Drug Resistant Tuberculosis Management Guideline

Government of Nepal
Ministry of Health and Population
Department of Health Services
National Tuberculosis Centre
Thimi, Bhakatapur
END
TB
2019
NATIONAL GUIDELINES ON
Drug Resistant Tuberculosis
Management

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
TABLE OF CONTENTS

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

viiN A T I O N A L G U I D E L I N E S O N D R U G R E S I S T A N T T U B E R C U L O S I S M A N A G E M E N T
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

ixN A T I O N A L G U I D E L I N E S O N D R U G R E S I S T A N T T U B E R C U L O S I S M A N A G E M E N T
• It is recommended that any patient – child or adult – with RR-TB in whom isoniazid resistance
isabsentorunknownbetreatedwitharecommendedMDR-TBregimen,eitheralongerMDR-
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 onTB 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
• DelamanidmaybeincludedinthetreatmentofMDR/RR-TBpatientsaged3yearsormoreon
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 RRTB patients
• It is desirable for sputum culture to be repeated at monthly intervals.
THE MAIN CHANGES IN THE WHO 2019
RECOMMENDATIONS

1.1 BACKGROUND
NationalTB programme is moving forward with the vision ofTB 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
Objective3:ToprovideDRTBdiagnoseservicesto50%ofthepresumptiveMDRTBpatients
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.
INTRODUCTION
C H A P T E R 1

2 N A T I O N A L G U I D E L I N E S O N D R U G R E S I S T A N T T U B E R C U L O S I S M A N A G E M E N T
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,160,684casesofMDR/RR-TBweredetectedandnotifiedin2017(asmallincrease
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.

3N A T I O N A L G U I D E L I N E S O N D R U G R E S I S T A N T T U B E R C U L O S I S M A N A G E M E N T
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 DRTB cases in the country.The proportion of new cases with multidrug-resistantTB
(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.

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-susceptibilitytesting(DST):referstoin-vitrotestingusingeitherphenotypicmethodsto
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.
• Rifampicinresistance(RR-TB):resistancetorifampicindetectedusingphenotypicorgenotypic
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

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). ATB 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.

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

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 DRTBTreatment 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

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
• Organisesupportivesupervisionatthetreatmentandsub-centretoenhancetheperformance
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

• 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;

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

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.
DIAGNOSIS OF DR-TB
C H A P T E R 2

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.

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

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
Type of EP TB Specimen
Quantity* to be
collected
Type of
container
Tuberculous pleuritis Pleural Fluid 10-15 ml
Sterile
containers
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 TB
Intra-articular Fluid
Biopsy samples
Minimum 2 ml
TB pericarditis Pericardial Fluid Minimum 2 ml
TB peritonitis Ascitic Fluid 10-15 ml
TB of other organs
Other tissue samples e.g.
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
present (Genexpert centers),
the specimen, together with
the request form, will be taken
directly to the Genexpert
centers. At health facilities
Xpert MTB/RIF testing is not
available, samples will be
transported to the nearest
Genexpert Centers. Tripple
layer packaging must be
made for transportation
of the samples. The tightly
closed Falcon tube is sealed
with paraffin tape, wrapped
in absorbent paper and
placed in a proper packaging
as shown in diagram and
must be properly sealed. The
package together with the
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.
Waterproof
Cap
Primary receptacle
(leakproof or siftproof)
Rack-type holder
(styrofoam, sponge)
Itemized list of
contents
(specimen record)
Rigid outer
packaging
Proper shipping
name
Package marking
To/From labels
Secondary
packaging )
leakproof or
siftproof)
Absorbent
packing
material
D3. Sputum sample package

2.3.2.4 Xpert MTB/RIF testing results
TABLE 2.2: Results of the Xpert MTB/RIF test
Label Result and
Interpretation
Action to be taken
T
MTB detected,
rifampicin resistance not
detected
Diagnosis of TB confirmed. Treat with first-line TB regimen.
RR
MTB detected,
rifampicin resistance
detected
If presumptive MDR- TB case: send to DR-TB Centre.
If new TB case: consider repeat Xpert MTB/RIF test. If RR result
is confirmed, send to DR-TB Centre.
TI
MTB detected,
rifampicin resistance
indeterminate
Diagnosis of TB is confirmed. Start treatment with first-line TB
regimen and send new sputum specimen to repeat the test.
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.
I
Invalid/no result/error Send new sputum specimen to repeat the test. Pay special
attention to quality of sputum sample, conditions of storage
and transportation and speed of shipment
TheresultiswrittenontheXpertMTB/RIFrequestformandsentbacktotherequestinghealthfacility.
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.

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
resistance to
FQ.
Phenotypic result Clinical Implication
gyrA Mut 1 +/- gyrA WT 2
probe
Low/
Moderate/
High
• Levofloxacin:
Resistance detected.
• Moxifloxacin: Low
level resistance
detected.
High level Mfx
susceptibility results
to be reported
within 2 months.
Mfx could be used
at higher dose. The
regimen should be
re-evaluated based
on phenotypic DST
results at CB.
gyrA Mut 2 +/- gyrA WT 2
probe
Moderate/
High
gyrA Mut 3A +/- gyrA WT 3
probe
Low
gyrB Mut 1 +/- gyrB WT probe Moderate
gyrB Mut 2 +/- gyrB WT probe Moderate
gyrA Mut 3B +/- gyrA WT 3
probe
Moderate/
High
• Levofloxacin:
Resistance detected
Moxifloxacin: High
level resistance
detected.
Mfx even at a high
dose cannot be
considered as an
effective medicine.
gyrA Mut 3C +/- gyrA WT 3
probe
sHigh
gyrA Mut 3D +/- gyrA WT 3
probe
High
gyrA gyrA WT 1 probe
missing
Moderate/
High
• Levofloxacin:
Resistance detected.
• Moxifloxacin: Low
level resistance
detected.
High level Mfx
susceptibility results
to be reported
within 2 months.
Levofloxacin is not
effective.
Mfx could be used
at higher dose. The
regimen should be
re-evaluated based
on phenotypic DST
results at CB.
missing
Moderate/
High
gyrA gyrA WT 1 and WT
2 probe missing
Low to High
missing
Moderate/
High
Basedon“LineprobeassaysfordrugresistanttuberculosisdetectionInterpretationandreporting
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
to Am and Cm
eis eisWT 1 probe missing
eis eis WT 2 probe missing
eis eis WT 3 probe missing Susceptible to Km, Am, Cm

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
Type of EP TB Specimen
Quantity* to be
collected
Type of
container
Tuberculous pleuritis Pleural Fluid 10-15 ml
Sterile
containers
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
TB
Intra-articular Fluid
Biopsy samples
Minimum 2 ml
TB pericarditis Pericardial Fluid Minimum 2 ml
TB peritonitis Ascitic Fluid 10-15 ml
Genito-urinary TB Urine 100-200 ml
Endometrial Biopsy

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.
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:
Number of colonies
No colonies after 8
weeks
Exact number 10-100 101-200 >200
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
• Negative for Mycobacterium tuberculosis complex
D3. Sputum sample in
cold box
D4.MGIT culture result

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

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.

FIGURE2.1:DecisiontreeforthediagnosisandtreatmentofDRTB
BoxA.PresumptiveDRTBcases
1.DRTBclosecontacts
2.AllRetreatmentpatients(includingfailure,
losstofollowupandrelapse)
3.Non-convertersbymonth2orsubsequent
follow-up
4.Notgettingbetter/gettingworseduringthe
continuationphaseofthefirstline
treatment
XpertMTBRif
Tests
BoxB:SpecialgroupsforXpertMTB/Riftesting
1.AllNewPulmonaryTBpatientsregisteredBUTwhodidn’tprior
haveXpertMTB/Riftestingdone
2.ExtrapulmonaryTBpatients(EPsamples)
PresumptiveTBcases:
3.Children<14years
4.PLHIV,DMandotherimmunocompromised
5.X-raysuggestiveofTB,butsmearnegative
6.Healthcareworkers
7.ContactsofIndexTBcasesandpeoplelivingincongregatesetting
8.AllpresumptiveTBcaseswithaccesstoXpertMTB/RifTesting.
MTBDetectedRif
ResistanceDetected
(RR)#
Noresult,erroror
Invalidtest(I)
RepeatXpertMTB/Rif
testandmanage
accordingly
MTBnotDetected(N)
Performadditional
investigationsand
clinicaljudgement
followedbyCultureDST
MTBDetected,Rif
ResistanceNotDetected
(T)
MTBDetectedRif
Indeterminate(TI)
-InitiatefirstlinetreatmentTx
-RepeatXpertMTB/RifTest
andmanageaccordingly
(performcultureifrequired)
SLLPACulturefollowedbyDST
ShorterMDRregimen
foreligiblepatients,
andLR1forthosenot
eligibleforSSTR
FQsensitive&
SLISensitive
FQsensitive&
SLIResistant
FQresistant&SLI
SensitiveorResistant
Indeterminateresult
InitiateLR2
RepeatdirectSLLPAand
evaluateculturereport-ContinueSSTR
-ContinueLR1
(forthosenot
eligibleforSSTR
inthe
beginning)
-InitiateLR1for
thosewhowere
initiallyonSSTR
-ContinueLR1for
thosewhoare
alreadyonLR1
1.ContinueSSTRorLR1andmonitorthetreatment
responseunlessFQresistanceisreported
2.IfFQresistancereported,switchtoLR2
InitiateFirstLineTreatment
(ForRetreatmentcases,considerclinicaljudgementandifrequired
otheradditionaltests:smear,culture,etc.)
LPAfirstlineonlyforpoints2,3,4ofBoxA
H-ResistanceH-Sensitive
InitiateHrTBregimenand
sendforSLLPAand
manageaccordingly
ContinueFirstline
treatment
NOTE:
1. #FornewcaseswithlowriskofRR-TBcliniciancandecidetorepeatincaserequired
2. Asperinterpretationofresults,pleasefollowTreatmentalgorithmsbothforDSTBandDRTB
3. AllPresumptiveTBcaseswithaccesstoXpertMTB/RIFTesting,XpertTB/RIFshouldbefirstdiagnotictools.

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.

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.
IfthepresumptionofMDR-TBispresentintheabsenceofclearclinicalorbacteriologicalevidence
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.

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 treatedTB 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.
REGISTRATION CATEGORY
OF DR-TB
C H A P T E R 3

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.)
• Thepatient’sknowledgeandunderstandingofhis/herroleinachievingasuccessfultreatment
outcome is an essential component for treatment selection.
TREATMENT OF
DR-TB
C H A P T E R 4

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
and understanding of
Disease
What is TB and DR TB, difference between TB & DR TB, treatment for
DR TB,duration of injectables (if applicable) and treatment, monthly
follow ups and routine investigations, benefits of regular treatment
and harms of interruption of treatment.
2 Prevention of Spread of
DR TB
What measures are to be taken to prevent spread of DRTB at household
and community level, close contact screening, importance of regular
intake of medicine
3 Information about
possible side effects
What most common side effects patient may experience and how
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
Responsibilities
Explain patients’ role in treatment completion, what are patient rights
and responsibilities during whole period of treatment.
5 Role& Responsibilities
of Treatment Supporter
Clearly explain the role and responsibility of TS, daily supervised DOT
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
throughout Treatment
Patients should be supported by the counsellors and to provide
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
confidentiality
The PMDT health team should explore the need of the patient to
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.

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
NationalTB 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
TheprobabilityoftreatmentsuccessinRR/MDR-TBpatientsdependsuponpatients’willandstrong
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

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
regimen, if no contraindication
Levofloxacin OR
Moxifloxacin
Lfx /Mfx
Bedaquiline Bdq
Linezolid Lzd
B
Add one or both Medicine
Clofazimine Cfz
Cycloserine OR
Terizidone
Cs, Trd
C Add to Complete regimen and
when medicines from Group A
and Group B cannot be used
Ethambutol E
Delamanid Dlm
Pyrazinamide Z
Imipenem-cilastatin OR
Meropenem
Imp,Cln, Mpm
Amikacin (OR Streptomycin) Am(S)
Ethionamide OR
prothionamide
Eto , Pto
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

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.

• 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
• TheadditionofPyrazinamide(Z)intheregimenisusefulasithassynergisticeffectswhenused
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
treatingphysicianandinlinewithspecialistadvisethesemedicinescanbeusedwithprecautions.

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,
ventricular arrhythmias or severe
coronary artery disease
Baseline ECG with QTcF > 500 ms
(repeated)
Use with caution if QTcF >
450/470 ms in male/female
patients.
Weekly ECG monitoring and
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
peripheral neuropathy (based
on Basic Peripheral Neuropathy
Screening (BPNS), subjective sensory
neuropathy scoring )
Severe Myelosuppression and
Anemia, moderate neutropenia
Special precautions when used in
combination with Cs, high dose
INH and diabetics.
In mild to moderate
Myelosuppression and Anemia
Lzd can be used with lower
doses, 300 mg daily or 600
mg alternative days with close
monitoring
Drug-Drug Interactions and Overlapping Toxicities with Bdq, Dlm and Lzd
Itisessentialtoconsiderthedrug-druginteractionswithBdq,DlmandLzdasusinginconcomitant
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.

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 AntiTBTherapy (HRZE), as these drugs appear to reduce level of Dlm OverlappingToxicity
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
Serotonin5-HT1receptoragonistsMAOinhibitors:phenelzine,isocarboxazidOtherserotoninergic
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/
MDRTB 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/MDRTB 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
BACKGROUND HISTORY
REGIMEN COMMENTS
LR1 Standard longer RR/MDR
TB Regimen for adults and
children 6 yrs and above
Non-eligible for SSTR and
for those whose FQ results
unknown/ awaited/sensitive
Bdq(6), 18 Lfx,Lzd,Cfz,Z
1. In case of toxicity or need
to decrease or substitute Lzd
with Cs refer to aDSM relevant
section
2. If Lzd is well tolerated, should
be continued throughout the
treatment duration

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
of FQ resistance/
FQ resistance at
baseline (Pre-XDR)
and XDR TB
Bdq (12),18Lzd,
Cfz, Cs,Z
1. High dose Lfx or Mfx can be added once
resistance level to FQs are known
2. In cases with intolerance/toxicity to Lzd,
stopping Lzd, replacing with Dlm can may be a
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
standard treatment
(LR1) /Relapse or
recurrence of MDR
TB
6 Am, Dlm, Eto,
PAS (Cs), Cfz
(Mfx/Lfx) – 12
Dlm (6), Eto, PAS
(Cs), Cfz, (Mfx/
Lfx)
1. DST to FLD and SLDs should guide further
modification where necessary
2. Use Am if documented susceptibility to it, design
regimen based on previous exposure to SLDs
and likely effective drugs.
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
XDR (FQ and SL
Inj. Resistance)
and Exposure to
standard MDR
regimen such as
failure/relapse/LTFU
to LR1
2. Failure of LR2
LR4.1 18
Dlm(12),Cs, Imp/
Clv (10), Eto,PAS,
Cfz,Z
LR 4.2 18
Dlm(12), Imp/
Clv (10), Eto,PAS,
Cfz, Z
1. DST to FLD and SLDs should guide further
modification where necessary
2. Design regimen based on previous exposure to
SLDs
3. Dlm extension through out treatment may be a
good option
4. Clinical case discussion with DR experts before
initiation of LR4 (Case discussion panel)

TABLE4.5Adultdrugdosagesinthelongregimen(LR)
DrugFormulationDailydose30–35kg36–45kg46–55kg56–70kg>70kg
Moxifloxacinstandarddose400mgtab7.5-10mg/kg1tab1tab1tab1tab1tab
Moxifloxacinhighdose400mgtab1-1.5tab1.5tab1.5-2tab2tab2tab
Levofloxacin(highdoseupto1500mg
daily)
250mgtab
500mgtab
750mgtab
15-25mg/kg/day3tabs
1.5tabs
1tab
3tabs
1.5tabs
1tab
4tabs
2tabs
1.5tabs
4tabs
2tabs
1.5tabs
4tabs
2tabs
1.5tabs
Amikacin1
<60years500mg/2ml
pervial
15mg/kg1x/day
(max1gr)
2.5ml3ml3-4ml4ml4ml
≥60years10mg/kg1x/day
(max750mg)
2ml2.5ml2.5ml2.5-3ml3ml
Ethionamide250mgtab15-20mg/kg/day2tab2tab3tab3tab4tab
Clofazimine100mgcap100mg/day1cap1cap1cap1cap1cap
Cycloserine250mgcap10-15mg/kg/day2cap2cap2cap3cap3cap
Pyrazinamide400mgtab20–30mg/kg/day3tab4tab4tab4tab5tab
Ethambutol400mgtab15–25mg/kg/day2tab2tab3tab3tab3tab
Isoniazidhigh-dose300mgtab10mg/kg/day1.5tab1.5tab2tab2tab2tab
PAS4gmsachet150-200mg/kg/day1sachet
bd
1sachet
bd
1sachet
bd
1sachet
bd
1-1.5
sachetbd
Linezolid600mgtab600mg/day1tab1tab1tab1tab1tab
Delamanid50mgtab200mg/day2tabbd2tabbd2tabbd2tabbd2tabbd
ClavulanicAcid125mgwithAmoxicillin
&Meropenem
250mg/day125mgbd125mgbd125mgbd125mg
bd
125mgbd
Imipenem-cilastatin500mgvial4gm/day1gmbd1gmbd1gmbd1gmbd1gmbd
Bedaquiline100mgtab400mgoncedailyfor2weeksfollowedby200mg3timesperweekfor22weeks
Meropenemtobeusedwithclavulanicacid1000mgvial20ml1vial3timesor2vials2timesdailyIV

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.
TreatmentOutcomesforRR-TB/MDR-TB/XDR-TBpatientstreatedusingsecond-linetreatment
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.

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
Continuation phase
5 months (fixed)
4 (+1 or 2) months
Amikacin
Ethionamide
Isoniazid high-dose
Moxifloxacin high-dose
Clofazimine
Pyrazinamide
Ethambutol
FIXED
4-6 Am Mfxh
Eto Hh
Cfz E Z / 5 Mfxh
Cfz E Z

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
30-35
Weight group (Kg)
36-45 46-55 56-70 >70
Amikacin1
(vial 500 mg-
2ml)
<60
years
15mg/kg
(maximum 1
gram)
500mg
(2ml)
625 mg
(2.5ml)
750 mg
(3)
875mg
(3.5)
1000
mg
(4ml)
≥60
years
10mg/kg
(maximum 750
mg)
350mg
(1.5ml)
450mg
(2ml)
500mg
(2ml)
500mg
(2ml)
750mg
(3ml)
Ethionamide2
(tablet 250mg)
15-20mg/kg/d 500mg
(2 tab)
500mg
(2 tab)
750mg
(3 tab)
750mg
(3 tab)
1gm
(4 tab)
Isoniazid high-dose
(tablet 300mg)
10mg/kg/d 300mg
(1 tab)
450mg
(1.5 tab)
600mg
(2 tab)
600mg
(2 tab)
600mg
(2 tab)
Moxifloxacin high-dose
(tablet 400mg)
10-15mg/kg/d 600mg
(1.5 Tab)
600mg
(1.5 Tab)
600-
800mg
(1.5-2
Tab)
800mg
(2 Tab) 800mg
(2 Tab)
Clofazimine
(capsule 100mg)
2-3mg/kg/d 100mg
(1 tab)
100mg
(1 tab)
100mg
(1 tab)
100mg
(1 tab)
100mg
(1 tab)
Pyrazinamide
(tablet 400mg)
20-30mg/kg/d 1000mg
(2.5 tab)
1200mg
(3 tab)
1600mg
(4 tab)
2000mg
(5 tab)
2000mg
(5 tab)
Ethambutol
(tablet 400mg)
15-25mg/kg/d 800mg
(2 tab)
800mg
(3 tab)
800mg
(3 tab)
1200mg
(4 tab)
1200mg
(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
2x/d
½ tab
2x/d
½ tab
morning 1
tab evening
1 tab
2x/d
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
4x/w
1 cap
6x/w
1 cap/d 1 cap/d
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

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

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

Treatment regimen of SSTR and Failure to SSTR (Modified LR2)
SSTR Standard Shorter
Treatment
Regimen(SSTR)
4-6 Amk,Mfxh
, Cfz, Eto, INHh
, E,
Z/5 Mfxh,Cfz, Z,E
1.As per standard protocol (Km
replaced with Am)
2. In case of toxicity and SSTR
cannot be continued, then
switch to LR1
Modified
LR2
Failed by SSTR 18 Bdq(12), Dlm(6), Lzd,Cs,Cfz,
PAS
DST to FLD and SLDs should
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
months
culture at 5
months
culture at 6
months

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