TECHNICAL GUIDE OF

TREATMENT FOR PATIENT WITH DRUGS RESISTANCE TB

IN SHORT-TERM STANDARD ALLOWS
IN HEALTH CARE FACILITIES FOR DRUGS RESISTANCE TB

MINISTRY OF HEALTH OF THE REPUBLIC OF INDONESIA

DIRECTORATE OF GENERAL PREVENTION AND DISEASE CONTROL
2017

i | Technical Guidance of Medical Treatment of Short Term Standards

 DRAFTING TEAM

Referrer : H. Mohammad Subuh, dr, MPPM

Person in charge : Wiendra Waworuntu, dr, M.Kes
Editor : Asik Surya, dr, MPPM

Contributors:

1. Andriansyah, MSi, M.Biomed, PhD 26. Retno Kusuma Dewi, dr, MPH
2. Anis Karuniawati, dr, SpMK, PhD 27. Roni Chandra, M.Biomed
3. Ayu Hartini Pramadyani, dr 28. Sardikin Giri Putro, dr, SpP(K)
4. Bintang YM Sinaga, M.Ked, SpP(K) 29. Setiawan Jatilaksono, dr
5. Delyana Bangun, Dra, MM 30. Siti Asfijah Abdoelllah, SSi, Apt
6. Dina Frasasti, SKM 31. Soedarsono, Dr., dr, SpP(K)
7. Endang Lukitosari, dr, MPH 32. Suharna, SKM, MPH
8. Erlina Burhan, Dr., dr, SpP(K), MSc 33. Sulistyo, M.Epid
9. Fathiyah Isbaniah, dr, SpP, M.Pd.Ked 34. Thomas Handoyo, dr, SpPD(K)
10. Hanifah Rizky Purwandini Sugiarto, SKM 35. Tiar Salman, ST, MM
11. Indra Yovi, dr, SpP 36. Tiara Verdinawati, SKM
12. Koesprijani, dr, SpPK 37. Tintin Farihatini, drg, MScPH
13. M. Arifin Nawas, dr, SpP(K), MARS 38. Triana Yuliarsih, SKM
14. Mikyal Faralina, SKM 39. Wawaimuli Arozal, dr, M.Biomed
15. Murni Naibaho, dr 40. Yani Jane Sugiri, dr, SpP
16. Nafrialdi, dr, SpPD, PhD 41. Yulita Evarini, dr, MARS
17. Neni Sawitri, dr, SpP 42. Yusie Permata, dr, MIH
18. Nur Ani, SKM, M.Kes
19. Nurjannah, SKM, M.Kes
20. Parluhutan Siagian, dr, SpP(K)
21. Pompini Agustina, dr, SpP
22. Prayudi Santoso, dr, SpPD-KP, M.Kes
23. Purwantyastuti, Prof., Dr., dr, MSc, SpFK
24. Rahma Handari, Apt
25. Rena Titis Nur Kusumawardani, SKM

ii | Technical Guidance of Medical Treatment of Short Term Standards

 Contents

Drafting team .............................................................................. Error! Bookmark not defined.

Contents…………………………………………………………………………………………………...E
rror! Bookmark not defined.
List of Tables .............................................................................. Error! Bookmark not defined.
List of Figures ............................................................................. Error! Bookmark not defined.
List of Appendix .......................................................................... Error! Bookmark not defined.
Preface...………………………………………………………………………………………………….E
rror! Bookmark not defined.
list of Abbreviation ....................................................................... Error! Bookmark not defined.
CHAPTER I
Preliminary .................................................................................. Error! Bookmark not defined.
CHAPTER II
Diagnostic Algorithm for TB........................................................................................................ 3
CHAPTER III
A. Treatment Algorithm of Drug Resistance TB ......................................................................... 6
B. Alloy Treatment of Short Term Standards and The Ways of Giving .................................. 8
C. Dosage of Tuberculous Drugs on Short-Term Standards Alloy ......................................... 9
D. Administering Guidance ............................................................................................................ 9
CHAPTER IV ...............................................................................................................................
Initial Inspection and Treatment Monitoring ...............................................................................11
A. Initial Inspection and Treament Progress............................................................................. 11
B. Information and Education Counseling................................................................................. 13
C. Supervision of Drug Ingestion and Treatment Support ...................................................... 13
CHAPTER V ................................................................................................................................
Side Effects Management of Short-Term Standards Treatment AlloyError! Bookmark not
defined.
CHAPTER VI
Treatment for Patients with Irregular Meducal Treatment ..........................................................21
CHAPTER VII ..............................................................................................................................
End Result of Treatment of Drug TB RO ..................................................................................23
CHAPTER VIII .............................................................................................................................
Monitoring Drug Side Effects Integratedly ................................... Error! Bookmark not defined.
A. Stages of Monitoring Activity of Drug Side Effects ............................................................. 25
B. Algorithm of Information and Data......................................................................................... 29
CAHPTER IX ...............................................................................................................................
Monitoring and Evaluation .........................................................................................................30
APPENDIX.................................................................................. Error! Bookmark not defined.
REFERENCE ............................................................................................................................32

iii | Technical Guidance of Medical Treatment of Short Term Standards

 List of Tables

Table 1. Drugs On Short Term Standards Guide........................................................................ 8

Table 2. Antituberculous Drugs Dosage Based on Weight ......................................................... 9
Table 3. Initial Examination and During Treatment ....................................................................12
Table 4. Side Effects of Drugs Management .............................................................................15
Table 5. Drug Interaction...........................................................................................................19
Table 6. Reporting Schedule .....................................................................................................30

iv | Technical Guidance of Medical Treatment of Short Term Standards

 List of Pictures

Picture 1. Recent Tuberculosis Diagnosis Algorithm in Indonesia Based on Minister of Health

Regulation no. 67 years 2016
Picture 2.The algorithm of TB treatment alloys for patient with drug resistance TB in Indonesia
Picture 3. Implementation Structure of MESO-active drug resistance TB
PIcture 4. Algorithm of Information and Data

v | Technical Guidance of Medical Treatment of Short Term Standards

 List of Appendix

Appendix 1 Serious Unwanted Event Monitoring Form

Appendix 2 Drug Side Effects Form
Appendix 3 Medical Monitoring Form (Short-Term Alloy)
Appendix 4 Medical Monitoring Form (Individual Alloy)
Appendix 5 Patient Information Sheet
Appendix 6 Informed Consent

vi | Technical Guidance of Medical Treatment of Short Term Standards

 Preface

Thanks to the Almighty God that for Him we can finish the Technical Guidance of Medical
Treatment of Drug Resistance TB Patients with Short-Term Alloys in Drug Resistance TB
Healthcare Facilities.
Along with the increasing number of TB case findings in Indonesia today, what needs
attention is the emergence of cases of drug-resistant TB among tuberculosis cases as a result of
inadequate treatment and transmission of drug-resistant TB patients. One of the challenges in
the management of drug resistant TB is that every year there is an increase in the number of
cases of patients dropping out of treatment. This is due to the relatively long treatment of drug
resistant TB (20-24 months) accompanied by various side effects felt by the patient.
By 2016, WHO issues recommendations on short-term (9-11 months) use of alloys for
drug-resistant TB patients. The recommendations are based on research results in some
countries that have used a short-term treatment mixture, have a satisfactory success rate of
treatment. Therefore, with the combination of short-term treatment is expected to increase the
success rate of treatment and reduce the number of medication treatment of drug resistant TB
patients in Indonesia.
This technical manual is addressed to all health care facilities that perform treatment in
drug-resistant tuberculosis patients in Indonesia. This book is expected to guide the management
of drug resistant TB patients, especially for short-term treatment alloys.
To all those who have played an active role in the preparation of this technical manual,
we thank and appreciate the dedication and contribution of your thoughts. Hopefully this
technical guidance can provide positive benefits in control for TB in Indonesia.

Jakarta, August 2017

Director General of Disease Control
and Health Environmental (PP & PL)

dr. H. Mohammad Subuh, MPPM

NIP 19620119198902100

vii | Technical Guidance of Medical Treatment of Short Term Standards

 List of Abbreviation

AP Akhir pengobatan / Final Treatment

BPOM Badan Pengawasan Obat dan Makanan / Drug and Food Supervisory
Agency
BTA Batang tahan asam / Acid Resistant Bacteria
DM Diabetes melitus
DST Drug-susceptibility test (Uji kepekaan obat)
EKG Elektrokardiografi / Electrocardiography
FQ Fluoroquinolone
HIV Human immunodeficiency virus
INH Isoniazid
KIE Komunikasi informasi edukasi / Communication information and
education
KTD Kejadian tidak diinginkan / Unwanted event
ESO Efek samping obat / Drug side effect
LFU Loss to follow up (putus berobat)
LPA Line probe assay
MDR Multidrug-resistant
MESO Monitoring efek samping obat / Drug side effect monitoring
MTB Mycobacterium tuberculosis
MTPTRO Manajemen Terpadu Pengendalian Tuberkulosis Resistan Obat /
Integrated Management of Tuberculosis Control Drugs
NIK Nomor Induk Kependudukan / ID Population Number
OAINS Obat antiinflamasi non-steroid / Non-steroid anti inflamation drugs
OAT Obat antituberkulosis / Antituberculous drugs
P2P Pencegahan dan Pengendalian Penyakit / Disease Control and
Prevention
PMO Pengawas Menelan Obat / Drug Ingestion Supervisor
RO Resistan obat / Drug Resistant
RR Resistan Rifampisin / Rifampisin Resistant
RS Rumah sakit / Hospital
SLI Second line injection (Obat injeksi lini kedua)
TAK Tim ahli klinis / Team of clinical experts
TB Tuberkulosis / Tuberculosis
TCM Tes cepat molecular / Molecular rapid test
WHO World Health Organization
XDR Extensively drug-resistant

viii | Technical Guidance of Medical Treatment of Short Term Standards

 CHAPTER I
Preliminary

Integrated Management of Tuberculosis Drug Resistance Control (MTPTRO) has been

implemented in Indonesia since 2009. In that year, only Persahabatan Hospital and dr. Soetomo
Hospital became the reference hospital for drug resistant TB (TB RO). In its development,
Treatment service for TB RO is now available in 34 provinces in Indonesia.
Each year there is an increase in the number of RO TB cases found and treated. However,
along with the development of services, there was a decline in the success rate of treatment, from
67.9% in 2010 to 51.1% in 2013, and the increase in loss-to-follow-up (LFU) from 10.7% (2009)
to 28.7% (2013).
By 2015 there are an estimated 10.4 million TB case incidents worldwide, of which
580,000 are MDR / TB RR cases. From an estimated 580,000 cases of TB RO only 125,000 were
found and treated. WHO estimates that about 190,000 TB RO patients will die as there is no
access to effective TB RO treatment services. The current TB RO management in the world
requires a long period of time (at least 20 months), costly, both for the program and the patient.
Worldwide RO TB surveillance data also show unsatisfactory results in the success rate of
treatment with a long-term standard alloy, which is about 50% (WHO Global TB Report 2016).
In May 2016 WHO issued recommendations for the use of a standard 9-11 month short-
term standard treatment for three groups of patients, namely: Rifampicin resistant (RR) or MDR-
resistant TB patients with second-line anti-tuberculosis drugs; Or in patients with less likely
resistance; Or proven to be non-resistant to fluoroquinolones and second-line injectable drugs.
This recommendation is based on the results of studies from various observational studies on the
use of short-term treatment alloys in several Asian and African countries (Bangladesh, Benin,
Burkina Faso, Burundi, Cameroon, Central Africa, Congo, Niger, Swaziland and Uzbekistan)
Treatment with short-term standard alloys reached 84% (95% CLs: 79% - 87%) compared with
the treatment success rate using a long-term standard alloy which only reached 62% (95% CLs:
53% -70%)].

1 | Technical Guidance of Medical Treatment of Short Term Standards

 The National TB Control Program will implement short-term treatment for TB RR / MDR in
accordance with WHO recommendations as an effort to improve treatment enrollment, reduce
loss to follow up rates and improve treatment success rate for TB RO patients in Indonesia. In
principle, TB RO treatment in Indonesia consists of a combination of short-term standards and
individual alloys. Short-term standard alloys are given for eligible RR / MDR TB patients, whereas
individual alloys are administered to pre- / XDR TB patients and MDR TB patients under certain
conditions.

This Technical Guidance focuses on the treatment of TB RO with

short-term standard alloys. Matters related to other MTPTRO that not
covered in this book may refer to MTPTRO technical guidance book of
2014 and Addendum of MTPTRO technical guidance of 2016.

2 | Technical Guidance of Medical Treatment of Short Term Standards

 CHAPTER II
Diagnostic Algorithm for TB

Picture 1. Recent Tuberculosis Diagnosis Algorithm in Indonesia Based on Minister of Health

Regulation
Gambar 1.no. Alur
67 years 2016 TB terbaru di Indonesia berdasarkan Permenkes No. 67 tahun 2016
diagnosis

Susp. TB

3 | Technical Guidance of Medical Treatment of Short Term Standards

Algorithm explanation:

A. Princple diagnosis of TB:

1. Diagnosis of Pulmonary TB in adults should be established first with bacteriological
examination, which means a microscopical examination, molecular TB rapid test (TCM)
and culture.

2. TCM examination is used to ensure TB diagnostic, while monitoring of treatment progress

is still done with microscopic examination.

3. It is not justified to diagnose TB only by examining chest X-rays only. Chest X-rays do not
always give a specific picture of pulmonary TB, which can lead to overdiagnosis or
underdiagnosis.

4. It is not justified to diagnose TB by serological examination.

B. Enforcement of diagnosis based on health care facilities

1. Health care facilities that has the tool for TCM:

a) Health care facilities who have access to TCM examination, A definite diagnosis on
suspected TB is done by TCM examination. Under conditions where TCM testing is
not possible (eg TCM equipment exceeds inspection capacity, TCM equipment is
damaged, etc.), TB diagnostic enforcement is performed by microscopic examination.

b) If TB suspects are suspected TB RO group and suspected TB with HIV positive, should
still be attempted for TB diagnosis with TCM by referring to the nearest molecular rapid
test service either by referring the patient or the sample test.

c) The number of sputum samples required for TCM examination are 2 (two) with good
quality. One sample test for TCM examination, one sample test for temporary storage
and will be checked if necessary (eg. on indeterminate results, on the Rif Resistance
results in suspect of tuberculosis with no criteria of suspec of TB RO, On result of Rif
Resistance the sputum will be sent to LPA Laboratory for Line-2 Sensitivity test).

d) Examples of non-sputus test that can be examined with MTB / RIF consist cairan
serebrospinal (Cerebro Spinal Fluid/CSF), jaringan biopsy (tissue biopsy), bilasan
lambung (gastric lavage), and aspirasi cairan lambung (gastric aspirate).

e) Patients with Rifampicin Resistance MTB outcome but not derived from TB RO
suspected criteria should be re-examined with TCM. If there is a difference in outcome,
then the last TCM check result becomes the reference for the next action.

f) If the TCM results are indeterminate, re-exam with TCM. If the results remain the
same, give 1st line treatment for TB, do culture and sensitivity test

g) Standard treatment of MDR TB is immediately given to all RR TB patients, without

waiting for the results of the sensitization test of OAT line 1 and line 2 to come out. If
resistance results show MDR, continue MDR TB treatment. If there is additional

4 | Technical Guidance of Medical Treatment of Short Term Standards

 resistance to other OATs, treatment should be adjusted to the OAT susceptibility test
results.

h) Examination of sensitivity test using LPA (Line Probe Assay) Line-2 method or by
conventional method

i) Treatment of pre-XDR / TB XDR TB using standard TB alloys for pre-XDR or XDR TB

or using new drug alloys.

j) Patients with negative Mtb TCM results, should perform chest X-ray examination. If
the chest X-ray image supports TB and upon physician's consideration, the patient
may be diagnosed as a clinically confirmed TB patient. If the chest X-ray image does
not support TB, possibly it is not TB, another possible cause should be sought.

a) Health care facilities that do not have the equipment for Rapid molecular test

b) Health care facilities that do not have TCM equipment and difficulty accessing TCM,
TB diagnostic enforcement can be done using a microscope.

c) Number of sputum test samples for microscope examination are 2 (two) with good
quality. Test samples may come from Sputum at anytime for both or 1 at the Morning
and 1 at anytime.

d) Acid Resistant Backteria (BTA) (+) is if one or both of the sputum test samples show
the result of a positive smear examination. Patients who demonstrate the result of BTA
(+) on the first sputum examination, the patient may be immediately concluded as a
patient with BTA (+)

e) BTA (-) is if both sputum samples show negative smear results. If the microscopic
examination is negative, TB diagnosis can be performed clinically using the results of
clinical examination and advanced examination (at least the examination of chest X-
ray) as appropriate and determined by the physician.

f) If the microscopic examination is negative and does not have access to referrals
(radiology / TCM / culture) then do a broad spectrum antibiotic therapy (Non OAT and
Non quinolone) first for 1-2 weeks. If there is no clinical improvement after
administration of antibiotics, patients should be assessed for TB risk factors. Patients
with high TB risk factors can be diagnosed as Clinical TB. Risk factors for TB were:

- Proven contact with TB patients

- There is comorbid disease such as: HIV, DM

- Living in areas at risk of TB such as: prisons, refugee shelters, slums, etc.

5 | Technical Guidance of Medical Treatment of Short Term Standards

 CHAPTER III
Principle of Short Term Standards Treatment
A. Drug Resisten TB Treatment Algorithm
Picture 2. Algorithm of TB treatment alloys for TB RO in Indonesia

Suspected TB

Rapid Molecular Test

(TCM)

Negative MTB Sensitive Rifampisin TB Resistant rifampicin TB (RR)

Send specimen to 2nd line DST

Penatalaksanaan Pengobatan TB dengan (2nd line LPA or DST culture)
yang sesuai OAT lini pertama Start Treatment After evaluating
criteria below

Criteria for TB RO Short-term Standard Alloy

1. There is no evidence of resistance to
fluoroquinolone / second-line injectable drugs
2. No contact with TB patients pre / XDR
3. Never receive any second line OAT for ≥ 1 month
4. There is no intolerance to drugs in standard short-
range alloys
5. Not pregnant
6. Not extra pulmonary TB case
7. There is no risk of unfavorable outcome *

Matching the Criteria Did not Match the

Criteria

Paduan standar
TB RO Treatment Alloy Paduan individual
jangka pendek

Sensitive / tolerance Resistant / Resistant / Sensitive / tolerance against

Guidance changes intolerance against F
against FQ and or intolerance against FQ and or SLI
based on: SLI Q and or SLI
FQ and or SLI
 2nd line DST result
 Drug Tolerance CONTINUE the CHANGE to individual CONTINUE individual CONTINUE individual alloy
short-term alloy alloy alloy while consulting TAK for any
possible alloy according to DST
result and clinical condition

6 | Technical Guidance of Medical Treatment of Short Term Standards

Algorithm explanation:
 For all RR TB patients, takes three (3) good quality test samples, one (1) test sample for second-
line LPA and two (2) sputum examination for culture and sensitivity testing.
 If there is no risk of intolerance and / or resistance to fluoroquinolone (FQ) and / or second-line
injectable drugs (SLI) based on anamnesis and / or sensitivity test results, the patient will start
short-range standard alloy treatment.
 If there is a risk of intolerance / resistance to FQ and / or SLI based on anamnesis, sensitivity
test, or risk factors for poor treatment outcomes (such as severe TB), patients should be given
individual alloys.
 When the sensitivity test results out, the treatment alloy should be re-evaluated, with the
following 5 options:
1. For patients who have obtained short-term standard alloys and sensitivity test resulting of
no resistance to FQ / SLI, short-term standard alloy treatment may proceed.
2. For patients who have received a short-term standard alloy and the sensitivity test results
indicate additional resistance to FQ / SLI, the patient's treatment should be changed into
individual alloys based on sensitivity test (treatment started from the beginning).
3. For patients who have received individual alloys and are confirmed to be resistant to FQ /
SLI based on sensitivity test results, individual alloy treatment is continued.
4. For patients who receive individual alloys based on consideration of intolerance to FQ / SLI,
alloys should be reevaluated and adjusted (if required) based on sensitivity test results.
5. For patients who obtain individual alloys but are not proven to be resistant to FQ / SLI based
on sensitivity test results, The treatments are continued in consultation with the Team of
clinical experts (TAK) for possible alteration changes based on sensitivity test results and
clinical conditions patients do not change to standard short-term alloys when already
receive treatment with individual alloy > 1 month.
 *Included in the unfavourable outcome is the elongation of QTcF> 500 ms waves; Increased
SGOT-SGPT> 5x normal levels, creatinine clearance <30 cc / min, severe TB disease (multiple
cavities, extensive pulmonary parenchymal damage).
 In cases of Kanamycin intolerance (eg, sensory hearing loss, impaired renal function, impaired
balance, pregnancy during treatment), Kanamycin may be replaced by Kapreomycin at the
same dose as Kanamycin.

7 | Technical Guidance of Medical Treatment of Short Term Standards

 1. Treatment of short-term standards is given to patients with RR / MDR TB who
meet all of the above criteria. If any of the criteria are not met then the patient
will receive an individualized treatment alloy.

2. The National Program will start implementing the short-term standard treatment
by 2017. RR / MDR TB patients who meet all the inclusion criteria for short-term
alloys, but because the drugs are not available then the patients are receiving
long-term standard treatment. During the transition period, patients who have
undergone long-term standard treatment for ≤1 months may be considered for
continuing treatment with standard short-range alloys when short-term standard
alloying drugs are available.

B. Alloy Treatment of Short Term Standards and The Ways of Giving

1. Here is the alloy of standard short-term treatment:

4–6 Km – Mfx – Eto (Pto) – HDT – Cfz – E – Z / 5 Mfx – Cfz – E – Z

Table 1. Drugs On Short Term Standards Guide

Initial Stage Advanced Stage

(Administered every day for 4-6 (Administered every day for 5
months) months)

1. Kanamisin (Km) 1. Moxifloxacin (Mfx)

2. Moxifloxacin (Mfx) 2. Clofazimin (Cfz)
3. Etionamid (Eto) / Protionamid (Pto) 3. Etambutol (E)
4. Isoniazid (H) dosis tinggi (DT) 4. Pirazinamid (Z)
5. Clofazimin (Cfz)
6. Etambutol (E)
7. Pirazinamid (Z)

8 | Technical Guidance of Medical Treatment of Short Term Standards

C. Dosage of Tuberculous Drugs on Short-Term Standards Alloy
The dose of the drug based on weight grouping can be seen in the following table:

Tabel 2. Antituberculous Drugs Dosage Based on Weight

Dosage Based on Weight

Drugs
<33 kg 33 – 50 kg >50 – 70 kg >70 kg
Kanamycin* 0,5 g 0,75 g 0,75 g 1g
Moxifloxacin 400 mg 600 mg 800 mg+ 800 mg+
Clofazimin 50 mg 100 mg 100 mg 100 mg
Etambutol 600 mg 800 mg 1000 mg 1200 mg
Pirazinamid 750 mg 1500 mg 2000 mg 2000 mg
IsoniazidDT** 300 mg 600 mg 600 mg 900 mg
Etionamid 500 mg 500 mg 750 mg 1000 mg
Protionamid 500 mg 500 mg 750 mg 1000 mg

*) Kanamycin is given a maximum of 0.75 g for patients> 45 years of age. If kanamycin

can not be administered, it can be replaced with Kapreomycin at the same dose.
**) Especially for INH, patients with weight 33-40 kg were given 450 mg; > 40 kg given 600
mg.
+)
In administering of Mfx the need to anticipate is the prolonged of QTc> 500 ms;
Treatment should be initiated in the MTPTRO referral hospital and a more rigorous ECG
monitoring is performed at the beginning of treatment.

D. Administering Guidance:
1. Patients will receive short-term standard alloy treatment for at least 9 months, consisting
of 4 months of initial stage and 5 months of advanced stage.
2. In the initial stages, oral and injectable medications are administered daily (7 days,
Monday to Sunday) for 4 months and in advanced stages, oral medications are
administered daily (7 days, Monday to Sunday).
3. In circumstances where no BTA conversion occurs at the 4th month, the initial stage is
extended to 6 months so the duration of total treatment becomes 11 months (6 months
initial stage and 5 months advanced stage). In the 5th and 6th months, injection drugs are
administered 3x a week (intermittent) and oral medications are still administered daily (7
days, Monday to Sunday).
4. If there is no BTA conversion in the 6th month, then therapy with short-term standard
alloys is stopped and treatment results will be recorded as "failed treatment". Patients are
referred to the RO TB reference health care facility for further evaluation and treated with
individual alloys.
5. The choice of Etionamid or Protionamid depends on the availability of the drug program.
6. All doses of treatment should be administered under the direct supervision of the Drug
Swallowing Supervisor (PMO).

9 | Technical Guidance of Medical Treatment of Short Term Standards

 7. Patients who receive short-term standard alloys with no complication are strongly
recomended to continue the treatment at the nearest health care facility according to the
patient's residence. The steps of decentralization of the patient based upon the
procedures of the MTPTRO guidance that have been applied.

Conversion is that if BTA smear examination 2 (two) times in a row with 30

day inspection distance shows negative result.
Reversion is that if BTA smear examination back to positive on 2 (two)
consecutive examination after conversion has been achieved before.

E. Decentralization of Services
Patients with TB RO who start their treatment at referred hospital or health care
facilities for TB RO, can decentralize the service to health care facilities satellite.
Decentralization of services is intended to bring the TB RO treatment service closer to the
nearest health care facilities according to the patient's residence so that the patient can
complete the treatment. The referral process for the decentralization of patients from referred
hospital or health care facilities for TB RO to Health care center / health care facilities satellites
is done with prior preparation. Communication between referred hospital or health care
facilities for TB RO with Health care center / health care facilities satellites is done routinely in
order to a problems related to patient treatment can be anticipated and acted upon quickly.
District / Provincial Health Offices coordinate and provide the facilitation in the process of
patient decentralization.

10 | Technical Guidance of Medical Treatment of Short Term Standards

 BAB IV
Initial Inspection and Treatment Monitoring

A. Initial Inspection and Treament Progress

Before starting standard short-term treatment, a baseline should be followed:
1. Anamnesis
2. Physical / clinical examination (weight)
3. Sputum examination : BTA, culture, sensitivity test
4. ECG
5. Hearing test
6. Vision test
7. Chest X-ray
8. Complete blood check
9. Fasting and 2 hours after load glucose check
10. Renal function: Ureum And Creatinin
11. Electrolyte
12. Liver function: SGOT, SGPT, bilirubin
13. TSH/TSHs
14. Pregnancy test
15. HIV test
Short-term treatment is initiated up to 7 days after the diagnosis of RR / MDR TB is concluded,
without having to wait for all initial preliminary results. Preliminary checks that must be present
before starting the treatment are ECG, renal function, liver function, and pregnancy test.
During the treatment, various checks were also conducted to monitor the progress of
treatment. Examination and schedule of treatment monitoring can be seen in the following
table:

11 | Technical Guidance of Medical Treatment of Short Term Standards

 Table 3. Initial Examination and During Treatment

Month of Treatment
Initial stages for 4 month Advanced stages for
Examination (can be extended to 6 month) 5 month
0 1 2 3 4 5 6 7 8 9
0 1 2 3 4 5 6 7 8 9 10 11
Anamnesis √ √ √ √ √ √ √ √ √ √ √ √
Physical / clinical
examination √ √ √ √ √ √ √ √ √ √ √ √
(weight)
BTA sputum √ √ √ √ √√* √√* √√* √ √ √√*
Culture of sputum √ √ √ √ √ √ √ √ √ √
Second line LPA √
Sensitivity test √ √**
ECG+ √ √ √ √ √ √ √ √ √ √ √ √
Hearing test*** √
Vision test++ √
Chest X-ray √ √ √ √
Complete
√
blood***
Fasting and 2
hours after load √
blood glucose***
Ureum-creatinin
√ √ √ √ √ √ √
serum
Electrolyte √ √ √ √ √ √ √
SGOT, SGPT,
Total of Bilirubin √
***
TSH/TSHs √
Pregnancy test*** √
HIV test*** √

Explanation:
*) BTA examination is done every month by collecting 1 (one) morning sputum. In the 4th, 5th,
6th month and end of the treatment, BTA is tested from two (2) consecutive morning sputum.
At a later stage, BTA smear and culture examination are performed every 2 months (on months
5, 7 and 9 or 7, 9, and 11 months)
**) Sensitivity testing for second-line OAT will be repeated if the BTA smear results is positive
at month 6 or BTA reverse occurs or culture on advanced stage.
***) Examination may be repeated as indicated (if required)
+)
ECG are performed at baseline, 2nd day, 7th day, and 1st month of treatment and as
indicated; Conducted at the referral hospital

12 | Technical Guidance of Medical Treatment of Short Term Standards

 ++)
The vision test that is done are color blind test and a simple visual field
Notes:
Microscopic examination (BTA), culture and sensitivity tests are performed in a certified
referral laboratory. BTA results are informed and entered into the eTB manager within a
maximum of 3 days.

B. Information and Education Counseling

Health counseling, information, education (KIE), and motivation activities to drug-resistant TB
patients and family members of patients about the disease and the need for regular treatment
to completion are very important. This activity is provided to all patients and family members
at all levels of health care facilities.
KIE begins since the patient arrives as a suspected TB RO and during the patient's treatment
to completion. Before starting the treatment, patients are asked to sign an informed consent,
including changes to the alloy (duration of treatment) that may occur if there is additional
resistance based on sensitivity test or treatment response.
KIE on symptoms of side effects of treatment should also be done before the patient initiates
short-term standard treatment because there is a possibility that the patient will discontinue
treatment (lost to follow-up) without informing the TAKs or health care facility attendant when
treatment side effects arise.

C. Supervision of Drug Ingestion and Treatment Support

All drugs should be ingested under direct supervision and recorded by trained drug ingestion
supervisors (PMO) (health care workers or other trained personnel) in TB RO health care
facilities as well as in the community during the advanced stages. Psychosocial support is
given during treatment to improve treatment success.
A PMO and a treatment companion should be identified for each patient. Some of the
responsibilities that can be done by PMO are:
 Supervising for patient’s drug ingestion
 Observing the side effects
 Managing patient\s treatment card
 Contact the patient if they do not come for treatment on schedule and coordinate with the
Health Office in patient tracking
 Ensure the suitability of drug alloys and doses, as well as the availability of patient drugs
During the course of treatment patients should have a treatment companion, ie from peer
educators or trained cadres. treatment companion are tasked to provide support and
motivation to patients in order to ensure continuity of treatment to completion.

13 | Technical Guidance of Medical Treatment of Short Term Standards

 CHAPTER V
Side Effects Management of Short-Term Standards Treatment Alloy

Monitoring of drug adverse events is important during TB RO treatment. All OATs used
for the treatment of RR / MDR TB patients have the possibility of mild, moderate or severe side
effects. Healthcare workers should always monitor the adverse effects and provide management
as soon as possible. Handling good and adequate side effects is the key to successing the
treatment.
1. The principle of monitoring the side effects during treatment:
a. Early detection of side effects during treatment are very important because the faster it is
found and handled, the prognosis will be better. For that, monitoring of the side effects of
treatment should be done daily.
b. The side effects of OAT are related to the doses administered.
c. The symptoms of side effects of treatment should be known to the health care workers
who handle the patient and also by patients and their families.
d. All of the side effects of the treatment experienced by the patient should be recorded in
the adverse treatment form.

2. Place for side effect management:

a. TB RO health care facilities, TB RO referred health care facilities and helath care facilities
satellites become a place for management of the side effects of treatment, depending on
the severity of the symptoms.
b. Mild to moderate side effects can be handled by physician on TB RO health care facilities
satellites and need to be reported to TB RO / referred TB RO health care facilities
c. Patients with severe side-effects and patients who do not show improvement after
receiving treatment for mild or moderate side effects should be referred immediately to the
TB RO / referred TB RO health care facilities.

3. The various adverse effects of MDR OAT and its management are described in the following
table (Table 4):

14 | Technical Guidance of Medical Treatment of Short Term Standards

 Table 4. Side Effects of Drugs Management

Side Effect OAT Treatment Strategy Annotation

1. Teratogenic Pto, Km Pto and Km should not be used during If an injectable drug
pregnancy so that short-term standard can not be avoided
alloys are not given for pregnant women. during the first
Pregnant women with TB RO will get an trimester of
individual alloy. pregnancy, Cm can be
used to replace Km.
Consideration from
Gynecologist (Sp.OG)
are needed in
handling the case of
TB RO with
pregnancy.
2. Heart Mfx, Cfz 1. Perform ECG monitoring regularly or The TAKs need to
impairment more strictly if there is any indication involve a competent
2. 2. Discontinue the treatment of Mfx physician in the
and CFz when elongation of QTc> assessment of cardiac
500 ms problems.
3. Referring to TAK on referred TB RO
health care facilities
3. Peripheral H, Km, Eto 1. Treatment of short-term standards The sustainability
neuropathy continues. decision of INH is
2. Administer the vitamin B6 up to 200 based on the results
mg per day. of TAK consultations
3. Reduce the INH dose by ¼ to 1/3 of and expert physicians
the original dose. related.
4. Consult a neurologist in case of
severe neuropathy symptoms (pain, Provision of vitamin
difficulty walking) B6 doses above
200mg / day will
interfere with INH
absorption.
4. Hearing Km 1. Check the baseline data to ensure Hearing loss is a
Impairment that hearing loss is caused by OAT or common, so
as a worsening of pre-existing hearing documenting baseline
loss.
hearing results is
2. Refer the patient immediately to the
TB RO health care facilities / TB RO important.
referred health care facilities to Kapreomycin may be
examining the cause and consulting considered to replace
the TAKs. Kanamycin due to its
3. 3. If the treatment are late the hearing more severe side
loss can develop into a persistent effects than
deafness.
Kanamycin.

15 | Technical Guidance of Medical Treatment of Short Term Standards

 4. Evaluate hearing loss and get rid of
other causes such as ear infections,
ear plugs, trauma, etc.
5. Consider replacing the drug or
treatment alloy based on the TAK
decision .
5. Depression H, Mfx, 1. Do group or individual counseling. Some patients require
Pto/Eto Chronic illness can be a risk factor for antipsychotic therapy
depression. even though the MDR
2. Refer back to the referred TB RO
TB treatment is
health care facilities, if symptoms
become severe and can not be complete.
resolved in TB RO health care
facilities or satellites
3. TAK together with the psychiatrist will
analyze further and if necessary will
start anti depression treatment.
4. The recommended anti-depressant
option is amitriptyline or SSRI group
(Serotonin Selective Re-Uptake
Inhibitor) eg Sentraline / Fluoxetine
5. Previous history of depression is not a
contra indication for drug use but risk
of depression during treatment.
6. If possible lower the dose of the
causative agent.
7. Discontinue related drugs for 1-2
weeks until the psychological problem
is resolved
6. Hypothyroid Pto/Eto 1. Treatment are done at referred TB RO If the symptom
health care facilities by TAK alongside showing are directing
an endocrinologist or internist. to hypothyroid, scoring
2. Symptoms and signs are dry skin, can be continued with
fatigue, weakness and can not stand Billewicz (checklist
to cold weather attached).
3. Diagnosis of hypothyroidism is based
on elevated levels of TSH (normal
levels <10 mU / l).
4. The endocrinologist and internist
recommend the TAK for treatment
with levothyroxine / natiroxin and its
evaluation.
7. Sleep disorder Mfx 1. Give a quinolone group OAT in the
morning or long time before the
patient's bedtime
2. Do counseling about good sleep
patterns
3. If necessary consult the patient to a
psychiatrist for treatment

16 | Technical Guidance of Medical Treatment of Short Term Standards

 8. Eto, Pto, 1. Treatment continues, while evaluation Antacids or
Gastrointestinal Cfz, H, E, Z, is conduct. sucralfates can not be
disorder(nausea, Mfx 2. Monitor the patient for the severity of administered
the complaints.
vomiting, simultaneously with
3. Get rid of other causes such as liver
dyspepsia, acute disorders, diarrhea due to infection, or OAT (distance of at
abdomen) other drugs. least 2 hours).
4. If necessary, give anti-emetic, PPI
(Proton Pump Inhibitor), H2
antagonist (Ranitidin), Mg (OH) 2 or
Sacralfate Group Antacids.
5. If there are no respond to the above
treatment, consider hospitalization for
advanced assessment and
rehydration of IV fluids, and evaluation
of electrolytes and urea and creatinine
serum.
6. If there are signs of an acute
abdomen, consider consulting a
surgeon.
7. The TAK will consider the continuation
of the treatment.
9. Liver Z, H, 1. Stop all the OAT, the patient
impairment Eto/Pto, E, immediately referred back to the TB
Mfx RO referred health care facilities
2. Check for SGOT, SGPT, total bilirubin
3. If the SGOT-SGPT result is more than
3 times normal or total bilirubin levels
more than 2 mg / dl, the patient is
hospitalized
4. Rule out possible causes other than
drug-induced liver injury (drug-
induced hepatitis)
5. TAK will consider the continuation of
the treatment.
10. Renal Km, Cm 1. In case of impaired renal function
impairment (diuresis disturbance, elevated serum
creatinine level), the patient is referred
back to the TB RO referred health
care facilities.
2. The TAK along with the nefrologist /
internist will consider the continuation
of patient treatment.
11. Optical E 1. Any symptoms of vision impairment Aminoglycosides may
neuritis need to be evaluated and consulted also cause vision
with an ophthalmologist. impairment.
2. The TAK will consider the continuation
of the provision of Etambutol based
on the evaluation of the
ophthalmologist.
12. Artralgia / Z, Mfx, Eto, 1. Perform uric acid examination.
arthritis INH 2. 2. If there are symptoms of atralgia
accompanied by elevated levels of

17 | Technical Guidance of Medical Treatment of Short Term Standards

 uric acid, NSAIDs can be
administered and physiotherapy
without having to stop administering
Pyrazinamide.
3. 3. If the symptoms are not relieve and
bothering then the patient is referred
back to TB RO referred health care
facilities to get a recommendation
treatment by the TAK alongside a
rheumatologist or internist.
4. In case of acute Gouty arthritis,
Pyrazinamide will be discontinued.

13.Changes in Cfz Patients are given KIE about the cause

skin colour of skin discoloration and its tempoary
effect.
14. Mfx 1. Tendinopathy symptoms
Tendinopathy, characterized by swelling, tenderness,
tendon rupture warm, and redness
2. Rupture of the achilles tendon is
diagnosed with Thompson's test (loss
of plantar flexi when the calf is
pressed)
3. Examination are done with ultrasound
and MRI. USG will show a hypokinetic
area with tissue degeneration and
tendon thickening. While MRI can
detect tendinopathy and the risk of
rupture.
4. Patients are given analgesic / anti-
inflammatory drugs
5. Physiotherapy may be performed
including diathermy ultrasound,
electrotherapy.
6. In the event of tendon rupture
operative action should be
considered.
7. Once a diagnosis of tendinopathy is
confirmed, the patient should no
longer be given fluoroquinolone
(short-term standard treatment
discontinued).

18 | Technical Guidance of Medical Treatment of Short Term Standards

 Table 5. Drug Interaction

Other drugs / foods that Effects of Drug Interactions and

OAT
can interact Medication Advice
 Antacids can increase the pH of the stomach so as to
decrease the absorption of INH.
1. Antacids
 Antacids (Aluminum hydroxide) or ranitidine should be
given 1 hour after administration of INH.
2. Anticonvulsants:  INH is a cytochrome P450 inhibitor that can increase
phenytoin, plasma concentrations of some drugs to toxic levels.
carbamazepine,  The plasma concentrations of anticonvulsant drugs
benzodiazepines can be increased when used in conjunction with INH.
 Carbohydrates will reduce uptake of drugs up to 57%
and decrease drug concentration on plasma by 30%.
Isoniazid (INH) 3. Carbohydrates,
 INH should not be consumed with drinks containing
beverages containing
glucose or lactose.
glucose, lactose
 INH should be taken 30-60 minutes before meals or 2
hours after meals
 INH inhibits the enzyme monoamine oxidase, so this
4. Foods containing
drug should not be taken in conjunction with foods
tiramine, histamine:
containing tyramine and histamine.
cheese (Swiss, Chesire),
 Symptoms that appear in this interaction are
tuna and herring, alcohol
palpitations, sweating, redness, chills, headache,
(red wine)
diarrhea, erythema and pruritus.
Probenecid has the potential to increase the effect of
1. Probenecid
pyrazinamide.
Pirazinamid Zidovudine may decrease the effect of pyrazinamide.
2. Zidovudin *A consultation to an expert physician are needed for
patient with HIV receiving short-term alloy.
1. Antacids Reduces Moxifloxacin absorption

Increases the risk of ventricular arrhythmias when taken

2. Anti-arrhytmias
in conjunction with Amiodarone or Disopiramide

Increases the risk of ventricular arrhythmias when taken

3. Antidepressants
in conjunction with Tricyclics
Increases the risk of ventricular arrhythmias when taken
Moksifloksasin
4. Antimalaria together with Chloroquine, Hydroxychloroquine,
Meflokuin and Quinine
Increases the risk of ventricular arrhythmias when taken
5. Antipsychostics together with Benperidol, Droperidol, Haloperidol,
Phenothiazetin, Pimozide and Zuklopentiksol
Increases the risk of ventricular arrhythmias if taken in
6. Antiviral
conjunction with Saquinavir

19 | Technical Guidance of Medical Treatment of Short Term Standards

 Increases the risk of ventricular arrhythmias when taken
7. Beta-blocker
in conjunction with sotalol
8. Cyclosporine Increases the risk of nephropathy

Increases the risk of ventricular arrhythmias when taken

9. Erythromycin
together with erythromycin IV
10. Iron Reduces moxifloxacin absorption

11. NSAIDS Increased seizure risk

Moksifloksasin
12. Petamidine Increases the risk of ventricular arrhythmias
Increases seizure risk.
13. Theophylline
Reduce theophylline levels and monitor its levels
14. Zinc Reduces moxifloxacin absorption
Use with caution when the patient is taking class IA and
15. Drugs known to increase
III anti-arrhytmias drugs, tricyclic antidepressants,
QT intervals
macrolides and antispikotics
Increases the risk of optic neuropathy caused by
Ethambutol INH
ethambutol.
INH increases the concentrations of Cfz on plasma and
1. INH urine; and decrease the concentration of the drug on the
Clofazimin skin
2. Fluorokuinolon,
Increases the risk of elongation of QT intervals
Bedaquiline

20 | Technical Guidance of Medical Treatment of Short Term Standards

 CHAPTER VI
Treatment for Patients with Irregular Medical Treatment

The health worker should make sure that RR / MDR TB patients that treated with short-
term standard alloys are not loss to follow up. If it does, the management should be considering:
a. The length of treatment that has been undertaken
b. The length of loss to follow up
RR / MDR TB patients which is loss to follow up should undergo a complete examination by
physcian in TB RO health care facilities to receive the recomendation treatment. Management for
a loss to follow up patient can be seen in the table below:

Tabel 6. Management of TB RO Patients with Irreguler Medical Treatment

Length of
Length of
patients
patients
treatment Management
loss to
has been
follow up
undertaken
< 8 weeks No matter 1. Conducting intensive counseling to patients and
how long families.
2. Continue treatment with short-term standard alloys and
add the number of missed doses to the duration of
treatment.
3. The MDR TB 01 treatment card is continued, it is
necessary to note how long the patient has missed drug
ingestion.
> 8 weeks ≤ 4 weeks 1. MDR TB 01 treatment card is closed, the patient is
declared as lost to follow-up.
2. Patients receiving another KIE which emphasize on
medication adherence.
3. Treatment can be started from beginning with a short-
term standard alloy without waiting for sensitivity test
results.
4. The patient category remains the same as at the
beginning of the previous treatment.
5. Replacement into individual alloys is performed when
second-line sensitivity test results are out and the
patient has not met the standard short-range standard
inclusion criteria.

21 | Technical Guidance of Medical Treatment of Short Term Standards

 Length of
Length of
patients
patients
treatment Management
loss to
has been
follow up
undertaken
> 8 weeks > 4 weeks 1. MDR TB 01 treatment card is closed, the patient is
declared as a patient lost to follow up.
2. Patients receiving another KIE which emphasize on
medication adherence.
3. Patients are treated as suspected TB RO from the
beginning.
 Perform a rapid confirmation test
 If rapid test results of Rifampicin Resistance,
perform culture checks and sensitivity tests for
second-line OAT.
4. Treatment begins after sensitivity test results.
5. Patient include in this criteria are patients who returns
for treatment after lost to follow up from treatment with
second-line OAT.
6. Patients with short-term standard alloys should change
to conventional / individual alloys according to
sensitivity test results.

Notes:
Treatment decision for RR / MDR TB patients which return after loss to follow up are decided by
the TAK in TB RO referred health care facilities or trained physician in TB RO health care
facilities

22 | Technical Guidance of Medical Treatment of Short Term Standards

 CHAPTER VII
End Result of Treatment of TB RO

The definition of patient treatment outcomes with these short-term standard alloys will be
adjusted to the WHO definition:
 Cured
- The patient completes the treatment according to the duration of the prescribed treatment
- BTA examination at the end of treatment (month 9 or 11) results are negative
- Examination of culture 3 times in a row with a minimum range of 30 days with negative
results in the advanced stage.
 Complete treatment
- The patient completes the treatment according to the duration of the prescribed treatment
- There is no evidence to be declared cured or failed.
 Failed
- BTA examination at the end of the 6th month was positive, or
- BTA examination at the end of treatment (AP) results positive, or
- There is a revere (BTA or culture back to positive again) at the advanced stage. In the
event of a reversion, the examination of BTA and culture is repeated in the next month.
- There are severe side effects that result in stopping the short-term standard treatment
- There is additional resistance to second-line OATs of quinolones and / or second-line
injections
 Death
Patient dies during treatment by any cause.
 Loss to follow up
The patient stops the treatment 2 consecutive months or more.
 Not evaluated
- The patient changing health care facilities without knowing or reporting back the end of
the treatment
- Patient with no treatment result until the reporting period

Monitoring After Finish Treatment

Monitoring for patients who have completed treatment were performed at months 6 and
12 after the end of treatment, or when symptoms of TB appear. Sputum will be collected for
microscopic examination and culture examination (one morning sputum) to assess the presence
or absence of recurrence. There is a possibility that the patient will require another examination
at the time of visit, depending on the patient's condition. The results of the tests performed and
the results should be recorded on the patient's treatment card (TB 01)

23 | Technical Guidance of Medical Treatment of Short Term Standards

 CHAPTER VIII
Monitoring Drug Side Effects Integratedly

The treatment of TB RO with short-term standard alloys requires active monitoring and
management of drug side-effects (aDSM) or better known as active monitoring of drug side-
effects (MESO-active) in Indonesia. MESO-active is an active and systematic clinical and
laboratory assessment process in all patients receiving TB treatment with new alloys. This
activity aims to detect, manage and report the incidence of unwanted events (KTD) on drugs.

All KTD that occurs on patients require appropriate clinical management. In an effort to
strengthen the MESO system in patients receiving TB treatment with second-line OAT, it is done
by strengthening MESO record and reporting. The recording and reporting of serious and non-
serious MESOs follows the current algorithm established by the Indonesian Drug and Food
Supervisory (BPOM).

Implementation of monitoring and management of drug side effects will be done in all TB
RO health care facilities. The collection and reporting of side effects monitoring data will be
performed by health workers available at all levels. Data collection and reporting using pre-defined
form and e-TB Manager information systems, so that all interested parties can access the data
easily, accurately, valid and up-to-date.

24 | Technical Guidance of Medical Treatment of Short Term Standards

 Picture 3. Implementation Structure of MESO-active drug resistance TB

National TB Program National Pharmacovigilance Executor

(Sub Directorate of Tuberculosis) (BPOM)

Drug safety
monitoring(MESO-
TB RO health active) KTD reporting via eTB
manager
care facilities
Monitoring treatment
of patients with:
- ESO checklist Further analysis for
• Treatment - Regular lab checks signal detection /
for TB RO for drug safety
monitoring Serious KTD is causality assessment
• MESO-active reported soon in and communication
24 hours

- Recording the
entire KTD
- Serious KTD
reporting using Collaborative
Changes related MESO-active form implementation of signal
- Detection of signal / detection, causality
to treatment
causality assessment
policies / Update information
assessment by
treatment for TB regarding TB drug
BPOM and P2TB
RO safety profile at
national and global
levels

new evidence

A. Stages of Monitoring Activity of Drug Side Effects

MESO delegation is divided into several series of activities including:
a. Discovery of KTD
b. Recording
c. Management of KTD
d. Reporting

1. Discovery of KTD / ESO

The meaning of KTD is any unwanted medical event that occurs in the patient after
receiving the drug and does not always have causality relation with the drug. Such
unwanted medical events can be symptoms such as nausea, vomiting, diarrhea,

25 | Technical Guidance of Medical Treatment of Short Term Standards

 headache, dizziness and so on, signs such as changes in blood pressure, changes in
body temperature, skin rashes and so on, changes in laboratory test values to clinically
significant abnormalities , or a diagnosis that occurs after drug use. The event has a
temporal relationship in which the condition or diagnosis is detected after administration
of the drug.

ESO is a response to an adverse and unwanted drug, occurring at a dose normally used
in humans for the prevention, diagnosis, or treatment of the disease or the modification of
physiological function.

Manifestation of KTD / ESO may be a serious and non-serious (mild) medical event.
Referred to as serious KTD / ESO is KTD which causes the following:
a. Death
b. Life-threatening condition
c. Permanent disability
d. Require hospitalization
e. Requires an extension of hospitalization time
f. Congenital abnormalities in infants
g. Other clinically significant clinical events

Medical and scientific assessment should also be made in determining the side effects of
drugs experienced by patients who are a serious category but not in the serious categories
of points a, b, c, d, e, f mentioned above. As an example is intensive treatment in
emergency rooms in patients with alergic bronchospasm but does not require
hospitalization.

2. Recording
The recording of the patient's medical records should consider the patient's privacy
(confidential). All KTDs that occur during TB RO treatment, whether serious or non-serious
KTD, should be recorded on TB01 form. For serious KTD, it should be reported using the
MESO-active form. Completion of the MESO-active form is performed by pharmacists or
clinical pharmacies in coordination with a team of clinical specialists in health care
facilities. Based on the invention of KTD, the recording would be about:
a. Individual charateristics:
- Name,gender, address
- Age, weight, height, pregnancy
- Main disease
- Other disease or condition accompanying
b. Drugs name:
- The name of the drug used by the patient includes other medications,
supplements, or traditional medications used at the same time. The name of the
drug can be written with a generic name or trade name according to the type of
drug given..
- Dosing forms

26 | Technical Guidance of Medical Treatment of Short Term Standards

 - Dosage and type of administration
- Date of start and end of treatment
- Frequency of drug administration
- Recorded incomplete / completed treatment and the reason
c. KTD manifestation:
- Description of KTD manifestations and terminology of serious KTD
- The starting date of the KTD occurs
- End date of KTD (healed, healed with residual, not recovered, died, unknown)
- History of KTD ever experienced
- Laboratory test data if available
d. Results of laboratory examination
e. Other information from the interviewer
f. Additional information: it may be possible to relate directly or indirectly to symptoms of
drug side effects such as the rate at which KTD and ESO occur, reactions after
medication are stopped or given back, medication / action given to resolve the KTD,
treatment alloy changes, dosage changes, and others.

3. Management of KTD

The resolution of KTD should considering patient safety and treatment required. For mild
KTD, patients need to be motivated to stay regularly continue treatment. For KTD requiring
additional examination and treatment, laboratory examination and drugs needed should
be available and provided by the program.

If the drug suspected to cause KTD needs to be stopped / excluded from the treatment
alloys, the replacement drugs may be necessary, especially in the intensive phase where
bacillary load is still high. Substitution of the drug should take into consideration according
to the clinical condition and bacteriological status of the patient. Make sure that in alloys
there are at least 4 drugs that are known to be effective. Each decision should be based
on careful case study.

4. Reporting

The reported KTD is a serious KTD experienced by the patient. Serious fatal KTD is
reported via eTB Manager (http://indonesia.etbmanager.org) by pharmacists or clinical
pharmacies as soon as possible within 24 hours of the onset of the KTD, while serious
non-fatal KTD is reported as soon as not more than 15 calendar days since the occurrence
of the KTD. The eTB manager information system will inform directly to all interested
parties who have access.

The incoming KTD reporting will be verified by the verification team from the
Pharmacovigilans Team of BPOM and the TB Directorate General of P2P Ministry of
Health. Investigations and assessments will be conducted if there are serious KTD / ESO

27 | Technical Guidance of Medical Treatment of Short Term Standards

 reports. Investigations and assessments were undertaken by teams from the BPOM, the
Ministry of Health and the Pharmacovigilans Committee of Drug Resistance TB, and other
related teams. The process starts from the assessment of causality per individual and is
done routinely every six months. If the signal of the drug safety risk were found,
assessement of benefit risk will be done by the expert team and the result of the
assessment will be submitted in the form of recommendation to BPOM and Directorate
General of P2P Ministry of Health RI. Each serious KTD report received, after an
evaluation of causality and signaling relationships, it is sent periodically to the WHO
Uppsala Monitoring Center which manages the WHO ICSR database (Individual Case
Safety Report).

Feedback on each reported KTD / ESO conducted by the central (BPOM RI and
Directorate General of P2P Ministry of Health RI) to the Provincial Health Office and TB
RO referred health care facilities.

28 | Technical Guidance of Medical Treatment of Short Term Standards

B. Algorithm of Information and Data
The Algorithm of data information begins when the KTD is experienced by the patient and
confirmed through a physician / health worker. Pharmacy / clinical pharmacists fill out the
MESO form and enter the data into the e-TB manager. The algorithm of information and data
can be seen in the picture below.

Picture 4. Algorithm of Information and Data

Badan POM Directorate General

of P2P

FARMAKOVIGILANS COMMITTEE
TB RESISTANT DRUG

E-TB MANAGER
INFORMATION
SYSTEMS

Keterangan:
: Coordination / consultation
: Flow of information and data Responsible MESO Hospital

Health Workers at Referred

Hospital of Drug Resistance

Patient / Family

29 | Technical Guidance of Medical Treatment of Short Term Standards

 CHAPTER IX
Monitoring and Evaluation

1. Recording
The recording of TB RR / MDR treatment patients with these short-term standard alloys will
use the available MTPTRO forms and registers. All treatment data will be stored and managed
on e-TB manager according to standard provisions.

In addition to the standard recording system, health care facilities using short-term standard
alloys should fill out forms for monitoring drug side effects (MESO forms). This form is filled
by the physician in charge of treatment (or pharmacist / clinical pharmacist) when serious KTD
occurs.

2. Reporting
The reporting period will follow the schedule in the following table:

Tabel 6. Reporting Schedule

Forms / reports Indicators viewed Schedule

TB 07 MDR The number of patients Every 3 months, for patients starting
initiating TB RO treatment 3 months (1 quarter) before.
treatment both short-
term standard alloys
and individual treatment
alloys
TB 11 MDR Interim results of Every 3 months, for patients starting
treatment (month 6) treatment 9 months (3 quarters) before
TB 08 MDR Final result of treatment Every 3 months, for patients starting
(9 -11 months) treatment 12 months (4 quarters) before
Serious KTD report Serious Unwanted Immediately, if there is serious KTD
form events (KTD)
TB 13 A, B, C Availability and logistic Every 3 months
demand for OAT and
non OAT

In addition to reports of TB 07, TB 11, and TB 08 MDR available in the e-TB Manager, each
health care facilities are obliged to make an official report signed by the relevant health care
facilities management. The report is sent to the District Health Office with a copy of the
Provincial Health Office, for recapping and forwarded to the Ministry of Health cq Subdit TB.

Preliminary outcomes of treatment will be evaluated quarterly based on bacteriologic

examination results at 3, 6, and 9 months of treatment (including if the patient fails, dies, or
drops out). Evaluation of preliminary treatment outcomes was emphasized at month 6
because at this time decisions regarding the continuation of treatment should be taken.

30 | Technical Guidance of Medical Treatment of Short Term Standards

 The end result of treatment of patients with short-term standard alloys will be evaluated and
reported in the same quarter of the following year.

3. Treatment Monitoring Activities

One of the problems of treatment of drug resistant TB is the high number of loss to follow up
(LFU) and treatment failure. For that, all TB RO health care facilities are expected to make
efforts to ensure patient treatment success by conducting monthly minicohort and quarterly
cohort studies (ECR: enhanced cohort review).

Monitoring activities are also conducted at the District Health Office with the aim of ensuring
that all TB RO patients are confirmed to receive treatment according to the standards and
ensure the success of patient treatment through monthly MTPTRO interim cohort analysis
(MICA: monthly interim cohort analysis). In addition, the District Health Office needs to carry
out an evaluation of temporary treatment outcomes of TB RO patients through a quarterly
interim cohort analysis (QICA: quarterly interim cohort analysis).

31 | Technical Guidance of Medical Treatment of Short Term Standards

 REFERENCES

World Health Organization. Global tuberculosis report 2016. Geneva, Switzerland: WHO, 2017.

World Health Organization. Active tuberculosis drug-safety monitoring and management (aDSM):
Framework for implementation. Geneva, Switzerland: WHO, 2015.

World Health Organization. WHO treatment guidelines for druqqwg-resistant tuberculosis.

Geneva, Switzerland: WHO, 2016.

Kementerian Kesehatan RI. Petunjuk teknis manajemen terpadu pengendalian TB resistan obat.
Jakarta, Indonesia: Kementerian Kesehatan RI, 2014.

Kementerian Kesehatan RI. Peraturan Menteri Kesehatan Nomor 67 Tahun 2016 tentang
Penanggulangan Tuberkulosis. Jakarta, Indonesia: Kementerian Kesehatan RI, 2016.

Global Drug-resistant TB Initiative (GDI). The evaluation of effectiveness and safety of a shorter
standardized regimen for multidrug-resistant tuberculosis. GDI, 2015. http://www.stoptb.org/Wg/
Mdrtb/assets/documents/Generic%20protocol%20shorter%20treatment_%202015.pdf

World Health Organization. Frequently asked questions about the implementation of the new
WHO recommendation on the use of the shorter MDR-TB régimen under programmatic condition.
WHO, 2016. http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/FAQ
shorter_MDR_regimen.pdf

Challenge TB. Generic programmatic and clinical guide for the introduction of new drugs and
shorter régimen for treatment of Multi/Extensively Drug-Resistant Tuberculosis. 2016.

Badan Pengawas Obat dan Makanan (BPOM). Pedoman Penyelenggaraan Farmakovigilans

Obat Program Tuberkulosis. Jakarta, Indonesia: BPOM, 2017.

32 | Technical Guidance of Medical Treatment of Short Term Standards

 APPENDIX

33 | Technical Guidance of Medical Treatment of Short Term Standards

Appendix 1

REPORTING FORM OF SERIOUS KTD SERIOUSLY

Report ID No. (filled by BPOM):

Report form of Serious KTD of TB Drugs .........................
(site code / Initial patient / serial number)
Patient Information
Name (inisial): Gender: Age:
□ Man
□ Woman
weight: height: □ Pregnant Ethnic:
□ Not Pregnant
□ Unknown

Main disease: Other disease / condition History of KTD ever

accompanying: experienced before:
□ HIV
□ DM
□ Heart impairment
□ Renal impairment
□ Others, Specify………..

TB drugs used
OAT for children
 1st OAT Category  2nd OAT Category 
category
 Short-term Standard Alloy  Individual Alloy

Still in use
Initial date No
TB Drugs Dosage Dosing form (Date/Month/ End date
Year) Yes
(Date/Month
/Year)

34 | Technical Guidance of Medical Treatment of Short Term Standards

 Still in use
Drug Name Initial date No,
Dosage Dosing form (Date/Month/ End date
(Trade/Generic) Yes
Year) (Date/Month
/Year)

Description of the serious KTD Terminology of the KTD

Initial date of KTD (Date/Month/ Year)

................................

End date of KTD (Date/Month/ Year)

……………………….

Examination data (write down laboratory results, x-ray, etc. and check date)

Additional Information (eg: treatment / action given to

relieve KTD, treatment alloy change, dose change,
Type of serious KTD
drug reactions discontinued and / or re-administered
etc)
Choose one (x):
□ Death
□ Life threatening
□ Require hospitalization
□Extension of hospitalization
□ Causing disability
□ Causing congenital anomalies

35 | Technical Guidance of Medical Treatment of Short Term Standards

 Notes:
Serious fatal KTD occurring must be
reported to eTB manager and e-MESO
BPOM within 1x24 Hours.
After serious KTD
□ Cured
□ Cured with remission
□ Not cured yet
□ Death
□ Unknown

Reporter Information
Reporter Name: Employment: Date reported

Health care facilities: Reporter phone number: Sign

Health care facilities address:

36 | Technical Guidance of Medical Treatment of Short Term Standards

Appendix 2
Drug Side Effect Form

37 | Technical Guidance of Medical Treatment of Short Term Standards

Appendix 3

38 | Technical Guidance of Medical Treatment of Short Term Standards

Appendix 4

39 | Technical Guidance of Medical Treatment of Short Term Standards

Appendix 5

Patient Information Form

TB RO Health care facilities / referred health care facilities

Address : …………………………………………...
Phone number : ……………………………………………
Email : ……………………………………………

Information for RO TB patients

Tuberculosis or TB is a lung disease caused by TB germs, mycobacterium tuberculosis. The disease
is transmitted through droplets of a sputum smear positive TB patients when talking, coughing
or sneezing. Tuberculosis Resistance Drugs or often called TB RO is a TB disease whose germs are
immune to anti-tuberculosis drugs. For patients who have germs that are immune to at least
Rifampicin, patients will be treated with second-line anti-TB drugs plus first-line anti-TB drugs
that are still effective. TB RO treatment is approximately 19-24 months with daily medication
monitoring in front of health workers. Indonesia has treated more than 7,000 patients since 2009
with a fairly good rate of treatment success. By 2016, WHO has recommended the use of a
combination of standard drug resistance treatment for short-term Drugs 9 to 11 months.

Your Role
If the results of your laboratory examination show TB Drug Resistance, you may undergo this
treatment with your consent.
Adherence to the treatment of drug resistant TB is essential to ensuring the success of treatment
and preventing transmission to families and people around you. During treatment the patient
will perform sputum checks regularly and other necessary examination.
You will get RO TB treatment with short-term standard Alloys, but under certain conditions, for
example:
 Proven resistance / resistance to fluoroquinolone / second-line injectable drugs
 There was a history of contact with TB patients pre / XDR
 Already receive a second line OAT for ≥ 1 month
 There is intolerance to drugs in short-range standard alloys
 Pregnant
 Extra-pulmonary TB cases
 There is a risk of unfavorable outcome *
Then you will still get treatment with individual standards, according to your condition.

Initial Examination and Progress of Treatment

Before starting standard short-term treatment, a baseline should be conducted including:

40 | Technical Guidance of Medical Treatment of Short Term Standards

 1. Anamnesis
2. Physical / clinical examination (Weight)
3. Sputum examination: BTA, culture, sensitivity test
4. ECG
5. Hearing tes
6. Chest x-ray
7. Complete blood examination
8. Fasting blood sugar and 2 hours PP
9. Kidney function: Ureum Creatinin serum
10. Electrolyte
11. Liver function: SGOT, SGPT, bilirubin
12. TSH / TSHs
13. Pregnancy test
14. Test HIV

During the treatment, various examination also conducted to monitor the progress of treatment.
Examination and schedule of treatment monitoring can be seen in the following table:

Advanced Examination During Treatment

Month of Treatment
4 months of Initial stage 5 months of Advanced
Type of
(can be extended up to 6 months) Stage
Examination
0 1 2 3 4 5 6 7 8 9
0 1 2 3 4 5 6 7 8 9 10 11
Anamnesis √ √ √ √ √ √ √ √ √ √ √ √
Physical / clinical
examination √ √ √ √ √ √ √ √ √ √ √ √
(weight)
BTA sputum √ √ √ √ √√* √√* √√* √ √ √√*
Culture sputum √ √ √ √ √ √ √ √ √ √
Sensitivity test √ √**
ECG+ √ √ √ √ √ √ √ √ √ √ √ √
Chest X-ray √ √ √ √
Ureum-Creatinin
√ √ √ √ √ √ √
serum
Elektrolyte √ √ √ √ √ √ √

Explanation:

41 | Technical Guidance of Medical Treatment of Short Term Standards

 *) BTA examination is done every month by collecting 1 (one) morning sputum. In the 4th
month, 5th, 6th and end of treatment, BTA was tested from two (2) consecutive morning
sputum.
At a later stage, smear and culture examination are performed every 2 months (on months
5, 7 and 9 or 7, 9, and 11 months)
)
** Sensitivity test for second-line OAT will be repeated if smear results at 6 months are positive
or smear or culture become positive again in the follow-up phase.
***) Examination may be repeated as indicated (if required)
+) In patients receiving Moxifloxacin, an ECG examination was performed on preliminary

examination, day 2, day 7, and month 1 of treatment and performed at the referred hospital.

Determination of Treatment
Treatment may be initiated based on the history of previous medical history and laboratory tests
in accordance with the Clinical Experts Team's decision.
One of the important things in the treatment of short-term standard of TB RO is that patients are
shown to be non-immune / resistant to fluoroquinolone / second-line injectable drugs. Because
at this time the lab results take a longer time, then the new results will be obtained within about
2 months, there may be differences in laboratory results, and if based on the lab results indicate
resistance to second-line anti-TB drugs, your treatment will be adjusted into individualized
treatment according to the pattern of germ resistance and your condition.

Treatment of Drug Resistance TB

Drug-resistant TB disease can be treated with second-line anti-tuberculosis drugs and first-line
drugs that are still effective. There are three differences between short-term alloy treatment and
individual alloys; which is:

Standard of short-term alloy Individual alloy

Treatment length 9 – 11 month
Number of drugs Initial stage with injection for
4 - 6 months (5-6 types of
oral medication, 1 injection)
Advanced Stage without
injection for 5 months (3-4
types of oral medication)
Type of drugs Km – Mfx – Eto (Pto)- HDT –
Cfz – E – Z / 5 Mfx – Cfz – E –
Z
Minimum of 20 month
Initial stage with injection
min 8 months (6 types of oral
medication and 1 injection)
Advanced stages without
injection 12-16 months (3-5
types of oral medication)
Adjust with the germs
resistance pattern

During the treatment, you will be asked to come and ingest the medicine daily in front of the
health worker. Discontinuation of treatment will cause your condition worsen due to increased
immunity of TB germs in the body. Increased immunity of TB germs will lead to incurable diseases
and also harm the family and people around you who are at high risk of becoming infected.

42 | Technical Guidance of Medical Treatment of Short Term Standards

Benefits
RO TB can cause you to fall ill or even die. This RO TB can be transmitted from you to another
through droplets, especially if not detected and treated. If the laboratory diagnosis shows the
presence of TB RO germs in your sputum, you will soon be given treatment with RO-TB drugs
provided by the Ministry of Health. Treatment with these short-term standard alloys is much
shorter than individual treatment, hopefully you can get treatment regularly until healed.

Side Effects and Handling Efforts

This anti-tuberculosis drug is beneficial in addition to having side effects. Possible side effects
with this short-term standard alloy treatment include nausea, vomiting, hearing loss, renal
failure, joint pain and discoloration of the skin while (only occurs during treatment). In the course
of treatment you will get supervised ingesting the medicines by a trained health worker to
observe the side effects of the drug quickly. You are requested to immediately convey to your
health care counselor / health care team / clinical team if you experience any side effects of the
medication to be treated promptly according to the severity of your side effects.

During treatment you will undergo sputum examination and other examinations periodically to
monitor side effects. In the event of severe drug side-effects, standard alloys of short-term
treatment will be discontinued / adjusted with individual alloys.

Pregnancies that occur during treatment in these short-term standard alloys require adjustment
of alloys and length of treatment to be longer so that patients are expected to use contraception
during treatment to prevent pregnancy. At this time, the safety of this drug has not known its
effect on the fetus.

Two drugs used in short-term treatment alloys (clofazimine and moxifloxacin) potentially cause
a risk of heart activity disorders, but these drugs have been used in RO TB alloys for several years
with no significant severe side-effects. In order to avoid harmful consequences for the patient,
an ECG examination will be performed on a regular basis as required.

If there is a drug side effect, you are not expected to discontinue treatment unilaterally as side
effects can be handled quickly and accurately if known earlier.

Procedure undergoing treatment

After you agree to receive treatment and sign the approval letter, you will get a schedule of visits,
taking medicines, schedules of sputum and laboratory checks and meeting schedules with your
doctor. During the process you will be monitored by a health worker or doctor and a Clinical
Expert Team.

Data Confidentiality

43 | Technical Guidance of Medical Treatment of Short Term Standards

All of these treatment data are owned by RS and Ministry of Health which will be very useful for
the treatment of drug resistant TB patients throughout Indonesia to come. Patient data will be
kept confidential.

Additional information
If after this information you still need additional information, you can contact the program
implementer:
Name of TAKs physician (Person in charge) : ………………………..
Phone Number : …………………………
Office Address : …………………………
Name of TB RO carer (Person in charge) : ………………………..
Phone Number : …………………………
Office Address : …………………………

44 | Technical Guidance of Medical Treatment of Short Term Standards

Appendix 6

Informed Consent

Voluntary Participation
You will not be forced to undergo this treatment if you do not want it. You undergo this treatment
on your own consciousness. If after treatment there are complaints, it can be submitted to the
team of doctors and nurses to find a solution to your problems so that you can still undergo
treatment. The Clinical Expert Team may decide that you have stopped taking treatment. This
decision is taken by always paying attention to what is best for you, which is to protect you
against possible ill effects of the drug, or to avoid giving drugs you do not need.

Sign
I have read or read to me, the things listed above. I have been given the opportunity to ask
questions and discuss the treatment of drug resistant TB. I understand the purpose, risks,
benefits and duration of treatment and treatment procedures of drug resistant TB.
By signing this form, then I (circle to your liking):
a. Affirm my voluntary participation in this treatment
b. Not willing to undergo treatment

I have received a copy of this letter of consent.

_______________________________
Patients Sign and Name Date: ……………………………

_______________________________
Family Sign and Name Date: …………………………

_______________________________
Health worker Sign and Name Date: …………………………

45 | Technical Guidance of Medical Treatment of Short Term Standards