hyperactive 4 = clonus 8 = unable to or did not assess

R L 134 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Nylon Monofilament Test (Source: a practical guide to DM, 7th edition)

The Semmes-Weinstein monofilament: The standard American Diabetes Association (ADA) criteria will mention that it is only necessary to do a 2 g and a 10 g monofilament testing. In leprosy or TB, up to 300 g may be utilized.

Form to be completed on monthly visit while patient is on Lzd/Cs and or Diabetics : The Brief Peripheral Neuropathy Screen Tool (Refer to next page) NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 135

BRIEF PERIPHERAL NEUROPATHY SCREENING NIAID ADULT AIDS CLINICAL TRIALS GROUPS

Patient number date of patient visit Protocol Number Institution Code Form week key operator code

INSTRUCTIONS FOR RECORDING SUBJECTIVE ELICITED SYMPTOMS: • Ask the subject to rate the severity of each symptom listed in question 2 (a-c) on a scale of 01 (mild) to 10 (most severe) for right and left feet, legs. • Enter the score for each symptom in the column marked Presence/Severity. • If a symptom has been present in the past, but not since the last visit, enter ‘00-Currently Absent’ • If the symptom has never been present enter ‘11-Always Been Normal.’ • The use of “-1” is not acceptable as an answer to any question.

1. Was a subjective elicited peripheral neuropathy evaluation completed?...... (1-Yes, 2-No) If Yes, go to question 2. If No, complete ‘a’ and go to question 4

a. If not completed, indicate reason why: ………...... ……1 - Subject declined, specify 2 - Subject missed clinic visit 9 - Other reason, specify If ‘1-Subject declined’ or ‘9-other reason’, specify [30]:

Always Been Normal Currently Absent Mild Severe 11 00 01 02 03 04 05 06 07 08 09 10

2. SYMPTOMS PRESENCE/SEVERITY Right Left a. Pain, aching, or burning in feet, legs: ...... b. ‘Pins and needles’ in feet legs: ...... c. Numbness (lack of feeling) in feet, legs: ......

INSTRUCTIONS FOR GRADING SUBJECTIVE ELICITED SYMPTOMS:

Use the single highest severity score from 01-10 In question 2 (a-c) above to obtain a subjective peripheral neuropathy grade. If all severity score is ‘00’ or ‘11’, the subjective peripheral neuropathy grade will equal ‘0.’

Presence/Severity score of: 01 – 03 = Grade of 1 04 – 06 = Grade of 2 07 – 10 = Grade 3 11 or 00 = Grade 0

3. Subjective peripheral neuropathy grade …………………………………………………

Source: JH McArthur 136 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Annex 6. Forms, records and registers

Government of Nepal Ministry of Health & Population Department of Health Services National Tubeculosis Center DRTB 05 aDSM Adverse Event Reporting Form - Nepal

A. Patient and Health Facility Information Patient ID number (as in DRTB Treatment Centre: Register: Date of Birth (or Age): Province: Sex:  Male  Female HIV status:  Non-reactive  Reactive Pregnancy:  No  Yes Trimester: Weight (kg): Height (cm): BMI: B. Adverse events experienced by patient (including abnormal investigations) Adverse event Onset date End date Severity grade Seriousness * Outcome §

* Please select: D died LT life threatening HA caused or prolonged hospital admission PD permanent disability OS other medically serious CA congenital abnormality NS not serious § Please select: A recovered B recovering C recovered with residual effects D died E not recovered F unknown Detailed description of adverse event(s):

Was treatment of adverse event required?  No  Yes (please specify):

C. Laboratory assessment: Results of tests and procedures Test performed Test date Result Unit Reference range

NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 137

D. Medicines: DR-TB Regimen and other concomitant medicines, vaccines, traditional / herbal medicines and dietary supplements  Tick if medicine suspected of causing adverse event Medicine Dose Frequency Route Start date Stop date Reason for use Action taken † Response ‡            † Action taken in response to AE: DW drug withdrawn DR dose reduced DI dose increased DNC dose not changed UK unknown NA not applicable ‡ Response to action taken: RA recovered NE no effect on AE FA fatal AE UN unknown NA not applicable E. Re-challenge information List any medicines that were restarted and indicate effect on adverse event Medicine adverse event recurred adverse event did not recur unknown                      F. Other relevant information e.g. medical history, concurrent illnesses, smoking, alcohol use and Hospital Management

G. Causality Assessment at Treatment Center Level

1. Certain 2. Probable 3. Possible 4. Unlikely 5. Unassessed 6. Un-assessable

Comments:

138 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

H. Final AE/SAE Summary

Adverse Events Description: Event Start date Event End date Severity Grading Event classified: 1. Serious 2. Not – Serious (Based on Annex 2) Narrative / Additional information (Final Result):

G. Reporter Information Name: Phone number: Email: Occupation:  Doctor  Nurse  Paramedics  Other (please specify): Signature: Date

Submit form to: Email to: M&E Unit, NTC: [email protected]

NTC Use Only: Date received by NTC: Causality assessment:  Certain  Probable  Possible  Unlikely  Unassessed  Un-assessable Comment:

Reported to DDA:  No  Yes Date reported to DDA:

NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 139

Annex 7: Gastric aspirate Job aid: 140 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Annex 8: Monitoring and Evaluation Checklist (Programmatic & Clinical) for DR-TB Treatment Site

National TB Control Program, Nepal Monitoring and Evaluation Checklist (Programmatic & Clinical) for DR-TB Treatment Site

Name of DR-TB Treatment Site: District/ Region: Name & Designation of Visitor & Co-visitor Date of Visit: Objective of the Visit: Period covered for review:

Yes (report Observations/ # Indicators to Monitor is attached if No Remarks applicable) 1 Meeting with Stake Holders 1.1 Hospital Administration ( MS/ DMS) 1.2 DR-TB Site Focal Person 1.3 DR-TB Site Supporting Staff 1.4 SLDs Pharmacist 1.5 Others 2 DR-TB Management Site Site Identified as DR-TB care service provider 2.1 (Board Displayed) Facility visited by NTP/RTO/MDR-focal in 2.2 Reviewing Period Updated DR-TB National Guidelines 2.3 available on site 2.4 DR-TB National Guidelines implemented Staff Trained on the National Guidelines? 2.5 if not please provide names of and designation TB and DR-TB Related IEC Material on 2.6 display DR TB ward available (#of beds), if in the 2.7 hospital 3 Infection Control An Infection Control Committee or Person is 3.1 designated in this site A written Infection Control (IC) plan or check 3.2 list is available for this site 3.3 TB-IC training for all staff has been done. Facility design and patient flow have been 3.4 assessed (best use of space & ventilation). IC measures in ward (ventilation, distance 3.5 between beds etc NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 141

Yes (report Observations/ # Indicators to Monitor is attached if No Remarks applicable) Triage of Patients with cough more than 2 3.6 weeks is done upon entering facility. Patients with cough more than 2 weeks are 3.7 separated from others and "fast tracked" to caregivers Natural and/or mechanical airflow is monitored daily by staff (especially in 3.8 waiting rooms, sputum collection room if available, and at least one exam room). Regular maintenance for directional and 3.9 extractor fans is conducted. Signage is in place to keep doors and 3.10 windows open when feasible. If UV lighting is used, routine maintenance is 3.11 scheduled. Patients are not crowded in hallways or 3.12 waiting areas. N95 or FFP2 respirators are readily available 3.13 for staff. Staff has been trained on proper fit of 3.14 respirators. Supplies are available to coughing patients 3.15 (tissues, cloths,surgical masks, trash bins, etc.). Staff is provided continuing education 3.16 opportunities and annual exams on TB-IC. 4 DR-TB Management DR-TB 01 Patient’s Treatment Card 4.1 Adequately Filled and updated (check random cards) Past TB history mentioned, Supporting 4.2 Documents are attached with DR-TB 01 Treatment regimens designed correctly and 4.3 appropriately as per guidelines Practices to stop Injectable are as per 4.4 guidelines? Are side effects being identified timely and 4.5 managed appropriately? Audiometry, baseline and follow up investigations done, reports available? 4.6 Who is performing audiometry and is trained? DR-TB 03 ENRS Register adequately Filled 4.7 and updated(lab results, smear, xpert, CL/ DST),body weight recorded correctly DR-TB 01 and DR-TB 03 tallies with each 4.8 other 142 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Yes (report Observations/ # Indicators to Monitor is attached if No Remarks applicable) Patients files maintained properly in serial 4.9 order DR-TB 04 Laboratory Register adequately 4.10 filled and maintained DR-TB 03(patient identity booklet) and DR- 4.11 TB 04(lab register for DR TB) tallies with each other Number of MDR TB patients with Diabetes, 4.12 outcomes and glycemic control status Treatment outcomes declared and 4.13 mentioned appropriately as per guidelines Quarterly and Annual Reports are 4.14 maintained Total Number of Cases Detected last Quarter 4.15 (DR-TB 04) and total enrolled Time lapse between G. Xpert result and Enrolment (Please check 4 files of last quarter) RR detected Date: Enrolment Date: 1. 2. 3. Reasons for delay of enrolment: 4.16 Time lapse between baseline /3rd month CL/ DST requested and reports available CL/DST request Date: Result Date: 1. 2. 3. Reasons for delay of results: Number of results with contaminated 4.17 cultures and or not done Number of patients with missed 4.18 appointments and loss of follow up and what actions have been taken for retrieval? Post treatment outcome follow up being 4.19 done and recorded? 5 Contact Screening Staff receives an evaluation for TB at least 9.1 annually. Close contact screening for DR-TB patients 9.2 are done and documented on DR-TB 01 Number of patients enrolled through contact 9.3 screening 10 MDR TB/HIV NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 143

Yes (report Observations/ # Indicators to Monitor is attached if No Remarks applicable) 10.1 All DR-TB patients are tested for HIV MDR TB/HIV co-morbid patients are referred 10.2 for ART 11 SLD Management Drugs Standard Storage Condition in practice (comment on General condition of 11.1 stores and availability of racks for stacking drugs etc) SLDs available for current patients on 11.2 treatment for the next 3 months 11.4 Store Temperature maintained and recorded 11.5 SLDs arranged in FEFO manner Stock Status Record maintained properly, 7.6 main, daily stock books 7.7 Consumption Matrix maintained properly 7.8 Consumption Matrix tallies with DR-TB 03 SLDs Stock out Reported for on treatment 7.9 Cases (GLC) – name of drug and Days out of stock 7.10 Ancillary Drugs in Stock Stock Status Record cross checked with 7.11 physical stock available on shelves 8 DR-TB Laboratory Is the Laboratory register filled in correctly 8.1 and up to date? Number of patients smear/CL positive at 8.2 the end of intensive phase and Smear/CL positive at month 3,4? Facility linked for xpert and Culture/DST? 8.2 please mention linked Laboratory. How is the system of sample transportation 8.3 to labs(xpert,CL,DST),how often samples re sent to next level labs Monthly Smear, Culture and other 8.4 Laboratory Tests performed for patients who are on treatment (DR-TB 01 &DR-TB 03) Sputum samples are collected in a 8.5 designated area and away from others. Health care workers which assist during 8.6 sputum collection take precautions. Processing of sputum samples is expedited 8.7 to lab. There is a tracking mechanism to monitor the turn-around time of lab results. 8.8 Gene Xpert available and functional 144 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Yes (report Observations/ # Indicators to Monitor is attached if No Remarks applicable) 8.9 Electricity Backup System in place Laboratory Reagents and other stock 8.10 available Laboratory under External Quality Assurance 8.11 System 8.12 Laboratory wastes properly disposed Interview with MDR TB patients (please randomly select 2 patients) 1: Do you know how MDR TB is spread and how to prevent spread? 2: How many tablets are you taking every day, when do you take the medicine and does anyone observe you when you take the medicine? 9 3: When do you take injection, by whom? 4: Do you know name of your DOT supervisor? 5: Do you receive socio-economic support during your Treatment?

Other Activities Undertaken: 10 Issues/Challenges Identified: 11 Actions Taken: 12 Follow-up on the Recommendation of Pervious Visit: 13 Recommendation to the Site:

Submitted By: NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 145

Annex 9: Modified Shorter Regimen and Future STR Options

People living with DR-TB, their doctors, and treatment programs face important and difficult decisions because there is no clear evidence that one regimen is better than another. Both the shorter and longer regimen performed much better in the STREAM trial than the average MDR-TB treatment success rate of about 50% normally observed worldwide in regular treatment programs. Now WHO has recommended all Injectable free longer RR/MDR TB regimen and advised shared based decisions with patients to choose right regimen. WHO has also now recommended that NTPs should move forward with operational research on modified injectable free shorter regimens.

Futures focus globally is on STRs and many Trials are ongoing around the globe because; STRs are of much less duration, equally effective, cheaper, promising to scale up DR TB program for NTPs.

Following is the information on studies being conducted and planned around the globe for shorter regimens even for pre-XDR and XDR TB.

STR New Studies

Globally now all studies are focusing on all oral STR with different drug combinations and searching for effective, safer and shorter treatment option for MDR, Pre XDR and XDR TB patients (6 months, 9 months, 11 months)

Nix TB clinical study- with combination of Pretomanid, Bedaquiline and Linezolid (6-9 months) for MDR, Pre XDR and XDR showing high treatment success rates.

TB PRACTECAL- Bdq, Pretomanid in combination with preexisting new and repurposed drugs for treatment of MDR,Pre XDR,XDR TB.

End TB clinical Trial part 1: from 2015-2019, nearly 750 patients, different combinations of Bdq, Dlm, Lzd, FQs, CFZ, Z in FQ susceptible patients.

End TB Clinical trial part 2: duration 2017-2019, combination of Bdq, Lzd, Dlm, Cfz in different arms for 6 months, 9 months and 20-24 months in FQ resistant TB

Bpal Trial: with addition of Pretomanid in combination with Lzd, Bdq(after FDA approval of Pretomanid)

Modified shorter treatment regimen – MSTR Under OR 1. 9 Bdq, 9-12 Lfx, Lzd, Cfz,Z(Destroy TB operational research) 2. 6-8 Bdq,Lfx(high dose)hh, Cfz, Cs, INHh, E, Z/5 Mfxh,Cfz,Cs, Z,E 3. 6-8 Bdq,Lfx(high dose)hh, Cfz, Eto, INHh, E, Z/5 Mfxh,Cfz, Z,E

Option 1 regimen contains all best bactericidal, sterilizing activity and resistance prevention characteristics with extended use of Bdq

Option 2 is with adjustments, bdq can be extended to 8 months if delayed response and if Bdq is stopped by month 6 then switch Lfx to high dose Mfx, Cs replaces Eto.

Option 3, is just replacing Inj with Bdq, but after Bdq is stopped switch Lfx to high dose Mfx

Maximum duration for all three regimens is 12 months (9-12)

The cost of all these three regimens varies. 146 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Annex 10 : Triple Layer Packaging of Samples

Transport conditions

 Sputa should be transported to the laboratory as soon as possible with in 24-72 hours.

 Keep specimens cool (refrigerated but not frozen). Specimens should preferably be kept in a refrigerator at 4C. If none is available then cold boxes can be used with a small amount of dry ice, as long as it is ensured specimens do not freeze. Refer to below for packaging instructions.

 Up to a week in cold conditions will not significantly affect the positivity rate of smear microscopy/Xpert test; however, the additional growth of contaminants will result in an increased contamination rate on culture media after 7 days.

Transport packaging

The basic packaging system for local surface transport of all specimens consists of three layers

1) Primary receptacle – the specimen container Primary receptacle – packaged with enough (leakproof or siftproof) Waterproof absorbent material to absorb Cap all fluid in case of breakage. Rack-type holder (styrofoam, sponge) Absorbent 2) Secondary packaging – a packing second durable, watertight, material Itemized list of contents leak-proof packaging to (specimen record) enclose and protect the primary receptacle(s). Several cushioned primary Secondary Rigid outer packaging receptacles may be placed packaging ) leakproof or in one secondary packaging, siftproof) Proper shipping but sufficient additional name

absorbent material must be Package marking used to absorb all fluid in To/From labels case of breakage. For cold transportation conditions, ice or dry ice shall be placed outside the secondary receptacle. Wet ice shall be placed in a leak-proof container;

3) Outer packaging – secondary packaging are placed in outer shipping packaging with suitable cushioning material. Outer packaging protects its contents from external influences, such as physical damage, during transit. NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 147

Annex 11: Forms, Records and Registers

The following documents for recording and reporting are used are:

S.N TB Number Tools 1 TB 01 Presumptive TB register 2 TB 02a Laboratory Request Form 3 TB 02b Laboratory Report Form (LPA and Culture DST) 4 TB 03a Laboratory Register (Microscopy) 5 TB 03b Laboratory Register (GeneXpert) 6 TB 03c Laboratory Register (Culture DST) 7 TB 03d Laboratory Register (LPA) 8 TB 03e Culture / DST Reporting Form 9 DRTB 01 DR-TB Register 10 DRTB 02 DR-TB Treatment Card 11 DRTB 03 DR-TB Patient Identity Card 12 TB 07 Contact Investigation Form 13 TB 08 Contact and TBPT Register 14 TB 10 Referral / Transfer Slip 15 TB 11 Referral Form (Community, Private, Contact) 16 DRTB 04 Commitment Form 17 DRTB 05 aDSM Recording and Reporting Form 18 DRTB 06 DR-TB Drug Order Form 19 DRTB 07 DR-TB Reporting Form (for cohort reporting) 20 DRTB 08 Six-monthly Report on Detection and Enrolment of DR-TB 148 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 21 21 21 21 21 21 21 Remarks Remarks Remarks Remarks Remarks Remarks Remarks 20 20 20 20 20 20 20 Status of TreatmentStatus Status of TreatmentStatus of TreatmentStatus of TreatmentStatus of TreatmentStatus of TreatmentStatus of TreatmentStatus 2. Not Enrolled in Tx 3. Died 2. Not Enrolled in Tx 3. Died 2. Not Enrolled in Tx 3. Died 2. Not Enrolled in Tx 3. Died 2. Not Enrolled in Tx 3. Died 2. Not Enrolled in Tx 3. Died 2. Not Enrolled in Tx 3. Died 1. Enrolled in Tx 1. Enrolled in Tx 1. Enrolled in Tx 1. Enrolled in Tx 1. Enrolled in Tx 1. Enrolled in Tx 1. Enrolled in Tx 19 19 19 19 19 19 19 Treatment) Treatment) Treatment) Treatment) Treatment) Treatment) Treatment) Referred to(For Referred to(For Referred to(For Referred to(For Referred to(For Referred to(For Referred to(For Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center Name of DOTs Center 2 2 2 2 2 2 2 18 18 18 18 18 18 18 No No No No No No No 17 17 17 17 17 17 17 1. DS TB 1. DS TB 1. DS TB 1. DS TB 1. DS TB 1. DS TB 1. DS TB 2. DR TB DR 2. TB DR 2. TB DR 2. TB DR 2. TB DR 2. TB DR 2. TB DR 2. 1 1 1 1 1 1 1 Yes Yes Yes Yes Yes Yes Yes TB Diagnosis TB Diagnosis TB Diagnosis TB Diagnosis TB Diagnosis TB Diagnosis TB Diagnosis 16 16 16 16 16 16 16 3. EP 3. EP 3. EP 3. EP 3. EP 3. EP 3. EP 2. PCD 2. PCD 2. PCD 2. PCD 2. PCD 2. PCD 2. PCD 1. PBC 1. PBC 1. PBC 1. PBC 1. PBC 1. PBC 1. PBC 2 2 2 2 2 2 2 15 15 15 15 15 15 15 No No No No No No No 1 1 1 1 1 1 1 14 14 14 14 14 14 14 Yes Yes Yes Yes Yes Yes Yes Lab result received Lab result received Lab result received Lab result received Lab result received Lab result received Lab result received DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY 13 13 13 13 13 13 13 DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY Diagnosis) Diagnosis) Diagnosis) Diagnosis) Diagnosis) Diagnosis) Diagnosis) Name of Lab of Name Name of Lab of Name Lab of Name Lab of Name Lab of Name Lab of Name Lab of Name Referred to(for Referred to(for Referred to(for Referred to(for Referred to(for Referred to(for Referred to(for S / X / C / L / Other S / X / C / L / Other S / X / C / L / Other S / X / C / L / Other S / X / C / L / Other S / X / C / L / Other S / X / C / L / Other Name of Lab Tests requested Name of Lab Name of Lab Name of Lab Name of Lab Name of Lab Name of Lab Tests requested Tests requested Tests requested Tests requested Tests requested Tests requested 2 2 2 2 2 2 2 12 12 12 12 12 12 12 X-ray X-ray X-ray X-ray X-ray X-ray X-ray 1 1 1 1 1 1 1 Screened By Screened By Screened By Screened By Screened By Screened By Screened By 11 11 11 11 11 11 11 Symptom Symptom Symptom Symptom Symptom Symptom Symptom 10 10 10 10 10 10 10 1. DS TB TB DR 2. 1. DS TB TB DR 2. 1. DS TB TB DR 2. 1. DS TB TB DR 2. 1. DS TB TB DR 2. 1. DS TB TB DR 2. 1. DS TB TB DR 2. Types of Types of Types of Types of Types of Types of Types of Presumptive TB Presumptive TB Presumptive TB Presumptive TB Presumptive TB Presumptive TB Presumptive TB 9 9 9 9 9 9 9 Contact No Contact Contact No Contact No Contact No Contact No Contact No Contact No Contact 8 8 8 8 8 8 8 Address Address Address Address Address Address Address 7 7 7 7 7 7 7 M M M M M M M Age Age Age Age Age Age Age

F 6 6 6 6 6 6 6 F F F F F F

Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity Code Ethnicity 5 5 5 5 5 5 5 4 4 4 4 4 4 4 Name of Patient Name of Patient Name of Patient Name of Patient Name of Patient Name of Patient Name of Patient Surname Surname Surname Surname Surname Surname Surname Name of Patient Surname Name of Patient Surname Name of Patient Surname Name of Patient Surname Name of Patient Surname Name of Patient Surname Name of Patient Surname 3 3 3 3 3 3 3 OPD Number OPD Number OPD Number OPD Number OPD Number OPD Number OPD Number 2 2 2 2 2 2 2 Date Date Date Date Date Date Date Screened Screened Screened Screened Screened Screened Screened DD /MM/ YY DD /MM/ YY DD /MM/ YY DD /MM/ YY DD /MM/ YY DD /MM/ YY DD /MM/ YY (DD/MM/YY) (DD/MM/YY) (DD/MM/YY) (DD/MM/YY) (DD/MM/YY) (DD/MM/YY) (DD/MM/YY) TB 01 Presumptive TB Register TB Register TB 01 Presumptive 1 1 1 1 1 1 1 SN SN SN SN SN SN SN NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 149

TB 02 Laboratory Request and Reporting Form

HMIS 6.1

Government of Nepal Health Management Information System Laboratory Request and Reporting Form Date…………/………/….. 1. Name of Health Facility………………………………….2. Presumptive/OPD/Contact Reg No… 3.DR/ TB Reg. No………..….. 4. Name of Patient………………………………………………………….. 5. Age……………. 6. Sex………..…………... 7. Ethnicity …………………………………. 8. Code ……………………… 9. Address: Province………District……….M/RM…………………………………. ward……………… Tole ………………………….. 10. Name of Guardian ………………………………………………………………….…11. Contact no……………………………… 12. Purpose for Examination. i- Diagnosis. ii- Follow-up (...... month) iii- RR detection:

1-LABORATORY REQUEST Part (A)-for Detection of TB Microscopy and Xpert/MTB RIF (to be filled at OPD/DOTS centre) 13. History of Treatment for TB: (a) No previous Treatment (b) Previous History of Treatment (c) Current on Treatment- (i- New ii- Retreatment iii- Others) 14. Specimen Type: i- Sputum ii- Other (specify)...... 15. Test Request for: i- Microscopy ii-. Xpert MTB/RIF

Part (B)-For INH Resistance identification For patients who meet all three below mentioned criteria; i. Retreatment cases, ii. Rifampicin Sensitive (via Xpert MTB/RIF), iii. Smear Positive (to be filled at OPD/DOTS centre) 16. Test Requested: i. LPA 17. Specimen Type: 1. Sputum 2. Other(specify)...... 18. Details of Past TB Treatmen: i. New ii- Relapse ii- Tx After Failure iii- Tx After LTFU iv- Others Previously Treated vi. Unknown Previous TB Treatment History 19. History of Contacts with known TB: 1. Yes 2. No If yes, Mention DST result of: i- INH…………. ii-Rif…………iii- Others:……….. 20. Retro Status: i – Reactive ii – Non-reactive iii- Unknown

Part (C)- For Presumptive DR TB cases MTB not detected, or MTB detected with Rif Indeterminant through Xpert MTB/RIF testing (to be filled at OPD/DOTS centre) 21. Test Requested: i. Culture/DST 22. Specimen Type: 1. Sputum 2. Others (specify)...... 23. Details of Past TB Treatment: i- New ii- Relapse iii- Tx After Failure iv- Tx After LTFU v- Others Previously Treated vi – Unknown Previous TB Treatment History 24. Retro Status: i – Reactive ii – Nonreactive iii- Unknown

Part (D) – For DR TB Baseline and follow up cases 25 i ) Routine collection for 0 month: Collect 2 samples ii) Routine collection for follow up months : …….. Collect 1 sample 150 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

26. Specimen Type: 1. Sputum 2. Others (specify)...... 27. Details of Past TB Treatment: i- New ii- Relapse iii- Tx After Failure iv- Tx After LTFU v- Others Previously Treated vi – Unknown Previous TB Treatment History Date of Sample Collection: ………………………

Part (E)- For all cases Detected with TB (All Forms of TB)

28. Test Request for HIV o (“ü” if HIV Test Requested)

Requested by: Name:...... Designation:...... Contact Number:...... Signature:......

2- LABORATORY TEST RESULT

Name of Laboratory/GeneXpert Site:…………………………………………………………………………………….. Lab no...... Result Date:………./………../…..

1. Microscopy Test Results

Visual Appearance Result Examined by:

Neg () Positive (circle the grading) Name Signature and date

Sample NHPC No A B M S Scanty 1+ 2+ 3+

B B M S Scanty 1+ 2+ 3+ (B) blood-stained (M) mucopurulent (S) saliva Neg.=(0 AFB/100 OF), Scanty= (1-9 AFB /100 OF) 1+=(10−99 AFB/100 OF),2+ = (1−10 AFB/ OF), 3+=(>10 AFB/ OF),

2. Xpert MTB/RIF test result

Mycobacterium tuberculosis: 1. Detected 2. Not detected 3. Invalid / No result / Error Rifampicin Resistance: 1. Detected 2. Not detected 3. Indeterminate

3. HIV Test Result a) (A1) Determine Test i - Reactive ii- Non-Reactive b) (A2) Uni-Gold Test ii- Reactive ii- Non-Reactive c) (A3) Stat pack Test iii- Reactive ii- Non-Reactive

Examined by: Name:...... Designation: ...... NHPC No...... Signature and date ...... NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 151

TB 02b Laboratory Report Form (LPA and Culure DST) TB O2b National Tuberculosis Programme Nepal National Tuberculosis Centre National T.B. Reference Laboratory Thimi, Bhaktapur (Phone no. 01-6630706, 6630832, Ext no. 107)

LABORATORY REPORT (LPA and Culture DST) 1. Name of Health Facility…………...... ………… 2. Presumptive/OPD Reg No./Contact No….. 3. DR/TB Reg. No…….. 4. Name of Patient………………………………….. 5. Age. 6. Sex…… 7. Address: Province……… District……………..M/RM……………… ward…. Tole ….. 8. Specimen Type: 1. Sputum 2. Other (specify)...... 11. Date of Sample Collection: ……………….. 12. Date of Sample Receipt: ………………………….. 12. If for Follow up (Month): …………..

REPORTS ON CULTURE

Lab No. :

Tests Smear Microscopy (Concentrated Sample) Culture*

Result

*Please see remarks below

REPORT ON LPA

Result on LPA from: i) Direct Specimen ii) Culture

Identification M. tuberculosis Complex Drugs Genes Mutation Result/ Interpretation* Rifampicin rpoB Isoniazid KatG Inh A Fluoroquinolones gyr A gyr B Second Line Injectable rrs eis

*Please see remarks below Drug Susceptibility Test (Phenotypic) Drugs H Z Lfx Mfx 0.25 Mfx 1.0 Cfz Lnz Am Bdq Dmn Other µg/ml µg/ml Result* Note:Interpretation: H-Isoniazid , Z-Pyrazinamide,S: Susceptible Eto-Ethionamide, R: Resistance Lfx- C: Levofloxacin, Contaminated Mfx- Moxifloxacin, ND: Not Done. Bdq-Bedaquiline, Lnz- Linezolid, Cfz-Clofazimine, Am- Amikacin, Dmn- Delamanid *Please see remarks below Remarks:

Reported By: ………...... ……………… Verified By: ….....…………………. Date: ...... ……………………………… 152 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 25 HMIS 6.2 HMIS Remarks 24 Reactive Reactive Reactive Reactive Non Reactive Non Reactive Non Non Reactive Non Non Reactive Non HIV Test ResultHIV Test 23 Signature Tested by Signature Signature Signature Signature Name post Name Name post Name post Name Name post Name post Name 22 Result Result Result Result Result Test date Test date Test date test date test date test Specimen B Result Result Result and date and Result 21 Result Result Result Result Result Test date Test date Test date Test date Test date Test

Specimen A

Result Result Follow up Follow 20 ……. ……. ……. …….

Month Month Month Month

test Diagnosis

1 1 1 1 Purpose of Purpose 19 Others

5 18 Retreatment Retreatment

4 17 New

CurrentTreatmenton

3 16

of Treatment Treatment of

Previous Treatment History Treatment Previous History Previous 2 15

Treatment No previous previous No 1 14 13 HIV Status 1.Reactive 1.Reactive 2.Non- Reactive 3.Unknown 1.Reactive 2.Non- Reactive 3.Unknown 1.Reactive 2.Non- Reactive 3.Unknown 1.Reactive 2.Non- Reactive 3.Unknown

�यरोग �यरोग ÷ ÷ . . 12 दता셍 नं दता셍 नं for test for test for test for test for Institution /Contact TB Registration no Registration no Name Health of Name Health of Name Health of Name Health of Registration no Registration Presum/ OPD /TB /TB OPD Presum/ /TB OPD Presum/ Name of Health requesting for test requesting Presumptive/ OPD Institution requesting Institution requesting Institution requesting Institution requesting OPD दता셍 नं OPD दता셍 नं 11 Name of Guardian/ Family Member Tuberculosis Laboratory Register (Microscopy) 10 M/RM M/RM M/RM M/RM M/RM Contact no Contact no Contact no Contact no Contact no Address

9 ward no ward District District District District District

ward no ward no ward no ward no

(TALF) Treatment after lost follow up, (OPT) Other previously Treated, (OTHU) treatment History Unknown Male 8

Age Female Female

7 Ethnicity Code Ethnicity 6 city city city city code code code code Ethni Ethni Ethni Ethni 5 Name of Patient Surname Surname Surname Surname Surname Name of Patient Name Name of Patient Name of Patient Name Name of Patient Name 4 YY 3 MM 2 Sample collection Date collection Sample DD 1 TB 03a Laboratory Register (Microscopy) Register TB 03a Laboratory Lab no Lab Lab no Lab no Lab no Lab no TB 03a TB Month 27 Remarks HMIS 6.2 HMIS 26 Signature Tested by Signature Signature Name post Name post Name post 25 DD/MM/YY DD/MM/YY result/Invalid) Test Failure (No Failure Test 24 Error/Code DD/MM/YY DD/MM/YY 23 MTB+Rif DD/MM/YY DD/MM/YY indeterminate Test Result 22 MTB+Rif resistance DD/MM/YY DD/MM/YY 21 sensitive MTB + Rif DD/MM/YY DD/MM/YY NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 153 20 MTB Not Detected

DD/MM/YY DD/MM/YY Sample received date received Sample 19 DD/MM/YY DD/MM/YY 18 Type

Specimen HMIS 6.2 Detection RR

17 Diagnosis 16

Purpose of test Others

15 Retreatment Retreatment

14 New Current on Treatment Current 13 12 History ofTreatment for TB Previous History ofHistory Treatment Treatment Tuberculosis Laboratory Register (GeneXpert) Register Laboratory Tuberculosis 11 No previous previous Treatment 10 HIV Status 1.Reactive 2.Non- reactive 3.Unknown 1.Reactive 2.Non- reactive 3.Unknown 27 Remarks HMIS 6.2 HMIS 9 for test for test Institution Registration no Registration no Registration Name of Health Name of Health 26 Presum/ OPD /TB OPD Presum/ /TB OPD Presum/ Name of Health Presumptive/ OPD requesting for test Institution requesting requesting Institution requesting Institution /TB Registration no Signature Tested by Signature Signature Name post Name post Name post 8 (TALF) Treatment after lost follow up, (OPT) Other previously Treated, (OTHU) treatment History Unknown Name of Guardian/ Tuberculosis Laboratory Register (GeneXpert) Tuberculosis Family Member 25 DD/MM/YY DD/MM/YY result/Invalid) Test Failure (No Failure Test 7 M/RM M/RM M/RM 24 Contact no Contact noContact Contact noContact Address Error/Code DD/MM/YY DD/MM/YY

6 ward no ward District District District

ward no ward no ward 23 Male MTB+Rif 5 DD/MM/YY DD/MM/YY indeterminate

Test Result Age Female 4 22 MTB+Rif resistance 3 DD/MM/YY DD/MM/YY code code Ethnicity Ethnicity Ethnicity Ethnicity Ethnicity code 21 sensitive MTB + Rif 2 DD/MM/YY DD/MM/YY Name of Patient Name of Patient of Name Patient of Name Surname Surname Surname 20 1 MTB Not Detected Lab no Lab Lab no Lab no

TB 03b Month DD/MM/YY DD/MM/YY TB 03b

TB 03b Tuberculosis Laboratory Register (GeneXpert) Register Laboratory TB 03b Tuberculosis Sample received date received Sample 19 DD/MM/YY DD/MM/YY 18 Type

Specimen RR Detection RR

17 Diagnosis 16

Purpose of test Others

15 Retreatment Retreatment

14 New Current on Treatment Current 13 12 History ofTreatment for TB Previous History ofHistory Treatment Treatment Tuberculosis Laboratory Register (GeneXpert) Register Laboratory Tuberculosis 11 No previous previous Treatment 10 HIV Status 1.Reactive 2.Non- reactive 3.Unknown 1.Reactive 2.Non- reactive 3.Unknown 9 for test for test Institution Registration no Registration no Registration Name of Health Name of Health Presum/ OPD /TB OPD Presum/ /TB OPD Presum/ Name of Health Presumptive/ OPD requesting for test Institution requesting requesting Institution requesting Institution /TB Registration no 8 (TALF) Treatment after lost follow up, (OPT) Other previously Treated, (OTHU) treatment History Unknown Name of Guardian/ Family Member 7 M/RM M/RM M/RM Contact no Contact noContact Contact noContact Address

6 ward no ward District District District

ward no ward no ward Male 5

Age Female 4 3 code code Ethnicity Ethnicity Ethnicity Ethnicity Ethnicity code 2 Name of Patient Name of Patient of Name Patient of Name Surname Surname Surname 1 Lab no Lab Lab no Lab no TB 03b Month 39 Remarks 38 reporting L J: Date of of Date L J: 37 L J: Result 36 MGIT: Date of reporting 35 Others 34 Dlm 33 Lfx 32 Eto 31 Mfx (L) 30 Mfx (H) 29 Lzd MGIT: DST 28 Cfz 27 Bdq 26 Am 25 Z 24 H R 23 22 Date of MGIT DST Inoculation 21 MGIT: Result 20 Result Smear Microscopy: 154 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 19 Date of Processing 39 18 Remarks Non- Cold chain refrigerated/ Refrigerated/ 38 reporting 17 L J: Date of of Date L J: Sample Receive Dates of of Dates 37 Tuberculosis Laboratory Register (Culture) L J: Result 16 sample Dates of of Dates collection 36 15 MGIT: Date of reporting nce Visual Appeara 35 Others 14 Specimen 34 Dlm 13 month 33 Lfx Category & 12 32 2. Non Result Eto Reactive HIV Test 1. Reactive 3. Unknown 3. 31 11 Mfx (L) test Institution Institution Institution Registration no Registration Name of Health requesting for Registration no Registration Presum/ OPD /TBPresum/ OPD Name of Health requesting for test Presum/ OPDPresum/ /TB 30 Mfx (H) 10 Family Family Name of Member Guardian/ 29 Lzd MGIT: DST M/RM M/RM 28 Cfz Contact no Contact no Contact 9 Address 27 District District Bdq ward no ward 26 Ward no Tuberculosis Laboratory Register (Culture) Register Laboratory Tuberculosis Am 8 Male 25 Age Z 7 Female 24 H 6 code R 23 Ethnicity Ethnicity code 5 Name of Patient Name of Patient Surname Surname 22 Date of MGIT DST Inoculation 4 YY YY 21 MGIT: Result 3 MM MM 20 Sample Collection Date Collection Sample Result Smear 2 DD DD Microscopy: 19 1 Date of Lab no Lab no Lab TB 03c Laboratory Register (Culture DST) (Culture Register TB 03c Laboratory Processing TB 03c Month TB 03c Month 18 Non- Cold chain refrigerated/ Refrigerated/ 17 Sample Receive Dates of of Dates Tuberculosis Laboratory Register (Culture) 16 sample Dates of of Dates collection 15 nce Visual Appeara 14 Specimen 13 month Category & 12 2. Non Result Reactive HIV Test 1. Reactive 3. Unknown 3. 11 test Institution Institution Institution Registration no Registration Name of Health requesting for Registration no Registration Presum/ OPD /TBPresum/ OPD Name of Health requesting for test Presum/ OPDPresum/ /TB 10 Family Family Name of Member Guardian/ M/RM M/RM Contact no Contact no Contact 9 Address District District ward no ward Ward no 8 Male Age 7 Female 6 code Ethnicity Ethnicity code 5 Name of Patient Name of Patient Surname Surname 4 YY YY 3 MM MM Sample Collection Date Collection Sample 2 DD DD 1 Lab no Lab no Lab TB 03c Month 37 Remarks 36 reporting LPA: Date of LPA: Date 35 Interpretation 34 Mut eis 33 WT AMG 32 Mut rrs 31 WT 30 Mut gyrB 29 WT FLQ 28 Mut gyrA 27 WT 26 LPA DST LPA Mut Inh A 25 WT H 24 Mut KatG 23 WT 22 Mut R rpob 21 WT 20 Identification 19 Culture ResultCulture 18 D)Direct Specimen Type C)Culture 17 Smear Result Microscopy

NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 155 16 Date of Processing Date 37 Remarks 15 36 Date of Received Sample reporting LPA: Date of LPA: Date 35 14 Interpretation 34 Date of sample collection of sample Date Mut eis 33 WT AMG 13 32 Mut rrs Specimen Type 31 WT 30 Mut Thimi, BhaktapurThimi, gyrB 29 WT 12 National Tuberculosis Centre Centre Tuberculosis National FLQ 28 Mut Category & month Category gyrA 27 TB 03d Laboratory Register (Line Probe Assay) Probe (Line Register Laboratory 03d TB WT 26 LPA DST LPA Mut 11 Inh A 25 WT H Treatment Centre Treatment 24 Mut KatG 23 10 WT 1. Reactive 1. Reactive 3. Unknown 3. Unknown HIV Test ResultHIV 2. Non Reactive 2. Non 2. Non Reactive 2. Non 22 Mut Thimi, Bhaktapur R rpob National Tuberculosis Centre Tuberculosis National M/RM M/RM M/RM 21 WT Contact no Contact no Contact Contact no Contact 9 TB 03d Laboratory Register (Line Probe Assay) (Line Probe TB 03d Laboratory Register Address District District District 20 ward no ward no ward Identification Ward no Ward 8 Male Age 19 7 Female Culture ResultCulture 6 Ethnicity code Ethnicity code Ethnicity Ethnicity code Ethnicity 18 D)Direct Name of Patient Name of PatientName Name of PatientName 5 Specimen Type C)Culture Surname Surname Surname 17 Smear Result 4 YY YY YY Microscopy 3 MM MM MM Date 2 DD DD DD Sample Collection Collection Sample 16 1 Lab no Lab Lab no Lab Lab no Lab Date of Processing Date TB 03d Laboratory Register (LPA) Register TB 03d Laboratory 15 Date of Received Sample 14 Date of sample collection of sample Date 13 Specimen Type Thimi, BhaktapurThimi, 12 National Tuberculosis Centre Centre Tuberculosis National Category & month Category TB 03d Laboratory Register (Line Probe Assay) Probe (Line Register Laboratory 03d TB 11 Treatment Centre Treatment 10 1. Reactive 1. Reactive 3. Unknown 3. Unknown HIV Test ResultHIV 2. Non Reactive 2. Non Reactive 2. Non M/RM M/RM M/RM Contact no Contact no Contact Contact no Contact 9 Address District District District ward no ward no ward Ward no Ward 8 Male Age 7 Female 6 Ethnicity code Ethnicity code Ethnicity Ethnicity code Ethnicity Name of Patient Name of PatientName Name of PatientName 5 Surname Surname Surname 4 YY YY YY 3 MM MM MM Date 2 DD DD DD Sample Collection Collection Sample 1 Lab no Lab Lab no Lab Lab no Lab 156 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 0 0 0 0 0 0 0 0 0 0 0 0 0 Total Total Total 0 0 M M M Unknown Unknown 0 0 F F F Unknown treatment history [B] 0 0 M M M Age ≥15 Non Reactive HIV TestHIV Result 0 0 0 0 0 0 0 Previously treated [A] F F F Total Previous anti-TB status treatment Previous Reporting Period:______to______Period:______Reporting by______Verified Report 0 0 M M M M New 0–14 Reactive 0 0 F F F F TB 03e Culture/Dst Reporting Format Reporting TB 03e Culture/Dst Grand Total Grand Total Grand Results of first-line drug susceptibility testing in pulmonary TB patients pulmonary in testing susceptibility drug of first-line Results of MDR-TB patients) (number status between andHIV (ii): 1 association line in DST results with patients Among MDR-TB between of andage patients) (ii): 1 association (number line in DST results with patients Among Results of second-line drug susceptibility testing 1 patients(ii) Among reported (i), in of number patients DST available with results for isoniazid (H) and rifampicin (R) (iv) patients Among reported (ii), in of number patients resistance with to R but not H 2 R) to and H both (resistant MDR-TB (a) (b) Not MDR-TB (drug susceptible resistance plus any that is not MDR-TB) 3 R) to and H both (resistant MDR-TB (a) (b) Not MDR-TB (drug susceptible resistance plus any that is not MDR-TB) 4 (i) Total of number MDR-TB pulmonary patients DST with results for fluoroquinolone any agent (2LI) injectable second-line (FQ) and any MDR-TB(ii) Among patients reported (i), in ofnumber patients susceptible to both FQ and 2LI MDR-TB(iii) Among patients reported (i), in of number resistance patients any with to FQ (iv) MDR-TB Among patients reported (i), in of number resistance patients any with to 2LI (v) MDR-TB Among patients reported (i), in of number resistance patients any with to both (XDR-TB) 2LI and FQ (vi) Number of pulmonary TB patients with positive identification for M. Tuberculosis complex complex Tuberculosis M. for identification positive with patients TB pulmonary of Number (vi) assay line-probe and/or culture by confirmed not who and are alone MTB/RIF Xpert by confirmed Name of Reporting Unit: ______Unit: of Reporting Name by:______Prepared Report ______DD/MM/YYY date:___ submission Report complex Tuberculosis M. for identification positive with patients TB pulmonary of Number i) Xpert by confirmed patients for below (vi) line (Use assay. line-probe and/or culture by confirmed MTB/RIF only) R Hnot to but resistance with patients of number (ii), in reported patients Among (iii) H R to and (MDR-TB) resistance with patients of number (ii), in reported patients Among (v) i) in reported those to additional be should cases (these be should cases R (these to resistance with patients of number (vi), in reported patients Among (vii) v) and iv in reported those to additional TB 03e Culture / DST Reporting Format Reporting / DST TB 03e Culture NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 157 DRTB 01 DRTB R/S Others Cfz R/S No. household of members screened for TB R/S Eto R/S Lzd Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month CBDOTS Serious Event 1. Yes 2. No 1. Yes Number Not- of Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total R/S CPT Bdq Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month Adverse event (Severity) event Adverse Total no.of household member Number of Serious Event 1. Yes 2. No 1. Yes Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total Number in a Total 1 2 R/S Am ART 1. Yes 2. No 1. Yes Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result R/S Lfx 3. Unknown 3. Disease Type (Circle) Type Disease Regimen: R/S Mfx HIV Status 2. Non-Reactive Pulmonary Extra Pulmonary Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result 1 2 3 E R/S 1. Reactive Z R/S 2. No t lt DM Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Resu C. Result C. Result C. Result C. Result C. Result C. Result C. Resul R R/S 6. Not evaluated / Date 1. Yes Regimen: Patients Referred / Diagnosed by (Circle) by Diagnosed / Referred Patients H R/S DRTB RegisterDRTB Private Health FacilityPrivate Community Contact Investigation Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result 5. LTFU / Date 5. LTFU 9 1 2 3 4 5 6 7 8 Regimen/Lab result Regimen/Lab Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result 4. Died / Date Registration Category (Circle) Regimen: Contact no. Tin /Institution Tin 1. New 2. Relapse 3.1. After failure first of line Treatment with FLD 3.2. After failure Re-Treatment of with FLD 3.3. After failure Treatment of with Hr TB Regimen 3.4. After failure Treatment of with SLD TALFU 4. 5. Other Previously Treated 6. Unknown Previous TB Treatment History Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result 3. Failed / Date End DST Status: DST Age: 2nd 2. Male Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No Lab No C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result C. Result F/U Months F/U 1st 2. Completed / Date 1. Female Regimen: 0 Status of Exposure to smoking inside the home (Y or N) or (Y home the inside smoking to of Exposure Status Sex: Treatment start date: Ward/ tole: Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. Lab No. S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result S.MC Result 1. Cured / Date 1. Cured End

Ethnicity code Ethnicity Treatment sub Center: Tobacco Smoking Result Test/ of Type Date/ Enrolment 2nd XDR

F/U Months F/U Enrolment Date/ Type of Test/ Result Test/ of Type Date/ Enrolment 1st Status of (S,R,Q,) Smoking Status Pre- XDR Registration Date

Type of DR S: Current Smoker, Q: Smoker, R: Relapsed Quitter Result Test/ of Type Date/ Enrolment DR TB regimen 0 MDR Outcome

18 Dlm(12),Cs, Imp/Clv (10),Eto,PAS,Cfz, Z Z (10),Eto,PAS,Cfz, Imp/Clv 18 Dlm(12),Cs, 4-6 Am,Mfxh, Cfz, Eto, INHh, E, Z/ INHh, Eto, Am,Mfxh,4-6 Cfz, Z,E 5 Mfxh,Cfz, 18Bdq(6), Lfx,Lzd,Cfz,Z (12),18Lzd,Bdq Cfz, Cs,Z 6 Am, Dlm, Eto, Cfz (Cs) (Mfx/lfx) PAS 12 Dlm (6) Eto Cfz, (Cs) PAS (Mfx/Lfx) Z Cfz, ,Eto,PAS, (10) 18 Imp/Clv Dlm(12), Lzd,Cs,Cfz,PAS Dlm(6), (12), 18 Bdq Z Lzd,Cfz,Cs, 18 Lfx, 18 Lzd,Cfz,Cs,INHh,Z,Eto 18 Lzd,Cfz,Cs,Dlm(6),Z Z PAS, Cs, Cfz, 18Lfx, Enrolment Date/ Type of Test/ Result Test/ of Type Date/ Enrolment 2 2 2 2 2 2 No RR SSTR LR1 LR2 LR3 LR4.1 LR4.2 Modified LR2 CLR1 CLR2.1 CLR2.2 PLR1 1 1 1 1 1 1 Yes Smoking Tobacco (Current) Tobacco Smoking Months Registration No: Name: Treatment Center: 0 month 1 month 2 month 3 month 4 month 5 month 6 month 7 month 8 month 9 month 10 month 11 month 12 month 13 month 14 month 15 month 16 month 17 month 18 month 19 month 20 month 21 month 22 month 23 month 24 month M/RM : DRTB 1 DRTB Register 1 DRTB DRTB 158 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

Photo HMIS 6.3HMIS Outcome -aminosalicylic acid -aminosalicylic p Eto=Ethionamide Cfz- Clofazimine PAS= Cilastatin / Imp/Cln=Imipenem Lzd=Linezolid Second-line drugs Second-line Drug Abbreviations Am=Amikacin Am=Amikacin CS=Cycloserine Lfx=Levofloxacin Mfx=Moxifloxacin Bdq=Bedaquiline Dlm=Delamanid Amx/Clv=Amoxicillin/Clavulanate Base line Investigations and Results H=Isoniazid R=Rifampicin E=Ethambutol Z=Pyrazinamide Regimen (write regimen in abbreviations) regimen drug (write Regimen First-line drugs Previous Tuberculosis Treatment History Treatment Tuberculosis Previous  Notation method for DST: for method Notation R=resistant, S=susceptible, C=contaminated Community Based Based Community  CBC Blood Glucose LFT RFT Hep B Hep C ECG Audiometry Pregnancy Acuity Visual Uric Acid Others: Start Date unknown(if put year) Other No. OTHER INFORMATIONOTHER Dlm Contact Investigation: Contact 7 2 3 4 5 6 1 Lfx Type of DOT: Health Facility Based Based Facility Health DOT: of Type Eto Name of Treatment Sub Center Referred for Treatment: Treatment: for Referred Center Sub Treatment of Name Mfx(L) Name of Treatment Center: Center: Treatment of Name Mfx(H) Lzd Name of DOTName Provider of Number: Contact i - No. of close contact Traced ii -No. TB with Diagnosed iii -No. Treatment to Linked -No. iv Unknown 3. Non-Reactive 2. Reactive 1. Status: Retro DD/MM/YY Result: Test: of Date DD/MM/YY Date: / N Y ART: on Started DD/MM/YY Date: / N Y CPT: on Started Cfz : (Circle) Bdq Regimen DR TB regimen DR TB regimen Am NATIONAL TUBERCULOSIS CONTROL PROGRAMME E Risk Category of DR-TB suspectsRisk DR-TB of Category DRUG RESISTANT TUBERCULOSIS TREATMENT CARD TUBERCULOSIS RESISTANT DRUG Z 4-6 Amk,Mfxh, Cfz, Eto, INHh, E, Z/ 5 Mfxh,Cfz, Z,E Z,E Mfxh,Cfz, 5 Z/ E, INHh, Eto, Cfz, Amk,Mfxh, 4-6 Bdq(6),Lfx,Lzd,Cfz,Z 18 Bdq(12),18Lzd, Cs,Z Cfz, 6Am, Dlm, 12 Dlm Eto, PAS (6) Eto PAS (Mfx/lfx) Cfz (Cs) Cfz, (Mfx/Lfx) (Cs) Z (10),Eto,PAS,Cfz, Imp/Clv Dlm(12),Cs, 18 Z Cfz, ,Eto,PAS, (10) Imp/Clv Dlm(12), 18 Bdq18 (12), Dlm(6), Lzd,Cs,Cfz,PAS Lzd,Cfz,Cs, Z Lfx, 18 Lzd,Cfz,Cs,INHh,Z,Eto 18 Lzd,Cfz,Cs,Dlm(6),Z18 Z PAS, Cs, Cfz, 18Lfx, R H Used second-line drugs second-line previously? Used If Yes, specify: ______Yes, specify: If Others (Specify): Others Re-treatment Non- Converter DR-TB contact TB/ HIV Worker Care Health New SSTR LR1 LR2 LR3 LR4.1 LR4.2 Modified LR2 CLR1 CLR2.1 CLR2.2 PLR1 Weight 1 2 3 Date DST result Phone No: 1 2 Districts: : / Tole No Ward Date: DD/MM/YY 8 9 7 1 2 3 4 5 6 Age: 1.Normal 2.Abnormal 3.Not Done Remarks Remarks Chest X-Ray at Start X-Ray Chest Culture result Culture No. of household members screened household No. of for TB : Site Smear Result Sputum MicroscopySputum / Culture DST method (liquid solid, LPA, X-pert) LPA, solid, (liquid method DST Lab No. Expert Group meetings Group Expert 2. Male Pulmonary Extra-pulmonary site: extra-pulmonary,If specify 1 2 3 4 Date Province Registration Group (Circle) Group Registration Initial Lab Results Initial Lab Decision 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Type of resistance: of Type 1. Female 1. Date sputum collection sputum Date M/RM: Month of Treatment of Month Address: DR TB 02 Patients of Name Sex Initial Weight (Kg): Name Guardian's member Total household no.of 1. New 2. Relapse FLD with Treatment line first of failure After 3.1. FLD with Re-Treatment of failure After 3.2. Regimen TB Hr with Treatment of failure After 3.3. SLD with Treatment of failure After 3.4. 4. TALFU treated previously Other 5. History Treatment TB Previous Unknown 6. Smear Xpert LPA Date SUSCEPTIBILITY TESTINGDRUG (DST) RESULTS Culture DST RR Pre-XDR XDR comments gm); or (mg dosages treatment; of month each for REGIMEN TREATMENT MDR TB DRTB 02 DRTB Treatment Card Treatment 02 DRTB DRTB NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 159

Photo HMIS 6.3HMIS Outcome -aminosalicylic acid -aminosalicylic p Eto=Ethionamide Cfz- Clofazimine PAS= Cilastatin / Imp/Cln=Imipenem Lzd=Linezolid DATE Second-line drugs Second-line Comments COMMENTS regimen, etc.) 1 2 3 4 5 6 Drug Abbreviations Circle one Circle (Reasons for changes in dosage, Am=Amikacin Am=Amikacin CS=Cycloserine Lfx=Levofloxacin Mfx=Moxifloxacin Bdq=Bedaquiline Dlm=Delamanid Amx/Clv=Amoxicillin/Clavulanate 31 Died Cured Failed Others Completed Base line Investigations and Results OUTCOME Not evaluated H=Isoniazid R=Rifampicin E=Ethambutol Lost to follow-up Z=Pyrazinamide Regimen (write regimen in abbreviations) regimen drug (write Regimen 30 First-line drugs 1)...... Previous Tuberculosis Treatment History Treatment Tuberculosis Previous 2)...... 29 28 SO = stockout AE = adverse effect AE = adverse = stockout SO Z 27 26 PAS Notation method for DST: for method Notation R=resistant, S=susceptible, C=contaminated H Community Based  Based Community 25 CBC Blood Glucose LFT RFT Hep B Hep C ECG Audiometry Pregnancy Acuity Visual Uric Acid Others: Start Date unknown(if put year) 24 Other 23 No. OTHER INFORMATIONOTHER Imp-Cln Dlm Contact Investigation: Contact 22 7 2 3 4 5 6 1 Lfx Type of DOT: Health Facility Based  Based Facility Health DOT: of Type 21 Eto Name of Treatment Sub Center Referred for Treatment: Treatment: for Referred Center Sub Treatment of Name Eto 20 Mfx(L) Name of Treatment Center: Center: Treatment of Name Mfx(H) Day E 19 Lzd Name of DOTName Provider of Number: Contact i - No. of close contact Traced ii -No. TB with Diagnosed iii -No. Treatment to Linked -No. iv Unknown 3. Non-Reactive 2. Reactive 1. Status: Retro DD/MM/YY Result: Test: of Date DD/MM/YY Date: / N Y ART: on Started DD/MM/YY Date: / N Y CPT: on Started Cfz : (Circle) Bdq 18 Regimen Amx-Clv DR TB regimen DR TB regimen Am NATIONAL TUBERCULOSIS CONTROL PROGRAMME 17 Am E Risk Category of DR-TB suspectsRisk DR-TB of Category DRUG RESISTANT TUBERCULOSIS TREATMENT CARD TUBERCULOSIS RESISTANT DRUG 16 Dlm Z 4-6 Amk,Mfxh, Cfz, Eto, INHh, E, Z/ 5 Mfxh,Cfz, Z,E Z,E Mfxh,Cfz, 5 Z/ E, INHh, Eto, Cfz, Amk,Mfxh, 4-6 Bdq(6),Lfx,Lzd,Cfz,Z 18 Bdq(12),18Lzd, Cs,Z Cfz, 6Am, Dlm, 12 Dlm Eto, PAS (6) Eto PAS (Mfx/lfx) Cfz (Cs) Cfz, (Mfx/Lfx) (Cs) Z (10),Eto,PAS,Cfz, Imp/Clv Dlm(12),Cs, 18 Z Cfz, ,Eto,PAS, (10) Imp/Clv Dlm(12), 18 Bdq18 (12), Dlm(6), Lzd,Cs,Cfz,PAS Lzd,Cfz,Cs, Z Lfx, 18 Lzd,Cfz,Cs,INHh,Z,Eto 18 Lzd,Cfz,Cs,Dlm(6),Z18 Z PAS, Cs, Cfz, 18Lfx, 15 Cs R 14 H 13 Used second-line drugs second-line previously? Used If Yes, specify: ______Yes, specify: If Others (Specify): Others Re-treatment Non- Converter DR-TB contact TB/ HIV Worker Care Health New Cfz SSTR LR1 LR2 LR3 LR4.1 LR4.2 Modified LR2 CLR1 CLR2.1 CLR2.2 PLR1 12 for evening dose) √ 11 Weight 1 2 3 Date DST result Mfx Phone No: 10 1 2 9 Districts: : / Tole No Ward 8 Date: DD/MM/YY for morning dose and and dose morning for Lnz 7 8 9 1 2 3 4 5 6 √ Age: 1.Normal 2.Abnormal 3.Not Done Remarks Remarks Chest X-Ray at Start X-Ray Chest 7 Culture result Culture No. of household members screened household No. of for TB 6 5 : Site Bdq 4 Smear Result 3 Lfx Sputum MicroscopySputum / Culture DST method (liquid solid, LPA, X-pert) LPA, solid, (liquid method DST (one line per month): Lab No. Expert Group meetings Group Expert 2. Male Pulmonary Extra-pulmonary site: extra-pulmonary,If specify 2 1 2 3 4 Date Province Registration Group (Circle) Group Registration Initial Lab Results Initial Lab 1 = Drugs Not Taken N = Not supervised φ Weight (KG) Decision 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Type of resistance: of Type = Directly observed (if split dose is used for Cs, Eto or PAS, mark mark PAS, or Eto Cs, for used is dose split (if observed Directly = 1. Female 1. √ 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Date sputum collection sputum Date M/RM: Months Month Month of Treatment of Month Address: Smear DR TB 02 Patients of Name Sex Initial Weight (Kg): Name Guardian's member Total household no.of 1. New 2. Relapse FLD with Treatment line first of failure After 3.1. FLD with Re-Treatment of failure After 3.2. Regimen TB Hr with Treatment of failure After 3.3. SLD with Treatment of failure After 3.4. 4. TALFU treated previously Other 5. History Treatment TB Previous Unknown 6. Xpert LPA Date SUSCEPTIBILITY TESTINGDRUG (DST) RESULTS Culture DST RR Pre-XDR XDR comments gm); or (mg dosages treatment; of month each for REGIMEN TREATMENT MDR TB ADMINISTRATION OF DRUGS Comments: ______Mark in in Mark 160 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT Comments 3 minutes) 1 2 1 2 1 2 1 2 Yes / No 1 = yes 2 = no 2 = yes 1 = Cessation support provided to patient (1- patient to provided support Cessation Comments 1 minute) 1 2 1 2 1 2 1 2 Yes / No 1 = yes 2 = no 2 = yes 1 = Brief adviceBrief given patient (30 to seconds- 1 2 1 2 1 2 1 2 Yes / No your home? 1 = yes 2 = no 2 = yes 1 = Does anyone smoke inside inside anyone smoke Does Section on ABCSection Smoking Cessation >30 min >30 Ask you usually have your first first your have usually you How soonHow after you wake do cigarette? 1 = <30 min or 2 = 2 = or min <30 1 = cigarette? Yes S Do you smoke?* Yes / No S , R , Q , L , D , L , R , Q S , D , L , R , Q S , D , L , R , Q S puff—in the last 2 the puff—in last 3 months) weeks?(months 0, 2, 5, End) weeks?(months Have you smoked at all—even a all—even at smoked you Have No Date DD/MM/YY S for current smoker (has smoker in Scurrent the for smoked then at follow-up at follow-up then examination visit: examination : If a: patient If is registered0, month after draw a line through patient month(s) the when was not registered. = quitter: has at not smoked all in last the visit, the 2 before weeks a puff not even = relapsed smoker: has smoked in the last 2 weeks before the visit but has made at least one quit attempt of at least 24 hours since the last visit. the since 24 hours least at of attempt quit one least at made has but visit the before last 2 weeks the in smoked has smoker: relapsed = = died. = lost to follow-up: did not attend their appointment. At start TB of treatment = smoker: has current in last the smoked visit the 2 before weeks quit and has any not attempt made since last the visit (quit attempt = patient tried to at quit for least and succeeded 24 hours). Month of Treatment 0 1st up follow up 2nd follow End *Definitions for status of smoking of status for *Definitions For month 0, For months 2, 5, S, End, of R, one enter Q, D or L: S R Q D L Note NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 161 Remarks 2 2 2 2 2 2 2 2 2 2 No Total Number of Household Member: ______Member: Household of Number Total Date enrolled: __ enrolled: Date TBPT? 1 1 1 1 1 1 1 1 1 1 Yes If no symptoms of TB among TB among of no symptoms If children (<5 years), referred for for referred years), (<5 children 2 2 2 2 2 2 2 2 2 2 Patient Referred Signature: 1 1 1 1 1 1 1 1 1 1 courier Sputum Sputum Referred to further diagnosis further to Referred Sex: 1. Male 2. Female 2. Male 1. Sex: National TB Program National TB Program National TB 07 Contact Investigation Form Investigation 07 Contact TB Telephone Number/s: ______Number/s: Telephone TB 07 Contact Investigation Form Investigation TB 07 Contact Age:______0. None Persistence of: 1. Cough Night / Grade) Low / Rise (Evening 2. Fever Sweats Appetite of 3. Loss Loss 4. Weight Pain 7. Chest Blood/Sputum 8. Coughing Symptoms (code) =>) (15 years Adult for TB Symptoms, If Yes then Mention Coode (eg. 1, 2, etc) 2, 1, (eg. Coode Mention then Yes If TB Symptoms, marks: Re 1, 2 etc 1, 2 etc 1, 2 etc 1, 2 etc 1, 2 etc 1, 2 etc 1, 2 etc 1, 2 etc 1, 2 etc 1, 2 etc 1, Relationship with index case index with Relationship M ii. Drug Resistant TB Drug ii. 0 - None Persistence of: 1.Cough 2. Fever 3. Not eating well thrive to Failure \ Loss 4. Weight 5. Fatigue playfulness 6. Reduce Symptoms for Children(0-14Symptoms for years (code) old) Age F ______i. Drug Sensitive TB Sensitive Drug i. Name(s) of contacts contacts of Name(s) Address: TB Type: TB / DRTB Registration Number (Index case): (Index Number Registration TB DRTB / Case): (Index Name 2 3 4 5 6 7 8 9 1 10 SN TB 07 Contact Investigation forms Investigation TB 07 Contact Household contact: contact: Household sleeps who andSomeone eats in house with same the the Index TB case. DEFINITIONS TB-07 1 Interviewer: Remarks Outcome DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY worker to worker Date of home visit of health health of visit monitor TBPT TBPT monitor intake (D/M/Y) intake DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. 3 Month Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. 2 Month TBPT Collection Date Collection TBPT Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. 1 Month DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY Date TBPT Started 2 2 2 2 2 2 2 2 2 No TBPT? 1 1 1 1 1 1 1 1 1 Yes Child Eligible for for Eligible Child 2 2 2 2 2 2 2 2 2 No 1 1 1 1 1 1 1 1 1 Treatment? Treatment? Yes Enrolled in TB in TB Enrolled Lab No. Lab GeneXpert 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1.MTB not Detected not Detected 1.MTB 2.MTB Rif Sensitive Sensitive Rif 2.MTB 3. MTB Rif Resistant 3. MTB Sputum Results Sputum 2.Pov 1.Neg 1.Neg 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 Microscopy

162 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT for Sputum Test Sputum for Microscopy / GeneXpert Center 4 4 4 4 4 4 4 4 4 Sputum Sputum to Transported Facility Health 3 3 3 3 3 3 3 3 3 If PresumptiveIf TB (HB) Referred to Health facility Contacts Directly Directly Contacts 2 2 2 2 2 2 2 2 2 No 1 1 1 1 1 1 1 1 1 Presumptive TB Yes Contacts of the IndexTB Cases the of Contacts TB 08_Contact and TBPT and TB Register 08_Contact 2 2 2 2 2 2 2 2 2 Home Based (HB) Home 1 1 1 1 1 1 1 1 1 Type of Contact Investigation: or or Investigation: Contact of Type Based (HFB) Health Facility Facility Health Remarks Outcome DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY Guardian's Name worker to worker Date of home visit of health health of visit monitor TBPT TBPT monitor intake (D/M/Y) intake DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY Contact Numbers Contact Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. 3 Month Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. 2 Month Address TBPT Collection Date Collection TBPT Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. Wt. No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. Tab No. 1 Month M Age F DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY DD/MM/YY Date TBPT Started 2 2 2 2 2 2 2 2 2 No TBPT? 1 1 1 1 1 1 1 1 1 Name of Family Members Name Yes Child Eligible for for Eligible Child 2 2 2 2 2 2 2 2 2 No 1 1 1 1 1 1 1 1 1 Treatment? Treatment? Yes Enrolled in TB in TB Enrolled Members No. of Family Family of No. Lab No. Lab TB) Type of TB (DS or TB DR TB, Hr FCHV Others...... FCHV GeneXpert 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1 / 2 / 3 1.MTB not Detected not Detected 1.MTB 2.MTB Rif Sensitive Sensitive Rif 2.MTB 3. MTB Rif Resistant 3. MTB Sputum Results Sputum 2.Pov 1.Neg 1.Neg 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 1 / 2 Name of Index TB Index of Name Microscopy Index TB Cases : Health Worker √) TB Reg. No Reg. TB for Sputum Test Sputum for S.N Microscopy / GeneXpert Center Month Contact Name Tracer Number Contact Name of HealthName Facility Year of ContactType ( Tracer TB 08 Contact and TBPT Register Register and TBPT TB 08 Contact 4 4 4 4 4 4 4 4 4 Sputum Sputum to Transported Facility Health 3 3 3 3 3 3 3 3 3 If PresumptiveIf TB (HB) Referred to Health facility Contacts Directly Directly Contacts 2 2 2 2 2 2 2 2 2 No 1 1 1 1 1 1 1 1 1 Presumptive TB Yes Contacts of the IndexTB Cases the of Contacts TB 08_Contact and TBPT and TB Register 08_Contact 2 2 2 2 2 2 2 2 2 Home Based (HB) Home 1 1 1 1 1 1 1 1 1 Type of Contact Investigation: or or Investigation: Contact of Type Based (HFB) Health Facility Facility Health Guardian's Name Contact Numbers Contact Address M Age F Name of Family Members Name Members No. of Family Family of No. TB) Type of TB (DS or TB DR TB, Hr FCHV Others...... FCHV Name of Index TB Index of Name Index TB Cases : Health Worker √) TB Reg. No Reg. TB S.N Name of HealthName Facility Year Month Contact Name Tracer Number Contact of ContactType ( Tracer NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 163 Print 2070/71 FY: Date ward no … … / … … / ……..… … / … / Date … … / … … / …..… … / … / signature …………..District Government of Nepal age Acknowledgement slip Acknowledgement …………...Hospital/ PHC/HP/HC/CHU Health Management Information System Information Management Health …………..Municipality/ Rural Municipality

Local Level Local Contact no sex Address District Date of contact Service provided Name of Responder….. Position: Name of client /patient Dear sir sir Dear of ………………………………………….Name Referred institution ………………………………………….Address of institution institution your thisby reached institution referred and are we client/patient The as in case Transfer in this institution. treatment TB continuing ------    Other Result Age ward no Date: Signature lab no / (+ / + / + +) Institution Edema on both Feet Date MUAC (mm)MUAC Examination and Result Sex Test X-ray X-ray Others Sputum Height (cm) Height Xpert MTB/RIFXpert Reasons (Specify)………………………………………………………… Reasons Transfer/ Referral Position: …………..District (For TB Patient only) Patient TB (For M/RM Government of Nepal Referral/Transfer slip Referral/Transfer Weight (kg) …………..Municipality/ Rural Municipality Health Management Information System ………………………………...Hospital/ PHC/HP/HC/CHU Respiration Temp District PCD , 3. EP (Site……………………) Pulse

७१ /

२०७० Province BP : TB 10 Referral / transfer Slip / transfer TB 10 Referral TB 10 TB Further examination needed …………… Patient of condition other and signs Vital Type of TB: 1. PBC, 2. Registration Category Name Name of Client/ Patient Address Contact no of Patient: ProvidedDrug for transferred …… while being days to patient the TALFU 4. Failure T. 3. after Relapse 2. New 1. 5. Other previously Tx Pt. 6. Unknown previous TB Tx history Regimen:……………………………………. Treatment reaches your institution. Contact no Dear sir …………………………………………...... …(Name Institution) of Referred Institution) …………………………………………...... …(Address of Referred we are the above sending detailed client/ patient to your institution for further service. Please inform after us referred client/patient Referred by

प�रमािज셍त 164 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 4. Sex / M : F ...... 3. Age Date: ...... /...... /...... Date: 2. TB cases follow TB 2. up : Address: ...... Address: Contact number: ...... number: Contact Tole Ward ...... M / RM diagnosis further For 1. of presumptive TB including Others 3. SAEs: TB 11 - Referral Form (Community / Private / Contact) District 1. Community1. Contact 3. Investigation Private 2. Province ...... Note: The original copy should be sent with the patient to the referred health facility and the carbon copy should be kept with the referring the referred the be and to carbon the kept with copy should patient the person facility with be health sent copy should The original Note: TB 11 Referral forms (Community, Private, Contact) Contact) Private, (Community, forms TB 11 Referral 1. Name of Health facility referred to: 2. Name of the person referred: ******************************************************************************************************************************* ** Referred by: Type of Referral Name: Signature 5. Address 6. Reason for referral NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 165

DRTB 04 Community form DRTB 04

Patient Commitment Form

Part 1:Signed atTreatment center Patient commitment I am aware that in order to be cured of this form of tuberculosis, I need to take anti-TB drugs daily till the end of my treatment. If I do not take these drugs daily, I am putting my own health at risk as well as the health of family and community members. I commit to taking these drugs at this health center (sub-center) till the end of my treatment. If I decide to leave this treatment, I understand the risk and consequences of this disease.

Name: Address: Date: Signature:

Treatment center DR-TB focal person commitment

I have explained the importance of taking these drugs and potential difficulties during treatment. I will do my best to support him/her in completing a full course of treatment and ensuring cure/completion. I also commit to ensuring proper documentation and reporting as per NTP guidelines

Name: Address: Date: Signature:

Part 2: Signed at Treatment Sub-Center

Sub-centre DR-TB focal person commitment

I have explained the importance of taking these drugs and potential difficulties during treatment. I will do my best to support him/her in completing a full course of treatment and getting cured. I also commit to ensuring proper documentation and reporting as per NTP guidelines

Name: Address: Date: Signature:

Treatment provider Commitment I commit to supporting his/her in completing a full course of treatment. I will encourage him/her to comply with the treatment and commit to informing the treatment sub-center if I know that s/he has stopped taking drugs.

Name: Address: Date: Signature: 166 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

DRTB 05 aDSM Recording and Reporting Form

Government of Nepal Ministry of Health & Population Department of Health Services National Tubeculosis Center DRTB 05 aDSM Adverse Event Reporting Form - Nepal

A. Patient and Health Facility Information Patient ID number (as in DRTB Treatment Centre: Register: Date of Birth (or Age): Province: Sex:  Male  Female HIV status:  Non-reactive  Reactive Pregnancy:  No  Yes Trimester: Weight (kg): Height (cm): BMI: B. Adverse events experienced by patient (including abnormal investigations) Adverse event Onset date End date Severity grade Seriousness * Outcome §

* Please select: D died LT life threatening HA caused or prolonged hospital admission PD permanent disability OS other medically serious CA congenital abnormality NS not serious § Please select: A recovered B recovering C recovered with residual effects D died E not recovered F unknown Detailed description of adverse event(s):

Was treatment of adverse event required?  No  Yes (please specify):

C. Laboratory assessment: Results of tests and procedures Test performed Test date Result Unit Reference range

NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 167

D. Medicines: DR-TB Regimen and other concomitant medicines, vaccines, traditional / herbal medicines and dietary supplements  Tick if medicine suspected of causing adverse event Medicine Dose Frequency Route Start date Stop date Reason for use Action taken † Response ‡            † Action taken in response to AE: DW drug withdrawn DR dose reduced DI dose increased DNC dose not changed UK unknown NA not applicable ‡ Response to action taken: RA recovered NE no effect on AE FA fatal AE UN unknown NA not applicable E. Re-challenge information List any medicines that were restarted and indicate effect on adverse event Medicine adverse event recurred adverse event did not recur unknown                      F. Other relevant information e.g. medical history, concurrent illnesses, smoking, alcohol use and Hospital Management

G. Causality Assessment at Treatment Center Level

1. Certain 2. Probable 3. Possible 4. Unlikely 5. Unassessed 6. Un-assessable

Comments:

168 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

H. Final AE/SAE Summary

Adverse Events Description: Event Start date Event End date Severity Grading Event classified: 1. Serious 2. Not – Serious (Based on Annex 2) Narrative / Additional information (Final Result):

G. Reporter Information Name: Phone number: Email: Occupation:  Doctor  Nurse  Paramedics  Other (please specify): Signature: Date

Submit form to: Email to: M&E Unit, NTC: [email protected]

NTC Use Only: Date received by NTC: Causality assessment:  Certain  Probable  Possible  Unlikely  Unassessed  Un-assessable Comment:

Reported to DDA:  No  Yes Date reported to DDA:

NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 169 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total order DRTB 06 DRTB To: Expiry date Stock on hand on Stock 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 From: Total Total requirement Approved By: Approved Signature: Date: Name: Designation: 240 360 120 600 120 CLR2.2 360 360 360 120 600 120 Order Period, FY: CLR2.1 360 360 120 600 120 CLR1 480 120 240 360 480 600 120 SSTR Child 480 240 188 120 120 LR2 Modify Modify 240 480 240 360 480 480 480 120 DR Drug Order Form LR4.2 National Tuberculosis Program Tuberculosis National Verified By: Signature: Date: Name: Designation: 240 480 240 360 480 480 480 240 120 LR4.1 Factors used for calculating total requirement 288 360 112 480 240 120 LR3 240 188 120 120 480 LR2 188 480 120 120 480 LR1 200 120 360 360 120 240 240 480 200 SSTR Adult Date: Name: Signature: Designation: Medicines Treatment center: Regimen cases No. of mg 500 Amikacin Amoxycillin 875 mg+ Clavulanic acid 125 mg 100 mg Bedaquilline 100Clofazimine mg mg 250 Cycloserine 50 mg Delamanid 400 mg Ethambutol 250 mg Ethionamide 500 Imipenem-Cilastatin mg Isoniazid 300 mg Isoniazid 100 mg 250Levofloxacin mg Linezolid 600 mg 400Moxifloxacin mg PAS 4 g mg 400 Pyrazinamide 5 ml for injection Water 150Moxifloxacin mg DT 50Clofazimine mg 125 DT mg Ethionamide Isoniazid 100 mg DT 100 DT mg Ethambutol 150 DT mg Pyrazinamide 100Levofloxacin mg DT mg 150 Cycloserine Prepared By: DRTB 06 DRTB Drug Order Form Form Drug Order 06 DRTB DRTB 170 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 9.3

HMIS ...... of

14 13 FY: 2070/71 Circle 207 207 service

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/ / number

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Name 10 12 11 Circle Signature within Year Designation Session Clinic Approved area

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0 10 20 ‐ Age >= 1 5 6 3 4 2 SN 2070/71 Ref. Fiscal District Sub: DRTB 07 DRTB Reporting Form (for cohort reporting) cohort (for Form Reporting 07 DRTB DRTB Revised: NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 171 12 PLR1

the home (Y 3 7 Male CPT CLR2.2 or N) of Treatment Print FY: 2070/71 Sex to smoking inside at End CLR2.1 LD 6 TB Patients on 2 of Exposure Female Smoking Status 9 10 11 HIV +ve 45 ART Quitted, D: Died, L: LTFU of Tobacco LR2 CLR1 Q: Q 8 or L) Modified at the END of Treatment or (S,R,Q,D Smoking 7 Relapsed Smoker, 2=>30 Min R: of Smoking walking to first cigarette 1= <=30 Min for Outcome ‐ Status HIV Positive Status R Total Block 5:HIV status Time after Case care 56 LR3 LR4.1 LR4.2 Block 6.1: Tobacco S: Current Smoker, and Block 7:Contact Investigation ‐ Xdr, XDR ‐ register 23 1 treatment 34 TB/DRTB LR1 LR2 S 3 45 (MDR,Pre Patients Tested for HIV (Current) Tracing of Registered with 12 3 to TB/DRTB [41] 2 Tobacco SSTR Contact Male Smoking Female

M 1 Male Female [3] number diagnosed number linked number of close contacts number contact traced 1 of Total Total Total Total of Cases Block 6.2:All DR TB patients F 12 Registered No TB Regimen by Treatment Male Sex of Sex of At the Female 4 1 2 3 Patient Patient Block 4:Registration Treatment At the Time of TB Diagnosis beginning 19 XDR FM M to ‐ XDR Pre F Switched reporting) M 15 16 17 18

19 14 MDR (LR) Previous M 19 History XDR MF 18 13 TB Treatment F Format (For cohort 18 Unknown

F M MF 17 17 Not Evaluated to Other ‐ XDR ‐ up treated F M 16 11 12 previously Pre F 16 FM ≥ 65 Years Switched to follow F M 10 Lost DRTB 07 Reporting M M 15 15 16 17 TALFU F p M

MDR LR

F F 14 14 55 ‐ 64 Years Died of F 8 M 13 14 15 with SLD failure M 13 M 13 F 12 After Treatment

7 M F 12 MM 45 ‐ 54 Years Not Evaluated F Positive 12 Hr TB failure Regimen M 10 11 11 (Interim cohort analysis) with (Cases Reg. at 12 After of Treatment M 11

Ago) Died of 9 F 10 FLD Month Conversion F 35 ‐ 44 Years 10 failure F with 6 ‐ Treatment Re Outcome After Negative result at 6 months 9 M up

M of

7 M F MF with Culture

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FLD to Follow failure 8 F 25 ‐ 34 Years first line F 8 68 Lost After Block 7:Treatment Treatment 5 M 7 M MF Positive 7 M Relapse F 15 ‐ 24 Years (Cases Reg. at 8 Month Completed ago 5 MF F 6 Treatment F 4 Negative ‐ 14 Years New F 4 result at 4 months 5 M FM Cured Smear F 4 39 M 3 M FM 23 0 ‐ 4 Years 5 Register 26 F F 2 Register 1 2 3 45

[3]

Pulmonary Pulmonary Pulmonary Pulmonary of DR 24 24

Extra Pulmonary Extra Pulmonary Extra Pulmonary Extra Pulmonary 24 Age of months 1 ‐ XDR 1 1 ‐ XDR XDR RR [2] (Cases Reg XDR Ago) MDR Pre MDR (LR) Conversion Pre MDR (SSTR) Block 1 : Case Registration Ago) Ago) Ago) Registration BLOCK 2: ‐ XDR RR XDR ‐ XDR (Cases Reg MDR Types of DR TB [..] Pre TB Cases: No completed treatment Sputum 16 Month MDR LR (Cases Reg Month XDR (Cases Reg Month Pre MDR SSTR Month Revised:2070/71 172 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

LR

______On DRTB 08

Enrolment ______nded e SSTR

On

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:

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Summary NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 173

>15 year

6

5

4

3

<15 yrs 2

1

12 ------

------

: 11 ------

year

10 enrolled patient regimen Report due

9 TB - regimen Current

8 TB - XDR

7 Summary Summary

6

5

4

3

2

Patient started Pre on Aged Sex breakdown an of the Male Female HIV positive among enrolled patient 1 Patient started XDR on

Reporting period 174 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT 175 176 NATIONAL GUIDELINES ON DRUG RESISTANT TUBERCULOSIS MANAGEMENT

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