National DR-TB Guidelines - 2021

FEDERAL MINISTRY OF
HEALTH
DEPARTMENT OF PUBLIC
HEALTH NATIONAL TUBERCULOSIS,
LEPROSY & BURULI ULCER CONTROL
PROGRAMME
NATIONAL GUIDELINES FOR CLINICAL AND

PROGRAMMATIC MANAGEMENT OF DRUG RESISTANT
TUBERCULOSIS IN NIGERIA.
(PMDT GUIDELINES – 3RD EDITION)
May 2021
Forward
Nigeria has the Sixth highest tuberculosis (TB) burden in the world and the highest in
African, lagging behind five countries, China, India, Pakistan, Indonesia and
Philippines. The increasing emergence of Drug-resistant strains of TB (DR-TB) is due
to treatment “loss to follow ups” and other challenges ranging from delays in enrolment
of patients into treatment, poor infection control in health facilities and new infections.
These guidelines are intended for use by health care professionals involved in the
complex and difficult task of managing Drug Resistant Tuberculosis, using the newly
recommended all oral drug resistant Tuberculosis treatment regimen in Nigeria. The
guidelines focus on the clinical management, referral mechanisms and models of care.
However, psychosocial support to ensure comprehensive management of the patients,
strategies for infection prevention and control, and community-based service by health
care workers (HCWs) are also covered.
Management of DR-TB is an evolving strategy and needs to be adapted through

evidence-based information. These guidelines contain recommendations based on the
most recent scientific evidence, with the WHO recommendations. Comments and
suggestions from those working in the field are also essential to ensure a dynamic
process, aimed at optimal control of DR-TB in Nigeria and theses stakeholders were
part of the review of the document.
I believe this will be a useful document for all health care workers to manage their
patients effectively in line with the international standard for TB care.
Dr. Osagie E. Ehanire MD, FWACS

Honourable Minister for Health
ii
Acknowledgement
There are many people to thank for their active participation in making this review
of 3rd edition of the National Guidelines for Clinical and Programmatic
Management of Drug Resistant Tuberculosis a comprehensive and well-reasoned
document. The development of this guidelines was coordinated by the National
tuberculosis and leprosy control Programme and supported by the KNCV Nigeria
and the Clinton Health Access Initiative (CHAI) under the leadership of National
Coordinator NTBLCP who worked tirelessly to synchronize the needed support for
this work.
We want to acknowledge the immense support, financially and technically by the

following organisations; WHO, USAID, KNCV, CHAI, DFB, IHVN and GLRA and
other stakeholders that are not mentioned here.
We equally thank all our colleagues in NTBLCP of the Federal Ministry of Health for
their support and participation in the development of this document.
We sincerely want to thank in particular Dr. Babawale Victor (TB Specialist) and Dr.
Sam Ogiri (WHO) who both facilitated the development and editing of the
document.
Dr. M. O. Alex-Okoh
Director Public Health
iii
Abbreviations/Acronyms
AFB - Acid Fast Bacilli

AIDS - Acquired Immune Deficiency Syndrome
ART - Anti-Retroviral Therapy
CPT - Co-trimoxazole preventive therapy
DOTS - Directly Observed Short course strategy
DR-TB - Drug Resistant Tuberculosis
ACSM - Advocacy Communication & Social Mobilization
AE - Adverse Events
aDSM - Active Drug Safety Management
GF - Global Fund
ALAT - Alanine Amino Transaminase
ASAT - Aspartate Amino Transaminase
Am - Amikacin
Amx/Clv - Amoxicillin Clavulanic Acid
Cm - Capreomycin
Cfz - Clofazimine
Dlm - Delamanid
Bdq - Bedaquilline
CSF - Cerebrum Spinal Fluid
CTB - Challenge TB
ECG - Electrocardiography
EMA - European Medicines Agency
FDA - Food & Drugs Administration
FLD - First-Line Drugs
FMoH - Federal Ministry of Health
FQ - Fluoroquinolones
GDF - Global Drug Facility
gDST - Genotypic Drug Susceptibility Testing
pDST - Phenotypic Drug Susceptibility Testing
iv
H - Isoniazid
Hh - Isoniazid High Dose
HIV - Human Immuno-Deficiency Virus
HCT - HIV Counselling and Testing
SBCC - Social Behavioural Change Communication
ILEP - International Federation of anti-Leprosy Organizations
PMDT - Programmatic Management of Drug Resistant TB
PLHIV - People Living with Human Immuno-Deficiency Virus
PSM - Procurement and Supply Management
LGTBLS - Local Government Tuberculosis and Leprosy Supervisor
LTFU - Lost To Follow Up
LPA - Line Probe Assay
Lzd - Linezolid
MGIT - Mycobacterium Growth Incubator Tube
NPO-TUB - National Professional Officer for Tuberculosis
NRL - National TB Reference Laboratory
NTBLCP - National Tuberculosis and Leprosy Control Programme
Mfx - Moxifloxacin
Mpm - Meropenem
SLDs - Second Line Drugs
R&R - Recording and Reporting
SMoH - State Ministry of Health
SOPs - Standard Operating Procedures
STBLCO - State Tuberculosis and Leprosy Control Officer
HAF - Heath Alive Foundation
TB - Tuberculosis
TS/CV - Treatment Supporter/Community Volunteers
WHO - World Health Organization
Z - Pyrazinamide
v
List of Contributors:
SN FULL NAME ORGANIZATION
1 ABOKI Danjuma PM-STBLCP Nasarawa
3 ADETIBA Temitayo IHVN
4 AHMAD Muhammad Ozi NTBLCP
5 ALHASSAN Shuaibu NTBLCP
6 AKPAKPAN Rita NTBLCPS
7 AMIN Jamila NTBLCP
8 ALI Taofeekat IHVN
9 ANAGO Chux CHAI
10 ATIKU Abubakar Chika NTBLCP
12 BABAWALE Adekunle Victor NTBLCP
13 CHIJIOKE-AKANIRO Obioma NTBLCP
14 DUNGA Amos Jacob ATBTH BAUCHI
15 DUTT Saswata IHVN
16 ELOM Emeka NTBLCP
19 FALOKUN Victor KNCV Nigeria
20 ITOHOWA Uko NTBLCP
21 KIFASI Rimamtswab Ephraim NTBLCP
22 LAWAL Umar ABUTH ZARIA
23 LAWANSON Adebola NC-NTBLCP
25 MGBEMENA Chiagozie IHVN
26 MOBOLAJI Raji NTBLCP
27 MOSES Grace Olabisi NTBLCP

vi
28 MOMOH Idris NTBLCP
29 NWAFOR Dozie CHAI
30 OCHEI Kingsley Chinedum MEASURE EVALUATION
31 ODUME Bertrand KNCV Nigeria
32 ODUSOTE Temitayo USAID
33 OSMAN eltayeb DFB
36 OMONIYI Amos Fadare WHO

37 OMOSEBI Oluwafunmilayo NTBLCP
39 OSHO John Adewale ARFH
40 OGIRI Sam WHO
41 SHESHI Michael Audu SHOPS PLUS
42 UBOCHIOMA Emperor NTBLCP
42 TUBI Abiola NTBLCP
44 UCHE Valentine J&J
45 URHIOKE Ochuko NTBLCP
46 USENI Sani KNCV Nigeria
vii
Table of Contents
1 Forwards………………………………………………………………………………………....ii
2 Acknowledgments.........................................................................................iii
3. Abbreviation/Acronyms...............................................................................iv
4. List of Contributors……………………………………………..............................…..vi
5 Table of Contents……………………………………………………………………...………1
6. Executive Summary……………………………………….........................................4
1. Identification of Presumptive DR-TB Cases................................................6
1.1 Detection of Drug-Resistantant Tuberculosis.............................................6
1.2 Case Finding Strategies................................................................................7
2 Diagnosis of Drug Resistant Tuberculosis...................................................8
2.1 Organisation of Laboratory Services...........................................................8
2.2 Diagnosis Of Drug-resistant Tuberculosis..................................................8
2.3 Diagnosis of Extra-pulmonary Tuberculosis(EP-TB).................................12
2.4 Diagnosis of Drug-resistant Tuberculosis in Children................................14
3 Treatment of Drug Resistant Tuberculosis .................................................19
3.1 Eligibility criteria for starting DR-TB treatment regimens.........................19
3.2 Patient triage approach to select the appropriate
DR-TB regimen ............................................................................................20
3.3 The following scenarios to be considered when receiving
second-line DST............................................................................................20
3.4 DR-TB Treatment Regimens .......................................................................23
4 Management of Drug Resistant Tuberculoisis in Special
Situations......................................................................................................36
4.1 Pregnant and Lactating Women.................................................................. 36
4.2 Children .......................................................................................................37
5 Ensuring Adherence and Management of Treatment
Interruption .................................................................................................45
5.1 Factors Affecting Adherence........................................................................45
5.2 Poor Adherence............................................................................................46
1
5.3 Adherence Intervention Strategies..............................................................46
5.4 Management of Treatment Interruption.....................................................47
6 Monitoring of Drug Resistant Tuberculosis Treatment ...........................48
6.1 Monitoring Progress of Treatment .............................................................48
6.2 Monitoring Adverse Events.........................................................................50
6.3 Clinical monitoring of adverse drug reactions (ADRs) .............................. 51
6.4 Educational, Psychological, and Social Consultation ................................51
6.5 Laboratory monitoring of AEs ...................................................................51
6.6 Severity grading scale of adverse events and main

laboratory parameters................................................................................. 52
7 Management of Adverse Drug Reaction ....................................................54
7.1 Potential overlying and additive toxicities of anti TB and ARVS ...............54
7.2 Pharmacovigilance in programmatic management of Adverse Drug
Reaction in DR-TB ......................................................................................62
7.3 Basic definitions used in pharmaco vigilance ............................................62
7.3 Basic definitions used in pharmaco vigilance ............................................62
7.4 Common adverse reactions to the anti-TB drugs........................................63
7.4 Key considerations in management of adverse drug reactions...................65
7.5 General Management Strategies for ADR ...................................................75
8 Diagnosis and Treatment of DR-TB in HIV Infected Patients .................77
8.1 Drug-resistant TB and HIV Co-Treatment ................................................78
8.2 Bedaquiline interactions with ARVs (NNRTI and PIs).............................. 78
8.3 Use of Bedaquiline and Delamanid with ART........................................... 79
8.4 Use of Bdq with ART ...................................................................................79
9 Supply Chain Management System of Drug Resistant
Tuberculosis (DRTB) ..................................................................................84
9.1 Purpose of Supply Chain Management ......................................................84
9.2 Logistics Management Information System..............................................84
9.3 Key Data Elements of NTBLCP Logistics System .....................................84
2
9.4 Logistics Records .........................................................................................84
9.5 Logistics Management Information System Tools..................................... 85
9.6 Responsibilities of Service Providers in the Management of
DR-TB Commodities ...................................................................................86
9.7 Receive TB Commodities............................................................................. 86
9.8 Entering received items in the Stock Cards ................................................86
9.9 Storing TB Commodities ............................................................................86
9.10 Keep medicines and other supplies safe .....................................................86
9.11 Keep the store in good condition .................................................................86
9.12 Arrangement of Medicines and supplies in the store..................................87
9.13 Visual inspection of medicines and packaging ...........................................87
9.14 Use regimen guide correctly to determine dosage and
quantities .....................................................................................................87
9.15 Recording of Items issued on stock card.....................................................87
9.16 Issuing from a Storage facility.....................................................................87
10 Monitoring and Evaluation........................................................................ 95
10.1 Role of Monitoring and Evaluation.............................................................95
10.2 Information Flow System............................................................................ 95
10.3 Supervision.................................................................................................. 98
10.4 Programme Monitoring ..............................................................................98
10.5 DR-TB Programme Indicators ....................................................................98
References ..............................................................................................................108
Annexes ..................................................................................................................109
A Second line Anti TB Drugs Formulations............................................................109
B. How to Administer The Dispersible Tablets and Capsules (Ethionamide,
Isoniazid, Levofloxacin, Linezolid, Moxifloxacin, Pyrazinamide, Ethambutol
and Cycloserine).....................................................................................................110
C. Dosing Of Medicines Used In Second-line Regimens by Weight Band in
Patients Under 15 Years .........................................................................................112
D. Dosage By Weight Band For Medicines Used In Second Line Regimens,
Adults And Children Older Than 14 Years .............................................................119
3
EXECUTIVE SUMMARY
th th
Nigeria is ranked 6 among 30 high-burden TB countries globally and among the 14
countries for DRTB based on estimated incidence of MDR/RR TB. The national
MDR/RR TB burden is estimated to be 21,000 annually, however, case notification is
suboptimal, with only 2,384 cases diagnosed, representing an abysmally low 11% case
notification rate in 2019. This huge notification gap can be attributed to low DSTB case
finding, suboptimal access to rapid molecular diagnostics, challenging clinical and
programmatic management system.
These revised guidelines outline key recommendations for the implementation of the
all-oral, shorter regimen for DRTB treatment, including diagnosis and bacterial
confirmation of drug resistance, treatment regimen design, monitoring of treatment
efficacy and safety, and programmatic evaluation.
The eligibility criteria for initiation of all oral DRTB regimen remains and primarily
includes capacity to rule out resistance to key second line medicines (fluoroquinolone,
Bedaquilline and Linezolid), the 2019 WHO evidence-based guidelines for the
treatment of drug-resistant TB have introduced additional criteria for the use of the
shorter, all-oral regimens in DRTB management.
Based on foregoing, the National TB and Leprosy Control Program (NTBLCP) aligns
with the global consensus to phase out the use of injectable-containing treatment
regimens, especially for MDR/RR-TB patients without previous exposure to second-
line treatment (including Bedaquilline) without fluoroquinolone resistance and no
extensive TB disease or severe extra pulmonary TB.
Key changes to the treatment of DRTB contained in this revised guideline includes the
beneficial value of effective administration of all oral shorter treatment regimen for all
patients with MDR/RR-TB, including those with additional resistance to
fluoroquinolones, under programmatic conditions. The use of individualized regimen
using WHO priority grouping of medicines was recommended in 2018 for MDR/RR-TB
patients with extensive TB disease, severe forms of Extrapulmonary TB, those with
resistance to fluoroquinolones or those who have been exposed to treatment with
second-line drugs.
4
Furthermore, a third treatment regimen option lasting 6–9 months, composed of
Bedaquiline, Pretomanid and linezolid (BPaL), may be used in MDR-TB patients with
resistance to fluoroquinolones, who have either had no previous exposure to
Bedaquiline and linezolid or have been exposed for not more than 2 weeks under
operational research conditions.
Scale up of Xpert MTB/RIF assay continues to provide the needed laboratory support
for timely detection of rifampicin resistance. In addition to the 403 GeneXpert
MTB/RIF machines in the country as of December 2020, all 10 reference laboratories
have the capacity for second line drug susceptibility testing. Similarly, there are now 10
laboratories providing line probe assay for first line TB drugs in the country, an 100%
increase from the 5 existing ones in 2016.
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CHAPTER 1
IDENTIFICATION OF PRESUMPTIVE DR-TB CASES
1.1 DETECTION OF DRUG-RESISTANT TUBERCULOSIS
The diagnosis and treatment of persons with DRTB begins with the proper
identification of a presumptive DRTB case. Therefore, it is important that all those who
provide health services to TB patients should always identify persons with presumptive
DR-TB and to ensure that this identification is done early, to enable prompt diagnosis
and appropriate treatment.
To increase surveillance for DR-TB in Nigeria, the NTBLCP has recommended that all
health care providers give priority to the following persons who present with symptoms
of TB in their facilities:
v All presumptive TB cases
v Anybody who has met the criteria of a confirmed DR-TB patient and shows
symptoms of TB.
v Any person whose AFB result is smear positive when repeated at the end of
month two of 'Regimen-1' treatment.
v All previously treated Drug Susceptible TB Patients:
Ø Relapse
Ø Treatment after failure to Regimen 1
Ø Treatment after loss to followup
Ø Other previously treated patients.
In addition to screening all presumptive TB cases and the priority group above, the
NTBLCP has identified a second priority group to expedite early diagnosis and improve
the quality-of-service delivery. This group includes:
v All persons living with HIV (PLHIV) who present with symptoms of TB
v All health care personnel who present with symptoms of TB
v All children who present with symptoms of TB
v All persons with symptoms suggestive of Extrapulmonary TB. Such specimens
could be collected for Xpert MTB/RIF test. Example of such is cerebrospinal
fluid (CSF) for examination as in TB meningitis.
v All persons diagnosed with TB LAM and AFB smear should have Xpert/MTB/Rif
test done.
6
1.2 CASE FINDING STRATEGIES
The National MDR/RR-TB case notification rate is 11%, thus emphasizing the need for
robust scale-up of case finding activities. The National Plan for the Introduction of New
Drugs and Shorter Regimens (ND&R) highlights the following case finding-related
activities:
v Assess and address factors related to low utilization of Xpert MTB/RIF test by
Conducting campaigns and sensitization activities to improve demand for tests
by clinicians and expanding laboratory capacity (Xpert MTB/RIF, TRUENAT,
LPA, culture, and DST)
v Active case finding activities at Health unit level which entails screening of TB in
HIV patients (consultation and counselling rooms); screening for TB in OPDs,
antenatal care, paediatric consultations (specific focus in malnourished
children); screening of TB in waiting areas and reinforcing request of genotypic
and phenotypic DST for all TB retreatment patients.
v Screening for TB amongst Nomads, IDPs, Prisons, Diabetic clinics, etc
v Investment and scale up of TB service delivery in the private sector (PPM).
v Sensitize the staff at DS-TB & DR-TB wards, OPDs and DOT centres to
systematically request Xpert MTB/RIF assay and chest X-ray (when required)
from all symptomatic TB Contacts (special focus on children). Perform contact
investigation through home visit by volunteers.
v Engaging local CBOs to provide targeted community education and outreach for
active case finding (focus in densely populated areas such as urban slums and
identified hotspots).
7
CHAPETR 2
DIAGNOSIS OF DRUG RESISTANT TUBERCULOSIS
2.1 ORGANISATION OF LABORATORY SERVICES

The NTBLCP laboratory network is organised in a pyramidal fashion consisting of four
levels. Each level has specific requirements for infrastructure and biosafety which are
defined by the various activities and diagnostic methods being performed in the
laboratories. The programme enjoys the services of private, faith based, military and
paramilitary health facilities. The laboratory plays critical role in the diagnosis of DR-
TB.
There are many procedures involved in the detection of TB which includes: isolation of
microbial agent, identification of the causative species and determining drug
susceptibility of the isolates. The success of the control programme is directly
dependent on the diagnostic ability of the laboratory network.
2.2 DIAGNOSIS OF DRUG-RESISTANT TUBERCULOSIS

2.2.1 Clinical presentation
The clinical features of DR-TB are not particularly differentf rom those of
drugsusceptible TB(PTBand EPTB). Clinicians should be alert to the complications of
TB, which may be more common in patients with DRTB.
Bacteriological diagnosis is the gold standard for diagnosing DRTB. However, in

patients where bacteriological confirmation is unlikely, such as symptomatic children,
PLHIV or those with extra-pulmonary TB who are also close contacts of known DRTB
patients, a provision for the clinical diagnosis of DRTB can be putinplace.
2.2.2. Bacteriological diagnosis

The laboratory diagnosis of DRTB is done by genotypic and phenotypic drug
susceptibility tests (gDST/pDST)). The primary test is the XpertMTB/RIF test. A
positive clinical specimen tested by the Xpert MTB/RIF showing resistance to
rifampicin will further be subjected to the Line Probe Assay (first- and second-lineLPA)
and culture/DST (seeAlgorithm1).
8
Table 1. Turnaround time for diagnostic tools
s/n TYPE OF TEST DIAGNOSIS TURNAROUND TIME

1 Xpert MTB/RIF PTB & EPTB 24 hours
2 Truenat MTB/RIF PTB 24 hours
3 Solid Culture PTB & EPTB 4 – 8 weeks (Negative 8 9 weeks)
–
4 Liquid Culture PTB & EPTB 2 – 3 weeks (Negative 6 – 7 weeks)

5 Line Probe Assay PTB 2 weeks
6 Phenotypic DST (Liquid PTB 2 – 3 weeks
Culture)
7 Phenotypic DST (Solid PTB & EPTB 4 – 5 weeks
Culture)
NOTE: Sequencing for resistance pattern will be utilized.
Figure 1: Diagnostic Algorithm of presumptive TB
ALL PERSONS WITH SYMTOMS OF TB

(cough of 2 weeks or more +/- weight loss, night sweats, swelling in any part of the body etc)
For PLHIV use current cough; contacts of DR-TB patients
Do the following:
i. Collect I biological specimen (sputum, body tissues or other body fluids, stool) and send to the Lab.
For Xperts MTB/Rif test
ii. Provide “HTS to those with unknown HIV Status
If Xpert result is: If Xpert result is: MTB not detected If Xpert result is:
MTB not detected Rif resistance Not detected MTB detected
Rif resistance detected
Classify as: Drug Resistance

Refer patient to the Medical Classify as: Drug TB (DR-TB)
Officer for further evaluation susceptible TB (DS-TB) case
Send specimen for 1st & 2nd

LPA, culture & DST
TREAT AS DRUG.
SUSCEPTIBLE TB: Do other baseline tests
Start first-line anti TB and Manage as DRTB case
treatment in consultation with the
State DR-TB term
9
This algorithm focuses on persons being evaluated for TB include adults and children
with signs or symptoms suggestive of TB or with a chest X-ray with abnormalities
suggestive with TB. It may also be used for persons being evaluated for extra pulmonary
TB (with other specimens a slymphnode aspirate, CSF etc.). Priority patients for Xpert
MTB/RIF are PLHIV, children and risk of DRTB (previously treated, non converters:
smear positive at end of intensive phase, DRTB contacts). If patient is high risk of DRTB
(retreatment cases more than two times, non converters: smear positive at end of
intensive phase, DRTB contacts) send additional samples for FL and SLLPA with
culture/p DST
2.2.3 Approach to discordant Results:

Discordant results are not uncommon, usually when comparing culture-based
results with molecular results. Each discordant result will need to be investigated, on
a case by case basis. DNA Sequencing can solve the dilemma (when available in
future). General considerations of discrepancies of results are as follows:
I. Xpert MTB/RIF: MTB detected but culturenegative.

The Xpert MTB/RIF result should be used to guide treatment decision. Cultures
from persons with pulmonary TB diagnosed by Gene Xpert may be negative for a
variety of reasons including:
v If patient is already being treated for TB.
v Transport or processing problems that inactivated the tubercle bacilli.
v Cultures lost to contamination.
v The discrepancy may be due to laboratory or clerical error.
Follow-up actions:
v Revaluate the patient. If patient is improving on treatment continue
treatment, if not improving, assess for other reasons.
II. Xpert MTB/RIF: MTB not detected with clinical evidence for TB.
Treatment decision should be based on the clinical evidence
The clinician should treat patients based on clinical presentation
v The culture positive result should be considered as bacteriological

confirmation of TB (culture is more sensitive).
v Xpert MTB/RIF sensitivity is lower in PLHIV, children, and other specimen
10
types such as CSF.
v False positive cultures are very rare(due to laboratory errors such as cross
contamination and sample labelling problems).
Follow-up actions:
v Treat based on clinical evidence and send specimen for LPA and Culture with
1st & 2nd DST
v Re-evaluation of the patient
III. Xpert MTB/RIF: MTB detected, rifampic inresistance detected but

Rifampicin susceptible by phenotypic DST.
The Xpert MTB/RIF result should be used to guide treatment decisions.
The possible reasons:
v Certain mutations are known to generate this discordant result, particularly
in the BACTECT MGIT system (i.e, a false susceptible phenotypic result).
v In some lowDR-TB prevalence settings, silent mutation shave been observed
that generate a false resistant MTB/RIF result, but these tend to be very rare.
Follow-up actions include:

v Treat for MDRTB.
IV. Xpert MTB/RIF MTB detected, rifampicin resistance not detected but
rifampicin resistant by phenotypic DST.
Treatment decisions should be based on the phenotypic DST result.
False rifampicin susceptible Xpert MTB/RIF results are rare but have been observed:
v 1-5% of TB cases tested in various epidemiologic settings.
Mutations in the region of the rpoB genesampled by the Xpert MTB/RIF tests
have been shown to account for 9599% of rifampic in resistance. The
remainder of rifampicin resistance arises from mutations out side the
sampled region, which produce an Xpert MTB/RIF result of rifampicin
resistance not detected.
Follow-up actions include:

v Treat for DRTB
11
V. Xpert MTB/RIF MTB detected rifampicin resistance not detected
but FL LPA rifampicin resistance detected.
Treatment decision should be based on FL LPA (Rif resistant).
v This discordance is rare, due to Hetero resistant strains. Different populations
of bacteria are co-existing with varying susceptibility to TB drugs (some are
resistant and some sensitive). Depending on the treatment and "fitness" of the
bacteria, different DST results from different samples may
occur (especially if an interval has elapsed). Rifhetero-resistance can
be detected in FLLPA (detect absence of wild type & mutations)
but not always in Xpert MTB/RIF (detects resistance by absence of wild type
and single copy target of rpoB). The culture and pDST results can vary too
(Rif sensitive or resistant), according to the prevalent population.
Follow up actions include.

v Treat for DRTB
2.3 DIAGNOSIS OF EXTRA-PULMONARY TUBERCULOSIS(EP-TB)

The clinical features of DR TB are not different from those of drug susceptible TB
(PTB and EPTB).
The clinical features of Pulmonary DR-TB
v Cough lasting 2 weeks or more (Current Cough in PLHIV)
v Fever
v Night sweats
v Weight loss (Failure to thrive or poor weight gain in children)
v Difficulty in breathing
The clinical features of Extra - Pulmonary DR - TB

The clinical features of Extra-Pulmonary DR-TB depends on site of disease and
characteristically are persistent, progressive and may be associated with weight loss
or poor weight gain.
12
Table 2 Below lists typical clinical features of forms of EPTB and the
suggested investigations for each category.
Extrapulmonary Site Clinical features Investigations

Pleural TB Non-productive cough, chest Imaging studies e.g. chest x-ray & CT
pain, fever, anorexia, weight loss, Scan. Xpert MTB/RIF assay on sputum
pleural effusion or pleural aspirate, pleural biopsy for
histology
TB lymphadenitis Enlarged, firm and painless Lymph node biopsy or aspiration
lymph nodes
Osteoarticular TB: vertebral Vertebra TB: Back pain, angular Imaging studies e.g. radiographs and CT
(Pott’s disease) and joint TB deformity of the spine, gibbus, scan, Xpert MTB/RIF or culture of
cold abscess. abscess
TB of the joint: monoarticular
arthritis,
TB of the digestive tract Difficulty in swallowing, Abdominal ultrasound scan, AFB and
abdominal pain, doughy culture of ascitic fluid. Biopsy, Fine
abdomen, malabsorption, ascites, needle aspiration and cytology
weight loss
Cerebral and meningeal TB Malaise, irritability, change in CSF Xpert MTB/RIF assay, lumbar
behavior, anorexia, weight loss, puncture for CSF analysis
fever, convulsions, altered
consciousness and
hemi/paraplegia
Genitourinary tract TB Abdominal or pelvic pain, Pelvic ultrasound scan, biopsy for
abdominal mass, infertility, or histology
ectopic pregnancy. Men with
genital TB will often present with
epididymo-orchitis.
Renal TB: nocturia, dysuria,
sterile pyuria, hematuria
Cutaneous TB Chronic, painless cutaneous Skin biopsy for TB culture and DST
lesions, longstanding ulcer
despite antibiotic treatment,
draining pus, erythema nodosum,
lupus vulgaris, scrofuloderma
13
The diagnosis of EPTB is based on the result from at least one specimen with confirmed
Mycobacterium Tuberculosis by Molecular test (Xpert MTB/RIF assay or LPA),
culture or histology. However, diagnosis can be made based on strong Clinical
evidence consistent with EPTB, followed by clinician's decision to treat with a full
course of anti - TB medicines.
2.4 DIAGNOSIS OF DRUG-RESISTANT TUBERCULOSIS IN

CHILDREN
The diagnosis DR-TB in children is mainly based on careful and thorough
clinical assessment with support of complementary investigations e.g. AFB sputum
smear microscopy, Xpert MTB/RIF assay, culture chest x-ray and other tests.
2.4.1 Children at risk of DR-TB

The following categories of children are at risk of DR-TB include:
v Close contact with confirmed DR-TB patient
v Close contact with patient that died from TB, failed or is not adherent to TB
treatment
v History of previous TB treatment (in the past 6-12 months)
v Not improving after 2 months of first line TB treatment, including persistence of
positive smear or culture, persistence of symptoms and failure to gain weight
(radiological improvement is frequently delayed).
2.4.2 Clinical Features of TB in children

The common symptoms and signs of PTB in children are:
v Cough of 2 or more weeks, current in PLHIV children). Fever and/or night
sweats
v Weight loss or failure to gain weight.
v History of contact with an adult with confirmed DRTB.
v Fatigue, less active, Failure to thrive and reduce playfulness
NB: Two or more of these symptoms are highly suggestive of TB disease.
14
2.4.3 Clinical Features of EPTB in children.
The symptoms and signs of EPTB in children are presented in Table 2 on

page 20.
NB:
There is a higher risk of TB in children less than 2 years, with more risk for dissemination
and severe disease.
For children above 10 years (adolescents), the presentation and diagnosis of pulmonary TB
is like that of adults.
Key considerations:
2.4.4 Considerations for diagnosing childhood DR-TB:
v History of contact with an adult with confirmed DR-TB is very important when
evaluating a child for DR-TB.
v It is difficult to get quality sputum in children below five years.
v The Xpert MTB/RIF assay result if children may be negative because children
often have paucibacillary disease, nevertheless, every effort should be made to
bacteriologically confirm DR-TB in children.
v In culture-negative children who have clinical evidence of active TB and close
contact with documentedDR - TB, the child's treatment should be guided by
results of DST and history of use of anti TB medicines of the contact.
v Counselling of patient and family members is critical, especially at the onset of
therapy.
Nutritional assessment through anthropometric measurement is important in

eliciting weight loss, poor weight gain or altering weight.
15
Contact Investigation - An important feature of Childhood TB Diagnostic Work -
up
· Close contact: when the source TB patient living in the same household or has frequent
contact with the child (e.g., neighbour, relative, caretaker)
· If no source case is identified, always ask about anyone in the household or frequent
visitor with TB symptoms or who recently died.
· In older children the contact with a TB source case may be outside the household, e.g.
school
· Timing of contact: children usually develop TB within 2 years after exposure
and most (90%) within the first year.
· Assess if the contact has risk or confirmed DR-TB (If the contact died, failed the
treatment or is not adherent).
2.3.4 Investigations for Diagnosing TB in children

v Bacteriological investigations:
Bacteriological confirmation is important. However, this is not always feasible due to
difficulty in collection of some specimens (sputum, CSF and gastric lavage in Children)
as well as paucity of bacilli in the specimens when collected. Nevertheless, all
efforts should be made to collect and send samples. Xpert MTB/RIF assay
is the recommended diagnostic test for DRTB in Children. (AFB) smear microscopy is
not recommended for diagnosing DRTB. Xpert MTB/RIF assay will only be positive
in less than one third of Children with TB, hence a negative result does not exclude TB.
Other bacteriological tests, culture, first and second-line Line Probe Assay
(LPA) should be explored.
16
· Sputum, stool, cerebrospinal fluid (CSF), lymph node aspirate, gastric
aspirate/lavage, pleural or ascitic fluid, joint aspirate etc can be sent for Xpert
MTB/RIF assay.
· Stool for Xpert MTB/RIF assay is particularly useful f or diagnosing pulmonary
TB in children.
v Chest x-ray in diagnosis of Childhood TB.

Chest x-ray remains an important tool for the diagnosis of TB in children, many of
whom are smear negative, Xpert MTB/RIF negative, or cannot produce sputum.
The following abnormalities on chest x-ray may suggest TB:
ØEnlarged hilar lymph nodes and opacities in the lungs.
ØMiliary mottling in the lungs.
ØLung parenchymal cavitation's.
ØPleural or pericardial effusion.
· In a child with no signs of respiratory difficulty (no fast breathing or chest in -

drawing), chest x-ray findings may still be supportive of TB diagnosis.
· A normal chest x-ray finding does not necessarily exclude pulmonary TB.
17
FIGURE 2 DIAGNOSTIC ALGORITHM FOR DRUG RESISTANT TB in
CHILDREN AND ADOLESCENTS
Presume DR. TB in a child if any of the following is present:

a. Symptoms of pulmonary of extra pulmonary TB with risk of DR TB risk of DR-TB in children in dude
Ÿ Close contact with confirmed DR-TB patients
ŸClose contact with patient that died from TB. Failed of is not adlherent to TB treatment
ŸHistory of previous TB treatment (in the past 6-12months)
ŸNot improving after 2 months of DS-TB treatment.
ŸCollect appropriate specimen (e.g. sputum stool lymph nodegastric aspirate, broncho advelar lavage,
cerebrospinal fluid, body fluids, abscesses and put) for laboratory analysis
ŸPerform HIV testing2
If specimen is available
Perform Xpert MTB RIF assay
If specimen is unavailable (e.g) presumptive

EPTB)3 MTB detected, MTB detected,
1. History of contact with DR-TB MTB not RIF RIF
2. Physical sign suggestive of TB detected Resistance Resistance
3. TB suggestive imaging features (e.g. chest
not Deteted Deteted
x-ray and computed tomography scan).
Medical Officer of Specialist should make a
decision to manage the child 4
Treat as Drug inform State

Medical Officer of Specialist should Susceptible TB TB
make a decision to manage the child. (DS-TB) if child is not Programme
a contact of DR-TB and LGA
case and monitor Supervisor to
closely Initiate DR.TB
Treatment
1. Symptom of PTB include lasting 2 week or more (current cough in PLHM), unexplained fever, weight loss of failure to
gain weight.
2. If HIV status is unknown, perform HIV testing and if positive, manage as appropriate.
3. Clinical diagnosis is recommended if all effort at bacteriological confirmation of DR-TB using Xpert MTB/RIF assay is
not possible. For every child with presumed EPTB, also collect stool specimen for Xpert MTB/RIF assay. When in
doubt, contact State or National Consilium of DR-TB experts.
4. Place child on anti-biotics for 1 week for lower respiratory tract infection. Collect specimen (e.g) stool and other EPTB
specimen) for line probe assay, culture and DST for first second line anti. TB medicines. Mother the child closely and
manage child based on clinical status and/or laboratory results.
5. If child is a contact of DR.TB, treat as DS-TB and monitor more closely.
18
CHAPTER 3
TREATMENT OF DRUG RESISTANT TUBERCULOSIS
CLASSIFICATION OF DRUG RESISTANT TUBERCULOSIS

Drug Resistant Tuberculosis is classified in categories based on drug
susceptibility testing (DST) of clinicisolates confirmed to be M.
tuberculosis.
The classification is as follows:

ŸMonoresistance: resistance to one first line anti TB drug only
Ÿ Poly resistance: resistance to more than one anti TB drugs (other
than both isoniazid and rifampicin)
Ÿ Multi drug resistance: resistance to at least both isoniazid and
rifampicin
Ÿ Pre XDR-TB is Multidrug Resistant Tuberculosis plus resistance to
fluoroquinolones
Ÿ Extensive drug resistance: Multidrug Resistant Tuberculosis plus
resistance to Bedaquilline and or Linezolid.
Ÿ Rifampicin resistance: resistance to rifampicin (monoresistance,
multidrug resistance, poly resistance and extensive drug resistance)
Effective treatment of TB, including its drug-resistant forms, relies on the

use of several medicines administered in combination for an adequate
duration. Significant progress has been made in recent years in identifying
more efficacious, safer medicines and shorter treatment regimens.
3.1 Eligibility criteria for starting DR-TB treatment regimens

v Patients (adults and children) with confirmed rifampicin resistance.
v All patients enrolled in care in the implementation sites who have been
diagnosed with DR-TB (RR/MDR/FQ Resistance/XDR-TB) are eligible for the
DR-TB treatment.
19
v Other patients at high risk for RR-TB to be considered for enrolment.
Ø In the absence of bacteriological confirmation of DRTB, the following are
eligible for second-line treatment after considering all circumstances around
the patient:
Ø Young children who are diagnosed with active TB, with a close contact,
(especially a parent or caregiver) who has bacteriologically confirmed DR-TB
Ø PLHIV with active TB who are close contacts of known DR-TB patients
Ø EPTB patients who are in close contact of a known DR-TB patient
Ø Failure of first-line TB treatment
3.2 Patient triage approach to select the appropriate DR-TB

regimen
v All patients with DRTB are eligible to start DR-TB treatment without delay. A
systematic approach must be followed to determine if the patient should be
treated with the shorter DR-TB regimens or all-oral longer DR-TB
regimen.
v The approach includes clinical evaluation to determine the patient's risk of
resistance or intolerance to Second Line TB Drugs (SLDs) and
bacteriological testing of pre-treatment specimens to determine if strain is not
resistance to FQ or other SLDs.
v Before starting treatment, two sputum samples must be sent for SL-LPA/ Xpert
MTB/XDR assay and culture, as well as first line and second-line phenotypic
drug susceptibility tests.
v Ensure timely availability of DST results to allow one to revaluate the initial
regimen and adjust to the appropriate regimen if necessary. 3.3
The following scenarios to be considered when receiving

second-line DST:
v For patients that started with the shorter regimen, if genotypic second-line, DST
results reveal no additional resistance to FQ and/or other SLDs and are
tolerating well then, the shorter regimen can be continued
v For patients that started with the shorter regimen and genotypic results show
additional resistance to FQ, the patient should switch to (starting from the
beginning of the treatment duration) all-oral longer regimen for now (based on
the culture and DST results).
v For patients with intolerance/toxicity to any drug in STR, the patient should be
switched to individualized regimen. (the duration and composition of the
20
regimen should be guided by DST results).
v For patients that started with an all-oral longer regimen based on intolerance to
FQ and other SLDs, the regimen should be revaluated and put him on
individualized regimen based on the phenotypic DST results.
v For patients that started with an individualized regimen based on resistance for
FQ and/ other SLDs which is not confirmed by phenotypic DST results, they
should continue the treatment whilst consulting experts on potential regimen
adjustment based on DST results and clinical status.
Preferable if all detected TB patients are tested for both FL and SL resistance. If not
feasible, SL DST could be limited to only those TB patients who have detected R
resistance. Treatment initiation for DR-TB patients should not be delayed while waiting
for results with a 2-weeks cut-off time frame for result safety of treatment “delay” to be
judged by expert group / Concilium. If the patient is detected to be H resistance with
both inh A and kat G resistant mutations present, then they should not receive the all-
oral STR.
Ideally, all DR-TB patients are to be tested for resistance to FQ and/or other SLDs before starting any
DR-TB treatment, and efforts should be made to ensure that rapid molecular DST for FQ and other
SLDs is available for all DR-TB patients with prompt turn-around time of results.
21
RR-TB patient #
Send sample for 1st and 2nd line-LPA, culture and phenotypic DST
EVALUATE PATIENT USING THE FOLLOWING ELIGIBILITY CRITERIA FOR SHOR TER DR-TB TREATMENT REGIMEN
1. Confirmed resistance, or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen(excluding resistance to isoniazid)
2. Previous exposure for >1 month to a second -line medicine included in the shorter MDR -TB regimen
3. No known intolerance to drugs in the shorter regimen.
4. Not pregnant.
5. Children >6 years of age
6. No Severe EPTB * includes Pleural effusion (for adult and Children) and TB lymph node in children.
7. No other risk of unfavorable outcome which includes extensive or a dvanced TB disease (multiple cavities or extensive
parenchymal damage)
Initial treatment regimen
Eligible Ineligible
Regimen adjustment
Long oral MDR/RR-TB regimen
based on: Shorter DR-TB
or Individualized DR-TB
SL LPA (DST) treatment regimen
treatment regimen
results
·
Treatment
tolerance
No Resistance/intolerance No
FQ Resistance/intolerance
resistance/intolerance resistance/intolerance
to FQ
to FQ to FQ
Change to long oral Continue long oral

Continue treatment
MDR/RR-TB regimen MDR/RR-TB regimen
Continue shorter DR-TB whilst consulting
BPaL or individualized BPaL or individualized experts on potential
treatment regimen
DR-TB treatment DR-TB treatment
regimen adjustment
regimen regimen
#
Includes patients with high risk of rifampicin resistance as contacts of RR/MDR-TB patients and failure of first line TB treatment.
* Non-severe forms of EPTB that can be eligible for the shorter treatment regimen include TB pleural effusion (adults and children)
and TB lymph node (children).
** Risk of unfavorable outcome includes extensive or advanced TB disease (multiple cavities or extensive parenchymal damage)
22
3.4 DR-TB TREATMENT REGIMENS
3.4.1 Shorter all-oral bedaquiline containing regimen (STR)

A shorter all-oral bedaquiline-containing regimen is recommended in eligible patients
with confirmed RR or MDR-TB who have not been exposed to treatment with second-
line TB medicines used in this regimen for more than 1 month, and in whom resistance
to fluoroquinolones has been excluded.
4-6 Bdq -Mfx-Cfz-Pto-Z-E-Hh / 5 Mfx-Cfz-E-Z.
3.4.1.1 Eligibility Criteria for the shorter all-oral Bed aquiline

containing treatment regimen
v Patients without resistance or intolerance of a drug in the shorter regimen
(except isoniazid resistance)
v Patients without exposure to previous treatment with second-line medicines in
the regimen for more than 1 month (unless susceptibility to these drugs is
confirmed)
v Patients with no extensive TB disease and with no severe extra-pulmonary TB
v Children from 6 years of age
v HIV infected patients
3.4.1.2 Exclusion criteria for the shorter all-oral bedaquilline containing regimen
v Confirmed resistance to FQ
v Known intolerance to drugs in the shorter regimen.
v Other risks of unfavourable outcome including extensive or advanced TB
disease, (disseminate, multiple cavities or extensive parenchymal
damage/severe meningeal or CNS TB)
v Any extrapulmonary disease in HIV patients)
.3.4.2 REGIMEN COMPOSITION AND DURATION.

The shorter all-oral bedaquiline-containing regimen consists of an intensive phase of 4
months that may be extended to 6 months, and a continuation phase of 5 months,
giving a total duration of 9–11 months.
Determined by mutations in either inhA or katG genes (not both) or phenotypic DST. The presence of mutations in both the inhA promoter and katG suggests that
isoniazid at high dose and thioamides are not effective, and that the shorter regimen should not therefore be used.
Extensive TB disease is defined as the presence of bilateral cavitary disease or extensive parenchymal damage on chest radiography. In children aged under 15
years, advanced disease is usually defined by the presence of cavities or bilateral disease on chest radiography.
Severe extrapulmonary TB is defined as the presence of miliary TB or TB meningitis. In children aged under 15 years, extrapulmonary forms of disease other
than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression) are considered as severe.
23
Table: 3 WHO approved Bedaquilline based short oral regimen
Regimen Composition Duration
WHO approved 4-6 Bdq(6 m)-Mfx- Cfz-hH-Pto-E-Z/ 5Mfx-Cfz-E-Z 9-11
Bedaquilline based months
shorter oral regimen
The shorter regimen is given as a standardized regimen with little or no room for
customization with substitutions or switches during treatment.
v The criteria to shift to the continuation phase is based on smear conversion and
clinical response. The patient should have smear-negative results and be clinically
improving. All attempts should be made to send monthly samples for culture and
trace results. It is important to have FL-LPA,SL LPA, culture, and SL phenotypic DST
results available, to exclude resistance to FQ, FL and other SLD (though SL LPA test-,
when performed in smear-negative samples, can have uninterpretable results).
v If the smear conversion is not achieved at month four, the intensive phase shall be
extended to a maximum total duration of six months (until smear conversion and
one negative culture result is achieved).
v If the patient remains smear and/or culture-positive at six months, will be declared
as a treatment failure and switched to an individualized regimen.
v Failure declaration and a switch to an individualized treatment will be considered
earlier than six months in patients with a clear lack of response (clinically, smear
grading, culture). The decision to switch earlier must be made by the expert
committee of state Concilium (and if required national Concilium).
In addition, other reasons to switch to an individualized longer regimen are:

v treatment of a patient is interrupted for 2 months or more after being treated for
more than 1 month; or another disqualifying criterion emerges (e.g. intolerance or
toxicity to a medicine in the regimen, or clinical deterioration).
3.4.2 Modified all-oral shorter MDR-TB regimen

A modified all-oral shorter MDR-TB regimen called “Bestream” is used at selected DR-
TB sites under operational research. It is very similar to the WHO approved shorter
treatment regimen. However, the difference is in the drug composition which is slightly
different.
24
Table: (2) Modified Bedaquilline based short oral regimen “Bestream” (Operational
research)
Modified Bedaquilline 4-6 Bdq (4)-hLfx-Lzd-Cfz- /5Bdq (2)–hLfx-Lzd-Cfz 9-11 onths
based short oral
regimen
3.4.3 Long oral regimen for MDR/RR-TB

3.4.4.1 Regimen composition and duration
v Patients with DRTB who are not eligible for treatment with the shorter regimen
will be treated with the Longer regimen; total duration is 18 months.
v The regimen will be designed based on WHO grouping of medicines, see table 3
and the patient's most recent DST results and history of previous drug use
and/or exposure.
v The all-oral longer MDR-TB regimen has no intensive phase. The duration of use
of different medicines will depend on their clinical indication (e.g.bedaquiline 6
months, but this period may be prolonged), patient tolerability (e.g. linezolid
used for as long as no serious adverse event emerges), until completion of the
expected total duration of treatment.
Table 3. W.H.O. Grouping of medicines recommended in longer MDR-TB

regimens
Group A Group C
Levofloxacin Lfx Ethambutol E
Moxifloxacin Mfx Delamanid Dlm
Bedaquiline Bdq Pyrazinamide Z
Linezolid Lzd Imipenem-Cilastin Imp-Cln
Meropenem Mpm
Group B Amikacin Am
Clofazamine Cfz Prothionamde/ Pro/ Eto
Ethionamide
Cycloserine or Terizidone Cys/Trd P-aminocyclicac PAS
25
Table: 4 Long all-oral regimen
Long oral MDR/RR* · 6Bdq-Mfx-Cfz -Lzd/ 12Mfx-Cfz-Lzd 18 months
* Those who may benefit from the all-oral long regimen are as follows:
v All MDR/RR-TB patients who have been exposed to treatment with second-
line TB medicines including bedaquiline (for >1 month),
v Patients in whom resistance to FQ has not been excluded,
v Patients with extensive TB disease or severe extra-pulmonary TB.
Table: 5 All -oral shorter treatment regimen in case of MDR-TB with FQ resistance.
This regimen being used under operational research in only 4 states.
BpaL · bedaquiline (Bdq) + pretomanid (Pa) + linezolid 6-9 months
(Operational research)
Table: 6 Individualized all oral regimenfor Pre XDR-TB with fluoroquinolone

resistance
Pre XDR-TB FQ résistant 6Bdq-Cfz-Lzd-Cs/ 12Cfz-Lzd-Cs 18 months
XDR-TB with Lzd 6Bdq-Cfz-Dlm-Cs/ 12Cfz-Dlm-Cs 18 months
Resistance
XDR-TB with Bdq 6Dlm-Cfz-Lzd-Cs/ 12Cfz-Lzd-Cs 18 months
Resistance
26
3.4.2.2 Prolonged use of Bedaquiline with concurrent use of Bedaquiline
and delamanid
v New evidence on the safety profile of the prolonged use of bedaquiline became
available that supports its safe use beyond 6 months in patients who receive
appropriate schedules of baseline and follow-up monitoring. However, there was
not enough evidence to assess the efficacy or effectiveness of bedaquiline when used
for longer than 6 months.
v New evidence from safety data on the concurrent use of bedaquiline and delamanid
suggests no additional safety concerns. Therefore, bedaquiline and delamanid may
be used in patients who have limited treatment options, provided that appropriate
treatment monitoring (including baseline and follow-up ECG and electrolyte
monitoring) is in place. However, there was insufficient evidence to assess the
efficacy or effectiveness of the concurrent use of bedaquiline and delamanid.
v Prolonged used of Bdq and concurrent use of Bdq and Dlm should be decided on a
case-by-case basis guided by the National Concilium.
3.4.3 BPaL Regimen

This is novel all-oral regimen composed of bedaquiline, pretomanid and linezolid
(BPaL) can be used at selected DR-TB treatment sites under operational research
condition for MDR/RR-TB patients with additional fluoroquinolone resistance and
MDR-TB patients with documented treatment intolerance or failure
3.4.3.1 Dosing and duration of the BPaL regimen

Table 6. Dosing of BPaL component drugs for adults
Drug Dose
· Bedaquiline (100 mg tablets) 400 mg once daily for 2 weeks, then 200 mg 3 times per
week afterward
· Pretomanid (200 mg tablets) 200 mg once daily
· Linezolid (600 mg tablets) 1200 mg once daily (adjustable)
27
Duration
The BPaL regimen is given for a duration of 6-9 months (26 – 39 weeks):
v The standard treatment duration is 6 months.
v If the sputum culture taken after the patient has taken 4 months of treatment is
still positive, the patient can receive an additional 3 months of treatment (total 9
months) as long as the patient is clinically well and /or improving.
3.4.3.2 Inclusion Criteria for BPaL Regimen

A patient, who:
1. is diagnosed with TB in any of the following circumstances:
v has a laboratory-confirmed resistance to at least rifampicin and
fluoroquinolones; or
v has strong clinical and radiological evidence of active TB and is a close
household contact of a TB patient with a laboratory-confirmed resistance to at
least rifampicin and fluoroquinolones; or
v Has been treated for MDR/RR-TB and has documented non-response to
treatment, and a decision has been made by the Expert Committee to shift the
patient to the BPaL regimen; or
v Has been treated for MDR-/RR-TB and has documented intolerance, and a
decision has been made by the Expert Committee to shift the patient to the BPaL
regimen; and
2. is willing and able to give informed consent to be enrolled in the operational

research (OR) and adhere to the OR procedures and the follow-up schedule (signed
or witnessed consent if illiterate);
3. is at least 18 years old at the time of enrolment; and
4. is willing to use effective contraception if a pre-menopausal woman
3.4.3.3 Exclusion criteria forBPaL regiment

A patient who:
1. Has a known severe allergy to any of the BPaL component drugs; or
2. Has DST showing resistance to any of the component drugs; or
3. Has been previously exposed to any of the component drugs or delamanid (Dlm) for
more than two weeks; or
4. has a form of extrapulmonary TB that would require treatment longer than would
be usual for pulmonary TB(e.g. TB meningitis, other central nervous system TB, or
TB osteomyelitis); or
28
5. Is pregnant or breastfeeding; or
6. Is unable to take oral medications.
3.4.3.4 BPaL regimen and HIV

People living with HIV may be included for treatment with the BPaL treatment
regimen. There some drug-drug interactions between antiretroviral drugs and
bedaquiline :
v Efavirenz: induces the metabolism of Bdq, reducing drug levels
v Ritonavir: inhibits metabolism of Bdq, increasing drug levels
v Antiretroviral therapy regimens including these drugs should be modified at
least one week before commencing an HIV-positive patient on treatment with
BPaL.
v Antiretroviral therapy including zidovudine should be used with special caution
as zidovudine and linezolid may both cause peripheral nerve toxicity and are
known to have myelosuppression cross toxicity.
3.4.3.5 Treating mono and poly-drug resistant TB

If the patient has monoor polydrug resistant TB with resistance to rifampicin
(susceptible to isoniazid), they should receive the same regimens as RR/MDRTB
(shorter or Longer according to eligibility criteria)
3.4.3.6 Isoniazid mono resistance:

In patients with confirmed rifampicin-susceptible, isoniazid-resistant tuberculosis,
treatment with Rifampicin, Ethambutol, Pyrazinamide, and Levofloxacin is
recommended for 6 months. It is foreseen that the Isoniazid resistance-TB treatment
regimen would apply in the following situations:
a) Isoniazid resistance TB is confirmed before TB treatment is started:
v Treatment with the (H)REZ-Lfx is started immediately.
v If the diagnosis is strongly presumed (e.g. close contacts of a confirmed
Isoniazid resistance - source case) but results of DST are still pending, the
regimen may be introduced.
v Should DST results taken at the start eventually show susceptibility to isoniazid,
then levofloxacin is stopped, and the patient continues treatment to complete a
2HREZ/4HR regimen.
29
b) Isoniazid resistance TB is confirmed after the start of treatment with
2HREZ/4HR regimen:
v Rapid molecular testing for rifampicin resistance must be done (or repeated)
v Once rifampicin resistance is excluded, a full 6-month course of (H)REZ-Lfx is
given.
v If rifampicin resistance is detected, the patient needs to be started on a
recommended MDR-TB
c) Addition of isoniazid.
v There was no clear evidence showing that the addition of isoniazid adds benefit
or harm to patients. For patient convenience and ease of administration, the 4-
drug HREZ FDCs may be used to deliver the Isoniazid resistance TBtreatment
regimen alongside levofloxacin
3.4.3.6 Adjuvant therapy

v Vitamin B6 (pyridoxine) preventive therapy at a dose of 100mg/day up to 150
mg/day should be given to all patients receiving isoniazid, cycloserine, or
linezolid to minimize peripheral neuropathy, neurological adverse event, and
myelosuppression.
v Corticosteroids (Prednisolone 1 mg/kg and gradually decreasing by 10 mg per
week when a long course is indicated) should be used in :
Ø TB Meningitis (and other compromises of CNS)and maybe used inTB
Pericarditis.
Ø Immune reconstitution inflammatory syndrome (IRIS).
3.4.3.7 Role of Surgery for patients on MDR-TB treatment

v Generally, at least two months of therapy should be given prior to resection
surgery to decrease the bacterial load in the surrounding lung tissue.
v In patients with RR-TB or MDR-TB, elective partial lung resection (lobectomy
or wedge resection) may be used alongside a recommended MDR-TB regimen.
v Even with successful resection, an additional 12-18 months of chemotherapy
should still be given.
30
v Treatment should be adjusted based on the histopathology and DST of the
resected material
v Resection of cavitary lesions or destroyed lobes that harbor great numbers of
tuberculosis organism improved patient outcomes when combined with medical
treatment.
v Partial lung resection for patients with MDR-TB is to be considered only under
conditions of good surgical facilities, trained and experienced surgeons, and
with careful selection of candidates
31
Dosage by weight band for medicines used in multidrug-resistant TB
regimens, adults.
Weight Weight bands for patients older than 14 yearsa Usual upper daily doseb
Group Medicine based Formulation 30-35 36-45 46-55 kg 56-70kg >70 kg Comments
daily kg kg
dose
250 mg tab 3 3 4 4 4
Levofloxacin -c 500 mg tab 1.5 1.5 2 2 2 1.5 g
750 mg tab 1 1 1.5 1.5 1.5
Standard 400 mg tab 1 1 1 1 1 400 mg
Moxifloxacin dosecd
A High 400 mg tab 1 or 1.5 1.5 or 2 2 2 800 mg
dosecd 1.5
Bedaquiline -c 100 mg tab 4 tabs od for first two weeks; then 2 tabs od for 22 weeks 400 mg
Linezolid -c 600 mg tab (<15 (<15 y) 1 1 1 1.2 g

y)
Clofazimine -c 50 mg cap or tab 2 2 2 2 2 100 mg
32
B 100 mg cap or tab 1 1 1 1 1 100 mg
Cycloserine or 10-15 250 mg cap 2 2 3 3 3 1g
terizidone mg/kg
Ethambutol 15-25 400 mg tab 2 2 2 2 2 -
mg/kg
Delamanid -c 50 mg tab 2 bd 2 bd 2 bd 2 bd 2 bd 200 mg
Pyrazinamide 20-30 400 mg tab 3 4 4 4 5 -
mg/kg 500 mg tab 2 3 3 3 4
Imipenem- -c 500 mg + 500 mg To be used with clavulanic

C cilastatin powder for injection, acid
vial (10 mL) 2 vials (1 g + 1 g) bd -
Meropenem -c 1 g powder for To be used with clavulanic
injection, vial (20 mL) 1 vial 3 times per day or 2 vials bd - acid
Amikacin 15-20 500 mg / 2 mL solution
mg/kg for injection, ampoulef
2.5 3 mL 3-4 mL 4 mL 4 mL 1g
mL
Streptomycin 12-18 1 g powder for injection,
mg/kg vialf Calculate according to the dilution used 1g
Ethionamide or 15-20 250 mg tab Once daily dose advised but
prothionamide mg/kg 2 2 3 3 4 1g can start with 2 divided doses
until tolerance improves
PAS sodium salt
8-12 g/day (equivalent to 4 g PAS
p-aminosalicylic in 2-3 acid) sachet 1 bd 1 bd 1 bd 1 bd 1 to 1.5 bd
acid divided PAS acid (4 g) 1 bd 1 bd 1 bd 1 bd 1 to 1.5 bd
doses 12 g
4-6 mg/kg Pyridoxine is given with
(standard 300 mg tab 2/3 1 1 1 1 isoniazid in patients at risk
dose)d (e.g. those with HIV or
- malnutrition)
Isoniazid
33
10-15
mg/kg
(high 300 mg tab 1.5 1.5 2 2 2
dose)d
Clavulanic acidh 125 mg clavulanic acid as Only to be used with
amoxicillin/clavunate, 1 bd 1 bd 1 bd 1 bd 1 bd - carbapenems.
-c 500 mg / 125 mg tabh
Currently not available in
market. Not used in persons
Gatifloxacin -c 400 mg tab 2 2 2 2 2 800 mg <18 years.
Only to be used as part of
BPaL regimen, together with
Pretomanidi -c 200 mg tab 1 1 1 1 1 200 mg Bdq&Lzd.
For children <15 years: follow the separate dose schedule for patients younger than 15
years of age; bd: two times a day; BPaL: regimen of bedaquiline, pretomanid and
linezolid for 6–9 months; cap: capsule; HIV: human immunodeficiency virus; im:
intramuscular; iv: intravenous; g: gram; kg: kilogram; mL: millilitre; mg: milligram;
M/W/F: Monday, Wednesday, Friday; soln: solution; susp: suspension; MDR-TB:
multidrug-resistant TB: MDR/RR-TB: multidrug- and rifampicin resistant
tuberculosis; tab: tablet; WHO: World Health Organization.
a. Dosages were established by the guideline development groups for the WHO
guidelines on drug-resistant tuberculosis treatment (2018 and 2020 updates)
and the WHO Global Task Force on the Pharmacokinetics and
Pharmacodynamics (PK/PD) of TB medicines and other experts. They are based
on the most recent reviews and best practices in the treatment of MDR/RR-TB.
For certain agents the dosages were informed by pharmacokinetic modelling
results based on the principle of allometric scaling (Anderson BJ, Holford NH.
Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev
PharmacolToxicol2008;48:303–32). Owing to the pharmacokinetic properties
of certain medicines, the doses proposed may exceed the mg/kg per day ranges
shown here in order to achieve blood concentrations similar to target levels in an
average adult patient. In patients <30 kg, the schedule for those aged <15 years
should be followed, unless otherwise indicated. If multiple dose options are given
for one weight band, the lower orhigher option should be selected, depending on
whether the patient is at the lower or higher limit of the body weight range.
Dosing more closely to the target mg/kg per day should be aimed for, and is more
feasible with oral or parenteral fluids, and when solid forms of different dosages
are available. Fractioning of tablets into halves or less should be avoided, if
possible. Therapeutic drug monitoring is advised when the dose is at the upper
and lower ends of the range, to minimize the adverse therapeutic consequences of
over- and under-exposure, respectively (especially for injectable agents, linezolid
and fluoroquinolones).
b. Clinicians may decide to exceed these values in particular cases to improve
therapeutic effect.
c. No weight-based dosing is proposed.
d. The higher dose may be used except when: there is risk of toxicity; levels are
expected to be lowered because of pharmacokinetic interactions, malabsorption
or other reasons; or the strain has low-level drug resistance.
34
e. Tablets are expected to become available in the near future.
f. The weight-based daily dose is for 6 or 7 days per week administration (M/W/F
scheduling may permit higher dosing). Volumes shown may differ by
preparation. Streptomycin may be diluted in three different ways. For iv use, the
volume may be increased.
g. Amoxicillin/clavulanic acid is only recommended as a companion agent.
Because of a lack of data from the latest analysis on longer MDR-TB regimens in
adults, gatifloxacin, isoniazid and thioacetazone are not included in the
grouping table of medicines used for longer regimens. Pretomanid is
recommended to be used only as part of the package of the BPaL regimen.
h. Only available in combination with amoxicillin as co-amoxyclav (e.g. 500 mg
amoxicillin/125 mg clavulanic acid fixed-dose combination). It is given with
each dose of carbapenem, either as 125 mg bd or 125 mg3 times daily.
i. Use for age 14 years or older.
35
CHAPTER 4
MANAGEMENT OF DRUG RESISTANT TUBERCULOISIS

IN SPECIAL SITUATIONS.
4.1 PREGNANT AND LACTATING WOMEN.
The intervention regimen contains ethionamide, which is usually contraindicated in

pregnancy, because animal reproduction studies have shown an adverse effect on the
fetus and there are no adequate and well-controlled studies in humans. Even though
more compelling evidence is needed on toxicity causes attributed to the use of specific
anti-TB drugs during pregnancy and lactation, individualized longer regimens can be
designed to avoid known toxicities until better safety profiles are established.
Pregnancy. Amikacin, streptomycin, prothionamide and ethionamide are usually

contraindicated during pregnancy. However, following the changes made in the 2018
guidelines update, these agents are expected to be used less frequently in longer
regimens. Knowledge about the safety of bedaquiline and delamanid in pregnancy and
breastfeeding is sparse. However, new evidence from an observational study in South
Africa was presented to the GDG in 2019; it included information on 58 mothers who
received bedaquiline during pregnancy. The results of this study indicated that fetal
exposure to bedaquiline in utero was associated with low birth weight (45% of babies
exposed to bedaquiline had a low birth weight compared to 26% of babies not exposed,
P=0.034) However, there were no other significant differences in infant outcomes,
pregnancy outcomes or maternal treatment outcomes, including weight gain in the
infants until 1 year of age.
In such cases, it is recommended that a longer regimen be individualized to include

components with a better-established safety profile. The outcomes of treatment and
pregnancy, including data from postpartum surveillance for congenital anomalies,
should be documented to help inform future recommendations for MDR-TB treatment
during pregnancy.
36
4.2 CHILDREN
Treating children for DR-TB is

important to reduce morbidity and
mortality. The treatment is
challenging especially in young
children because of limited options in
choice of medication, appropriate
dosing, and monitoring of adverse
events.
4.2.1 REGIMEN FOR TREATING DR-TB IN CHILDREN
Regimens for treating DRTB in children are generally like those of adults but with the
following suggested considerations as determined by the age group of the child as
well as the presence or absence of fluoroquinolone resistance.
4.2.1.1 CHILDREN LESS THAN 6 YEARS:

Fluoroquinolone susceptible
Lfx-Lzd-Cfz-Bdq
Additional medicines if needed are PAS and Eto
Fluoroquinolone resistant
Lzd-Cfz-Cs-Dlm-Bdq
Additional medicines if needed are PAS and Eto
(use of Dlm below the age of 3yrs should follow best practices in “off label” use and
must consult national DR-TB consilium of experts)
Table 5 REGIMEN FOR TREATING DR-TB IN CHILDREN

DRTB drug regimen for children
Resistance pattern Intensive Phase Continuation

Phase
Less than 6 Fluoroquinolone 6 Mfx-Lzd-Cfz-Bdq 6 Mfx-Lzd-Cfz
years Susceptible
Fluoroquinolone 6 Lzd Cfz-Dlm*–Bdq
- 6 Lzd-Cfz-Cs
Resistant
Above 6 years Same as adult DR-TB regimen
37
CHILDREN GREATER THAN 6YEARS
Adult DR-TB regimen is recommended for children greater than 6 years with
DR-TB.
Table 6 REGIMEN FOR TREATING DR-TB IN CHILDREN GREATER

THAN 6 YEARS
Shorter Regimen
Bedaquiline-based all 4-6 Bdq-Mfx-Cfz-Hh-Pto-E-Z/ 9 – 11 months
oral Shorter Regimen 5Mfx-Cfz-E-Z
Longer Regimen
Long oral for MDR/RR- 6 Bdq -Mfx-Cfz-Lzd-Cs/12Mfx-Cfz-Lzd- 18 months
TB and Pre XDR=TB Cs
(resistant to SLI)
Individualised Regimen
Pre-XDR-TB (resistant 6 Bdq-Cfz-Lzd-Cs/12Cfz-Lzd-Cs 18 months

to FQ)/XDR-TB
Beyond XDR-TB Dlm, Am, Meropenem + Am/Clv, Pto, Duration is
E, Z, PAS based on
culture
conversion
38
4.2.1.2 KEY CONSIDERATIONS FOR DR-TB TREATMENT IN
CHILDREN.
v The same inclusion criteria for adults should be applied while initiating
treatment in Children.
v Documentation of fluoroquinolone resistance, as well as history of prior
treatment with 2nd line medication may be taken from the adult index case if not
possible from the child due to absence of appropriate clinical specimen.
v Treat according to DST results from child or from likely source case (if results
from child not available)
v Give at least 3 or more drugs to which patient or adult source case is susceptible
v Ensure that once treatment starts it must be completed; “trial of TB treatment”
should not be used as a diagnostic tool. Adherence to the full course of treatment
should be emphasized and reinforced.
v Identify a caregiver as the DOT supporter for all ages including adolescents.
v Comorbidities should be adequately managed:
v For all HIV-infected children
Ø Commence Cotrimoxazole preventive therapy (CPT)
Ø Commence antiretroviral therapy (ART) within 2-8 weeks of
commencement of DR-TB treatment irrespective of CD4+ count.
Ø Address disclosure of HIV and DRTB status as soon as possible (children
above 5 years old). For further information on management of DR-
TB/HIV co-infection, refer to page
v Provide adequate nutritional support for all malnourished children (ready to use
therapeutic food, therapeutic milk when necessary.
v Delamanid is not currently recommended in children below the age of 3
(If it must be used in this age group, it should follow best practices in “off label”
use and must consult national DR-TB consilium of experts)
39
Dosage by weight band for medicines used in multidrug-
resistant TB regimens, 15years and below.
Weig Weight bands among patients not yet Usu

ht 15 years olda al
based Formulati 5-6 7-9 10- 16- 24- 31- >34 uppe Comme
Grou Medicine daily on kg kg 15 23 30 34 kg r nts
p doseb kg kg kg kg daily
dose
b
100 mg dt 1 1.5 2 3 (>1 (>1 (>1 1.5 g

Levofloxa 15-20 or or 4 4 4 y)
cin mg/kg 3 4 y) y)
250 mg 0,5 0.5 1 1.5 2 3 (>1 1.5 g
tab or or 4 y)
1.5 2
10-15 100 mg dt 0.8 1.5 2 3 4 (>1 (>1 400 Use 10
Moxifloxa mg/kg 4 4 y) mg mg/kg in
cin y) <6
400 mg 2 3 5 0.5 1 (>1 (>1 400 months.
tab mL mL mL or 4 4 y) mg
c c c
0.7 y)
A 5
- - - 2 tabs od 4 tabs od Only in
for 2 for 2 patients
100 mg weeks; weeks; >5 years
tab then 1 tab then 2 (lower
Bedaquilin - od tabs od - dose
e M/W/F M/W/F from 15-
for 22 for 22 29 kg;
weeks weeks higher
- - - 10 dts od 20 dts od dose
20 mg dt for 2 for 2 from >29
weeks; weeks; kg).
then 5 dts then 10
od dts od
M/W/F M/W/F
for 22 for 22
weeks weeks
Linezolid 15 20 mg/mL 4 6m 8 11 14 15 20
mg/kg susp mL L mL mL mL mL mLd
od in
<16 600
kg mg
10-12 600 mg 0.2 0.2 0.2 0.5 0.5 0.5 0.7
mg/kg tabc 5 5 5 5d
od in
>15
kg
40
50 mg cap 1 alt 1 alt 1 1 2 2 (>1 10 Give on
or tabe days days alt 4 y) 0 alternate
day mg days if
Clofazimin 2-5 s dose in
e mg/k mg/kg/day
g 100 mg cap M/W/ M/W/ 1 1 1 (>1 (>1 10 is too
B or tabe F F alt alt 4 y) 4 y) 0 high.
day day mg
s s
125 mg 1 1 2 3 4 (>1 (>1 1g
Cycloserin 15- mini 4 y) 4 y)
e or 20 capsule
terizidone mg/k (cycloserin
g e)c
250 mg cap 4-5 5-6 7- 2 2 2 (>1 1g
mLc mLc 10 4 y)
mL
c
Ethambutol 15- 100 mg dt 1 2 3 4 - - (>1

25 4 y) -
mg/k 400 mg 3 mLc 4 mLc 6 1 1 2 (>1
g tabc mL or 4 y)
c
1.
5
Only in
patients
aged >2
years (25
mg bd in
Delamanid - 50 mg tab - -f -f -f 1 1 2 20 3-5 years;
bd bd bd 0 50 mg bd
mg in 6-11
years; 100
mg bd in
12-17
years).
150 mg dt 1 2 4 4 or - - (>1
30- 5 4 y)
Pyrazinami 40 400 mg tab 0.5 0.75 1 1.5 2. 3 (>1
de kg/m or 2 5 4 y) -
g 500 mg tab 0.5 0.5 0.7 1.5 2 2.5 (>1
5 or 4 y)
1
500 mg + Not used
500 mg in patients
Imipenem- - powder for - - - - - - - - aged <15
cilastatin injection, years (use
vial (10 meropene
mL) m)
41
500 mg + Not used
500 mg in patients
Imipenem- - powder for - - - - - - - - aged <15
cilastatin injection, years (use
C vial (10 mL) meropene
m)
20-40 To be used
mg/kg 1 g powder with
Meropenem iv for 2 4 6 8-9 11 (>1 (>1 - clavulanic
every injection, mL mL mL mL m 4 y) 4 y) acid.
8 vial (20 mL) L
hours
500 mg/2
Amikacin 15-20 mL solution 0.4 0.6 0.8 1.2 2.0 (>1 (>1 1g
mg/kg for mL mL -1 - m 4 y) 4 y)
injection, mL 1.5 L
ampouleg mL
20-40 1 g powder (>1 (>1
Streptomyci mg/kg for Calculate according to the 4 y) 4 y) 1g
n injection, dilution used
vialg
Ethionamide 15-20 125 mg dt 1 1 2 3 4 4 (>1 1g
or mg/kg (ethionamid 4 y)
50 mg / 5 mL soln 8- 15 20 300 mg
10 m m isoniazide
m L L tablet can
L be used in
patients
>20 kg.
Pyridoxin
Isoniazi 15- - e is
de 20 always
Other mg/k 100 mg tab 1 1. 2 3 4 4 (>1 given with
medicin g 5 4 high-dose
esh (high y) isoniazid
dose in children
) (12.5 mg
od in
those aged
<5 years
and 25 mg
od in
those aged
>4 years
62.5 mg clavunic Only to be
acid as used with
Clavuni - amoxicillin/clavula 2 3 5 8 10 (>1 (>1 - carbapene
c acid nate, 250 mg / 62.5 m m m m m 4 4 ms
mg, powder for oral L L L L L y) y)
solution, 5 mL bd bd bd bd bd
i i i i i
42
(>14 y): follow the separate dose schedule for patients older than 14 years of age; alt:
alternate; bd: two times a day; cap: capsule; dt: dispersible tablet; g: gram; im:
intramuscular; iv: intravenous; kg: kilogram; mL: millilitre; mg: milligram; M/W/F:
Monday, Wednesday, Friday; soln: solution; susp: suspension; tab: tablet.
a. Dosages were established by the guideline development groups for the WHO
guidelines on drug-resistant tuberculosis treatment (2018 and 2020 updates)
and the WHO Global Task Force on the Pharmacokinetics and
Pharmacodynamics (PK/PD) of TB medicines and other experts. They are based
on the most recent reviews and best practices in the treatment of MDR/RR-TB.
For certain agents the dosages were informed by pharmacokinetic modelling
results based on the principle of allometric scaling (Anderson BJ, Holford NH.
Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev
PharmacolToxicol2008;48:303–32). Due to the pharmacokinetic properties of
certain medicines the doses proposed may exceed the mg/kg/day ranges shown
here in order to achieve blood concentrations similar to target levels in an
average adult patient. In patients >30 kg, follow the schedule for >14 years old
unless otherwise indicated. If multiple dose options are given for one weight
band select the lower or higher option depending on whether the patient is at the
lower or higher limit of the body weight range. Dosing more closely to the target
mg/kg/d+B48ay should be aimed for, and is more feasible with oral or
parenteral fluids and when solid forms of different dosage are available.
Fractioning of tablets into halves or less should be avoided if possible.
Therapeutic drug monitoring is advised when the dose is at the upper and lower
ends of the range to minimize the adverse therapeutic consequences of over- and
under-exposure respectively (especially for injectable agents, linezolid and
fluoroquinolones).
b. Clinicians may decide to exceed these values in particular cases to improve
therapeutic effect.
c. Dissolving in 10 mL of water may facilitate administration in patients in lower
weight bands and avoids fractioning solid formulations, although bioavailability
is uncertain (use of dispersible tablets is preferred if available).
d. In individuals >44 kg a dose of 600 mg od is proposed.
e. Tablets are expected to become available in the near future.
f. May be used in children 3–5 years of age. Giving half a 50 mg adult tablet in these
children does not result in the same blood levels observed in trials using the
special 25 mg paediatric tablet. Bioavailability may further be altered when the
43
50 mg tablet is split, crushed or dissolved.
g. Weight-based daily dose is for 6 or 7 days/week administration (M/W/F
scheduling may permit higher dosing). Volumes shown may differ by
preparation. Streptomycin may be diluted in three different ways. Dosing closer
to the upper limit of the mg/kg/day is more desirable. For iv use, the volume may
be increased.
h. T h e s e a g e n t s a r e o n l y r e c o m m e n d e d a s a c o m p a n i o n a g e n t
(amoxicillin/clavulanic acid) or not included because of a lack of data from the
latest analysis on longer MDR-TB regimens in adults (isoniazid).
i. Only available in combination with amoxicillin as co-amoxyclav. Only to be used
with carbapenems, in which case they are given together, e.g. 125 mg bd or 125
mg 3 times daily in the 24–30 kg weight band.
4.2.1.3 MONITORING OF DR-TB IN CHILDREN

For monitoring of DR-TB in children follows the same pattern as adult and can be seen
on the page for monitoring of treatment
44
CHAPTER 5 ENSURING ADHERENCE AND MANAGEMENT
OF TREATMENT INTERRUPTION
Adherence is the term used to describe a patient's behaviour of taking the right drugs, in
the right dose, with the right frequency and at the right time. Adherence of patients to
medication entails the following:
v Partnership between the patient, healthcare worker and treatment supporter.
v A critical aspect of adherence is the patient's involvement in deciding whether or
not to take the drugs at the point of enrolment. It is a decision they make for their
own health.
v Adequate information/counselling necessary for optimal adherence.
v Adherence Counselling:
v Reduces the risk of developing resistance to the medicine(s)
v Enhances curability
v Improves social stability of a TB patient
v Builds the patient's confidence in getting treatment
v Fosters strong and trusting patient - provider relationship
5.1 FACTORS AFFECTING ADHERENCE:
POSITIVE FACTORS NEGATIVE FACTORS

Patient Readiness/Commitment Forgetfulness
Social Support Life Travel away from home
Style/ Cultural belief Stigma
Belief in treatment adherence Low literacy level
Having treatment support Fear of Loved ones
Belief in Efficacy of treatment
5.1.2 PROVIDER-RELATED FACTORS

POSTIVE FACTORS NEGATIVE FACTORS
Consistent drug supplies Negative attitude towards patients ab ility to
adhere
Client comfort dealing with provider Neglecting to discuss patient feelings
Trust Neglecting to discuss patients feelings
Strong support and counselling skills Strong support and counselling skills
bottlenecks within the health system
45
5.2 POOR ADHERENCE
Poor adherence is patient's inability/unwillingness to take their drugs in the prescribed
manner.
This could be due to:
v Pill burden and dosing frequency.
v Treatment side effect.
v Poor health literacy.
v Poor patient/provider relationship.
v Poor health education and proper counselling.
Poor adherence may lead to:
v Increased TB germ load.
v Drug resistance.
v Increased mortality and morbidity arising from complications.
5.3 ADHERENCE INTERVENTION STRATEGIES:

v Provide health education and counselling in patient's own language.
v Educate treatment supporter to help patient's adherence to treatment.
v Prepare the patient well by educating him/her on basic drug information, reason
for treatment, importance/benefits of adherence, consequences of poor
adherence and drug side effects.
v Identify potential barriers and support system e.g. financial constraints,
transport cost, family and social supports as well as healthcare provider's
attitude.
v Regular monitoring and assessment of patient during treatment.
It is important that all TB cases continue and complete treatment uninterrupted. Case
holding implies that a patient on anti-TB treatment is monitored by a health care
provider to ensure that he/she continues and complete his/her treatment
uninterrupted. Health Workers should do all that is humanly possible to ensure that
patient's complete treatment in line with the national guidelines.
Every patient should adhere strictly to treatment to get cured and prevent from
developing Drug Resistant TB (DR TB)
Treatment Interruption: Any TB patient who has not come to receive his/her treatment
for two consecutive days either in the intensive or continuation phase should be
46
regarded as having interrupted treatment and therefore must be traced. It is the
responsibility of the LGTBLS to ensure a sound default-tracking plan is in place and
implemented at LGA level. Where applicable, it is the responsibility of the GHCW, the
LGTBLS and the CBOs in the community, community volunteers and/or other
stakeholders to locate a patient who has interrupted treatment.
All effort should be made to bring back any patient who interrupts treatment and a
report of the action(s) taken should be attached to the treatment card.
5.4 MANAGEMENT OF TREATMENT INTERRUPTION:

v Trace patient
v Find out the cause(s) of interruption
v Counsel/Solve the cause(s) of interruption
v Continue treatment and prolong it to compensate for missed the doses
47
CHAPTER6 MONITORING OF DRUG RESISTANT
TUBERCULOSIS TREATMENT
Every drug resistant Tuberculosis patient that is placed on treatment should be

monitored closely for signs of treatment failure and adverse drug reactions (baseline
and follow up examinations). Treatment can be monitored through clinical history,
physical examination, psychosocial assessment and adherence, chest radiography,
electrocardiography (ECG), audiometry, bacteriological test (smear and culture),
laboratory monitoring (Hematology, Creatinine, Potassium, LFT, TSH), baseline
pregnancy test, hepatitis B, C and HIV test (if positive CD4 and VL every six
months).Weight should be monitored monthly and drug dosages should be adjusted
accordingly.On all patients follow up monitoring is required: serum albumin (Dlm),
vision test charts (Snellen Chart/Ishara test), serum amylase/lipase.
6.1 Monitoring progress of treatment:

Patients should be monitored closely for signs of treatment failure. Monitoring
response to treatment is done through regular clinical monitoring (history taking,
physical examination), bacteriological monitoring and chest radiograph.
6.1.1 Clinical monitoring:

Patients should be asked about their TB symptoms and their weight should be recorded
at every hospital visit. Children's height and weight should be measured monthly to
ensure that they are growing normally. For adults, weight should be recorded monthly
(height is only recorded at the start of treatment). Persistent fever, weight loss or
recurrence of any of the classic symptoms of TB should prompt investigation of
treatment failure or untreated co-morbidities (bacterial pneumonia is very frequent in
patients with damaged lung due to TB).
6.1.2 Bacteriological monitoring:

6.1.2.1 Sputum smear and culture
Examination must be performed monthly throughout the entire treatment duration for
patients on both shorter and longer treatment regimens. (Molecular tests are not
recommended for treatment monitoring).
v Culture conversion is not equivalent to cure. A certain proportion of patients
may initially convert and later revert to positive sputum cultures.
v The most important evidence of improvement is conversion of the culture to
negative. While smear is useful because of its much shorter turnaround time, the
48
culture is much more sensitive to detect ongoing active disease and/or treatment
failure.
v For patients who remain smear or culture positive after four months of
treatment or who are suspected to have treatment failure, SL LPA and
phenotypic DST should be repeated.
v In addition to pointing to treatment failure, persistently positive sputum smears
may indicate colonization of damaged lungs by mycobacterium other than TB.
This may be confirmed by mycobacterium culture and specie identification
using appropriate kits (e.g.NTM) for. In such cases, DRTB should continue
being adequately treated and treatment for NTM added as well.
6.1.2.2 Drug Susceptibility Testing

Access to WHO-recommended rapid DST is essential, especially for detecting
resistance to rifampicin and fluoroquinolones before starting the shorter, all-oral,
bedaquiline-containing MDR-TB regimen. Baseline DST will confirm eligibility for
different regimen options.
v In patients with bacteriologically confirmed MDR/RR-TB, second-line LPA may
be used as the initial test, in preference to culture and phenotypic DST, to detect
resistance to fluoroquinolones. A first-line LPA can determine the effectiveness
of isoniazide at high dose and thionamides in the shorter regimen. In the absence
of information on mutation patterns for an individual patient, the decision can
be informed by knowledge of the frequency of the concurrent occurrence of both
mutations, obtained from drug resistance surveillance in this epidemiological
setting.
v Phenotypic DST for some medicines included in the regimen (i.e.ethambutol
and ethionamide) is not considered reliable and reproducible; therefore, it
should be employed with caution to inform the use of this regimen.
v DST for bedaquiline should be carried out at baseline, to monitor bedaquiline
resistance. Since bedaquiline and fluoroquinolones are the backbone of the
regimen, it is vital to monitor resistance to these medicines during treatment if
there is no culture conversion by month 6.
6.1.3 Radiological monitoring:

v The chest radiograph may appear unchanged in the first few months of
treatment or only show a slight improvement, especially in patients with chronic
pulmonary lesions.
v Chest radiographs should be taken at baseline, every six months and at the end of
the treatment to document progress and to use for comparison if the patient's
49
clinical condition changes.
v Chest radiography is also done when a surgical intervention (e.g pleural
effusion, heamoptysis, cavitorylessions, severe fibrosis, malignancy) is being
considered, or whenever the patient's clinical situation worsens.
At times, the shorter all-oral bedaquiline-containing MDR-TB regimen may need to be

switched to a longer MDR-TB regimen; this is most likely to happen when:
v reliable DST results show resistance to key drugs in the shorter all-oral
bedaquiline-containing regimen.
v MDR-TB regimen: this may reflect the actual situation at the start of treatment
(that was unknown at that time) or the acquisition of additional resistance
during treatment.
v There is lack of response to treatment (e.g, no sputum smear conversion from
positive to negative by 6 months, or deterioration of clinical condition despite
treatment);
v Treatment of a patient is interrupted for 2 months or more after being treated for
more than 1 month; or
v Another disqualifying criterion emerges (e.g, pregnancy, intolerance, or toxicity
to a medicine in the regimen, or clinical deterioration).
If the patient is assessed for a longer MDR-TB regimen, the treatment should be
designed based on established algorithms. Patients need to be made aware of this
before starting on the shorter all-oral bedaquiline-containing regimen. If the
interruption is for less than 2 months the clinician needs to decide whether the shorter
MDR-TB regimen can be continued based on clinical condition and repeat laboratory
test results, and whether the missed doses will be added to the rest of the treatment or a
longer regimen should be started.
6.2 Monitoring Adverse Events

All Adverse Events (AEs) including adverse drug reactions (ADR) should be monitored
in an active, systematic, and timely manner for early diagnosis and prompt
management (important component of aDSM). The assessment of patients under
DRTB treatment should include clinical examination, laboratory examination and
complementary tests such as ECG, blood chemistry, and vision tests. Psychosocial
consultation and patient education are also crucial for detection of AEs and
adherenceto the treatment.
50
6.3 Clinical monitoring of adverse drug reactions (ADRs)
Patients should be routinely screened for ADRs at least weekly during the first month of
intensivePhase, and monthly for the entire duration of the treatment.
Health care workers should be trained to screen patients regularly for symptoms of
common ADRs: rash, gastrointestinal disturbances (e.g., nausea, vomiting, and
diarrhea), psychiatric symptoms (e.g. depression, anxiety, suicidal ideation and
behavioral changes), jaundice, ototoxicity, peripheral neuropathy and symptoms of
electrolyte wasting (e.g. muscle cramping, palpitations). Health care workers should
also be trained in simple adverse effect management and when to refer patients for
expert care.
6.4 Educational, psychological, and social consultation

Patient education and psychosocial consultation should be done at baseline by
personnel trained in health education, psychological and social issues relevant to DRTB
management and adherence.patient education should include clear information about
adverse drug reactions (e.g. symptoms, importance of prompt consultation, basic
management).Patient education should be repeated during the treatment monthly at
every consultation. The patient should be referred to a social worker, psychologist or
psychiatrist when indicated.
6.5 Laboratory monitoring of AEs

Blood should be collected as indicated for monitoring: full blood count and
biochemistry.
This test should include the following:
6.5.1 Full blood count: if on linezolid, monitor weekly for first month, then monthly
or as needed based on symptoms (there is little clinical experience with prolonged use
of linezolid). For HIV infected patients on ART, monitor monthly initially and then as
needed based on symptoms.
6.5.2 Creatinine including calculation of clearance (CrCl) and electrolytes

potassium): Monthly monitoring while on treatment. Every two weeks in HIV
infected patients, diabetics, and other high-risk patients in the beginning and later if
needed. If hypokalaemia is diagnosed, also monitor calcium and magnesium. Monitor
electrolytes more frequently in patients with ECG abnormalities (prolonged QTcFr).
51
6.5.3 Liver function test (ALT/AST): Periodic monitoring (every 3months or as
indicated) in patients receiving pyrazinamide for extended periods or for patients at
risk for, or with symptoms of hepatitis. For HIV infected patients monthly monitoring is
recommended. For patients on Bdq, monitor monthly. For patients with viral hepatitis,
monitor everyone to two weeks for the first month and then every 24weeks.
6.5.4 Thyroid Stimulating Hormone (TSH): Monitor at baseline and every six
months if on ethionamide, prothionamide, or PAS. If levothyroxine replacement is
required, monitor every 30-45days to adjust the dosage.
6.5.5 Fasting blood glucose: At baseline and when required. Monitor frequently in
patients with diabetes.
6.5.6 Serum Albumin: If patient on Dlm, at baseline and every two months.
6.5.7 Serum amylase and lipase: Special attention to patients receiving Bdq, lzd,
and based on risk factors. Perform at baseline and when required.
6.5.8 Other baseline investigations: HIV test (if positive, CD4 and Viral Load),
pregnancy test, hepatitis B and C.
6.5.9 ECG Monitoring: At baseline, 2, 4, 6 weeks and monthly.
6.6.0 Audiometry:As indicated
6.6.1 Vision test charts; Weekly during intensive phase and then monthly during
continuation phase.
6.6 Severity grading scale of adverse events and main laboratory

parameters
All SAEs and AEs should be graded for severity according to the Severity Grading Scale
(Grades 1- 4). For those AEs not described in the Severity Grading Scale, the general
definition of clinical severity should apply.
52
Table: 5 Severity grading scale of adverse events
Grade 1 Grade 2 Grade 3 Grade 4
MILD MODERATE SEVERE LIFE-THREATENING
Transient or mild Mild to moderate Marked limitation of Severe limitation of
discomfort (<48 limitation of normal normal daily activities* normal daily activities*.
hours) without daily activities*. Medical intervention, Medical intervention and
limitation of Minimal medical therapy, stop or reduction corrective treatment
normal daily intervention or of the offending drug is required almost always in
activities*. No corrective treatment required. Possible a hospital setting.
medical required hospitalization
intervention or
corrective
treatment
required
*The term 'activity' covers basic selfcare functions such as bathing, dressing,
transfer/movement, feeding; but also, usual social and functional activities or adaptive
tasks and desirable activities, such as going to work, shopping, cooking, use of
transportation, pursuing a hobby, etc.
Table:6 Severity grading scale of main laboratory parameters
Hb Platelet Neutrophil AST ALT Creatine. K+ (mEq/l

(g/dl) s (/mm3 s (/mm3 ) (UI/l) (UI/l) (µmol/l) or
) mmol/l)
Normal >12 >150,000 >1,500 * * * 3.5 5.0
Values
Grade 1 10-11.9 100,000- 1,000-1,500 1.5-< 2.5 x 1.5-<2.5 1.1-1.5 x 3.2-3.4
149,999 ULN xULN ULN
Grade 2 8-9.9 50,000- 750-999 2.6-5.0 X 2.6-5.0 x 1.6 -3 x 2.8-3.1
99,999 ULN ULN ULN
Grade 3 6-8 20,000 500-749 5.110 x 5.110 x 3-6 x ULN 2.5-2.7
49,999 ULN ULN
Grade 4 <6 <20000 <500 >10 X >10 X >6 X ULN <2.5
ULN ULN
*Normal values vary from laboratory to laboratory and might be slightly different in
men, women and children. (Check normal parameters for your laboratory) ULN=
upper limit of normal
53
CHAPTER 7: MANAGEMENT OF ADVERSE DRUG REACTION
7.1 Potential overlying and additive toxicities of anti TB and ARVS

Treatment of drug susceptible tuberculosis (DS-TB) requires regimens containing first
line drugs (FLDs') whereas Drug Resistant Tuberculosis (DR-TB) are treated
with regimens comprising combination of both second line drugs (SLDs') and few
FLDs'.
Adverse drug reactions (ADRs') to these anti-tubercular drugs are quite common as
they are being used for longer duration. ADRs' may cause associated morbidity and
even mortality if not recognized early. There are major concerns regarding treatment
of DR-TB patients particularly with SLDs' in that they are expensive, have low efficacy
and more toxic as compared to FLDs'.
There may be a severe impact on adherence and higher risk of default and treatment
failure affecting outcome overall if such ADRs' are not properly managed.
54
Table 7: Management of Potential Toxicities
Potential toxicity Peripheral neuropathy

Anti-retro-viral d4T,ddI, Anti-TB agent Lzd, Cs, H, Eto/Pto, E
agents aminoglycoside
ŸIncrease pyridoxine by 50mg until desired effect is achieved to
Suggested maximum daily dose of not more 200mg/day.
management ŸChanging Injectables to Capreomycin if there is documented
strategies susceptibility.
ŸInitiate therapy with tricyclic anti-depressants like
amitriptyline, NSAID or acetaminophen may alleviate
symptoms.
ŸLower dose of suspected agent if this can be done with out
Compromising the regimen.
ŸDiscontinue suspected agent if this can be done without
compromising the regimen.
Comments
Avoid use of d4Tor ddI in combination with Cs or Lzd because
theoretically it is believed toincrease peripheral neuropathy.
Potential toxicity Central nervous system toxicity (Confusion, impaired
concentration, depersonalization, abnormal dreams,
insomnia, and dizziness etc.)
Anti-retro-viral EFV Anti-TB agent Cs, H, Eto/Pto,
agents Fluroquinolones
Suggested ŸConsult a psychiatrist
Management ŸWith hold suspected anti-TB agent for a short period of time
strategies (1-4 weeks) while psychotic symptoms should be managed
accordingly.
Continue to
Efavirenz has a high rate of CNS adverse effects in the first 2–3
adjust
Weeks, which typically resolve spontaneously.
antipsychotic
If these effects do not resolve on their own, consider treatment
therapy in
consultation options.
with a If still not resolved,then change the drug to individualized
Psychiatrist if regimen.
psychosis
55
Comments Always avoid combining ARV and anti TB drugs with potential
neuro psychiatric effect eg EFV with Cs
Potential toxicity Depression
Anti- EFV Anti-TB agent Cs, H, Eto/Pto,

retroviralagents Fluoroquinolones
Comments Avoid use of d4Tor ddI in combination with Cs or Lzd because

theoretically it is believed toincrease peripheral neuropathy.
Potential toxicity Central nervous system toxicity (Confusion, impaired

concentration, de personalization, abnormal dreams,
insomnia, and dizziness etc.)
Anti-retro-viral EFV Anti-TB agent Cs, H, Eto/Pto,

agents Fluroquinolones
Potential toxicity Peripheral neuropathy
Anti-retro-viral d4T,ddI, Anti-TB agent Lzd, Cs, H, Eto/Pto, E
agents aminoglycoside
Increase pyridoxine by 50mg until desired effect is achieved
Suggested to maximum daily dose of not more 200mg/day.
management Changing Injectables to Ca preomycin if t here is documented
strategies susceptibility.
Initiate therapy with tric yclic anti-depressants like
amitriptyline, NSAID or a cetaminophen mayalle viate
symptoms.
Lower dose of suspected agent if thiscan be done
Suggested Initiate therapy with tricyclic anti-depressants like amitriptyline
management
Comments Severe depression can be Seen in up to 2.4% of patients in
receiving EFV Consider substituting EFV if severe depression
develops.Socio-economic circumstances of many patients with
chronic disease Can also contribute to depression.
56
Potential toxicity Headache
Anti retro viral agents AZT,EFV Anti-TB agent Cs
Suggested Use of analgesics (ibuprofen,paracetamol) and good hydration may help; headache
management secondary to AZT, EFV and Cs is usually self-limiting.
strategies
Comments Rule out more serious causes of headache such as bacterial

meningitis, cryptococcal meningitis, CNS toxoplasmosis or tuberculoma etc
Potential toxicity Nausea and vomiting
Anti retro viral agents d4T, NVP, RTV & Anti-TBagent Eto/Pto, PAS, H, E, Z
others &others
Suggested ŸAssess for dehydration, initiate rehydration if indicated, Initiate anti-

management emetictherapy.
strategies ŸAdminister drugs one hour after Metoclopramide 10- 20mg tablet and or a course
of proton pump inhibitor or H2 receptor inhibitor (Omeprazole, Famotidine,
ranitidine). Ondansetron 8-10mg injection can be used in severe form of
vomiting not responding to treatment.
ŸMonitor electrolytes if needed (severe vomiting).
ŸLower dose of suspected anti-TB if this can be done without compromising the
regimen.
ŸIn severe condition discontinue suspected agent if this can be done without
compromising the regimen, rarely necessary.
Comments ŸARV-induced GI intolerance is generally self-limiting except for ddI induced

pancreatitis, which requires permanent cessation of therapy.
ŸSymptomatic treatments should be offered. (With AZT and Pls, nausea-vomiting
can be severe and prolonged and may require a Change of drugs).
ŸAnorexia, nausea and vomiting are frequent in early weeks of therapy and
usually can abated with time on treatment and supportive therapy
ŸToxicity of Pto to the gastric mucosa is enhanced with Cfz.
ŸAttention in case of severe abdominal pain (very rare AE due to accumulation of
crystals of Cfz): stop Cfz because this can be life threatening
Potentialtoxicity Abdominalpain
Antiretroviral agents AllART treatment May be Anti-TBagent Cfz,Eto/Pto,PAS
associated with abdominal
pain
57
Abdominal pain is a common adverse effect and often benign;
Comments however, abdominal pain may be an early symptom of severe
adverse effects such as pancreatitis, hepatitis, or lactic acidosis.
Potential Pancreatit is
toxicity
Anti retro viral d4T,ddI,ddC Anti-TB agent Lzd
agents
Comments Avoid use of these agents together.
If an agent causes pancreatitis suspend it permanently and do
not use any of the pancreatitis producing anti-HIV medications
(D4T, ddI,orddC) in the future.
Also consider gallstones or alcohol as a potential cause of
pancreatitis.
Potential Hepatotoxicity
toxicity
Anti-retro viral NVP, EFV &all Anti-TB agent H,R,E,Z,PAS,
agents Protease Eto/Pto
inhibitors
Suggested
ŸIf ALT is more than five times the basal level stop all therapy
management
pending resolution of hepatitis.
strategies
Ÿ Rule out other potential causes of hepatitis.
Ÿ Consider suspending the most likely agent permanently. Re-
introduce remaining antiTB drugs, one at a time with the
most hepatotoxic agents last first, while monitor liver
function.
ŸFor ART, replace the drug most Likely associated with the
condition or all three ARV start the same time if required
Comments History of prior hepatitis should be carefully analyzed to Determine
most likely causative agent(s); these should be avoided in future
regimens.
58
· Generally reversible upon discontinuation of suspected agent.
· Also rule out viral etiologiesas cause of hepatitis (hepatitis A,
B,C,&CMV).
Potential Lactic acidosis

toxicity
Anti- D4T, Anti-TB agent Lzd
retroviral ddI,AZT,3TC
agents
Suggested
1) Discontinue ART and give supportive treatment.
management
2) After clinical resolution resume ART replacing the
strategies
offending drug with ABC, TDF or 3TC.
Comments Lactic acidosis has been reported with the use of Lzd
Potential Diarrhea
toxicity
Anti retro All protease Anti-TB agent Eto/Pto, PAS
viral agents inhibitors, ddI
Suggested
Ÿ If severe, take care of hydration and manage electrolyte
management
strategies profile.
Comments
Also consider opportunistic infections as a cause of diarrhea, or
clostridium difficile (a cause of pseudo-membranous colitis).
Potential Skin rash

toxicity
Anti retroviral ABC,NVP,EF Anti-TB agent H,R,Z,PAS

agents V, d4T
59
Suggested
Ÿ If mild, treat with anti-histamines.
management
Ÿ If severe, withdraw the offending agent & treat with steroids,
strategies if necessary
Comments
Ÿ Do not re-challenge with ABC (can result in life-
threatening anaphylaxis)
Ÿ Do not re-challenge with an agent that causes Stevens-
Johnson Syndrome
Potential Renal toxicity
toxicity
Anti retro viral TDF(rare) Anti-TB agent Aminoglycoside, Cm
agents
Suggested Ÿ All drugs will be withheld; blood tests for renal

management parameters ordered and the patient will be referred, if
strategies available, to a nephrologist.
Ÿ Calculate the eGFR (140-age x weight (kg)/72 x Pcr(x1.1)
for male)
Ÿ Re-introduction of drugs will be under taken by the
attending physician, in consultation with either the
DOTS-Plus expert committee or nephrologists, along with
frequent monitoring of renal parameters throughout
treatment.
Comments
Ÿ Use TDF with caution in patients receiving
Aminoglyco side or Cm.
Ÿ Even without the concurrent use of TDF, HIV-infected
patients have an increased risk of renal toxicity secondary
to Aminoglyco side and Cm
Potential Anaemia
toxicity Headache
Anti-retro viral AZT Anti-TB agent

agents
60
Suggested
management
1) If severe (Hg<6.5g%), replace by an ARV with minimal or no
bone marrow toxicity (ABC or TDF) and consider blood
strategies
transfusion.
2) Granulocytopenia also seen with AZT
3) Discontinuation of Lzd should be considered, if it is the
confirmed cause.
Comments
Monitor blood counts regularly.
Also consider TMP/SMX as a cause if the patient is receiving the
medication
Potential Optic neuritis
toxicity
Antiretroviral ddI(phased Anti-TB agent E
Agents out)
Suggested Suspend agent responsible for optic neuritis permanently and

management replace with an agent that does not cause optic neuritis
strategies
Potential Hypothyroidism
toxicity
Antiretroviral d4T(phased Anti-TB agent PAS, Eto/Pto

agents
out)
Suggested Depending on the level of TSH estimation, thyroxin is replaced
management and titrated accordingto blood levels.
strategies
Comments Monitor monthly for signs & symptoms of hypothyroidism
61
7.2 Pharmacovigilance in programmatic management of Adverse Drug
Reaction in DR-TB
Pharmacovigilance is defined by the WHO as “the science and activities relating to the
detection, assessment, understanding and prevention of adverse effects or any other
drug-related problem.” Many of the second-line anti-TB drugs are more prone to cause
toxic reactions in patients than first-line drugs, making pharmaco vigilance more
important in the programmatic management of DR-TB. Good pharmaco vigilance will
also pick-upadverse effects quicker from the second-line anti-TB drugs in use and
should be considered as a standard of patient care.
The WHO recommends that as programs start to incorporate newly released drugs into
treatment regimens, they should also improve their capacity to undertake pharmaco
vigilance by recording the occurrence of adverse drug reactions for patients on
treatment, the country already has data collection inherent to pharmaco vigilance. All
ADR should be documented using the ADR Form. (Refer to the annex for a copy).
7.3 Basic definitions used in pharmaco vigilance

Adverse event (AE): Any untoward medical occurrence that may present during
treatment with a pharmaceutical product, but which does not necessarily have a
causal relationship with this treatment.
Adverse (drug) reaction (ADR): A response to a medicine, which is noxious and
unintended, and which occurs at doses normally used in humans.
Risk factor: A characteristic associated with an increased probability of occurrence
of an event. In the presence of a risk factor, a patient is more likely to develop an
adverse reaction.
Serious reaction: A serious reaction is an ADR which involves any of the following:
death or a life-threatening experience; hospitalization or prolongation of
hospitalization; persistent significant disability; congenital anomaly.
Signal: Reported information on a possible causal relationship between an adverse
event and a medicine; the relationship being unknown or incompletely documented
previously. Usually more than a single report is required to generate a signal,
depending on the seriousness of the event and the quality of the information.
The timely and intensive monitoring for and management of adverse effects caused by
Second-line drugs are essential components of DR-TB control programs. Poor
management of adverse effects increases the risk of loss to follow up (LTFU) or
irregular adherence to treatment, and may result in death or permanent morbidity.
62
7.4 Common adverse reactions to the anti-TB drugs
Quinolones: Levofloxacin, Moxifloxacin
v Gastro-intestinal symptoms: diarrhoea, vomiting, and abdominal pain
v CNS: dizziness and convulsions
v Photo toxicity and photosensitivity
v Tendinopathy and tendinitis
v Skin rash
v Cardiotoxicity–QTc prolongation
v Arthralgia
Pyrazinamide
v Arthralgia
v Hyperuricaemia
v Hepatitis
v Pruritus with or without rash
Prothionamide
v Gastrointestinal: epigastric discomfort, anorexia, nausea, metallic taste,
vomiting, excessive salivation, and sulphurous belching
v Psychiatric: hallucination and depression
v Hepatitis
v Hypothyroidism and goitre with prolonged administration
v Gynaecomastia
v Menstrual disturbances
v Impotence
v Acne
v Headache
v Peripheral neuropathy
Cycloserine
v CNS: dizziness, slurred speech, convulsions, headache, tremor, and
insomnia
v Psychiatric: confusion, depression, altered behaviour and suicidal tendency
v Hypersensitivity reaction
v Peripheral neuropathy and skin changes; skin problems include lichenoid
eruptions and Stevens-Johnson syndrome
63
PAS
v Gastro-intestinal: Anorexia, nausea, vomiting and abdominal discomfort
v Skin rash
v Hepatic dysfunction
v Hypokalaemia
v Hypothyroidism and goitrewith prolonged administration
Clofazimine
v Pink or red discoloration of skin, conjunctiva, cornea, and body fluids
v Gastrointestinal intolerance
v Severe abdominal symptoms, bleeding, and bowel obstruction
v Photosensitivity
v Retinopathy Dry skin, Pruritus, rash
Linezolid
v Bone marrow suppression (myelosuppression)
v Diarrhoea and nausea
v Optic neuropathy
v Peripheral neuropathy (symptoms of neuropathy(pain, numbness, tingling
or weakness in the extremities)
v Lacticacidosis
Amoxicillin/Clavulanate
v Diarrhoea and abdominal discomfort
v Nausea, vomiting, and rash
v Hypersensitivity
Bedaquiline
v Nausea
v Arthralgia
v Headache
v Increase transaminases (aspartate amino transferase, alanine amino
transferase increased, and other hepatic enzymes may be increased) Blood
amylase increase
v Hemoptysis
v Chest pain
v Anorexia
v Rash
64
7.4 Key considerations in management of adverse drug reactions
ADR should be managed according to the following guidelines:
v Before starting treatment, the patient should be instructed in detail about the
potential adverse effects that could be produced by the prescribed drug regimen,
and when they occur to notify a health care provider.
v The Pharmacist, DOT providers, nurses in the hospital and clinician will monitor
and record all adverse events routinely and laboratory screening tests will be
done on a routine basis as per the national guide lines. All ADR should be
documented on the ADR Form.
The initial base line investigations are important to identify patients who are at
increased risk for adverse effects or poor outcomes and may detect certain adverse
effects that are more occult, and before serious impairment is done. Laboratory
screening is important for detecting certain adverse effects that are more occult before
serious impairment is done.
Most adverse effects are easy to recognize and close monitoring of patients is necessary
to ensure that the adverse effects of the drugs are recognized early by healthcare
personnel.
It is important to have a systematic method of patient monitoring because of certain
patients being silent about reporting even severe adverse effects. The ability to monitor
patients for adverse effects daily is one of the major advantages of DOT over self-
administration of treatment.
Nurses and DOT providers should be trained to screen patients regularly for symptoms
of common adverse effects such as rashes, toxic epidermal necrosis, gastro intestinal
symptoms (nausea, vomiting, diarrhoea), psychiatricsymptoms (psychosis,
depression, anxiety) jaundice, Ototoxicity, peripheral neuropathy, symptoms of
electrolyte wasting (muscle cramping, palpitations),and convulsions.
Most ADRs can be managed by doctors at the LGA level with proper training, if
required. Patients should be hospitalized at a state hospital where an inpatient where
an inpatient facility is available or referred to a referral hospital or admission.
The State DR-TB Consilium would be consulted to take decisions regarding
reduction/termination of any drug and if any drug is withheld/terminated due to ADR,
it would be replaced with the appropriate substitute drug as per the State DR-TB
Consilium. If required, the National DR-TB Consilium should be consulted.
65
Proper management of adverse effects begins with pre-treatment counselling and
continued health education. Depending on the severity of ADRs, the following actions
may be indicated:
v If the adverse effect is mild and not serious, the best option is often to continue
the treatment regimen, with the help of ancillary drugs if needed.
v Most of the adverse effects of a number of second-line drugs are dose-
dependent Reducing the dosage of the off ending drug or terminating the
offending drug is another method of managing adverse effects, but should be
done after consultation with DR-TB experts or the DR- TB treatment centre.
v Psychosocial support is an important component of the management of adverse
effects. This may be provided through patient education and motivation by
nurses and DOT providers, patients support groups through group discussions
while in the hospital.
7.4.1 General perspective in management of adverse drug reactions

7.4.1.1 Gastro-intestinal symptoms (nausea and vomiting)
This may be due to the bulk of drugs and/or due to Pto/Eto, PAS and Pyrazinamide.
v Taken with juice Patients who complains of nausea or vomiting can be advised to
take the drugs embed in a banana or
v If vomiting persists, drugs will be administered one hour after one tablet of
Domperidone and/or a course of proton pump inhibitor (Omeprazole)or H2
receptor inhibitor (Famotidine, Ranitidine).
v Antacids cannot be given within two hours of fluoroquinolones as they interfere
with absorption of fluoroquinolones.
v Incase of severe vomiting the hydration status of the patient should be
monitored and rehydration therapy initiated if required.
v If the offending drug is Ethionamide, the drug is more acceptable if it is
administered with milk, or after milk, or at bed time to avoid nausea, however
note that milk interferes with absorption of fluoroquinolones and less tolerated
in patient with lactose intolerance.
v Administer anti emetics or antacids prior to medication or as needed,
Promethazine (Phenergen) 12.5 to 25 mg PO, IV, 30minutes before the dose and
every eight hours as needed. Metoclopramide (Reglan) 10 to 20mg PO or IV
every eight hours or as needed
v In refractory cases of vomiting Ondansetron a drug used to prevent vomiting in
patients on chemotherapy can be used iv 8-10mg slowly 30 minutes before
66
medication, ECG should be monitored for QTc prolongation associated side
effect of Ondansetron
v If vomiting is severe, drugs can be with heldtemporarily and tests should be
conducted to rule out other causes of vomiting like malaria, PUD, GERD, tumors,
uremia, hepatitis etc
v Pancreatitis can be caused by drugs like Dlm, Bdq, CFz, monitor serum and
urinary amylase and lipase, consider frequency dose adjustment , give mild
analgesics and anti-spasmodic, if the symptoms persist and the lipase and
amylase remain elevated consider stopping the drugs and individualize the
therapy.
7.4.1.2 Cardiac Toxicity
Qtc Prolongation
The responsible drug: Mfx, Bdq, Dlm and Cfz.
Conduct:
v Repeat ECG and confirm the prolongation.
v Check potassium, magnesium and calcium and maintain electrolyte
within normal range.
v If QTc <500ms, continue Mfx or Bdq or Dmd and check ECG weekly.
v If QTc ≥ 500ms replace Mfx with high dose of Lfx and consider to stop Bdq
and/or Dlm
v If arrhythmia occur refer to cardiologist for prompt management.
7.4.1.2 Management of arrythmias/ Torsad de pontes
v Non medical measures:

Ø Stop all drugs prolonging the QT.
Ø Identify and correct predisposing factors (hypokalaemia,
hypomagnesaemia and hypocalcaemia).
v Medical Measures
Ø Administration of magnesium is usually life saving
Ø Mg Sulfate IV: 3g IV then 6-12 g/day.
67
Ø Add Potassium (even if potassium levels are normal, it accelerates
repolarization).
Ø K Chloride 3-6 g/d.
Ø Accelerate heart rate: Isoprenaline (HR > 90 bpm). And consult cardiologist or
physician
7.4.1.3 Myelosuppression
v Responsible drug: Lzd.
v Treatment:
1. Stop Lzd immediately if severe suppression of white blood cells, red blood cells or
platelets occurs.
2. Consider blood transfusion for severe anemia.
3. Consider nondrug related causes of the haematological abnormality.
4. Restart a lower dose of Lzd (300mg instead of 600 mg) if myelosuppression
resolves and check CBC.
7.4.1.4 Renal toxicity

Common offending drug is Aminoglycoside.
v Prior to starting treatment, all patients will have renal function evaluated.
v During treatment of DRTB, if the patients present with symptoms and/or signs of
renal impairment (oliguria, anuria, puffiness of face, pedal oedema), renal function
tests should be done and, if required, Opinion of nephrologist should be sought.
v If there is a decrease in renal function, repeat a 24-hour createnine clearance.
v Ensure adequate hydration.
v Hold the Aminoglycoside agent for one to two weeks to allow renal function to
stabilize.
v Check serum electrolytes and correct if needed.
v Evaluate other drugs the patient is taking and adjust dose and/or dosing interval if
needed.
v If the clearance is less than 30ml/minute, adjust the doses of Prothionamide, Z,
some fluoroquinolones, cycloserine, all of the Aminoglycoside, and Capreomycin.
v For a createnineclearance between 30 and less than 50ml/min, twice per week
Aminoglycoside dosing at 12 mg/kg should be tried.
v For a createnine clearance between 50 and 70ml/min, the patient may tolerate
Aminoglyco side dosing at 12 to 15mg/kg three times per week.
v Monitor peak and trough drug concentrations. It is especially important that trough
concentrations be less than the critical value before another dose of the drug is given.
68
v Re-introduction of drugs will be undertaken by the DR-TB Centre committee in
consultation with a nephrologist, along with frequent monitoring of renal
parameters.
v Blood urea and serum createnine should be done every month for the first three
months after treatment initiation and then every three months thereafter whilst
injection Kanamycin is being administered. Silent renal toxicity may be picked up
by this routine monitoring.
v Follow-up on biochemical examinations If at anytime the blood urea or serum
createnine becomes abnormal, treatment should be withheld and further
management decided upon in consultation with the DR- TB Centre committee.
7.4.1.5 Arthralgia
Pain and tenderness of the muscles and joints are relatively common side effects
associated with a variety of drugs used to treat drug-resistant TB patients.
One or more of the following drugs may be implicated: Z, FQ, Pto and INH.
v Electrolyte disturbances associated with the aminoglycosides and

Capreomycin may also cause muscle pain and cramping.
v Hypothyroidism may also be a contributing factor.
v The most common offending drugs are likely to be Z/or FQ.
v Do not discontinue medications.
v Avoid use of diuretics as it can worsen the arthralgia
v NSAIDs are usually helpful but prolonged usage may cause GI ulcerations,
antacid or H2 blockers can be given
v If acute swelling, erythema, and warmth are present, evaluate for the presence
of inflammatory diseases.
v Aspirate joint for diagnosis if fluid is present.
v Evaluate for infection, gout, or autoimmune disease.
v Institute treatment (often indomethacin or any NSAID)
v If the diagnosis of gout is made if there is still no improvement, or if the
Arthralgia worsens, consult with a rheumatologist and evaluate
v For hypothyroidism or hyperthyroidism, the dosage of Pyrazinamide and/or
Levofloxacin should be reduced, or the drug withheld temporarily without
compromising the regimen.
69
7.4.1.6 Tendonitis and Tendon rapture
v Responsible drugs: FQs (all).
v Treatment:
Ø Give NSAIDs: Ibuprofen 400 mg 3 times a day (in case of tendonitis) after meals.
Take care of gastritis, if any.
Ø Rest the joint.
Ø Tendon rupture is more likely in diabetics and older patients but is rare in DR-TB
patients.
v If significant inflammation persist stop FQ and replace it with Bdq.
Consider treatment prolongation until 12 months.
7.4.1.7 Hypersensitivity reactions

v Hypersensitivity reactions such as Pruritusor rash, can occur with any of the drugs
used, and are commonly managed with antihistamines.
v For minor dermatologic reactions, various agents may be helpful and allow
continuation of the medication. They can be given prior to the anti-tuberculosis
drug or as needed.
v Diphenhydramine (Benadryl) 25 to 50mg PO, IV, or IM given before the
medication and then every four to six hours as needed may lessen skin irritation.
v Other anti histamines: Chlorpheniramine (Chlor-trimeton) 4 mg PO before the
medication and then every four to six hours as needed.
v Hydrocortisone cream can be used topically.
v Low-dose prednisone (10 to 20 mg/day) for several weeks can be tried If other
measures are not helpful.
v For severe reactions which do not respond to anti-histamines, attempt to identify
the offending drug by challenging with individual drugs.
v The dose of the offending drug may be reduced or the drug terminated if required.
v If there is a generalized erythematous rash, especially if it is associated with fever
and/or mucous membrane involvement, all drugs should be withheld immediately.
v When the rashes subside, the medications can be restarted one by one, at interval
for two to three days.
v The order of reintroduction will be Ethambutol, Cycloserine, Ethionamide,
Fluoroquinolone, Kanamycin and lastly Pyrazinamide.
v After identification and patient did not recover the offending drug will be
terminated without compromising the regimen.
v Evaluate other potential etiologist of rash and Pruritus:
70
Ø Scabies and insect bites may masquerade as a drug rash.
Ø Contact dermatitis (question patient about use of new lotions, soaps, perfumes,
etc.).
Ø Phototoxi city (may respond to sun screens, but these may cause contact
dermatitis).
Ø Other drugs, especially new agents, should be evaluate the possible etiologies.
Ø Other dermatologic causes; psoriasis, pityrias is, atopic dermatitis, etc.
Ø Dry skin, especially in diabetic patients, may be the cause of Pruritus. Consider
liberal use of lotions, such as petroleum jelly and lanolin
Ø Dry skin is a serious problem with clofazimine.
7.4.1.8 Hepatitis
This could be due to the combined effect of potentially hepatotoxic drugs such as
Pyrazinamide and Prothionamide.
Ø If a patient presents with symptoms/signs of hepatitis (anorexia, nausea, vomiting,
abdominal discomfort, and/or dark coloredurine), he/she will be examined for
clinical jaundice and liver enlargement.
Ø The ALT (SGPT) is the hepatocellular enzyme most directly associated with
hepatocellular damage. If the enzymes are normal, continue medications and treat
nausea and vomiting accordingly.
Ø The ALT (SGPT) is more specific for hepatocellular injury than the AST (SGOT).
Elevations in the AST may indicate abnormalities in the muscle, heart, or kidney.
Ø If the ALT is elevated more than the AST, this is consistent with liver inflammation.
Ø When the AST is elevated more than the ALT, the possibility of alcohol-related
elevation of the transaminases should be considered.
Ø Patients will be questioned carefully regarding symptoms suggestive of biliary tract
disease and exposures to other potential hepatotoxins, including alcohol and
hepatotoxic medications.
Ø If the hepatocellular enzymes are less than three times the upper limit of normal
and there is no evidence of jaundice (total bilirubin<3.0mg/dl), continue the
medications using strategies for managing nausea and vomiting and observe
carefully.
Ø If symptoms continue, consider repeating liver enzymes again to exclude
hepatotoxicity.
Ø If the bilirubin is increased but the hepatocellular enzymes are only mildly
elevated, this could still represent significant drug-induced liver injury.
71
Ø An evaluation for causes of direct and indirect hyperbilirubinemia should be done,
and if the bilirubin is>3.0mg/dl, generally, hepatotoxic medications should be
stopped.
Ø If the enzymes are more than three times the upper limit of normal, hold all
potentially hepatotoxic medications.
Ø If at least three medications remain in the treatment regimen that are not
hepatotoxic (for example the Aminoglycoside, Levofloxacin, or cycloserine), then
these can be continued. If not, then all antituberculosis medications should be
held.
Ø If the results of the liver function tests are normal, the treatment will be
resumed.
Ø Patients with abnormal liver function will be reviewed at weekly intervals
and liver function repeated when jaundice subsides clinically.
7.4.1.9 Neurological Symptoms

Peripheral neuropathy is likely to occur in patients with diabetes, alcoholism, HIV
infection, hypothyroidism, pregnancy, poor nutrition, and with inadequate dietary
intake of pyridoxine.
The common offending drugs are cycloserine, Prothionamide, linezolid and INH.
To prevent the occurrence of such adverse reaction, all patients should receive daily
Pyridoxine.
If peripheral neuropathy develops, increase pyridoxine to maximum daily dose
(200mg) If there is no improvement or symptoms worsen, initiate therapy with tricyclic
anti-depressants such as Amitriptyline 25mg. The dose of amytriptyline may be
increased (to 150mg maximum) if lower doses are not helpful.
7.4.2.0 Depression
v The common offending drugs are Cs and Pto.
v Depression can be relatively mild and managed with supportive attention from
family and healthcare providers.
v Some level of depression is to be expected for most patients who deal with the
difficulties of DR-TB therapy.
v Assess and address underlying psycho/social issues, assess patients for
coexisting substance abuse and refer to counseling if appropriate.
v When depression is more significant, give a trial of anti-depressant therapy
v Tricycle antidepressants should not be given to patients on linezolid.
72
v Question the patient regarding suicidal ideation any time depression is judged
to be more than mild.
v Reduce the dose of cycloserine and Prothionamide to 500mg daily to see if
depression is lessened.
v If depression progresses or is not improved by a trial of antidepressant therapy,
v Discontinue Cycloserine and, possibly, Prothionamide as well.
v Cycloserine should not usually be part of an initial treatment regimen if
significant depression is present.
v When no alternative drugs are available and depression is controlled on therapy,
some patients may
v Tolerate cycloserine and Eto.
v INH has been associated with depression, which has been reported as severe in
several case reports.
v Withdrawal of the drug is associated with rapid recovery.
v If no response these drugs will be withheld and further management of the
patient will be done in consultation with the psychiatrist.
7.4.2.1 Psychosis
v If severe psychosis is present, consider psychiatric consultation.
v Hold all medications that possibly contribute until the patient stabilizes.
v The most likely drugs to cause psychosis are cycloserine and fluoroquinolones.
INH can occasionally be responsible.
v Pyridoxine (150mg) should be given if not already part of the treatment.
v Start antipsychotic therapy –Haloperidol PO, IV, or IM0.5 to 5mg) at the earliest
sign of psychosis.
v When symptoms resolve, the least likely medications that contributed to the
symptoms should be reintroduced first, one at a time, with careful observation.
v If no alternative drug is available, cycloserine may be reduced to low dose. If
there is recurrence of psychotic symptoms, cycloserine should be promptly and
permanently discontinued.
v When the patient has stabilized and all medications have been successfully
restarted, and all symptoms have resolved, the antipsychotic drugs can be
tampered with careful observation of the patient.
v Consider and address all other etiologies, especially illicit drug use, alcohol, and
medical problems
73
o (meningitis, hypothyroidism, and depression).
v Some patients may tolerate cycloserine with an antipsychotic drug if no other
treatment options are available
v These patients require special observation, utilize this therapy only after
consultation with an expert in the management of drug-resistant TB, and
when the cycloserineis determined to be essential to the regimen and no
alternative is available.
v In case of suicidal ideation discontinue Cycloserine and request psychiatric
consultation.
v Initiate antidepressant therapy and lower the dose of Ethionamideto
500mg daily until the patient is stable.
7.4.2.2 Vestibulo-auditory disturbances

Offending drug is usually an Aminoglyco side. Patient may present with tinnitus,
unsteady gait or loss of hearing.
v Hearing loss is a direct effect of Injectable medication toxicity to the eighth
cranial nerve.
v Some degree of loss occurs in nearly all patients treated for DR-TB. High-
frequency loss usually occurs first and the effects are cumulative.
v Hearing loss may be reversible or permanent.
v Perform a baseline audiogram and repeat monthly.
v Monitor the ability of the patient to participate in normal conversation.
v Consider change of the Injectables to three times a week, after three to four
months, when the cultures are negative
v Avoid loop diuretics because they potentiate the Ototoxicity of aminoglycoside.
v Some patients must tolerate significant hearing loss in order to achieve a cure of
their DR-TB.
v When significant hearing loss occurs, it should be discussed with an expert in the
management of DR-TB
v And the patient. Early review by ENT specialist should be encouraged generally.
7.4.2.3. Hypothyroidism
Hypothyroidism may develop with either PAS or Pto; when both drugs are used, the
incidence of hypothyroidism may be 40% or greater.
Patients may present with slowing down of activities, puffiness of face and/or thyroid
enlargement.
74
v Assess baseline thyroid function prior to start of these medications and correct if
needed.
v Assess thyroid function every three months unless clinical assessment indicates
the need to evaluate sooner.
v Conduct monthly clinical assessments for hypothyroidism. Clinical assessments
may be a better indicator of thyroid function than laboratory values.
v When thyroid stimulating hormone (TSH) begins to increase, evaluate for
clinical evidence of hypothyroidism. Begin to monitor more frequently.
v When TSH rises to 1.5 to 2 times above upper limit of normal, begin thyroid
hormone replacement:
Ø Most adults will require 100 to 150mcg of thyroxin daily
ØYoung healthy adults can be started on 75 to 100mcg of thyroxin daily
ØOlder patients should begin treatment with 50mcg daily
ØPatients with significant cardiovascular disease should start at 25mcg
ØAdjust thyroid hormone replacement until the patient's TSH is within the
normal range
ØWhen TB treatment is complete, stop thyroid hormone replacement, the
thyroid gland will now be able to respond to endocrine stimulation with r e l e a s e
of thyroid hormone
Ø Breast enlargement can be a troublesome side effect of P to therapy,
especially for male patients, galactorrhea has also been reported. Encourage
patients to tolerate this side effect. Resolution occurs after treatment is
stopped.
7.4.2.4 ALOPECIA
Hair loss can occur with either Pto or INH. In the first month of treatment, there can be a
significant thinning of the hair, but this is temporary and not progressive during
treatment.
7.5 GENERAL MANAGEMENT STRATEGIES FOR ADR

v Reassurance and supportive measures and/or provision of anancillary drug
Ø Splitting dosage of some suspected agent – DOT for both doses.
Ø Replacement of suspected agent with same group or another anti-TB drug
– may not always be possible.
75
v Lowering the number of days (preferably) or dose of suspected agent by one
weight class and if necessary more without compromising the regimen.
v Temporary suspension of suspected agent.
v Discontinuation of suspected agent.
v Referral to a specialist, e .g.,
Ø endocrinologist for hypothyroidism, uncontrolled blood sugar.
Ø psychiatrist for psychosis, severe depression etc.
v Performing special diagnostics, e.g.,
Ø Thyroid stimulating hormone for signs of hypothyroidism.
Ø Gastros copy for bloody vomitus etc.
76
CHAPTER 8 DIAGNOSIS AND TREATMENT OF DR-TB IN HIV
INFECTED PATIENTS
People living with HIV/AIDS are at higher risk of developing TB (including DR-TB)
associated with increased mortality. Early diagnosis of DR-TB among PLHIV is key in
reducing TB associated mortality among PLHIV. Health worker must therefore ensure:
v PLHIV are clinically screened for TB at every visit
v PLHIV with TB symptoms are sent for Xpert MTB/RIF assay
v DR-TB patients are tested for HIV
The diagnosis of TB (including RR/MDR-TB and XDR-TB) in PLHIV is more difficult

and may be confused with other pulmonary or systemic infections. The presentation is
more likely to be extra-pulmonary or sputum smear-negative than in TB patients not
infected with HIV, especially as immuno-suppression advances. This can result in
misdiagnosis or delays in diagnosis, and in turn, higher morbidity and mortality
It is important to emphasize the use of clinical criteria and radiography especially for
seriously ill patients, and the prompt utilization of all available investigations including
Xpert MTB/RIF, FL and SL LPA, culture/phenotypic DST4. For patients with CD4 <
100cells/μl or those who are seriously ill, perform urine lateral flow
lipoarabinomannan (LF-LAM) assay where available, PLHIV with LF-LAM positive
result must be sent for Xpert MTB/RIF..
For patients with advanced HIV disease, molecular tests and/or mycobacterial culture
of other fluids (e.g., blood, pleural fluid, ascitic fluid, cerebrospinal fluid, and bone-
marrow aspirates) and histopathology (e.g., lymph node biopsies) may be helpful in
diagnosis4
Consider starting DR-TB treatment even in the absence of bacteriological confirmation

if the clinical evidence and risk factors are strong (clinically diagnosed TB/DRTB)4
Evaluate possible differential or concomitant diagnosis: non-tuberculosis
mycobacterium (NTM), pneumocystis jirovecii pneumonia (PCP), pulmonary Kaposi's
sarcoma, lymphoma, fungal pneumonia, herpes simplex or cytomegalovirus (CMV)
pneumonitis and lymphoid interstitial pneumonitis (LIP in pediatric patients).
77
8.1 Drug-resistant TB and HIV co-treatment
v Antiretroviral therapy (ART) should be started for all the patients living with
HIV and DR-TB, irrespective of CD4 cell counts and viral load. ART
should thus be initiated regardless of CD4 cell count and as soon as
antituberculosis treatment is tolerated, ideally as early as 2 weeks
and not later than 8 weeks after initiation of antituberculosis treatment
v However, for HIV-positive TB patients with profound immunosuppression
(e.g. CD4 counts less than 50 cells/ mm3), they should receive ART
within the first 2 weeks of initiating TB treatment
v If the patient is already on ARVs, request CD4 and viral Load for early
detection of ART failure. If the patient is failing ART, switch to second line ART
without delays (as early as possible).
v There is potential for overlapping, additive toxicities or drug–drug interactions
between some antiretroviral and anti-TB medicines. Adverse events are
frequent in PLHIV (see 6.2)
v Monitoring needs to be more intense to evaluate the response to therapy,
adverse events and IRIS.
8.2 Bedaquiline interactions with ARVs (NNRTI and PIs):

Bedaquiline is metabolized by the CYP3A4. Many drugs can either induce or inhibit the
CYP3A4, resulting in drug–drug interactions. Interaction with CYP3A4 inducers can
lead to loss of efficacy of bedaquiline (due to low blood concentration from increased
metabolism of the drug), and conversely, interaction with strong and moderate
inhibitors of CYP3A4 can lead to higher exposure (higher blood levels) of bedaquiline.
Efavirenz: co-administration with Bdq may result in reduced Bdq exposure and loss of
efficacy as EFV is a moderate inducer of CYP3A activity, hence this is not
recommended Nevirapine: co-administrated with Bdq in HIV-infected patients
has no clinically relevant effect, hence can be co-administered.
Lopinavir/ritonavir and other protease Inhibitors: when co-administered with
Bdq results in increased Bdq plasma concentrations, it is suggested to substitute the PI
with an integrase inhibitor (INSTI), such as dolutegravir (DTG) or raltegravir (RAL). If a
ritonavir-boosted PI must be used, use with caution, perform ECG every 2 weeks for the
first 8 weeks
78
8.3 Use of Bedaquiline and Delamanid with ART
8.3.1 Delamanid: has no interactions with ART and is preferable for PLHIV
eligible for individualized DR-TB treatment regimen containing new drugs.
8.3.2 Bedaquiline can be used in PLHIV taking the following into

consideration:
v Avoid the concomitant use with Efavirenz
v Use with caution with protease inhibitors. If the patient is on second
line ART and there is no access to integrase Inhibitors, PIs can be used
with frequent monitoring of ECG and LFT.
8.4 Use of Bdq with ART:
8.4.1 Patients not yet on ART:

Initiate DTG-based regimen; irrespective of the CD4 count and within 2-8 weeks.
8.4.2 Patients already on ART:

If the patient is already on ART with EFV, assess the viral load:
v If the viral load is undetectable, substitute EFV with DTG during all period of
therapy with Bdq.
v If the viral load is detectable, the patient should be switched to integrase
inhibitors (dolutegravir). If integrase inhibitors are not available or can't be used
in any patient, protease inhibitors (lopinavir/ritonavir) can be considered with
caution (monitoring more frequently ECG and LFT).
If the patient is already on Protease Inhibitors (lopinavir/ritonavir), assess the viral

load:
v If the viral load is undetectable, substitute lopinavir/ritonavir with
dolutegravir during all periods of therapy with Bdq. As soon as Bdq is completed
can be switched back to lopinavir/ritonavir. If integrase inhibitors are not
available continue with lopinavir/ritonavir with caution.
v If the viral load is detectable, the patient should be switched to integrase
inhibitors dolutegravir.
79
8.4.3 Potential overlapping and additive toxicities in the treatment of
DR-TB and HIV
In general, HIV patients have a higher rate of adverse drug reactions (ADRs) to both TB
and non-TB medications, and the risk increases with the degree of immuno-
suppression. Identifying the cause of the adverse event is difficult since many of the
medications used to treat DR-TB and HIV have overlapping or additive toxicities.
When possible, avoid the use of agents with shared toxicity profiles. However, if the
benefit of using drugs that have overlying toxicities outweighs the risk, it is
recommended to increase the monitoring of adverse events rather than disallowing
certain combinations.
80
Table 8 : Potential overlapping and additive toxicities in the treatment
of DR-TB and HIV.
TOXICITY ANTI-TB AGENT ANTIRETROVIRAL COMMENTS
AGENT
Gastrointestinal Eto/Pto, NNRTIs-NVP, If diarrhea, consider opportunistic
(Nausea, vomiting, PAS,Cfz, H, Z, PIs-RTV, infections as the probable cause.
diarrhoea). Bdq, Dlm and NRTIs-AZT, ddI& Persistent vomiting may be due to other
others. d4T causes (e.g., hepatitis, lactic acidosis,
meningitis, pregnancy etc).
Abdominal pain Eto/Pto, All ARVs Abdominal pain may be an early

PAS,Cfz, Lzd symptom of severe adverse drug
reaction such as hepatitis, pancreatitis
or lactic acidosis.
Dermatologic (Skin H, R, E, Z, FQ, NNRTIs:NVP & Do not re-challenge ABC as it can result
rash) Eto/Pto, Cfz EFV; in life threatening anaphylaxis. Do not
NRTI: ABC re-challenge with any agent that may

have caused Stevens Johnson
Syndrome.
Co-trimoxazole can also produce skin

rash.
CNS toxicity and/or Cs, Hh, FQ, Efavirenz (EFV) EFV CNS toxicity often resolve on their
psychiatric Eto/Pto, own after first 2 -4 wee ks of treatment.
symptoms Imipenem Rule out other causes.
(depression, (Imp)/Meropenem
psychosis) (Mpn)
Headache Cs, Bdq AZT, EFV Rule out more serious causes of
headache as meningitis, toxoplasma,
etc.
81
Peripheral Hh, Lzd, (less Stavudine (d4T), Patient receiving H h, Cs and/or Lzd
Neuropathy frequent: FQ , SLI, Didanosine (ddI) should receive prophylaxis with
Cs, Eto/Pto, E) pyridoxine (B6).
Avoid use of d4t and ddi with Cs and

Lzd.
If peripheral neuropathy is due to Lzd
and is grade ≥ 2 stop Lzd and don't
reintroduce.
Renal symptoms SLI (Am, Km, Tenofovir (TDF): Avoid concomitant use of TDF and SLI if
with hypokalemia Cm) Rare possible. Even without the concomitant
use of TDF, PLHIV have an increased
risk of renal toxicity secondary to SLI.
Frequent creatinine and electrolytes
monitoring is recommended. Adjust
medication doses if clearance <30
ml/min.
Hematological Lzd Zidovudine Monitor full blood count monthly when

(Bone Marrow (AZT) using Lzd. All patients with Lzd should
toxicity) receive pyridoxine (Vit B6) 100 mg
daily.
Consider other causes as cotrimoxazole,

HIV infection, opportunistic infections.
Hepatotoxicity Z, H h,Eto/Pto, NVP, EFV, all When ALT/AST are elevated > 5 times
PAS, Bdq NRTIs, all PIs stop both ART and anti TB agents and
restart the TB medication first (see
chapter on adverse event management).
Rule out other causes such as viral

hepatitis (A, B, C) and CMV.
Pancreatitis Lzd d4T, ddI Avoid the use of these agents together.
If an agent caused pancreatitis suspend

it permanently.
82
Optic Neuritis Lzd, E ddI Suspend permanently the agent that
caused optic neuritis and replace it.
Hypothyroidism Eto/Pto, PAS d4T Monitor Thyroid Stimulating Hormone

(TSH) and replace with levothyroxine
when necessary (TSH >10 mIU/l)
Dysglycaemia Gfx, Eto/Pto PIs Eto/Pto can make insulin control in

diabetic patients more difficult
(hypoglycemia and poor glucose
regulation).
Pis can cause insulin resistance and

hyperglycemia.
Arthralgia Z (less frequent PIs Arthralgia is very common with Z, also

FQ and Bdq) reported with FQ, Bdq and PIs.
QT Prolongation Bdq, Dlm, Mxf, ART has been Unknown data on additive effects of
Gfx, Cfz (less associated with Q T combining ART with second line anti-TB
frequently with prolongation drugs for prolonging QTc. If the QTc is
Lfx) prolonged >500ms stop DR -TB Qtc
prolonging drugs but do not stop ART.
83
CHAPTER 9 SUPPLY CHAIN MANAGEMENT SYSTEM OF
DRUG RESISTANT TUBERCULOSIS (DRTB)
9.1 Purpose of Supply Chain Management

The purpose of TB health product supply chain management is to make available
effective, affordable, safe and good quality pharmaceuticals and other health
commodities to all DR-TB patients / presumptive at all time.
9.2 Logistics Management Information System

In every logistic system, information is needed to make informed decisions. The
purpose of a Logistics Management Information System (LMIS) is to collect, organize
and report data that will be used to make logistics decisions.
9.3 Key Data Elements of NTBLCP Logistics System

It includes the following: -
v Opening balance: Stock on hand at the beginning of the reporting period.
v Quantity Received: Amount of stock received within the reporting period.
v Quantity Issued: Amount of stock issued / used within the reporting period.
v Losses and Adjustment; Losses are quantity of stock removed from the
pipeline for any other reason other than consumption by clients (e.g. due to loss,
expiration, damage and breakage etc.). Adjustments are made when quantities
are issued to or received from other facilities.
v Case-Load Adjusted Consumption Data: This is the quantity of
commodities issued to the bench for the specific number of tests within the
reporting period.
9.4 Logistics Records

Three types of records are kept to track logistics activities. The records are: -
v Stock Keeping Records: The primary purpose of stock keeping records is to
document information about items in storage.
v Transaction Records: It documents information about the movement of
commodities from one storage facility to another.
v Consumption Records: They keep information about commodities
consumed / used.
84
9.5 Logistics Management Information System Tools
Utilization of LMIS tools and templates to collect and collate data/reports facilitates
resupplies, quantification, forecasting and shipment of TB products. Some of the tools
used in LMIS are:
v QuanTB; This tool is used for commodity pipeline monitoring, forecasting,
quantification, detection of early warning signs to prevent stock outs and
expiries of TB medicines.
v Stock Card: The stock card is a stock keeping record that keeps information
about the movement and quantity of a product in the facility's storage area.
v Returning and transferring forms: This is a transaction record used to
track medicines and other commodities that are either returned or transferred
between facilities.
v Delivery Voucher: The delivery voucher is a transaction record that
accompany supplies being moved from a higher level to a lower level.
v Medicine Monitoring tool: This reporting tool used by the State TB
program for capturing quarterly information on the utilization of
DRTB medicines as well as patients on treatment.
v DRTB medicine tracker tool: It monitors the daily dispensing of medicines
to patients at the DOTs centres.
v National Electronic Tuberculosis Information Management System
(NETIMS): The medicine module of the NETIMS is used for the collection and
collation of logistic data at all levels. It also has a dash board where the medicine
pipeline can be viewed at a glance
v Laboratory QRRIF: This is used for the collation and reporting of logistic data
of Lab commodities on a quarterly basis.
v Treatment Centre QRRIF: This tool is for the recording and reporting for
DR-TB commodity utilization as well as patient data at the treatment centres.
v Nigeria Health Logistics Management Information System
v (NHLMIS). Is designed for the logistics management of TB medicines, as well
as other diseases (HIV, Malaria, RH and vaccines).
v Pharmacovigilance and aDSM forms: These forms are used for
reporting adverse drug reactions of all anti-TB medicines used in the
program.
85
9.6 Responsibilities of Service Providers in the Management of DR-TB
Commodities.
In always ensuring the availability of medicines the designated service provider in the
facility (Pharmacist, GHW and Laboratory Personnel) must perform the following
functions:
9.7 Receive TB Commodities

v Ensure that all TB commodities are accompanied by a delivery voucher.
v The person responsible must inspect items physically for wholesomeness
(ensuring the commodities are not damaged, soaked or broken).
v Count all items delivered and ensure that the quantity, batch numbers and expiry
date match those in the delivery vouchers before endorsement.
9.8 Entering received items in the Stock Cards

v All items received in the facility must be entered into appropriate stock cards
v Enter the date, batch number, quantity of items received in the appropriate
column and endorse the stock card.
9.9 Storing TB Commodities

Medicines and supplies are kept in the health facility's medicine store and managed by a
designated staff.
9.10 Keep medicines and other supplies safe

v Ensure that store rooms and /or cabinets are locked when not in use.
v Ensure that fire prevention measures are in place.
9.11 Keep the store in good condition
v The temperature of the store room should be kept at room temperature (25 ˚C -
28˚C).
v Storage conditions can be improved by some simple measures such as preventing
direct sun light.
v Maintain adequate humidity and ventilation
v Do not eat, drink or smoke in the store room.
86
9.12 Arrangement of Medicines and supplies in the store
v DR-TB medicines should be placed on the shelves and away from the walls and
floor.
v For all medicines and commodities expiring within six months and which may
not be used within the period, the state logistics officer and TBLS should be
informed for re-distribution or return to the State store.
v When issuing drugs, follow the FEFO rule (First to Expire, First Out).
v Items without expiry date should follow the FIFO rule (First In, First Out).
9.13 Visual inspection of medicines and packaging.

v Look out for the signs of defects in the medicines or packaging while in storage.
v Report and stop issuing medicines whenever there is change in the colour of
tablet or unusual deposit of solids particles in the solution is noticed.
9.12 Issuing of DRTB Commodities
9.14 Use regimen guide correctly to determine dosage and quantities.

Regimen should be based on patient weight. The service provider should classify
the patients based on the correct weight band and determine the correct number
of tablets/blisters required to complete treatment according to treatment
guidelines.
9.15 Recording of Items issued on stock card

v Pick the stock card for the item to be issued.
v Write the date, batch, and quantity of the item to be issued in the appropriate
column.
v When issuing medicines in health facilities the name of the patient should be
entered into column “received from/issued to” column. When issuing items in
State stores, the name of the facility where the item is being issued should be
entered.
v Endorse the stock card.
v Place stock card beside the items.
9.16 Issuing from a Storage facility.

v When items are being issued from a storage facility (National, Zonal or State
87
store) the delivery voucher must be filled and endorsed.
v Ensure a copy of the delivery voucher is kept in the facility.
7.4.5 Returning / Transferring of DRTB Commodities

All items to be returned or transferred must be done using the Return and Transfer
form. Returning and Transferring of commodities is usually done by the 3PLs, LGTBLS,
State logistics officers and treatment centre Pharmacist.
Returning of TB commodities
Medicines and other TB commodities should be returned to facilities where they were
received from (upper level) under the following conditions:
Ÿ Returning of commodity to the upper level of supply chain is determined by the
risk of expiry of the commodity as analysed through the Months of Stock and
Months of Stock Cover.
Ÿ When there is need for the destruction of expired commodities.
Transferring of TB Commodities
Medicines and other commodities could be transferred under the following conditions:
When there is urgent need for the commodity in a neighbouring facility.
ŸWhen there is a risk of expiry and a neighbouring facility has the capacity to utilize
the commodity. The assigned health worker must know how to calculate the Months of
Stock and Months of Stock Cover to determine the risk of expiry.
Filling the Returning and Transferring Form:

Ÿ Enter the name of the facility returning or transferring the items and the facility
receiving it.
Ÿ Enter the date, batch number, expiry date and quantity of items to be returned or
transferred
Ÿ State the reason for returning the item.
Ÿ Endorse the form and keep a copy.
Filling Stock card for Returned or Transferred Items

Ÿ· Pick the stock card for the items to be returned or transferred.
Ÿ Enter the date, quantity, batch number of the returned or transferred items
(Note: quantity transferred or returned should be recorded in the
losses/adjustments column).
Ÿ Endorse the stock card.
Ÿ Place stock card beside the items.
88
7.5 Quarterly Stock Management Activities.
7.5.1 Conducting Physical inventory.

Conducting a physical inventory is compulsory at the end of every quarter. It is however
recommended that a physical count be conducted monthly.
Ÿ Designate a day/period to conduct the physical count in the last week of the
month.
Ÿ On the designated date/period issuing or receiving items must be stopped.
Ÿ Separate usable stock from expired or damaged commodities.
Ÿ Conduct a physical count of all the usable stock and document on the stock card.
7.5.2 Quarterly Rule off on stock cards.

The rule-off is a summary of all the transactions conducted during the quarter on the
stock cards. The quarterly rule off is conducted at the end of every quarter.
ŸEnter date of the rule off.
Ÿ Under the column “Received From/Issue To” write “Quarterly Rule Off”
ŸSum all the quantities received, quantity issued and loses/adjustments during the
quarter and enter under quantity received column, the quantity issued column
and loses/adjustment column respectively.
7.5.3 Reporting and Ordering:

Reporting and ordering is done quarterly using the Quarterly Report Requisition and
Issue Form (QRRIF). The reports must be submitted before the end of the first week in
the new quarter.
7.5.4 Making an Emergency Order

Emergency ordering is initiated to prevent stock out of a particular item. This is
initiated when the stock level falls below one Month of Stock before the end of the
quarter.
Ÿ· The need for emergency supply should be communicated to the LGA supervisor
or the State logistics officer.
Ÿ A neighbouring facility may also be contacted (to initiate process for the transfer
of commodities).
7.6 Determination of Stock Position (How long your stock will last)
Ÿ The health worker should be able to tell how long available medicines in the
89
facilities would last in order to prevent stock outs or expiries.
Ÿ This is done by calculating the Months of Stock (MOS).
Ÿ This can be determined at any point during the quarter.
7.6.1 Calculation of the Months of Stock (MOS)

Ÿ Determine the stock on hand (SOH) by conducting a physical inventory.
Ÿ Divide the SOH by the last quarter average monthly consumption (AMC).
MOS =Stock on Hand
90
Average Monthly Consumption.
Actions to take after calculating MOS:

Ÿ 1 MOS or less = (Emergency) place emergency order immediately
Ÿ 2 MOS or less= (Below Minimum) monitor stock more frequently.
Ÿ 3-5 MOS = (Ok) No action necessary
Ÿ Above 5 MOS = (Over stock) Determine your Month of Stock Cover. If the Month
of Stock Cover is less than the MOS return or transfer the difference.
Ÿ
Months of Stock Cover (MOSC): This is the actual number of months your stock
will last before it expires.
7.6.2 Quality Check (10-Patient Index)

Continuous monitoring of commodity consumption is needed to minimize wastage of
TB medicines. It involves measuring the average number of kits used to treat 10 patients
in a specified period of time called patient index.
The 10-Patient index is mathematically determined by the quantity of kits used in a
specified period divided by number of patients reported within the period multiplied by
10.
Patient index = Quantity of Kits Used x 10

No of patients reported
7.7 Management of the Supply Box

The DR-TB kits used for the treatment of DR-TB patients is designed for patients within
the standard weight band of 55-70kg. However, in situations when the patient is
weight falls outside this weight bands, the need for creation of supply box to provide the
extra medicines becomes necessary.
7.7.1 Creation of supply box

The following steps are to be taken when creating a supply box:
1. Take a full (complete) DR-TB kit from the facility store;
2. Write supply box on the outside of the kit;
3. Separate the content of the kits (adult or paediatric DR-TB) into individual
medicines contained in the kit e.g.Pto/Eto-250mg, Z-400mg, Cs-250mg, Lfx-
250mg, Mfx-400mg, Cfz-100mg, E-400mg, H-300mg, Bdq-100mg, Dlm-
50mg, Lzd-600mg and PAS-4g.
91
4. Medicines remaining from kits of patients who were lost to follow-up, died or
were transferred out should be emptied into the supply boxes.
5. Open a stock card for each medicine in the supply boxes.
6. Excess components of the respective drugs in the supply box should be kitted if
it makes up a kit and returned to the shelf with appropriate adjustment of the
stock cards.
7.8 Kitting and packaging of MDRTB Medicines for community

management
Note that DR-TB medicines supply at the State level, are kitted in accordance with
standard weight as 1-month kit as shown in the table below.
Table 9 Standard Weights of DR-TB Medicines
S/N Regimen Phases Quantities of medicines in a kit
Intensive Bdq-100mg x Mfx-400mg x Cfz-100mg x H-300mg x Pto-250mg E-400mg x Z-500mg

WHO BDQ based 188 tabs 60 tabs 30 caps 60 tabs x 93 tabs 93tabs x 93 tabs
1
regimen
Continuation Mfx-400mg x Cfz-100mg x E-400mg x Z-500mg x
60 tabs 30 caps 93tabs 93 tabs
Bdq-100mg x Lfx-250mg x Cfz 100mg x Lzd-600mg

Intensive
Modified BDQ 188 tabs 93 tabs 60tabs x 30 tabs
2
Based regimen Lfx-250mg x Cfz 100mg x Lzd-600mg
Continuation
93 tabs 60tabs x 30 tabs
Bdq-100mg x Cfz 100mg x Lzd-600mg x Cs-250mg x

Long Oral Pre Intensive
188 tabs 30 caps 30 tabs 60 caps
3 XDR-TB FLQ
resistance Cfz 100mg x Lzd-600mg x Cs-250mg x
Continuation 30 caps 30 tabs 60 caps
Bdq-00mg x Cfz 100mg x Lzd-600mg x Mfx-400mg

Long Oral Pre Intensive 188 tabs 30 caps 30 tabs x 60 Tabs
4 XDR-TB FLQ
suceptible Cfz 100mg x Lzd-600mg x Mfx-400mg
Continuation 30 caps 30 tabs x 60 Tabs
Pead <6yrs Pre

Lzd-600mg x
5 XDR-TB FLQ one phase only Dlm-50mg x Cfz 50mg x Mfx-100mg
30 tabs
Suceptible 120 tabs 30 caps x 60 Tabs
Pead <6yrs Pre
6 XDR-TB FLQ one phase only Dlm-50mg x Cfz 50mg x Lzd-600mg x Cs-50mg x
Resistance 120 tabs 30 caps 30 tabs 60 caps
Bdq100mg x Pa -200mg x Lzd-600mg x
7 one phase only 188 tabs 30 tabs
BPAL 30 tabs
92
7.9 Pharmacovigilance and Active Drug Safety Monitoring and
Management
Pharmacovigilance (PV) is defined as the science and activities relating to the detection,
assessment, understanding and prevention of adverse effects or any other drug-related
problem.
Active TB drug-safety monitoring and management (aDSM) provides for the active and
systematic clinical and laboratory assessment of patients on treatment for new and
repurposed drugs, novel DR-TB regimens to detect, manage and report suspected or
confirmed drug toxicities. The recording and reporting of aDSM primarily target
serious adverse events (SAEs) as a basic requirement (as captured in National aDSM
Guideline).
7.9.1 Responsibilities of stakeholders

The roles and responsibilities of NTBLCP, NAFDAC and other stakeholders in
Pharmacovigilance and aDSM are as follows:
NTBLCP
Ÿ Coordinates all aDSM activities at all levels in Nigeria.
Ÿ Mobilize resources for aDSM activities.
Ÿ Shares data with the NAFDAC (NPC).
Ÿ Shares data related to Bdq and Dlm with the global drug facility (GDF).
Ÿ Receives reports from aDSM expert committee.
Ÿ Liaise with NAFDAC (NPC) and the aDSM expert committee to ensure causality
assessment is done for reported adverse events.
Ÿ Provides feedback to clinicians on report of causality assessment.
NAFDAC (NPC)
ŸReceives and provides feedback on drug safety data to NTBLCP.
ŸAssists NTBLCP in causality assessment and generating signals if necessary.
ŸShares data with global data base (WHO).
aDSM Expert Committee

ŸAnalyses all drug safety data from NTBLCP sources.
ŸAssists NTBLCP in causality assessment.
ŸReports findings and advises NTBLCP and NAFDAC (NPC) accordingly.
ŸEducate patients on rational use of medicines.
ŸEducate and counsel patients on the need to report ADRs and other medicine related
problems.
93
Ÿ Educate healthcare practitioners on pharmacovigilance and aDSM
States DRTB Focal person:

Ÿ Ensure prompt reporting of SAEs on aDSM and other ADR immediately it is
detected.
Ÿ Collect aDSM data and ADR forms from the LGAs.
Ÿ Transmit aggregated aDSM data and ADR forms to the NTBLCP through the zonal
pharmacovigilance centre (ZPC)/NAFDAC (NPC) and zonal meeting of NTBLCP.
LGAs (LGTBLS)
Ÿ Collate aDSM data and ADR forms from the facilities (DOTs, OPD sites and
treatment centres)
Ÿ Transmit aggregated aDSM data and ADR forms immediately to the State TB team
and during the state review meeting.
94
CHAPTER 10: MONITORING AND EVALUATION.
10.1 Role of Monitoring and Evaluation
The supervision, monitoring and evaluation of the programmatic management of DR-
TB in Nigeria is integrated into the National M&E system. It ensures the activities
conducted in management of DR-TB aligns with National guidelines with additional
focus on;
Ÿ Accessibility to laboratory diagnostic services
Ÿ Accessibility to second line anti TB drugs
Ÿ Case finding activities
Ÿ Treatment outcomes
Ÿ Drug utilization
Ÿ DR-TB/HIV related activities
Ÿ Quality of care
10.2 Information flow system

The NTBLCP M&E system starts from the health facility level to the Central Unit of the
programme. The M&E responsibilities at the various levels can be summarized as
follows:
1. At the DOTS clinic level, health staff records presumptive DR-TB cases and
patient information on the Clinic register for Presumptive TB case,
2. LGTBLS enter the information of all diagnosed cases on the DR-TB treatment
register where the unique LGA DR-TB number are generated.
3. LGTBLS will also register all patient information on e-tb manager
4. Decision are made in consultation with the state concilium whether the patient
will initiate treatment in the community or treatment centre
5. DOTS staff will open and enter information on DR-TB treatment card for patient
who initiates treatment in the community
6. DOTS staff will fill a DR-TB treatment supporter card for patients with identified
treatment supporter. Information from the treatment supporter card will be
used to update DR-TB treatment card during each follow-up appointment
7. For patient who opted for treatment at DOTS clinic, treatment card should be
used to update patient information and medicine taken during every visit (no
need for treatment supporter card).
8. LGTBLS will regularly update the DR-TB register with the information recorded
on the DR-TB treatment card
9. For patients who will initiate treatment at treatment centres, LGTBLS will fill
95
DR-TB referral form and send the patient to the nearest treatment centre.
10. DR-TB treatment centre complete the DR-TB treatment register and the e-tb
manager for patients who are treated at the centre.
11. In the event of patient sent to treatment centre without registration number or
referral form, the treatment centre will linkup with state DR-TB focal person,
who will retrieve registration number from the concerned LGTBLS of the LGA
from where the patient was referred.
12. LGTBLS collates all presumptive and diagnosed DR-TB case data into the
quarterly reporting formats and reports to State TBL control programme.
13. The State DRTB focal person regularly validates information on the e-tb
manager and subsequently complete the line list and quarterly statistical
reporting format.
14. The state sends all validated quarterly statistical reports to the M&E unit of the
central unit. (Similarly, the State is expected to collate the statistics of the
treatment centre in the state as part of the State statistical report).
15. State QA officer should fill the quarterly report form on Xpert MTB/RIF.
16. The State DRTB Focal Person and State QA officer must triangulate and
harmonize DR-TB cases diagnosed from the GeneXpert site with those on DR-
TB register on a quarterly basis.
17. The focal person at the reference Laboratory fills the laboratory register for
Culture/DST and send quarterly reports to Laboratory unit of NTBLCP.
18. At the national level, M&E unit collates and analyses all state DR-TB data on
quarterly basis and provides feedback to the states.
96
Figure 9.1: NTBLCP DR-TB DATA FLOW
LABORATORIES
LABORATORIES
Reference LAB
LAB REGISTER FOR AFB &
GENEXPERT MTB/RIF TEST DR-TB TREATMENT REGISTER
LAB REGISTER FOR AFB, Xpert Result Gx Alert DR-TB PATIENT TREATMENT CARD
CULTURE, DST & LPA
DR-TB PATIENT TREATMENT HAND
CARD
QUARTERLY REPORT FORM
FOR GENEXPERT TREATMENT SPECIMEN EXAMINATION
REQUEST FORM FOR TB
CENTRES
DR-TB REFERRAL /DISCHARGE
FORM
DOTS CENTRE LGA TBLS STBLCP NTBLCP
97
CLINIC REGISTER
CLINIC REGISTERFOR FOR tb MANAGER
DR-TB QUARTERLY
PRESUMPTIVE PTB CASES DR-TB TREATMENT CASE REGISTRATION
(FOR DS-TB & DR-TB) REGISTER FORM
DR-TB TREATMENT DR-TB QUARTERLY DRTB INTERIM
REGISTER CASE REGISTRATION OUTCOME FORM
FORM
DR-TB PATIENT TREATMENT DRTB FINAL OUTCOME
CARD DRTB INTERIM FORM FOR DR-TB CASE
OUTCOME FORM
DR-TB PATIENT TREATMENT QUARTERLY REPORT
HAND CARD DRTB FINAL OUTCOME FORM FOR GENEXPERT
FORM FOR DR-TB CASE
DR-TB PATIENT TREATMENT
SUPPORTER CARD E-tb MANAGER E-tb MANAGER
SPECIMEN EXAMINATION
REQUEST FORM FOR TB
10.3 Supervision
Supportive supervision is a way of ensuring staff competence and effectiveness through
observation, discussion, support and on-the-job training.
1. Supervision of DR-TB should be integrated into the existing supervision at
community, LGA, state and national levels.
2. Members of DR-TB Concilium will provide periodic mentoring, supervision and
mortality review to DR-TB program at all levels in collaboration with STBLCP.
3. The national reference Laboratory will conduct supportive supervision to zonal and
other laboratories.
4. Zonal reference laboratories will conduct supportive supervision to the state
reference laboratories
5. State reference laboratories will conduct supportive supervision to the peripheral
laboratories.
10.4 Programme Monitoring

Monitoring is very essential in a programme if a good outcome is required, hence the
following must be considered.
1. The concilium of experts meet quarterly and when the need arises to review difficult
cases.
2. The National DR-TB committee will meet quarterly to review the programme,
DR-TB issues will also be discussed at quarterly planning cell meeting
10.5 DR-TB Programme Indicators

Indicators are pointers in a programme which indicates if a programme is performing
well or not. The following indicators are used for PMDT monitoring and evaluation in
the NTBLCP.
9.5.1 DR-TB Case Notification indicators

Ÿ Proportion of presumptive DR-TB cases examined using rapid tests according to
the national diagnostic algorithm
Ÿ Proportion of DR-TB cases (Rifampicin Resistant TB) diagnosed using rapid
tests according to the national diagnostic algorithm
Ÿ Proportion of Rifampicin Resistant TB cases (RR-TB) that were confirmed to be
MDR-TB cases
Assessment is tracked using NTBLCP programmatic indicators defined in Table below:
98
Table 10. 1: DR-TB case Notification indicators
S/N Indicator Description Formula Source/Freq.

E-tb manager/
Total number of all presumptive Numerator: Total number of all NTBLCP quarterly
DR-TB cases tested using WHO presumptive DR-TB cases tested using
DR-TB case
1 approved rapid diagnostic tests WHO approved rapid diagnostic tests.
Proportion (%) of among total number of Denominator: Total number of finding reports
all presumptive presumptive DR-TB cases presumptive DR-TB cases notified
DR-TB cases tested notified. over the same period. Reported quarterly
E-tb manager/
Numerator: Total number of all DR- NTBLCP quarterly
Total number of all DR-TB (RR- TB (RR-TB) cases diagnosed using
DR-TB case
TB) cases diagnosed using rapid rapid tests according to the national
2 tests according to the national diagnostic algorithm. finding reports
Proportion (%) of diagnostic algorithm among Denominator: Total number of
all DR-TB (RR-TB) total number of presumptive presumptive DR-TB cases examined Reported
cases diagnosed DR-TB cases examined. over the same period. quarterly
Numerator: Total number of all DR- E-tb manager/
Total number of all DR-TB (RR- TB (RR-TB) cases confirmed to be
NTBLCP quarterly
TB) cases confirmed to be MDR- MDR-TB cases using culture/DST or
TB cases using culture/DST or LPA according to the national DR-TB case
3 finding reports
Proportion (%) of LPA according to the national diagnostic algorithm.
all DR-TB (RR-TB) diagnostic algorithm among Denominator: Total number of DR-
cases confirmed to total number of DR-TB (RR-TB) TB (RR-TB) cases examined over the Reported
be MDR-TB cases cases examined. same period. quarterly
9.5.2 DR-TB Enrolment for care Indicators

Ÿ Proportion of diagnosed DR-TB cases started on treatment
Ÿ Proportion of DR-TB cases started on treatment in the community
Ÿ Proportion of DR-TB (RR-TB) cases started on treatment and eventuall
confirmed MDR-TB cases.
99
Table 10.2: Case holding Indicators for DR-TB
Total number of diagnosed Numerator: Total number of e-tb manager/

NTBLCP DR-TB
DR-TB (RR-TB) cases started diagnosed DR-TB cases started on quarterly case
Proportion (%) of on second-line anti-TB second-line anti-TB treatment finding reports
1
diagnosed DR-TB treatment among total Denominator: Total number of
cases started on number of diagnosed DR-TB diagnosed DR-TB) cases notified Reported
treatment cases notified. over the same period. Quarterly
Numerator: Total number of
e-tb manager/
Total number of DR-TB (RR- diagnosed DR-TB cases started on NTBLCP DR-TB
Proportion (%) of TB) cases started on second- second-line anti-TB treatment in quarterly case
2 DR-TB cases line anti-TB treatment in the the community finding reports
started on community among total Denominator: Total number of
treatment in the number of DR-TB cases DR-TB (RR-TB) cases started on Reported
community. started on treatment. treatment over the same period. Quarterly
Numerator: Total number of DR-

Total number of DR-TB (RR- TB (RR-TB) cases started on
Proportion (%) of TB) cases started on second- second-line anti-TB treatment and
e-tb manager/
DR-TB (RR-TB) line anti-TB treatment and eventually confirmed to be MDR- NTBLCP DR-TB
3 cases started on eventually confirmed to be TB case quarterly case
treatment and MDR-TB case among total Denominator: Total number of finding reports
eventually number of DR-TB cases DR-TB cases started on second-line
confirmed MDR- started on second-line anti- anti-TB treatment over the same Reported
TB cases. TB treatment. period. Quarterly
9.5.3 Indicators at the end of intensive phase (Interim outcome)

Ÿ Proportion of DRTB cases started on second-line anti-TB treatment with a
negative culture result at the end of Intensive phase of treatment
Ÿ Proportion of DRTB cases started on second-line anti-TB treatment but died at
the end of intensive phase of treatment
Ÿ Proportion of DRTB cases started on second-line anti-TB treatment but lost to
follow-up at the end of intensive phase of treatment
Ÿ Proportion of DRTB cases started on second-line anti-TB treatment but not
evaluated at the end of intensive phase of treatment
Ÿ Proportion of DRTB cases started on second-line anti-TB treatment & had test
done but culture result not available at the end of intensive phase of treatment
Ÿ Proportion (%) of culture positive RR/MDR-TB cases initiated on DR-TB
treatment later found not to have RR/MDR-TB by the end of intensive phase
of treatment
100
Table 10.3: Case holding Indicators for DR-TB
S/N Indicator Description Formula Source

Proportion (%) of Numerator: Total number of culture
culture positive Total number of culture positive positive DRTB cases started on
DRTB cases started DRTB cases started on second- second-line anti-TB treatment with a E-tb manager/
on second-line line anti-TB treatment with a negative culture result at the end of NTBLC DR-TB
anti-TB treatment negative culture result at the end intensive phase of treatment quarterly
with a negative of intensive phase of treatment Denominator: Total number of interim reports
culture result at the among total number of culture culture positive DRTB cases started on
end of intensive positive DRTB cases started on second-line anti-TB treatment over the Reported
1 phase of treatment second-line anti-TB treatment same period. Quarterly
Total number of culture positive Numerator: Total number of culture
Proportion (%) of DRTB cases started on second- positive DRTB cases started on
culture positive line anti-TB treatment with no second-line anti-TB treatment with no E-tb manager/
DRTB cases started culture result due to death at the culture result due to death at the end NTBLCP DR-
on second-line end of intensive phase of of intensive phase of treatment TB quarterly
anti-TB treatment treatment among total number Denominator: Total number of interim reports
who died at the end of culture positive DRTB cases culture positive DRTB cases started on
of the intensive started on second-line anti-TB second-line anti-TB treatment over the Reported
2 phase of treatment treatment same period. Quarterly
Numerator: Total number of culture
Proportion (%) of Total number of culture positive positive DRTB cases started on
culture positive DRTB cases started on second- second-line anti-TB treatment with no
DRTB cases started line anti-TB treatment with no culture result due lost to follow-up at E-tb manager/
on second-line culture result due lost to follow- the end of the intensive phase of the NTBLCP DR-
anti-TB treatment up at the end of intensive phase treatment TB quarterly
who was lost to of the treatment among total Denominator: Total number of interim reports
follow-up at the number of culture positive culture positive DRTB cases started on
end of intensive DRTB cases started on second- second-line anti-TB treatment over the Reported
3 phase of treatment line anti-TB treatment same period Quarterly
Numerator: Total number of culture
Proportion (%) of Total number of culture positive positive DRTB cases started on
culture positive DRTB cases started on second- second-line anti-TB treatment with no
DRTB cases started line anti-TB treatment with no culture result because case was not E-tb manager/
on second-line culture result because case was evaluated at the end of intensive phase NTBLCP DR-
anti-TB treatment not evaluated at the end of of the treatment TB quarterly
who was not intensive phase of the treatment Denominator: Total number of interim reports
evaluated at the among total number of culture culture positive DRTB cases started on
end of intensive positive DRTB cases started on second-line anti-TB treatment over the Reported
4 phase of treatment second-line anti-TB treatment same period Quarterly
Proportion (%) of Numerator: Total number of DRTB
DRTB cases started Total number of DRTB cases cases started on second-line anti-TB
on second-line started on second-line anti-TB treatment & had test done but culture E-tb manager/
anti-TB treatment treatment & had test done but result not available at the end of NTBLCP DR-
& had test done but culture result not available at the intensive phase of treatment TB quarterly
culture result not end of intensive phase of Denominator: Total number of interim reports
available at the end treatment among total number DRTB cases started on second-line
of intensive phase of DRTB cases started on anti-TB treatment over the same Reported
5 of treatment second-line anti-TB treatment period Quarterly
Proportion (%) of Total number of culture positive Numerator: Total number of culture
culture positive RR/MDR-TB cases initiated on positive RR/MDR-TB cases initiated E-tb manager/
RR/MDR-TB cases DR-TB treatment later found not on DR-TB treatment later found not to NTBLCP DR-
initiated on DR-TB to have RR/MDR-TB by the end have RR/MDR-TB by the end of the TB quarterly
treatment later of the intensive phase of intensive phase of treatment interim reports
found not to have treatment among total number Denominator: Total number of
RR/MDR-TB by of RR/MDR-TB cases started on RR/MDR-TB cases started on second- Reported
6 the end of the second-line anti-TB treatment line anti-TB treatment over the same Quarterly
101
9.5.4 Indicators at the end of treatment
Ÿ Proportion of DR-TB cases cured (cure rate)
Ÿ Proportion (%) of DR-TB cases declared treatment completed (treatment
completion rate)
Ÿ Proportion (%) of DR-TB cases successfully treated (treatment success rate
Ÿ Proportion (%) of DR-TB cases that failed treatment (treatment failure rate)
Ÿ Proportion (%) of DR-TB cases that died (death rate)
Ÿ Proportion (%) of DR-TB cases loss to follow-up (lost to follow-up rate)
Ÿ Proportion (%) of DR-TB cases not evaluated (not evaluated rate)
Ÿ Proportion (%) of DR-TB cases still on treatment (still on treatment rate)
102
Table 10.4: Treatment outcomes indicators for DR-TB cases

E-tb manager/
Numerator: Total number of DR-TB NTBLCP
Total number of DR-TB cases quarterly DR-
cases initiated on 2nd line anti-TB
initiated on 2nd line anti-TB TB preliminary
Proportion (%) of treatment that was cured at the end of
treatment that was cured at the & final
DR-TB cases cured treatment
1 end of treatment among total treatment
Denominator: Total number of
(cure rate) number of culture positives outcome
culture positives cases initiated on 2 nd
cases initiated on 2nd line anti- reports
line anti-TB treatment over the same
TB treatment
period.
Reported
quarterly
E E-tb
Numerator: Total number of MDR- manager/
Total number of MDR-TB cases NTBLCP
TB cases initiated on 2nd line anti-TB
Proportion (%) of initiated on 2nd line anti-TB quarterly DR-
treatment that were declared
DR-TB cases treatment that were declared TB preliminary
treatment completed at the end of the
declared treatment treatment completed at the end & final
2 treatment
completed of the treatment among total treatment
(treatment number of culture positives outcome
completion rate) cases initiated on 2nd line anti- reports
TB treatment.
period.
Reported
quarterly
E-tb manager/
Total number of DR-TB cases Numerator: Total number of DR-TB NTBLCP
initiated on 2nd line anti-TB cases initiated on 2nd line anti-TB quarterly DR-
Proportion (%) of treatment that were cured plus treatment that were cured plus those TB preliminary
DR-TB cases those declared treatment declared treatment completed at the & final
3 successfully treated completed at the end of end of treatment treatment
(TB treatment treatment among total number Denominator: Total number of outcome
success rate) of culture positives cases culture positives cases initiated on 2 nd reports
initiated on 2nd line anti-TB line anti-TB treatment over the same
treatment. period. Reported
quarterly
E-tb
manager/
NTBLCP
Total number of DR-TB Numerator: Total number of DR- quarterly
Proportion (%)
cases initiated on 2nd line TB cases initiated on 2 nd line anti- DR-TB
of DR-TB cases
anti-TB treatment that TB treatment that failed preliminary
that failed
4 failed treatment among treatment Denominator: Total & final
treatment
total number of culture number of culture positives cases treatment
(treatment
positives cases initiated on initiated on 2nd line anti-TB outcome
failure rate)
2nd line anti-TB treatment. treatment over the same period. reports
Reported
quarterly
103
E-tb manager/
NTBLCP
Numerator: Total number of DR-TB
Total number of DR-TB cases quarterly DR-
cases initiated on 2nd line anti-TB
initiated on 2nd line anti-TB TB preliminary
treatment that died from any cause
Proportion (%) of treatment that died from any & final
while on treatment
5 DR-TB cases that cause while on treatment among treatment
died (death rate) total number of culture positives outcome
cases initiated on 2nd line anti- reports
TB treatment.
period. Reported
quarterly
E-tb manager/
NTBLCP
Total number of DR-TB cases Numerator: Total number of DR-TB quarterly DR-
initiated on 2nd line anti-TB cases initiated on 2nd line anti-TB TB preliminary
Proportion (%) of
treatment that was lost to treatment that was lost to follow-up. & final
DR-TB cases loss to
6 follow-up among total number Denominator: Total number of treatment
follow-up (lost to
of culture positives cases culture positives cases initiated on 2 nd outcome
follow-up rate)
initiated on 2nd line anti-TB line anti-TB treatment over the same reports
treatment. period.
Reported
quarterly
E-tb manager/
NTBLCP
Numerator: Total number of DR-TB quarterly DR-
Total number of DR-TB cases
cases initiated on 2nd line anti-TB TB preliminary
Proportion (%) of initiated on 2nd line anti-TB
treatment that was not evaluated. & final
DR-TB cases not treatment that was not evaluated
7 Denominator: Total number of treatment
evaluated (not among total number of culture
culture positives cases initiated on 2 nd outcome
evaluated rate) positives cases initiated on 2 nd
line anti-TB treatment over the same reports
line anti-TB treatment.
period.
Reported
quarterly
E-tb manager/
Total number of DR-TB cases Numerator: Total number of DR-TB NTBLCP
Proportion (%) of initiated on 2nd line anti-TB cases initiated on 2nd line anti-TB quarterly DR-
DR-TB cases still treatment that are still on treatment that are still on treatment. TB preliminary
8 on treatment (still treatment among total number Denominator: Total number of & final
on treatment rate) of culture positives cases culture positives cases initiated on 2 nd treatment
initiated on 2nd line anti-TB line anti-TB treatment over the same outcome
treatment. period. reports
104
THE RECORDING AND REPORTING TOOLS
The NTBLCP DR-TB information system is based upon, and is an extension of, the
basic DOTS information system.
The comprehensive collection of recording and reporting tools are listed below.
NTBLCP Recording tools for Drug Resistant TB activities

Laboratories register for
Each time specimen
AFB smear Results of
DR-TB is sent for exams at
microscopy/culture and smear/Culture and Laboratory
01 the AFB/Culture &
drug susceptibility DST
DST lab.
testing (DST)
Each time a DR-TB
Details of patient. patient is being
DOTS facility/
DR-TB DR-TB Patient Details of facility referred or
DR-TB Treatment
02 Referral/Transfer Form referring, and transferred from one
centre
facility discharged to service point to
another.
Patients primary
DOTS facility/ Each time a DR-TB
DR-TB DR-TB Patient information,
DR-TB treatment Case is being enrolled
03 Treatment Card treatment records
centre for treatment.
and progress
Patients details of
DR-TB Patient daily intake of LGA/DOTS Each time a DR-TB
DR-TB
appointment/Hand drugs, follow-up lab facility/DR-TB Case is being enrolled
04
Card results, details of treatment centre for treatment.
referring sites
105
Patients primary
DOTS facility/DR- Each time a DR-TB
DR-TB DR-TB Treatment information,
TB treatment Case is being enrolled
05 Register treatment records
centre for treatment.
and progress
Each time a DR-TB
Discharge form (from
DR-TB Patient’s treatment DR-TB treatment patient is being
DR-TB Treatment
06 and referral details. centre discharged from the
centre to DOTS Facility)
treatment centre.
Laboratory Tracking DOTS facility/
DR-TB Log Book for Samples Movement status of Laboratory/anywh When moving
07 sent for Culture and specimen ere sputum is samples
DST for Reference being moved from
106
NTBLCP Reporting tools for Drug Resistant TB activities
Details of all DRTB cases
DRTB 08 DRTB Quarterly Line diagnosed and enrolled in a Quarterly
listing quarter LGA/State
Quarterly Report on
DR-TB 09 DR-TB Case Enrolment Details of DR-TB Case LGA/State/ Quarterly
report Notification Zonal/ National
Details of patient culture &
DR-TB 10 DRTB Interim DST result after intensive LGA/State/ Quarterly
Outcome Assessment phase of treatment Zonal/ National
Annual Report of
107
Treatment Outcome of
DR-TB 11 Annually
patients on second line Details of patient treatment LGA/State/
treatment outcome at end of treatment Zonal/ National
Summary of all referrals and
DR-TB 12 Treatment Centre enrolments at treatment Treatment Quarterly
Trackers centres Centres only
Monitors the daily issues of
DR-TB 13 DRTB Medicine medicines to patients at the Facility/Treatm Daily
Tracker DOT centre ent centre
References
1. WHO. Companion handbook to the WHO guidelines for the programmatic

management of DR-TB. 2014, updated 2015 and 2016.
2. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant
tuberculosis treatment 2020
108
ANNEXES
STANDARD OPERATING PROCEDURES FOR DOSAGING
ANDADMINISTRATION OF PAEDIATRIC FORMULATIONS OF
SECOND-LINE TUBERCULOSIS MEDICINES
A. SECOND LINE ANTI TB DRUG FORMULATIONS
FORMULATIONS DRUGS TAB/ CAP/GEL STRENGTH (mg)

Dispersible Tablets Ethionamide 125
Isoniazid 100
Levofloxacin 100
Moxifloxacin 100
Linezolid 150
Pyrazinamide 150
Ethambutol 100
Capsule/tabs Cycloserine 125, 250
Clofazimine 50,100
Bedaquiline 100
Delamanid 50
109
B. HOW TO ADMINISTER THE DISPERSIBLE TABLETS AND CAPSULES
(ETHIONAMIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID,
MOXIFLOXACIN, PYRAZINAMIDE, ETHAMBUTOL AND
CYCLOSERINE)
I. Weigh the child and select the number of tablet(s) or capsule(s) for each
medicine according to child's weight.
II. For each medicine, add the appropriate number of tablet(s) or capsule(s) to 10ml
of water. For cycloserine, open and empty the contents of the capsule
and dissolve in water.
III. Rock gently until it is completely dissolved (dissolves in one minute)
IV. Once reconstituted, give an amount of mixture equivalent to the dosage for the
child immediately
V. Discard the left-over mixture.
VI. Educate the caregiver on the need for adherence
VII. Medicines should be given immediately it is constituted; do not reconstitute and
keep for subsequent use
VIII. Do not dissolve more than one type of medicine in the same container at the same
time.
IX. Storage of these medicines at home should be at room temperature or less than
25 0 Medicines should be prescribed in line with National Drug-Resistant TB
Guidelines.
110
How to administer the medicines
Step 1: Select the Step 2: Dissolves Step 3: Rock gently

appropriate number in water or (Dissolves
of tablet(s) other liquids’ immediately)
111
Step 4: Give the A Healthy Happy
child immediately TB-Free Child!!!
C. DOSING OF MEDICINES USED IN SECOND-LINE REGIMENS
BY WEIGHT BAND IN PATIENTS UNDER 15 YEARS
No. of tabs or volume (mls) by weight bands for children less than 15 years olda
Weight based
Group Medicine Formulation
daily doseb >34
5-6 kg 7-9 kg 10-15 kg 16-23 kg 24-30 kg 31-34 kg
kg
100 mg dt 1 tab 1 and ½ tabs 2 or 3 tabs 3 or 4 tabs * *
Levofloxacin 15-20 mg/kg *

1 or
112
½ ½ 1 and ½ or 2
250 mg tab 1 and ½ 2 tabs 3 tabs
tabs
tab Tab Tabs
¾ tabs 1 and ½
100 mg dtc 2 tabs 3 tabs 4 tabs
Moxifloxacin 10-15 mg/kg (8mls) Tabs

A.
* *
400 mg tabc
15 mg/kg daily
in ≤16 kg, 20 mg/ml susp 4 ml 6 ml 8 ml 11ml 14 ml 15 ml
10–12 mg/kg
Linezolid
daily in >16 kg
600 mg tabc ¼ ¼ ¼ ¼ ¼ ¼
Tab Tab Tab tab Tab Tab
113
50 mg cap or tab 1 tab on M/W/F 1 tab on M/W/F 1 tab on M/W/F 1 tab 2 tabs 2 tabs
Clofazimine 2-5 mg/kg
100 mg cap or tab M/W/F M/W/F 1 alt days 1 alt days 1

*
Cycloserine or
15-20 mg/kg 125 mg mini capsule 1 cap 1 cap 2 caps 3 caps 4 caps
terizidone
1 tab on 1 tab on
50 mg cap or tab 1 tab on M/W/F 1 tab 2 tabs 2 tabs
M/W/F M/W/F
Clofazimine 2-5 mg/kg
100 mg cap or tab M/W/F M/W/F 1 alt days 1 alt days 1

*
114
125 mg mini capsule 1 cap 1 cap 2 caps 3 caps 4 caps
Cycloserine or
15-20 mg/kg
terizidone
*
250 mg cap 4-5 mlc 5-6 mlc 7-10 mlc 2 caps 2 caps 2 caps
100 mg dt 1 tab 2 tabs 3 tabs 4 tabs - -
Ethambutol 15-25 mg/kg
1 or 1 and ½
C 400 mg tabc
115
3 mlc 4 mlc 6 mlc 1 tab Tab 2 tabs
Delamanid - 50 mg tab
- -e -e -e 1bd 1bd
2
Tabs
150 mg dt 1 tab 3 tabs 4 or 5 tabs - -
Pyrazinamide 30-40 mg/kg

¾ 1 tab or
400 mg tab ½ tab or 2 tabs 2.5 tabs 3 tabs
Tab 1 and ½ tab *
½ ½ ¾ tab 1 and ½ 2 and ½

500 mg tab
116
tab Tab or 1 tab tabs 2 tabs Tabs
Imipenem -
0.5 g + 0.5 g vial
Cilastatin
- - - - - - - -
20-40 mg/kg iv
Meropenem 1 g vial (20 ml) 2 ml 4 ml 6 ml 8-9 ml 11 ml
every 8 hours
Amikacin 15-20 mg/kg 500 mg/2 ml vialf 0.4 ml 0.6 ml 0.8-1.0 ml 1.2-1.5 ml 2.0 ml
*
Streptomycin 20-40 mg/kg 1 g vialf Calculate according to the dilution used

*
125 mg dt
1 tab 1 tab 2 tabs 3 tabs 4 tabs 4 tabs
Ethionamide or (ethionamide)
15-20 mg/kg *
prothionamide
½ ½
250 mg tab 1 tab 2 tabs 2 tabs 2 tabs
Tab Tab
PAS acid (4 g) sachet 0.5-0.75 g b d 0.75-1 g b d 1-2 g b d 2-3 g b d 3-3.5 g b d
117
p-aminosalicylic 200-300 mg/kg in
acid 2 divided doses
*
PAS sodium salt (4

0.5-0.75 g b d 0.75-1 g b d 1-2 g 2-3 g b d 3-3.5 g b d
g) sachet
*Refer to
PAS sodium salt (4 g)
0.5-0.75 g b d 0.75-1 g b d 1-2 g 2-3 g b d 3-3.5 g b d - the Adult
sachet
dose
b d *
PAS sodium salt 60% 8-12 g b

1.5 g b d 2-3 g b d 3-4 g 4 or 6 g b d 6 or 8 g b d 8-12 g b d -
(9.2 g) sachet d
b d *
PAS sodium salt 8-12 g

1.5 g b d 2-3 g b d 3-4 g 4 or 6 g b d 6 or 8 g b d 8-12 g b d
60% (9.2 g) sachet bd
bd
50 mg/5 ml soln 8-10 ml 15 ml 20 ml - - -
15-20 mg/kg
Isoniazid
(high dose) 1 and
118
½ tab *
100 mg tab 1 tab 2 tabs 3 tabs 4 tabs 4 tabs
250 mg
amoxicillin/62.5
Clavulanic acidh - 2 ml bdh 3 ml bdh 5 ml bdh 8 ml bdh 10 ml b dh * *
mg clavulanic
acid/5 ml susph
D. DOSAGE BY WEIGHT BAND FOR MEDICINES USED IN SECOND LINE
REGIMENS, ADULTS AND CHILDREN OLDER THAN 14 YEARS
Weight Usual
Weight bands for patients older than 14 yearsa
based upper
Medicine Formulation Comments
Group daily >70 daily
30-35 kg 36-45 kg 46-55 kg 56-70 kg
dose kg doseb
4
250 mg tab 3 tabs 3 tabs 4 tabs 4 tabs
tabs
1and 1and
½ ½ 2
Levofloxacin -c 500 mg tab 2 tabs 2 tabs 1.5 g
tab tab tabs
750 mg tab 1 tab 1 tab 1 tab 1 tab 1 tab
Standard 400
119
400 mg tab 1 tab 1 tab 1 tab 1 tab 1 tab
dosec,d mg
as used in
1 tab or
1 and 1 and the
1and ½
A standardized
shorter
Moxifloxacon tab ½ ½ RR/MDR-
High 2 800
400 mg tab 2 tabs TB regimen
dosec,d tabs mg
tab Tab
or 2 tabs
4 tabs daily for the first 2 weeks; then 2 tabs daily 400
Bedaquiline -c 100 mg tab
M/W/F for 22 weeks. mg
*Refer to the
Linezolid -c 600 mg tab * * 1 tab 1 tab 1 tab 1.2 g Paediatric
dose
50 mg cap or tab 2 tabs 2 tabs 2 tabs 2 tabs 2 tabs 100 mg
Clofazimine -c
100 mg cap or
B 1 tab 1 tab 1 tab 1 tab 1 tab 100 mg
tab
Cycloserine or 10-15
250 mg cap 2 tabs 2 tabs 3 tabs 3 tabs 3 tabs 1g
terizidone mg/kg
15-25
Ethambutol 400 mg tab 2 tabs 2 tabs 3 tabs 3 tabs 3 tabs -
mg/kg
Delamanid -c 50 mg tab 2bd 2bd 2bd 2bd 2bd 200 mg
20-30 400 mg tab 3 4 4 4 5

Pyrazinamide
mg/kg
120
500 mg tab 2 3 3 3 4
Imipenem-
-c 0.5 g + 0.5 g vial 2 vials (1 g + 1 g) bd -
C Cilastatin
Meropenem -c 1 g vial (20 ml) 1 vial 3 times per day or 2 vials b d -
15-20 500 mg / 2 ml
Amikacin 2.5 ml 3 ml 3 to 4 ml 4 ml 4 ml 1g
mg/kg viale
12-18
Streptomycin 1 g viale Calculate according to the dilution used 1g
mg/kg
Ethionamide or 15-20
250 mg tab 2 tabs 2 tabs 3 tabs 3 tabs 4 tabs 1g
prothionamide mg/kg
8-12 g/day PAS sodium salt

1bd 1bd 1bd 1bd 1 to 1.5b d
p-aminosalicylic in 2 -3 (4 g) sachet
12 g
acid divided
PAS acid (4 g) 1 to 1.5 b d
doses 1bd 1bd 1bd 1bd
sachet
2/3 of
4-6 mg/kg
121
tab
(standard 300 mg tab 1 tab 1 tab 1 tab 1 tab
(200
dose)d
mg)
Isoniazid -
1 and 1 and
10-15 ½ ½
mg/kg 300 mg tab tab Tab 2 tabs 2 tabs 2 tabs
(high dose)d
Clavulanic acidg -c 125 mg tabg 1bd 1bd 1bd 1bd 1bd -

NOTES/EXPLANATIONS:
Alt = alternate; bd = two times a day; cap = capsule; dt = dispersible tablet; g = gram; im
= intramuscular; iv = intravenous; kg = kilogram; ml = millilitre; mg = milligram;
M/W/F = Monday, Wednesday, Friday; soln = solution; susp = suspension; tab =
tablet.
a. Dosages were established by the Guideline Development Group for the WHO
treatment guidelines for rifampicin- and multidrug-resistant tuberculosis, 2018
update and the WHO Global task force on the pharmacokinetics and
pharmacodynamics (PK/PD) of TB medicines and other experts.
b. They are based on the most recent reviews and best practices in the treatment of
MDR/RR-TB. For certain agents the dosages were informed by pharmacokinetic
modelling results based on the principle of allometric scaling (Anderson BJ, Holford
NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev
PharmacolToxicol 2008; 48:303–32). Due to the pharmacokinetic properties of
certain medicines, the doses proposed may exceed the mg/kg/day ranges shown here
in order to achieve blood concentrations similar to target levels in an average adult
patient. In patients >30 kg follows the schedule for >14 year olds unless otherwise
indicated.
c. If multiple dose options are given for one weight band select the lower or higher
option depending on whether the patient is at the lower or higher limit of the body
weight range. Dosing more closely to the target mg/kg/day should be aimed for, and is
more feasible with oral or parenteral fluids and when solid forms of different dosage
are available. Fractioning of tablets into halves or less should be avoided if possible.
Therapeutic drug monitoring is advised when the dose is at the upper and lower ends of
the range to minimize the adverse therapeutic consequences of over- and under-
exposure respectively (especially for injectable agents, linezolid and
fluoroquinolones).
122
d. Clinicians may decide to exceed these values in particular cases to improve
therapeutic effect.
e. Dissolving in 10 ml of water may facilitate administration in patients in lower

weight-bands and avoids fractioning solid formulations, although bioavailability is
uncertain (use of dispersible tablets is preferred if available).
f. In individuals >44 kg a dose of 600 mg od is proposed.
g. May be used in children 3 - 5 years of age. Giving half of a 50 mg adult tablet in

these children does not result in the same blood levels observed in trials using the
special 25 mg paediatric tablet. Bioavailability may further be altered when the 50 mg
tablet is split, crushed or dissolved.
h. Weight-based daily dose is for 6 or 7 days/week administration (M/W/F

scheduling may permit higher dosing). Volumes shown may differ by preparation.
Streptomycin may be diluted in three different ways. Dosing closer to the upper limit of
the mg/kg/day is more desirable. For IV use, the volume may be increased.
i. Kanamycin and capreomycin are no longer recommended while

amoxicillin/clavulanic acid is used as a companion agent.
j. Only available in combination with amoxicillin as co-amoxyclav. Only to be used

with carbapenems, in which case they are given together, e.g. 125 mg b d or 125 mg 3
times daily in the 24 - 30 kg weight band.
123

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National DR-TB Guidelines - 2021

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FEDERAL MINISTRY OF

NATIONAL GUIDELINES FOR CLINICAL AND

(PMDT GUIDELINES – 3RD EDITION)

Management of DR-TB is an evolving strategy and needs to be adapted through

Dr. Osagie E. Ehanire MD, FWACS

We want to acknowledge the immense support, financially and technically by the

AFB - Acid Fast Bacilli

SN FULL NAME ORGANIZATION

1 ABOKI Danjuma PM-STBLCP Nasarawa

3 ADETIBA Temitayo IHVN

4 AHMAD Muhammad Ozi NTBLCP

5 ALHASSAN Shuaibu NTBLCP

6 AKPAKPAN Rita NTBLCPS

7 AMIN Jamila NTBLCP

8 ALI Taofeekat IHVN

9 ANAGO Chux CHAI

10 ATIKU Abubakar Chika NTBLCP

12 BABAWALE Adekunle Victor NTBLCP

13 CHIJIOKE-AKANIRO Obioma NTBLCP

14 DUNGA Amos Jacob ATBTH BAUCHI

15 DUTT Saswata IHVN

16 ELOM Emeka NTBLCP

19 FALOKUN Victor KNCV Nigeria

20 ITOHOWA Uko NTBLCP

21 KIFASI Rimamtswab Ephraim NTBLCP

22 LAWAL Umar ABUTH ZARIA

23 LAWANSON Adebola NC-NTBLCP

25 MGBEMENA Chiagozie IHVN

26 MOBOLAJI Raji NTBLCP

27 MOSES Grace Olabisi NTBLCP

29 NWAFOR Dozie CHAI

30 OCHEI Kingsley Chinedum MEASURE EVALUATION

31 ODUME Bertrand KNCV Nigeria

32 ODUSOTE Temitayo USAID

33 OSMAN eltayeb DFB

36 OMONIYI Amos Fadare WHO

5.1 Factors Affecting Adherence........................................................................45

5.2 Poor Adherence............................................................................................46

5.4 Management of Treatment Interruption.....................................................47

6 Monitoring of Drug Resistant Tuberculosis Treatment ...........................48

6.1 Monitoring Progress of Treatment .............................................................48

6.2 Monitoring Adverse Events.........................................................................50

6.3 Clinical monitoring of adverse drug reactions (ADRs) .............................. 51

6.4 Educational, Psychological, and Social Consultation ................................51

6.5 Laboratory monitoring of AEs ...................................................................51

6.6 Severity grading scale of adverse events and main

2.1 ORGANISATION OF LABORATORY SERVICES

2.2 DIAGNOSIS OF DRUG-RESISTANT TUBERCULOSIS

Bacteriological diagnosis is the gold standard for diagnosing DRTB. However, in

2.2.2. Bacteriological diagnosis

s/n TYPE OF TEST DIAGNOSIS TURNAROUND TIME

4 Liquid Culture PTB & EPTB 2 – 3 weeks (Negative 6 – 7 weeks)

NOTE: Sequencing for resistance pattern will be utilized.

Figure 1: Diagnostic Algorithm of presumptive TB

ALL PERSONS WITH SYMTOMS OF TB

Classify as: Drug Resistance

Send specimen for 1st & 2nd

2.2.3 Approach to discordant Results:

I. Xpert MTB/RIF: MTB detected but culturenegative.

v The culture positive result should be considered as bacteriological

III. Xpert MTB/RIF: MTB detected, rifampic inresistance detected but

Follow-up actions include: