Section 14

Section Editor: DP Singh

Tuberculosis
189. Newer Paradigms in the Management of 193. Association of Tuberculosis and COPD
Drug-resistant TB SM Mishra
D Behera, Ranjan K Behera
194. Exudative Pleural Effusion—Diagnostic Approach
190. National DR-TB Guidelines in 2021 Sanjay Kumar
Vishwanath Upadhyay, Surendra K Sharma
195. Tubercular Lymphadenitis—Challenges
191. Tuberculosis with Diabetes: How to Tackle? in Treatment
Shailendra Kumar Deependra Kumar Rai
192. Molecular Assays as Initial Tests for 196. Gastric Tuberculosis: An Often Unrecognized Entity
the Diagnosis of Tuberculosis Piyush Manoria, Vishal Yadav
DP Singh, SK Ghosh, Krishna Kumar

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MU-189 (Sec-14).indd 1216 29-01-2021 15:18:36
 CHAPTER
Newer Paradigms in the
189 Management of Drug-
resistant TB
D Behera, Ranjan K Behera

Abstract 
Drug-resistant tuberculosis is an important impediment to successful TB control in any country. India has the highest number
of MDR-TB cases in the world. Diagnosis and management of such cases are difficult; drugs are costly, of longer duration,
and are associated side effects that are sometimes unacceptable. Further, treatment outcomes are not very encouraging.
However, with availability of newer diagnostic opportunities, specifically CBNAAT, LPA for both the standard and second-
line drugs and liquid culture and drug susceptibility testing have changed the approach. Further developments with
availability of newer and efficacious drugs like bedaquiline, delamanid, and pretomanid have changed the paradigm of
our approach for treating these cases with better outcomes. The duration of therapy has further come down with these new
drugs and now we have the option of shorter courses of therapy to 6–9 months and the all oral longer duration of therapy
for 18 months are now realities with success rates of more than 80%. Another important advantage is the no necessity of
injectables so that patients accept these injection-free, all oral regimens with better compliance.

Introduction Results from a RNTCP (NTEP) accredited laboratory is

taken as confirmed case of DR-TB. These patients are then
The Revised National Tuberculosis Control Program
classified according to the following definition:
(RNTCP), now known as the National Tuberculosis
Elimination Program (NTEP) has notified around a total of Mono-resistance TB (MR): Biological sample—sputum
2.41 million TB patients of all types in 2019 according to the or fluid or tissue shown to be resistant to any one anti-
Nikshay dashboard.1 More than a quarter of TB patients in tubercular drug of the first-line only.
India have drug resistance to one or the other anti-TB drug
as per the 1st National Anti-TB Drug Resistance Survey Polydrug resistance TB (PDR): When the biological sample
(NDRS) of India (1914–1916). shows resistance to more than 1 first-line anti-tubercular
drug other than both INH (H) and rifampicin (R).
A case of presumptive DR-TB includes the following:
„„ Positive sputum smear during any follow-up visit while Rifampicin resistance (RR): When the sputum or the
on treatment with first line ATT; biological specimen shows resistance to rifampicin, when
„„ Pediatric TB non-responders; tested using phenotypic or genotypic methods and with or
„„ If the patient is a contact of a known DR-TB case; without resistance to other anti-TB drugs. It includes any
„„ Earlier treated patient; resistance to rifampicin, in the form of mono-resistance,
„„ TB-HIV coinfection; poly-resistance, MDR, or XDR. Most of the rifampicin
„„ All notified new TB patients. resistant cases will also show H-resistance, hence the

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 1218 SECTION 14 Tuberculosis

RNTCP (NTEP) has taken a considered decision that all RR-TB in the word in 2018. INH mono-resistance was
R-resistance cases will be treated as MDR-TB cases. reported in 7.2% of cases of new TB and 11.6% in previously
treated cases of TB globally in 2018. India in collaboration
Multidrug resistance TB (MDR): In this form of tuberculosis,
with WHO carried out the first National Anti-TB Drug
the biological specimen is resistant to both INH and
Resistance Survey (NDRS) between 2014–1916. The
rifampicin with or without resistance to other first-line
survey carried out drug susceptibility testing (DST) for 13
anti-TB drugs. These patients may also have additional
anti-TB drugs using the automated liquid culture system,
resistance to any/all fluoroquinolones or any/all second-
(the mycobacteria growth indicator tube, MGIT 960). The
line injectable (amikacin, kanamycin, and capreomycin)
main findings were: MDR-TB in 6.19% of cases (2.84%
anti-TB drug.
among new and 11.60% among previously treated TB
Pre-XDR-TB: MDR TB with demonstrable resistance to patients). Additional resistance to any fluoroquinolones
any one of the second-line injectable anti-TB drugs like was observed in 21.82%, and 3.58% of cases to any second-
amikacin, kanamycin, or capreomycin OR to any one of line injectable drugs amongst all MDR-TB cases. XDR TB
the fluoroquinolones. was present in 1.3% of cases.4 During 2007–2018, India
tested 2,798,599 patients using CB-NAAT and line-probe
Extensive drug resistance (XDR): When there is additional
assays (LPAs). These tests detected 236,725 drug-resistant
resistance to at least any fluoroquinolone (like ofloxacin,
TB patients. In 2019, the program notified a total of 66,359
levofloxacin, moxifloxacin, etc) and a second-line
Multi Drug Resistant/Rifampicin Resistant (MDR/RR) TB
injectables (like amikacin, kanamycin, or capreomycin) in
cases and 56,500 (85%) of them put on treatment, which is
a case of MDR TB.
an improvement of 7.6% over last year as reported by the
The following technologies are used nowadays (besides
India TB Report, 2020.
culture and DST methods):
„„ Line Probe Assay (LPA) for detection of MTB complex

and detection of resistance to first-line drugs rifampicin, Approach to Treatment of DR-TB

isoniazid, and second-line drugs (fluoroquinolones, Drug resistance emerges when anti-TB drugs are used
second-line injectables); inappropriately, poor TB control program, delayed
„„ CBNAAT (Catridge Based Nucleic Acid Amplification diagnosis, inappropriate drug regimen, inadequate
Test) Xpert MTB/Rif testing by using the Gene X pert initial therapy, incomplete duration of therapy,
platform; and inappropriate treatment modifications, addition of a
2
„„ TrueNat TB test. single drug to an already failing regimen, improper use
Drug-resistant tuberculosis is a great impediment to the of chemoprophylaxis, poor adherence and incomplete
achievement of End TB strategy because of the complexity follow up, failure to isolate MDR TB, failure to employ
of drug regimes against this form of tuberculosis, treatment DOTS, availability of over the counter anti-TB drug, and
outcome, and cost involved. However, with availability of faked drugs. Use of second-line drugs can cure MDR TB
newer drugs particularly bedaquiline (BDQ), delamanid, cases. However, second-line treatment options are limited
and pretomanid and experience of success with shorter and require long durations (up to 2 years of treatment).
durations of therapy have raised hope to handle this Besides the longer duration of therapy, other problems
form of the disease. An estimated 484,000 incident cases associated with these drugs are that they are expensive
of MDR/RR-TB were reported in 2018 globally. MDR/ and toxic. More severe drug resistance can develop in
RR-TB was reported in 3.4% of all new cases and 18% in some cases.
all previously treated cases of TB. The three high burden An independent expert panel of the WHO reviewed the
countries for this form of TB were India (27%), China latest evidence for treatment of drug-resistant TB in July
(14%), and the Russian Federation (9%). Around 123 2018. The committee recommended certain key changes
countries of the world have reported the presence of XDR- and issued a rapid communication.5
TB (extensive drug-resistant TB) in their population. The The programmatic management of drug-resistant TB
proportion of XDR-TB among MDR-TB patients is 6.2% (PMDT) was initiated in India in 2007 and the National
worldwide.3 About 214,000 deaths occurred from MDR/ Guideline scaled up the same which was achieved

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 Newer Paradigms in the Management of Drug-resistant TB CHAPTER 189 1219

Flowchart 1: Diagnostic algorithm for drug-resistant TB

TABLE 1 Conventional drug regimen (previously used) for MDR/RR; and XDR-TB

Category of TB case Drug regimen (intensive phase) Treatment regimen (continuation phase)
MDR TB/RR-TB (6–9 m) K anamycin, Levofloxacin, Ethionamide, (18 m) Levofloxacin, Ethionamide, Cycloserine, Etham­
Cycloserine, Pyrazinamide, Ethambutol (duration 6–9 butol (duration 18 months)
months)
XDR-TB (6–12 m) Capreomycin; PAS-para Aminosalicylic Acid; (18 m) PAS-para aminosalicylic Acid; Mfx-Moxifloxacin;
Mfx-Moxifloxacin; High dose INH; Cfz-Clofazimine; Lzd- High dose INH; Cfz- Clofazimine; Lzd-Linezolid; Amx/Clv-
Linozolid; Amx/Clv-Amoxicillin-Clavulinic acid Amoxicillin-Clavulinic acid

by March 2013. However, the success rate of MDR TB out pre-XDR and XDR-TB. Appropriate modifications
treatment has been around 46% consistently with a have to be made if there is additional drug resistance.
death rate of approximately 20% while the same figures Pretreatment investigations are carried out and drugs are
at the global level has been 52% and 17%, respectively. dispensed in patient-wise boxes on monthly basis. Follow-
Fluoroquinolone resistance in Indian patients was up is done with culture every month in intensive phase
responsible for such high rates of treatment failure and and every quarter in the continuation phase. However, the
death rates.6 major issues with these regimens are the longer duration
The diagnostic algorithm for DR-TB is shown in of therapy (24–27 months) resulting in poor compliance,
Flowchart 1. side effects, and the overall success rate was below 50%
The conventional DR-TB regimens consisted of the with approximately 20% death rates. These regimens
following drugs, which many countries including India were continued till 2016 starting from 2007 when PMDT
continued to use till recently. These are shown in Table 1. (Programmatic Management of Drug-resistant TB) was
However, this regimen is no more used by the National initiated in the country. With discovery and availability of
program. BDQ (2012) and delamanid (2014) the situation changed.
All MDR-TB isolates are subjected to liquid culture Bedaquiline (BDQ) is a newly developed drug and is
DST for kanamycin and levofloxacin at baseline to rule a diarylquinoline derivative. It targets the mycobacterial

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 1220 SECTION 14 Tuberculosis

ATP synthase. 7 It has strong bactericidal activity and „„ Shorter duration of therapy
tissue distribution is quite extensive and the distribution „„ Treatment of mixed drug-resistant cases
in the tissue can be there for up to 5.5 months after BDQ The regimen may or may not include bedaquilline/
is stopped. The most significant benefit with the drug delamanid and can be classified as treatment of:
is that it shortens the time for culture conversion quite „„ MDR/RR-TB

significantly. However, there was concern about cardiac —— Shorter MDR-TB regimen

toxicity with QTc prolongation, but subsequently it was —— Conventional regimens for MDRTB

found to be tolerated in most patients. The drug is given in —— MDR or RR TB and additional resistance to any

the following doses: or all fluoroquinolones or second line injectable

„„ Week 0–2: BDQ in a dose of 400 mg (4 tablets of 100 mg) drugs
per day (all 7 days of the week) along with an optimized —— XDR-TB

background regimen (OBR) „„ DR-TB (Mixed pattern)

„„ Week 3–24: BDQ 200 mg (2 tablets of 100 mg) 3 times —— with H mono + FQ/SLI/Lzd resistance

—— with MDR/RR-TB + FQ/SLI + Lzd resistance

per week + optimized background regimen (OBR)
th
„„ After 24 week, and from Week 25 (start of month 7): „„ H-Mono/Poly Drug-Resistant TB

Other drugs in OBR is to be continued

Delamanid (DLM) is a nitro-dihydro-imidazooxazole Treatment Regimens for INH-resistant
compound and acts by inhibiting the key mycolic acid Tuberculosis (HrTB)
synthesis of the Mycobacterium tuberculosis. The drug
The INH and other drug resistance produce significant
is administered orally as 100 mg twice daily (BID) for 2
problem in the success of TB treatment. Table 2 shows the
months followed by 200 mg once daily (QD) for 4 months
importance with various patterns of resistance that can
and is administered along with an optimized background
ultimately lead to MDR/RR TB.
regimen (OBR).
The World Health Organization (WHO) after reviewing
A number of societies, the WHO and the NTEP of
many observational studies (–33 database, n-5418 INH
India have recommended regimens for treating different
mono-resistant cases) and individual patient data (IPD)
forms of DR tuberculosis.5,8-11 These recommendations
came up with these specific guidelines for resistance
are for the treatment of MDR-TB, XDR-TB, INH-resistant
to isoniazid in the absence of R-resistance. Rifampicin,
tuberculosis, or a mixed form of drug-resistant TB cases.
levofloxacin, pyrazinamide, and ethambutol combination
The WHO published the consolidated guidelines
therapy is recommended for confirmed R-susceptible
for DR TB in 2019 that include a set of comprehensive
and H-resistant TB patients with confirmed rifampicin-
recommendations for the DR TB care and treatment.5 It
susceptible and isoniazid-resistant tuberculosis. The
includes eight guideline documents developed by WHO
treatment is for a period of 6 months. Streptomycin
over a period extending from 2011 till 2018. The document
injection or other injectable drug is no more needed in this
includes a consolidated policy recommendations for
regimen. The duration can be extended up to 9 months.
treatment regimens meant for INH-mono-resistant TB,
This will be true for extrapulmonary TB cases and TB with
(HrTB) and MDR/RR-TB. The treatment for the latter HIV also.
category includes both the longer and shorter regimens,
monitoring guidelines using culture and the timing of
starting antiretroviral therapy when this is associated. It
Conventional MDR-TB Regimen of
also includes the recommendations for surgery for MDR- MDR/RR-TB—Longer Duration Therapy
TB cases and an optimal model of care and treatment of The regimen shown in Table 1 is recommended for
such patients. R-resistant (RR) + H sensitive/unknown Or MDR–TB
The recommended treatments of drug-resistant TB are which was used till 2016. With the availability of new
in four groups: drugs, WHO has now grouped the anti-TB drugs used for
„„ Treatment of INH-resistant cases DR-TB for longer MDR-TB regimens into three groups
„„ Long duration (standardized) of therapy and has recommended how to include these drugs in

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 Newer Paradigms in the Management of Drug-resistant TB CHAPTER 189 1221

TABLE 2 Issues associated with H-mono- and polydrug-resistant TB (RNTCP data)

DST pattern Success (%) Failure (%) Progressed to Rif

Total No. with DST available = 2,422 (%age out of 2,422) resistance (%)
H-Mono (LJ/MGIT) n=819 (34%) 31 49 40
SH n=611 (25%) 25 54 52
SHE n=323 (13%) 16 67 53
S Mono n=442 (18%) 26 49 35
HE n=100 (4%) 31 54 64
SE n=68 (3%) 24 49 46
E Mono n=59 (2%) 29 56 59
H Mono (LPA) n=6426 53 24 41

Grouping of drugs recommended for use in MDR-TB drugs are to be added so that the regimen is complete.
TABLE 3 Injectable agents like kanamycin and capreomycin are no
(longer regimens)
more recommended in the longer regimen since BDQ is
Group and steps Drugs a part of the drug therapy. Levofloxacin or moxifloxacin
Group A Levofloxacin, Moxifloxacin are now a part of the longer treatment regimen for MDR/
All the three drugs to be included Bedaquiline RR TB. BDQ can be and should be a part of the regimen
Linezolid for MDR/RR TB in patients above the age of 6 years. If
Group B Clofazimine susceptibility is demonstrated, amikacin can be used in
Add one or both drugs Cycloserine, Terizidone adults above the age of 18 years with adequate measures
Group C Delamanid for safety monitoring. Streptomycin may be considered if
Add to complete the regimen Pyrazinamide
amikacin is not available.
and when drugs from Group A The conventional regimen as indicated above (with
and B cannot be used Imipenem-cilastatin OR
Meropenem BDQ for 6 months) is indicated in MDR/RR-TB with
Amikacin (OR Streptomycin) treatment duration of 24–27 months. If fluoroquinolone
is used for more than 1 month or a second-line injectable
Ethionamide or Prothionamide
drug like amikacin, kanamycin, or capreomycin, which
p-aminosalicylic acid
is not a part of the shorter MDR-TB treatment regimen
as described below, but that may cause cross resistance,
then it should be excluded. However, if a reliable DST has
the regimen (Table 3). This grouping is based on serious
excluded drug resistance to these two classes of drugs,
adverse events and relative risk for failure to treatment, or
the shorter regimen is a choice. BDQ is contraindicated
relapse and death compared to successful treatment.5 (not administered) in pregnancy and extrapulmonary
When a longer regimen is used for MDR/RR TB, all the case. Drug susceptibility tests for pyrazinamide, isoniazid,
three drugs in Group A and at least one agent from Group ethambutol, ethionamide, and fluoroquinolones are not
B must be included so that the treatment is ensured and recommended to decide therapy because of unreliability
is commenced with at least four anti-TB drugs which are of these tests.
likely to be effective, and at least three drugs should be Longer regimen for MDR/RR-TB is usually 18–20
included for the rest of the duration after BDQ is stopped months duration and can be used as a standardized one or
after 6 months. If the regimen includes only one or two in an individualized form. These regimens usually consist
drugs belonging to Group A, then both the drugs listed in of at least five medicines that are considered to be effective.
Group B are to be used. If it is not feasible and the regimen The following factors are taken into consideration to
cannot include drugs from Group A or B, then Group C determine the choice of drugs:

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 1222 SECTION 14 Tuberculosis

„„ Oral drugs are preferred over injectable drugs; The drug is indicated in patients who are 18 years of
„„ drug-susceptibility test (DST results); age or above and can be a part of the combination therapy
„„ reliability of the methods used for DST; for MDR TB.12-14 Of course, now it is also recommended for
„„ drug resistance levels in the population; children of 6 years age more.
„„ previous history of medicine used by the patient; The drug is recommended under RNTCP under the
„„ tolerability of the drugs used; and following conditions:
„„ issues pertaining to drug-drug interactions. „„ Patients who are aged 6 years or above; and can also

be used in patients with HIV, and who are not eligible

NTEP Recommendations for for short course MDR TB treatment regimen due to
resistance, other contraindications or inability to
Longer All Oral Regimen tolerate.
This longer all oral regimen (there is no injectable now) „„ Patients with MDR/RR TB and additional resistance
is now recommended for patients who are not suitable for to any or all fluoroquinolones and all second line
receiving shorter MDR-TB regimen (see later) due to: injectable anti-TB drugs
„„ Exclusion criteria for the shorter regimen
„„ Extensively Drug Resistance TB (XDR TB)
„„ Adverse drugs reactions to any component of the
„„ Patients with mixed pattern of Drug-Resistant TB and
shorter regimen who are failing to any regimen for a drug-resistant TB
„„ If there is resistance to any of the drugs in the regimen
regimen or who are not tolerating the drugs or there
(for inh A mutation ethionamide cannot be given, or are other reasons of contraindication or those patients
pyrazinamide resistance obtained from a certified lab). who come back after disruption or any new criteria
The all oral longer regimen consist of the following: of exclusion for shorter regimen or if the disease is
6–8 months of Bedaquiline (Bdq), Levofloxacin (Lfx), extensive or advanced and when there is a possibility
Linezolid (Lzd), Clofazimine (Cfz) Cycloserine (Cs)/12 of poor outcome at the baseline risk (Table 4).
Levofloxacin (Lfx), Linozolid (Lzd), Clofazimine (Cfz),
Cycloserine (Cs). Shorter MDR-TB Regimen
All regimens under RNTCP (NTEP) of longer duration To reduce the duration of therapy, a shorter duration of
(conventional MDR/MDRFQ/SLI/XDR-TB) are to be therapy, and known as The Bangladesh regimen was first
replaced with this longer oral regimen in adults. The tried in Bangladesh.15 The duration of therapy was for a
regimen can be used in children more than 6 years. If minimum period of 9 months of treatment. The regimen
resistant to FQ class on SL-LPA, levofloxacin is to be consisted of gatifloxacin, clofazimine, ethambutol, and
replaced with high dose moxifloxacin. pyrazinamide all throughout the treatment period of
This is the standard drug regimen now for all MDR/RR 9 months and was supplemented by prothionamide,
TH and XDR TB under the program. kanamycin injection, and high-dose isoniazid for a
minimum of 4 months (intensive phase). The relapse-
Delamanid (Dlm) in DR-TB free cure was 87.9% (95% confidence interval, 82.7–91.6)
WHO has given a conditional recommendation for the observed among 206 patients. The regimen was well
use of delamanid after reviewing all data and pending tolerated and infrequent major adverse drug reactions
further review later. The recommendation states that were observed and they could be manageable. The only
delamanid should only be added to the longer regimen issue with this regimen was that it was not a case control
for MDR TB only when the said treatment regimen cannot study, but an observational study. To establish the
be constituted according to the recommendations by the effectiveness further, a case control study was carried out
WHO. It further emphasizes that delamanid should not be subsequently.16 This short regimen consisted of high dose
added to an otherwise well tolerated and effective longer moxifloxacin, clofazimine, ethambutol, and pyrazinamide
MDR regimen. WHO does not recommend delamanid to administered over a 40-week period, with additional
be a part of the shorter regimen for MDR TB as sufficient kanamycin, isoniazid, and prothionamide in the first 16
data for the same is not there. weeks.16 There was provision of extension of the intensive

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 Newer Paradigms in the Management of Drug-resistant TB CHAPTER 189 1223

TABLE 4 Use of delamanid according to drug resistance

Resistance pattern DST-guided regimen class Intensive phase Continuation Principle of regimen
phase design

Regimen with new drugs for MDR-TB + FQ/SLI resistance:

MDR/RR + res to FQ class (6–9) Km Eto Cs (18) Eto Cs 0 GpA + 1GpB + 2

Z Lzd Cfz + (6) Dlm Lzd Cfz GpC + Z + add on
MDR/RR + resistance to FQ 2 GpC + 1 GpD2
class OR SLI class MDR/RR + res to SLI calss (6–9) Lfx Cm (18) Lfx Eto Cs 1 GpA + 1GpB +
Eto Cs Z LzD Cfz + (6) Dlm Lzd 2 GpC + Z + add on
2 GpC + 1 GpD2

Regimen with new drugs for XDR-TB:

XDR-TB (res to both FQ and XDR-TB (6–12) Cm Eto (18) Eto Cs 0 GPA + 1 GPB +
SLI) Cs Z Lzd Cfz E + (6) Dlm Lzd Cfz E 2 GpC + Z + add on
2 GpC + 1 GpD1 + 1 GpD2

Regimen with new drugs for mixed pattern DR-TB:

Mixed pattern MDR/RR-TB + res to FQ/SLI + Modifity the regimen with new drugs for XDR-TB
DR-TB Lzd or more

phase to 20 or 24 weeks for those who did not have reaction with severe deterioration after 4 months. The
sputum conversion by 16 or 20 weeks, respectively. The observations of the trial supported the efficacy, and hence
regimen was similar to that of the Bangladesh Regimen the use of shorter regimens.
except that moxifloxacin was substituted for gatifloxacin The WHO recommends the use of short regimens
because quality-assured gatifloxacin was not available. A of 9–12 months in place of long regimens in MDR/RR
similar prospective observational study was carried out TB patients provided that the patient has not received
in nine African countries in 1,006 MDR-TB patients. The second-line drugs for more than 1 month and there is no
regimen similarly comprised of a standardized 9-month resistance to fluoroquinolones and second-line injectable
regimen (moxifloxacin, clofazimine, ethambutol) (EMB) anti-TB drugs.4
and pyrazinamide (PZA) throughout and additional The National Technical Expert Group (NTEG) of the
kanamycin, prothionamide, and high-dose isoniazid NTEP, India, has now recommended the use of shorter
during the intensive phase of 4–6 months.17 The cohort regimens in all cases of MDR TB except under the
included 200 (19.9%) patients who were infected with the situations discussed in Table 5.
human immunodeficiency virus (HIV). Of these 1,006
patients, 728 (72.4%) were cured and 93 (9.2%) completed BPaL Regimen
therapy; thus causing a success rate of 81.6%. Failure rate Pretomanid, a new anti-TB drug was approved by the
was 5.9%, 78 (7.8%) died, and 48 patients (4.8%) were US FDA in August 2019 for use along with BDQ and
lost to follow-up. Death among HIV positive cases was linezolid (high dose); this regimen, referred to as the
more (19.0% vs. 5.0%). The treatment success rate was BPaL regimen, is administered for 6 months (extendable
not affected by HIV status. The main factor of failure to 9 months) to treat adults with pulmonary form of
was fluoroquinolone resistance. The bacteriological the extremely drug-resistant TB (XDR-TB), or treatment-
outcome was not affected by resistance to other drugs intolerant or non-responsive multidrug resistant
like pyrazinamide, ethambutol, or ethionamide. Hearing TB (MDR-TB). It inhibits the biosynthesis of mycolic
impairment of 11.4% was the most important adverse drug acid, thus blocking the production of cell wall by the

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 1224 SECTION 14 Tuberculosis

TABLE 5 Contraindications for shorter duration therapy

DST-based criteria Non-DST-based criteria

zz If DST/DRT result for FQ or SLI is resistant or zz Pregnancy
zz Presence of INH A mutation (for Eto) or zz Any extrapulmonary disease in HIV positive cases
zz Resistance to Z (whenever available) zz If the tuberculosis is disseminated, or TB meningitis, or tuberculosis

zz If result for DST (FQ, SLI, INH A mutation, Cfz & Z) is not available, of the central nervous system
history of use of high dose moxifloxacin (Mfx(h)), Kanamycin (Km), zz If the patient does not tolerate any drug in the shorter MDR TB

Ethionamide (Eto) or Clofazimine ( Cfz) for >1 month regimen or if there is a risk of toxicity to a drug in the regimen like
drug-drug interactions

mycobacteria. It acts in non-replicating mycobacteria as a surgery because of advanced and bilateral disease.
respiratory poison releasing nitric oxide under anaerobic Salvage therapy may be an option. Salvage therapy refers
situation. The regimen of the three drugs was investigated to the design of a regimen that combines both new and
in three sites in South Africa. The drug regimen was as previously used drugs in a final effort to attain sputum
follows: conversion before declaring treatment to have failed. A
„„ BDQ in a dose of 400 mg once daily for 2 weeks that combination of BDQ and delamanid along with other
was to be reduced to 200 mg thrice weekly for a period drugs may sometimes help with good results.19-22
of 24 weeks;
„„ Pretomanid—200 mg daily for a period of 26 weeks; General
and Surgery in very few cases will be required and whenever
„„ Linezolid of 1,200 mg daily for up to 26 weeks.
possible, should be offered. It is imperative that
The dose was adjusted according to toxicity. 18 The pretreatment evaluation including detailed drug history,
study enrolled 109 patients (XDR TB and unresponsive confirmation of DR TB using molecular methods, or liquid
MDR TB patients). After 6 months of the trial, an intention culture is a must to ascertain the type of drug-resistant TB.
to treat analysis was done. Around 98 patients (90%; with Pretreatment evaluation will need complete blood count,
CI of 83–95) showed favorable and 11 patients (10%) had liver, and kidney function tests including thyroid function
unfavorable outcomes. There were 7 deaths. One patient test, audiometry, cardiac assessment (for BDQ and DLM)
withdrew consent during treatment, relapse occurred and psychosocial evaluation. Nutrition is also important.
in two cases, and one patient was lost to follow-up. The The Government of India is providing Rs. 500 every month
linezolid toxicity included peripheral neuropathy (81%) to these patients through direct transfer (DBT). Provision
and myelosuppression (48%). Although these were of ancillary drugs, initial admission (not mandatory
common toxicities, they were manageable. Very often now), and prescribing appropriate drugs is very essential.
reduction of dosages or in some cases interruption of Besides, adverse drug reactions monitoring is equally
linezolid resolved the toxicities. The trial is named as important. Whenever there are associated conditions like
the Nix-TB Trial. This BPaL regimen consisting of BDQ, HIV, diabetes, COPD, or other ailments they need to be
pretomanid and linezolid continued to show favorable looked after with equal emphasis. Treatments of these
outcome till 6 months after treatment completion in most cases are usually carried out at the DR-TB center or DR-TB
cases even with high degrees of DR TB although some nodal center.
toxic effects were observed. Major Recommendations of NTEG (National Technical
Expert Group) for the treatment of MDR/XDR TB are as
Salvage Regimen follows: (held from 9-11 September 2020)
In spite all the above approaches, some patients continue There will be only two types of regimens for treating MDR/
to have sputum-culture-positive despite therapy with XDR-TB –
second-line TB drugs. For them treatment options are „„ All oral Longer MDR-TB reagimen (12-18 months); and

limited, especially if there is no scope of resectional „„ Shorter all oral bedaquiline (BDQ) containing regimen.

MU-189 (Sec-14).indd 1224 29-01-2021 15:18:37

 Newer Paradigms in the Management of Drug-resistant TB CHAPTER 189 1225

„„ Shorter all oral bedaquiline (BDQ) containing can be considered as a last resort by NTEP under
regimen, (4-6) Bdq (6 m) Lfx Cfz Z E Hh Eto/ (5) Lfx prevailing ethical standards in individual patients for
Cfz Z E ( (recommended by WHO) in adults (>18 yrs) whom the design of an effective regimen not possible
in individuals confirmed with pulmonary MDR/RR- as per recommendations.
TB, uncomplicated extra-pulmonary TB disease and „„ Post-treatment completion follow-up of all successfully
in PLHIV to be introduced in a phased manner starting treated TB patients at 6th, 12th, 18th and 24th months
with an implementation pilot in selected states to gain to be initiated under NTEP. Plan and expedite
programmatic experience to guide future expansion. introduction of Xpert-XDR test and drug susceptibility
This recommendation may be considered for children testing for the drugs Lzd, Z, Cfz, Bdq, Dlm
(6-17 years) given their special needs pan-India in „„ Consider second line drugs procurement adjustments
consultation with NTEG for paediatric TB. and forecasting (including child friendly formulations)
„„ Only those patients with mutations in both inhA and and capacity building planning.
katG will not be eligible for shorter regimen. However, „„ Strengthen mechanisms for improved patient follow-
patients with only inhA or only katG mutations will up and implementation of aDSM (Active TB drug-
be eligible for the shorter regimen provided other safety monitoring and management) as per the PMDT
conditions are met. guidelines.
„„ Preventive treatment among close contacts of „„ Expedite up-gradation of Nikshay for diagnostic
MDR-TB index patients (in whom FQ resistance
module, DR-TB case finding report and aDSM module
has been ruled out) using 6Lfx for all age groups
for improving monitoring of DR-TB patients.
to be introduced in a phased manner starting with „„ Build capacity of all providers (labs, DR-TBC, field
an implementation pilot in selected states to gain
staff ) in optimally utilizing Nikshay (electronic data
programmatic experience to guide future expansion.
monitoring system) for real-time data entry as well
This recommendation may be considered for children
as monitoring at state and district level in order to
given their special needs pan-India in consultation
improve the quality of care and timely regimen change
with NTEG for paediatric TB.
in DR TB patients.
„„ For all oral longer MDR-TB regimen, the revised
„„ Programme to issue DO to all DRTB Centres to
replacement drugs sequence recommended would be
consider admitting children requiring in-patient care
Delamanid, Amikacin, Pyrazinamide, Ethionamide,
for management of DRTB as per PMDT guidelines and
PAS, Ethambutol, Carbapenems.
„„ Extension of BDQ beyond 6 months to be considered proactively engage the available paediatricians (in-
in patients in whom an effective regimen cannot be house/honorary) for the management of paediatric
otherwise designed if only 2 of 5 drugs are available DR-TB patients.
from Groups A & B and adequate number of Group „„ Programme to issues Demi-Offcial letter for use of
C drugs are not available due to high background BDQ in children in the age-group 12-17 years for
resistance, non-availability or unreliability of DST. management of DR-TB
„„ Use of BDQ in pregnancy needs further discussion „„ National Task Force (NTF) mechanism to support the
with the concerned experts before taking a policy establishment and functioning of DR-TB centres in
decision for its use under the program setting. remaining Medical Colleges across India (also engaging
„„ Combined use of BDQ and DLM in the regimen is Paediatric Dept. for management of paediatric DR-TB
recommended for those M/XDR-TB patients in whom patients).
an appropriate regimen cannot be designed using all 5 „„ Programme to establish the mechanism to ensure
drugs from Group A and B. dissemination of any policy change to all stakeholders
„„ BPaL research proposal may be considered with especially Nodal/District DR-TB sites including
flexibility to adapt with anticipated results of ZeNix trial medical colleges. NTEP website to have all important
and submitted to the National Operational Research communications sent to states periodically uploaded
Committee for approval and implementation. BPaL so that it can be easily accessed by all concerned.

MU-189 (Sec-14).indd 1225 29-01-2021 15:18:38

 1226 SECTION 14 Tuberculosis

Conclusion 10. Falzon D, Schünemann HJ, Harausz E, et al. World Health

Organization treatment guidelines for drug-resistant tuberculosis,
The previously used longer but less effective drug regimen 2016 update. Eur Respir J. 2017;49(3):1602308.
that contained an injectable drug has now been replaced 11. Nahid P, Mase SR, Battista Migliori G, et al. Treatment of drug-
with all oral, injection free short-course and longer duration resistant tuberculosis: an official ATS/CDC/ERS/IDSA Clinical
(~18 months) therapy and is more effective. The National Practice Guideline. Am J Respir Crit Care Med. 2019;200:e93-e142.
TB Elimination Program has quickly adopted these changes 12. Mohr E, Hughes J, Reuter A, et al. Delamanid for rifampicin-resistant
and has introduced these forms of therapy throughout the tuberculosis: a retrospective study from South Africa. Eur Respir J.
2018;51(6):1800017.
country so that DR-TB cases are treated more successfully.
13. Guidelines for the use of delemanid in the treatment of drug
These are important developments that have been adopted
resistant TB in India, 2018. Revised National Tuberculosis Control
by the program so that marching toward End TB will be a
Program, Central TB Division, Govt. of India. Available from https://
reality. However, prevention, early diagnosis, and completion tbcindia.gov.in/WriteReadData/l892s/8131480597Guidelines%20
of therapy are important keys to success. for%20use%20of%20Delamanid%20for%20treatment%20of%20
DR-TB%20in%20India.pdf
14. Groote-Bidlingmaier F, Patientia R, Sanchez E, et al. Efficacy and
References safety of delamanid in combination with an optimised background
1. TB Division, Nikshay portal. https://tbcindia.gov.in/Central regimen for treatment of multidrug-resistant tuberculosis: a
[Accessed on 2nd June 2020]. multicentre, randomised, double-blind, placebo-controlled,
2. Nikam C, Kazi M, Nair C, et al. Evaluation of the Indian TrueNAT parallel group phase 3 trial. Lancet Respir Med. 2019;7(3):249-59.
micro RT-PCR device with GeneXpert for case detection of 15. Van Deun A, Maug AK, Salim MA, et al. Short, highly effective
pulmonary tuberculosis. Int J Mycobacteriol. 2014;3(3):205-10. and inexpensive standardized treatment of multidrug-resistant
3. Global tuberculosis report 2019 ISBN 978-92-4-156571-4 © World tuberculosis. Am J Respir Crit Care Med. 2010;182(5):684-92.
Health Organization 2019. Available from https://apps.who.int/iris/ 16. Nunn AJ, Phillips PPJ, Meredith SK, et al A trial of a shorter regimen
bitstream/handle/10665/329368/9789241565714-eng.pdf?ua=1 for rifampin-resistant tuberculosis. N Engl J Med. 2019;380:1201-13.
4. Report of the first National Anti-Tuberculosis Drug Resistance 17. Trébucq A, Schwoebel V, Kashongwe Z, et al. Treatment outcome
Survey India, 2014-16. Ministry of Health and Family Welfare, with a short multidrug-resistant tuberculosis regimen in nine
Government of India. Available from https://tbcindia.gov.in/ African countries. Int J Tuberc Lung Dis. 2018;22(1):17-25.
showfile.php?lid=3315 18. Conradie F, Diacon AH, Ngubane N, et al. Treatment of highly
5. WHO consolidated guidelines on drug-resistant tuberculosis drug-resistant pulmonary tuberculosis. N Engl J Med. 2020;382(10):
treatment, 2019. Available from https://www.who.int/tb/ 893-902.
publications/2019/consolidated-guidelines-drug-resistant-TB- 19. Ferlazzo G, Mohr E, Laxmeshwar C, et al. Early safety and efficacy of
treatment/en/ the combination of bedaquiline and delamanid for the treatment
6. India TB Report, 2019. The Revised National TB Control Program, of patients with drug-resistant tuberculosis in Armenia, India,
Annual Report. Central TB Division, Government of India. Available and South Africa: a retrospective cohort study. Lancet Infect Dis.
from WWW.tbcindia.gov.in 2018;18(5):536-44.
7. Borisov SE, Dheda K, Enwerem M, et al. Effectiveness and safety of 20. Sarin R, Vohra V, Singla N, et al. Early efficacy and safety of
bedaquiline-containing regimens in the treatment of MDR- and bedaquiline and delamanid given together in a “Salvage Regimen”
XDR-TB: a multicentre study. Eur Respir J. 2017;49(5):1700387. for treatment of drug-resistant tuberculosis. Indian J Tuberc.
8. Guidelines on programmatic management of drug-resistant 2019;66(1):184-8.
tuberculosis in India, Revised National Tuberculosis Control Program, 21. Maryandyshev A, Pontali E, Tiberi S, et al. Bedaquiline and delamanid
CentralTB Division, Govt of India, 2017. Available from https://tbcindia. combination treatment of 5 patients with pulmonary extensively
gov.in/index1.php?lang=1&level=2&sublinkid=4780&lid=3306 drug-resistant tuberculosis. Emerg Infect Dis. 2017;23(10):1718-21.
9. Lange C, Abubakar I, Alffenaar JW, et al. Management of patients 22. Seung KJ, Becerra MC, Atwood SS, et al. Salvage therapy for
with multidrug-resistant/extensively drug-resistant tuberculosis in multidrug-resistant tuberculosis. Clin Microbiol Infect. 2014;
Europe: a TBNET consensus statement. Eur Respir J. 2014;44(1):23-63. 20(5):441-6.

MU-189 (Sec-14).indd 1226 29-01-2021 15:18:38

 CHAPTER

190 National DR-TB

Guidelines in 2021
Vishwanath Upadhyay, Surendra K Sharma

Abstract 
Drug resistant-tuberculosis (DR-TB) is relatively difficult to treat than drug-sensitive-TB. Nearly 27% of global multi-drug
resistant/rifampicin resistant-TB (MDR/RR-TB) patients are in India. National guidelines for the treatment of DR-TB in
India [programmatic management of drug resistant-TB (PMDT)] have been essentially adapted from ‘WHO consolidated
guidelines for DR-TB treatment (2020)’. These national guidelines emphasize access of universal DST to all TB patients
and categorize DR-TB into rifampicin susceptible but isoniazid monoresistant-TB (Hr-TB), MDR/RR-TB, and extensively
drug resistant-TB (XDR-TB). As per PMDT guidelines, patients should be examined for Hr-TB and should be treated with
uniphasic rifampicin, ethambutol, pyrazinamide, and levofloxacin regimen for 6 months. Preferably, 7-drug injection-
free, pan-oral shorter (9–11 months) or 5-drug pan-oral longer (18–20 months) DST-guided, bedaquiline-containing
individualized MDR-TB treatment regimen should be constituted for intensive phases and 4-drug regimen for continuation
phases, respectively. Monthly smear and culture should be done during follow-up. Active TB drug-safety monitoring
and management (aDSM) is strongly recommended. Post-treatment, follow-up at 6th,12th,18th, and 24th months of all
successfully treated DR-TB cases under national-TB elimination programme (NTEP) is recommended.

Introduction confirming the presence of Mycobacterium tuberculosis

(Mtb) and subsequently demonstrating its resistance to
National Guidelines on drug resistant-tuberculosis
first-line and second-line anti-tuberculosis drugs on drug-
(DR-TB) in India [programmatic management of drug
susceptibility testing (DST). Various sub-entities of DR-TB
resistant-TB (PMDT)] 1 have been adapted from WHO
are defined in Box 1.1
Consolidated Guidelines on DR-TB treatment (2020). 2
Recently, American Thoracic Society/Centers for Diseases
Control and Prevention/European Respiratory Society/
Epidemiology
Infectious Diseases Society of America (ATS/CDC/ERS/ DR-TB is highly prevalent1,2 and continues to be a serious
IDSA) have jointly published comprehensive guidelines public health threat. According to the WHO Global TB
on treatment of DR-TB. 3 Table 1 compares various report 2020,4 worldwide there were 465,000 people (range
differences between these three guidelines.1-3 400,000–535,000) with new rifampicin resistant-TB (RR-
TB) diagnosis and 78% of these had multidrug resistant-
TB (MDR-TB). India (27%), China (14%), and Russian
DR-TB Definitions Federation (8%) contributed to almost half of these cases
The term DR-TB is a broader one encompassing several in 2019.4 Globally, 3.3% of new and 17.7% of previously
subentities, and is primarily a laboratory diagnosis treated patients had MDR/RR-TB.4

MU-190.indd 1227 29-01-2021 15:17:50

 1228

MU-190.indd 1228
TABLE 1 Comparison of WHO, ATS/CDC/ERS/IDSA and PMDT, India guidelines for the treatment of drug-resistant TB (DR-TB)

WHO consolidated guidelines, 2020 ATS/CDC/ERS/IDSA guidelines, 2019 PMDT, India, 2019-20
SECTION 14

Types of DR-TB Deals with Hr-TB, MDR/RR-TB and MDR-TB Deals with Hr-TB, MDR-TB,pre-XDR-TB and Deals with Hr-TB, MDR/RR-TB and XDR-TB
with additional FQs resistance XDR-TB
Does not cover RR-TB
DST if Mtb isolated Comprehensive DST if Mtb is isolated Microbiological data are required to Universal DST is strongly recommended to
constitute an individualized treatment constitute treatment regimen for DR-TB
regimen based on DST of the Mtb strain
Tuberculosis

isolated
Hr-TB Information on katG and inhA mutations No specific recommendation for Recommendation for genotypic DST is similar
on genotypic (molecular) DST is essential. genotypic DST to WHO 2020 guidelines
Hr-TB is treated with rifampicin, For HR-TB patients should be treated with About 10% of the Indian patients have inhA
ethambutol, pyrazinamide and rifampicin, ethambutol, isoniazid and mutations where Hh can be administered and
levofloxacin for 6 months [(6) R E Z Lfx]. pyrazinamide for 6 months. Eto can’t be used because of cross-resistance
If Lfx can’t be used, R E Z treatment is Duration of pyrazinamide can be
recommended shortened to 2 months in selected About 90% have katG mutations and where Eto
situations such as non-cavitary disease, can be used. Addition of levofloxacin (Lfx) is
low- burden disease, or intolerance to done without a split for 6 months [(6) R E Z Lfx]
pyrazinamide
Classification of Drugs Drugs are classified into ABC groups Recommendations: *Grouping of drugs has been adapted from
depending on safety and efficacy profiles. STRONG FOR: Bdq, later generation WHO guidelines 2020
fluoroquinolones (Lfx and Mfx)
Treatment regimen is preferably CONDITIONAL FOR: Lzd, Cfz Cs/Trd, E, Z
constituted from Groups A and B and if it is (provided susceptibility to Z).
not possible then from drugs can be added CONDITIONAL FOR: Injectables Am and
from Group C S, Imp-Cln and Mpm/Amx-Clv (if one of
these is essential to constitute a regimen)
CONDITIONAL AGAINST: Eto/Pto, Km
and Cm, PAS
STRONG AGAINST: macrolides
(azithromycin and clarithromycin), Amx-
Clv
Pan-oral Bdq- containing Intensive phase = at least 4 drugs Intensive phase = 5 drugs Intensive phase =5 drugs
longer regimen (based Continuation phase= 3 drugs Continuation phase= 4 drugs Continuation phase =4 dugs
on DST) Pan-oral 5-drug longer regimen is
constituted from Group A and B drugs and Regimen: (6- 8) Bdq (6) Lzd Lfx Cfz Cs/12 Lfx Lzdl
if it is not possible then Group C drugs are Cfz Cs
included from the replacement sequence
depending upon drug susceptibility profile
and tolerance
Contd...

29-01-2021 15:17:50
MU-190.indd 1229
Contd...

WHO consolidated guidelines, 2020 ATS/CDC/ERS/IDSA guidelines, 2019 PMDT, India, 2019-20
Pan-oral Bdq- containing A shorter all-oral Bdq-containing 7-drug Standardized 9- to 11-month shorter 9- to 11-month shorter pan-oral Bdq-containing
shorter regimen regimen of 9-12 months duration is MDR-TB regimen is not preferred as it has 7-drug regimen comprising of (4-6) Bdq (6)
recommended in eligible patients with injectables. A research recommendation Lfx Lfz Cfz Z E Hh Eto/ (5) Lfx, Cfz Z E to be
confirmed MDR/RR-TB who have not been has been given for the conduct of RCTs administered if there are no contraindications
exposed to treatment with second-line to evaluate the efficacy, safety and
TB medicines used in this regimen for > tolerability of newer oral drugs
1month, and in whom resistance to FQs
has been excluded
BPaL regimen Bdq, Pa and Lzd (BPaL) for pre-XDR-TB A total duration of treatment between 15 Combined use of Bdq and Dlm is recommended
(MDR-TB plus FQs) under operational and 24 months after culture conversion is for M/XDR-TB patients in whom an appropriate
research (OR) conditions who have no recommended in patients with pre-XDR- regimen can’t be made using all 5 drugs of
previous exposure or <2 weeks exposure and XDR-TB groups A and B
to Bdq and Lzd A 20-month treatment is recommended for XDR-
TB patients
BPaL regimen to be tried under OR conditions
Use of injectable Amikacin may be included in patients Use of injectables is not recommended. Amikacin or streptomycin can be used to
aged ≥ 18 years on longer regimens to However, Am/S may be included if one is constitute a 5-drug regimen in patients with
constitute a regimen. unable to constitute a 5-drug regimen and aged >18years, if it is essential and Mtb is
Use of injectables (especially Kanamycin Mtb is drug-sensitive susceptible to the drug depending upon
and Capreomycin) is avoided as far as tolerance of drugs and in vitro drug resistance
possible. Although, if all other options are
exhausted, for the use of streptomycin
in vitro drug sensitivity must be
demonstrated

Duration of treatment Intensive phase=6-7 months Intensive phase= 5–7 months after culture Intensive phase= 6–8 months (Bdq given for 6
for longer MDR-TB Total duration=18-20 months conversion months)
After culture conversion= 15-17 months Total duration= 15–21 months Continuation phase= 12 months (fixed duration)
In MDR/RR-TB patients, on longer regimens Total duration = 18–20 months
containing amikacin or streptomycin an Extension of intensive phase will depend on
intensive phase of 6-7 months is suggested culture conversion report at 4th month or beyond
for most patients. However, the duration
National DR-TB Guidelines in 2021

may be modified according to response to

treatment
Contd...
CHAPTER 190
1229

29-01-2021 15:17:50
 1230

MU-190.indd 1230
SECTION 14

Contd...
WHO consolidated guidelines, 2020 ATS/CDC/ERS/IDSA guidelines, 2019 PMDT, India, 2019-20
Surgery for lung In patients with RR-TB or MDR-TB, elective According to guidelines, an elective partial Lung resection surgery is not done usually due
Tuberculosis

resection partial lung resection (lobectomy or lung resection (e.g., lobectomy or wedge to lack of infrastructure and well-trained and
wedge resection) may be done along a resection) with a DST-guided MDR-TB skilled thoracic surgeons
constituted drug regimen in a centre with treatment regimen is more beneficial
a skilled and experienced thoracic surgeon compared with medical therapy alone
and with careful selection of candidates when clinical judgment, supported by
bacteriological and radiographic data,
suggests a strong risk of relapse or
treatment failure
Pneumonectomy is not recommended
Preventive therapy No specific recommendation for LTBI For LTBI for MDR-TB patients’ contacts, 6 No specific recommendation for LTBI
to 12 months of treatment with a later-
generation fluoroquinolone alone or with
a second drug, on the basis of DST of the
Mtb isolate of the source- case
*Replacement drugs sequence consists of the following order: delmanid (Dlm), amikacin (Am), pyrazinamide (Z), ethionamide (Eto), para-aminosalicylic acid (PAS),
ethambutol (E), penems. Use of Bdq during pregnancy is under consideration. Bdq may be used beyond 6 months if only 2 of 5 drugs from Groups A and B are available and
adequate no. of Group C drugs are not available due to high background resistance non-availibility or unreliability of DST
Note: ATS/CDC/ERS/IDSA guidelines (2019) and WHO Consolidated DR-TB guidelines (2020) categorise following drugs, Am/S and E, Hh differently whereas in PMDT, 2019-20
PAS has been preferred over E and carbapnems
Am, amikacin; Amx/Cln, amoxicillin -clavulanic acid; ATS/CDC/ERS/IDSA, American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and
Infectious Diseases Society of America; Bdq, bedaquiline; Cfz, clofazimine; Cln, cilastatin; Cm, capreomycin; Cs, cycloserine; Dlm, delamanid; DST, drug-susceptibility testing; E, ethambutol;
EPTB, extrapulmonary TB; Hh, high-dose isoniazid; Hr-TB, rifampicin sensitive but isoniazid resistant-TB; Imp, imipenem; Km, kanamycin; Lfx, levofloxacin; LTBI, latent TB infection; Lzd, linezolid;
Lzdl, low dose linezolid (300mg); MDR/RR-TB, multidrug-resistant/ Rifampicin resistant-tuberculosis; Mfx, moxifloxacin; Pa: pretomanid; PAS, p-aminosalicylic, acid; PLHIV, people living with HIV;
PMDT, programmatic management of drug-resistant tuberculosis; S, streptomycin; WHO, World Health Organisation; XDR-TB, extensively drug- resistant TB; Z, pyrazinamide
Source: WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2020; Treatment of Drug-Resistant Tuberculosis-An Official ATS/
CDC/ERS/IDSA Clinical Practice Guideline,2019; Guidelines on programmatic management of drug-resistant tuberculosis in India, 2019-20.

29-01-2021 15:17:50
 National DR-TB Guidelines in 2021 CHAPTER 190 1231

BOX 1 DR-TB diagnosis methods and definitions BOX 2 Risk factors for drug-resistant tuberculosis

Laboratory methods for DR-TB diagnosis zz Factors related to previous treatment

zz Genotypic (rapid molecular tests): provide early diagnosis Incomplete and inadequate treatment
—— Nucleic acid amplification tests
Inadequate treatment adherence
Cartridge-based nucleic acid amplification test (CBNAAT):
zz Virulence of Mtb strain, e.g., W-Beijing genotype is well-known
1.5 hours for multidrug resistance
*TrueNat (chip based): 1 hour for Mtb detection + 1 hour for
zz Presence of multidrug transporter proteins may lead to drug
Rifampicin resistance testing resistance in Mtb strain
—— First-line and second-line line probe assays (FL-LPAs and SL-
zz Lower anti-TB drugs levels due to either malabsorption of anti-TB
LPAs): 48 hours turn-around time
zz Phenotypic methods (culture methods): time-consuming, used
drugs or drug-drug interactions like rifampicin and moxifloxacin
zz Male gender
for confirmation and drug susceptibility testing (DST)†:
zz Older age
—— Liquid culture: 42 days
—— Solid culture: 56 days zz Low BMI

zz Diabetes mellitus
DR-TB definitions
zz HIV/AIDS
Monoresistance: refers to Mtb resistance to one of the first-line
zz Factors such as psychiatric illness, alcoholism, drug addiction,
anti-TB drugs. Isoniazid monoresistance (Hr-TB) is commonly
encountered and homelessness do predict non-adherence to treatment
Polydrug resistance (PDR): resistance to more than one first-line BMI, body mass index; HIV/AIDS, human immuno­deficiency virus/
anti-TB drugs other than both isoniazid and rifampicin acquired immunodeficiency virus; Mtb, Mycobacterium tuberculosis
Multi-drug resistant TB (MDR-TB): Mtb resistance to both Source: Adapted from Sharma SK, Mohan A. Multidrug-resistant
rifampicin and isoniazid tuberculosis: a menace that threatens to destabilize tuberculosis
Pre-XDR-TB: includes MDR-TB and resistance to either of control. Chest. 2006;130:261‐72.
flouroquinolones (FQs) or second-line injectables (SLIs)
‡
Extensively drug resistant TB (XDR-TB): a subset of MDR-TB that
includes additional resistance to FQs and SLIs. treatment. Various risk factors for DR-TB are described in
*TrueNat is a chip based battery operated nucleic acid amplification the Box 2.5
test system made in India. According to National Anti-tuberculosis Drug
In FL-LPA, mutations in Mtb for rifampicin and isoniazid resistance
and in SL-LPA the mutations for FQs (Mfx and Lfx) and injectables Resistance Survey (NDRS) in India,6 ~8% of Hr-TB patients
(amikacin, kanamycin and capreomycin) are tested are resistant to any fluoroquinolone (FQ) drug whereas
†
DST definitions: Critical concentration (CC), is the lowest resistance to linezolid (Lzd) is uncommon in MDR/RR-TB
concentration of an anti-TB drug in vitro that will inhibit the growth
and minimal in isoniazid (H) mono/poly-DR-TB. In India,
of 99% of phenotypically wild-type strain of Mtb complex. Minimal
inhibitory concentration (MIC) is the lowest concentration of an H resistant-TB (Hr-TB) occurs due to katG gene mutations
antimicrobial agent that inhibits growth of > 99% of a microorganism in ~90% patients and high dose H (Hh) may be ineffective
in a solid or broth dilution susceptibility test. Critical breakpoint (CB) in these patients whereas in the remaining (~10%) inhA
concentration(s) of an antimicrobial agent which defines an MIC above
the critical concentration that separates strains that will likely respond gene mutation confers low-level resistance to H7 and cross
to treatment. The CB is used in to guide individual clinical decisions in resistance to ethionamide (Eto). In this situation, Hh can
patient treatment
‡
be administered.1
As SLIs will no longer be recommended in the revised DR-TB
treatment guidelines, XDR-TB definition will require revision in future
Source: Guidelines on programmatic management of drug-resistant Integrated Diagnosis of DR-TB
tuberculosis in India, 2019–20
According to National Guidelines,1 it is essential to rapidly
characterize Mtb sensitivity or resistance to H, FQs, and
India had 66,255 laboratory-confirmed MDR/RR-TB second-line injectables (SLIs) with first line-line probe
in 2019, 55.5% of these were tested for second-line anti-TB assay (FL-LPA) and second line-line probe assay (SL-LPAs)
drugs and 3.5% had extensively drug-resistant-TB (XDR- respectively after receiving nucleic acid amplification tests
TB). MDR-TB developed among 2.8% of new and 14% of (NAAT) amplification report and treat according to DST
previously treated patients had MDR/RR-TB.4 Globally, report in order to avoid further amplification of DR-TB.
only one in three diagnosed MDR/RR-TB accessed DR-TB Subsequently, although time-consuming, phenotypic
treatment, and in India 48% of laboratory confirmed culture with DST is required to establish the diagnosis.
MDR/RR-TB and 30% of XDR-TB cases were initiated on DST-guided treatment is strongly recommended in the

MU-190.indd 1231 29-01-2021 15:17:50

 1232 SECTION 14 Tuberculosis

Flowchart 1: Integrated DR-TB diagnostic algorithm

Note: Vulnerable populations: As per WHO, children, pregnant women, elderly people, malnourished people, and people who are ill or
immunocompromised, are particularly vulnerable when a disaster strikes, and take a relatively high share of the disease burden associated with
emergencies. In H resistant Mtb ioslates, katG gene and inhA gene mutations can co-exist and it is considered as ‘high-level’ resistance only.
Am, amikacin; ATT, anti-tuberculosis treatment; Bdq, bedaquiline; CBNAAT, cartridge-based NAAT; Cfz, clofazimine; Dlm, delamanid; Eto, ethionamide;
FL-LPA, first-line drug-line probe assay; FQ, fluoroquinolone; H, isoniazid; hINH, high dose isoniazid; inhA-R, inhA gene mutation resistance; katG-R, katG
gene mutation resistance; LC-DST, liquid culture drug susceptibility test; Lzd, linezolid; Mfx, moxifloxacin; Mfxh, high dose moxifloxacin; MIC, minimum
inhibition concentration of drugs; NAAT, nucleic acid amplification test; PLHIV, people living with HIV; RR, rifampicin resistant; RS, rifampicin sensitive; SLI,
second line injectable agents; SL-LPA, second-line drug-line probe assay; TureNat, Chip based NAAT system made in India
Source: Guidelines on programmatic management of drug-resistant tuberculosis in India, 2019–20.

National TB Elimination Program (NTEP) 1-3 erstwhile molecular tests for the diagnosis of DR-TB. Various
known as Revised National TB Control Program (RNTCP) molecular tests include NAAT (cartridge based NAAT or
known to avoid further amplification of resistance and the chip based TrueNat) and FL-LPAs (GenoType MTBDRplus
integrated diagnostic algorithm (Flowchart 1) can be used V1, GenoType MTBDRplus V2) and Nipro (NTM plus
for this. As mentioned previously, it is established that MDRTB detection kit) and SL-LPAs (MTBDRsl V1 and
rapid molecular tests such as NAAT and LPAs provide early MTBDRsl V2).9 The NAAT test uses real time-polymerase
diagnosis of DR-TB and are helpful when used in tandem chain reaction (RT-PCR) principle and the result is
with phenotypic methods (solid and liquid cultures) as reported as Mtb detected/not detected with additional
latter take longer for DST results. finding of Mtb rifampicin sensitive or resistant. Under
The standard smear microscopy test has some inherent programmatic conditions where the laboratory capacity
limitations as it is usually difficult to diagnose TB when the is limited and facilities for FL-LPAs and SL-LPAs are not
bacillary load in the sputum specimen is <103/mL.8 The available, the report of NAAT as RR-TB is considered as
DST can be growth-based (phenotypic DST) on liquid a surrogate marker of MDR-TB and the patient is treated
culture (Bactec MGIT 960) or solid culture (Lowenstein- as MDR-TB as phenotypic tests with DST usually take
Jensen culture) or genotypic DST which employs rapid from weeks to months. While the test report from FL-

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 National DR-TB Guidelines in 2021 CHAPTER 190 1233

LPAs provides additional information of Mtb sensitivity or (GenoType MTBDRsl V1) showed pooled sensitivity and
resistance to H, SL-LPAs provide additional information specificity for the detection of fluoroquinolone resistance
on resistance to fluoroquinolones and SLIs.9 by direct testing of 86.2% and 98.6% respectively, and
LPAs are a family of deoxyribonucleic acid (DNA) a pooled sensitivity and specificity for the detection of
strip-based tests that determine the drug-resistance second-line injectable drugs resistance of 87% and 99.5%,
profile of an MTB1 complex strain through the pattern of respectively.9
binding of amplicons (DNA amplification products) to
probes targeting the most common resistance associated Treatment of DR-TB
with the mutations to first- and second-line agents and
to probes targeting the corresponding wild type (WT) Treatment of Isoniazid-resistant Tuberculosis
DNA sequence.9 LPAs are WHO-approved tests for rapidly (Hr-TB)
detecting drug resistance to the first- and second-line Substitution of H with levofloxacin (Lfx) is recommended
agents. They can be used for testing of culture isolates for the treatment of Hr-TB. Drug regimen consisting of
(indirect testing) and direct testing of acid-fast bacilli rifampicin, ethambutol, pyrazinamide, and levofloxacin
(AFB) smear microscopy specimens (FL-LPA), and both (REZ-Lfx) is administered for 6 months without split
smear positive and smear negative sputum specimens of intensive and continuation phases. 2 Although,
(SL-LPA). Mutations are detected by the binding of moxifloxacin (Mfx), arguably more potent than Lfx,
amplicons to probes targeting the most commonly has several limitations due to drug-drug interactions,2
occurring mutations (MUT probes) or inferred by the and QTc-prolonging ability when coadministered
lack of hybridization (lack of binding) of the amplicons with drugs with similar properties. Further, Mfx peak
to the corresponding WT probes.9 The post-hybridization plasma concentration and exposure declines when
reaction leads to the development of the colored bands coadministered with rifampicin, however, unlike Lfx, does
on the test strip detecting probe binding. LPA results not require dose modifications in chronic kidney disease.
are reported as “Resistance not detected” instead of Recent ATS/CDC/ERS/IDSA guidelines provide option of
“Susceptible” to define the bacteria resistance profile.9 shortening the duration of pyrazinamide (Z) to 2 months
Given the limitations of LPA and in particular the fact in presence of non-cavitary and low-burden disease,
that the resistance cannot be completely excluded even intolerance, or toxicity to Z.3
in the presence of all WT probes as not all mutations Treatment can be extended to 9–12 months as per
that confer resistance are covered by these tests or clinical, radiological, and microbiological responses,
mutations that are covered may be below the limit of especially in extrapulmonary TB involving bone, central
detection, it is more appropriate to report the result as nervous system (CNS) and/or miliary TB. Use of injectable
“resistance detected” or “resistance not detected.” 9 The agents like streptomycin and others is not recommended
term “resistance detected” is used whenever one or more in the guidelines. 1-3 In case of additional resistance,
MUT probes identifying specific mutations conferring intolerance or toxicity to a drug, its substitution can be
resistance to the drugs are developed regardless of effected by, in order of preference with linezolid (Lzd),
whether WT probes are developed or not. 9 The term clofazimine (Cfz), or cycloserine (Cs).
“resistance inferred” is used whenever one or more WT
probes in regions of the gene known to confer resistance Treatment of MDR/RR-TB
to the drug are not developed and none of the MUT probes Two evidence-based guidelines on DR-TB treatment have
in the corresponding region is developed. In this case been published in 2019. A propensity score-matched
the precise mutation cannot be reported, only the region meta-analysis of an individual patient data meta-analysis
where the mutation lies is identified.9 (IPDMA) from 12,030 patients in 50 studies from 25
FL-LPA showed sensitivity and specificity for the countries was used for making recommendations in these
detection of rifampicin resistance 96.7% and 98.8%, guidelines. Major differences between WHO Consolidated
respectively, and for the detection of H resistance, sensitivity Guidelines, ATS/CDC/ERS/IDSA Guidelines, and current
and specificity 90.2% and 99.2%, respectively.10 SL-LPA Indian Guidelines, 2019–20, are listed in Table 1. Current

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 1234 SECTION 14 Tuberculosis

BOX 3 Principles of drug-resistant TB management

zz Drug susceptibility testing(DST)-guided treatment is recommended for DR-TB and universal DST should be available to all TB patients
zz A bedaquiline based 5-drug regimen (3 drugs from Group A, two from Group B and if not possible from Group B then one or two drugs from
Group C; refer Table 2) should be constructed for MDR/RR-TB
zz A fully oral regimen is preferred and injectables like kanamycin and capreomycin are no longer recommended
zz Long-term bedaquiline-based drug regimen should have at least 5 drugs for initial 6 months and afterwards 4 drugs should be continued

for rest of the treatment duration

zz The individualized, longer MDR-TB regimen is to be administered for the duration of 18–20 months, and the duration is primarily based on

patient’s response to treatment or 15–17 months after culture conversion

zz In addition to smears, monthly follow-up cultures should be done from 1st month till the end of intensive phase. Decision on treatment

extension should be based on culture reports at 4th, 5th and 6th month
th
zz If patient’s culture is positive after 8 months from the specimen submitted at the end of 6 month, treatment failure will be declared
zz If drugs need to be discontinued due to intolerance or resistance on DST, then sequence of drug replacement should be according to the

guidelines
h
zz If fluoroquinolone (FQ) class resistance is detected on SL-LPA, replace Lfx with high dose moxifloxacin (Mfx )
zz Fluoroquinolone should not to be used, if resistance to high dose moxifloxacin with LC-DST (MIC, 1.0 μg) is reported,
zz In case of fluoroquinolone-resistant pre-extensively drug resistant (pre-XDR)-TB, a second line injectable drug (SLID) may be considered
zz Duration of XDR-TB treatment should be longer than MDR/RR-TB
zz Cascades of training are recommended for implementation and adoption of rapid changes in DR-TB management integrated with efficient

mechanism of active drug-safety monitoring and management (aDSM).

+ 2+ 2+
zz aDSM should focus on QTc monitoring (along with observation of serum K , Mg and Ca levels), myelosuppression, optic and peripheral

neuropathy and lactic acidosis

zz Ensure treatment adherence by different methods complemented with information and communication technology based adherence

monitoring and reminder systems

Note: As per WHO consolidated guidelines on drug-resistant tuberculosis treatment, duration of standardized shorter MDR-TB regimen is 9-12
months which is one month more than the original standardised shorter MDR-TB regimen used in trial, given that some patients required slightly
more than 11 months to complete a shorter regimen owing to brief interruptions.
LC-DST, liquid culture DST; Lfx, levofloxacin; MDR-TB, multi-drug resistant TB; Mfxh, high-dose moxifloxacin; MIC, minimum inhibitory
concentration; SL-LPA, second-line-LPA
Source: WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment (2020).

Indian guidelines for MDR/RR-TB have been primarily index (BMI<16)]. After 6 months of treatment, the Mtb
adapted from WHO Consolidated Guidelines, 2020 culture conversion was achieved in 83% of patients. The
(Box 3). median time to culture conversion was 60 days, higher
A new feature of guidelines is regrouping of DR-TB BMI was associated with faster culture conversion.
drugs into A, B, and C categories and the ranking is based Mortality was 12% and a majority of deaths (56%) occurred
on the efficacy profiles of drugs (Table 2).1,2 Based on within the first 6 months of treatment. While Bdq was
6-month culture conversion results in the Delamanid permanently discontinued in about 2%, its administration
(Dlm) Phase III trial, Dlm has been placed in group C.11,12 was temporarily interrupted in about 3% due to QTc
Dosages of drugs for MDR/RR-TB treatment as per weight interval prolongation and after correction of abnormalities
categories are detailed in Table 3.1 Interim analysis of of Mg2+, Ca2+, and K+, it could be successfully reintroduced.
an Indian study on safety and efficacy of bedaquiline Based on these results it was concluded that Bdq-based
under conditional access program (CAP) for MDR-TB in treatment for MDR/RR-TB is safe and can be scaled up
India was recently published.13 This feasibility study was with careful monitoring of QTc interval. According to
conducted between June 2016 and August 2017 under WHO Guidelines, decisions to start the standardized
programmatic conditions in the field settings at six sites shorter MDR-TB regimen should be made according to
of India. Of 620 MDR-TB patients, 57% patients had MDR- patient preference and clinical judgment (Box 4). Since
TB with additional drug resistance to fluoroquinolones some geographical areas in India are still implementing
(MDRFLQ) and 5% with additional second-line injectable standardized shorter MDR/RR-TB, a pan-oral, injection-
(MDR SLI) and 16% had extensively drug-resistant TB free drug regimen is strongly recommended in the current
(XDR-TB), 39% had severe malnutrition [body-mass National Guidelines of India.

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 National DR-TB Guidelines in 2021 CHAPTER 190 1235

TABLE 2 Grouping of anti-TB drugs for longer MDR regimen

Group and steps Drug Standard abbreviations

Group A zz Levofloxacin or Moxifloxacin Lfx/Mfx
Include all three drugs
zz Bedaquiline Bdq
zz Linezolid Lzd
Group B zz Clofazimine Cfz
Add one or both drugs zz Cycloserine or Terizidone Cs/Trd
Group C zz Ethambutol E
Add to complete the regimen and when drugs from Groups zz Delamanid Dlm
A and B can’t be used because of drug intolerance, toxicity or
some other contraindication zz Pyrazinamide Z
zz Imipenem-cilastatin or Meropenem Imp-Cln/Mpm
zz Amikacin (or Streptomycin) Am (S)
zz Ethionamide or Prothionamide Eto/Pto
zz p-aminosalicylic acid PAS
zz This table is intended to guide the design of individualized, longer MDR-TB regimens. Group C drugs are ranked by decreasing order of usual
preference for use subject to other considerations. The 2018 Individual Patient Data-Meta-analysis (IPD-MA) for longer regimens included no
patients on thioacetazone (T) and too few patients on gatifloxacin (Gfx) and high-dose isoniazid (Hh) for a meaningful analysis.
zz Evidence on the safety and effectiveness of Bdq beyond 6 months and below the age of 6 years was insufficient for review.
zz Evidence on the concurrent use of bedaquiline and delamanid was insufficient for review.
zz Use of linezolid for at least 6 months was shown to increase efficacy, however, drug toxicity may limit use. The analysis suggested that using

linezolid for the whole duration of treatment would optimise its effect (about 70% of patients on Lzd with data received it for >6 months
and 30% for 18 months or the whole duration). From the IPD-sub-analysis no patient predictors for early cessation of Lzd could be identified.
zz Evidence on the safety and efficacy of delamanid beyond 6 months, below the age of 3 years was insufficient for review.
zz Pyrazinamide is to be used only if DST results confirm susceptibility.
zz Every dose of Imp-Cln and meropenem is administered with clavulanic acid, which is only available in formulations combined with amoxicillin

(Amx-Clv). Amx-Clv is not counted as an additional effective TB agent and should not be used without Imp-Cln or meropenem.
zz Amikacin and streptomycin are only to be considered if DST results confirm susceptibility and high-quality audiometry monitoring for hearing

loss can be ensured. Streptomycin is to be used only if amikacin cannot be used (unavailable or documented resistance) and if phenotypic
DST results confirm susceptibility (streptomycin resistance is not detectable with second-line molecular line probe assays). Kanamycin and
capreomycin are no longer recommended for use in MDR-TB regimens.
zz These agents only showed effectiveness in regimens without bedaquiline, linezolid, clofazimine or delamanid, and therefore only proposed

when other options to compose a regimen are not possible.

Source: WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2020.

Current Indian guidelines recommend bedaquiline- class C drugs.9 High dose Mfx (Mfxh) is effective provided
based, preferably pan-oral 5-drug regimen as per DST susceptibility is proven in LC-DST to Mfxh (MIC,1.0μg)15
in the Intensive Phase and 4-drugs in the Continuation [in many settings SL-LPA detects specific mutations such
Phase: 6–8 Bdq (6) Lfx, Lzd, Cfz, Cs/12 Lfx, Lzdl, Cfz, Cs14 as A90V, S91P, D94A (gyrA) which contribute to low-level
(Box 5). Similar regimens have been endorsed in the ATS/ Mfx resistance]. In all MDR/RR-TB patients, SL-LPA is
CDC/ERS/IDSA Guidelines (Table 4). Bedaquiline should recommended which clarifies the additional FQ class
be stopped after 6 months and linezolid dose should be resistance and second-line injectable drugs resistance.
reduced to 300 mg once daily. Monthly sputum smear and Table 5 details the sequence of replacement drugs to
cultures should be done. In case sputum culture positivity modify the ongoing treatment in case of specific situations
persists after 3 months then treatment failure should be like drug toxicity or resistance.1
strongly suspected and the DST should be repeated. Management of extrapulmonary TB (EPTB) is similar
If SL-LPA detects FQ class resistance, then addition to pulmonary MDR/RR-TB and patients are monitored
of two drugs is preferred in the previous regimen from for clinical, radiological, and microbiological outcomes

MU-190.indd 1235 29-01-2021 15:17:54

 1236 SECTION 14 Tuberculosis

TABLE 3 Dosage of MDR/RR-TB drugs in adults

Drugs 16–29 kg 30–45 kg 46–70 kg >70 kg

Rifampicin (R)* 300 mg 450 mg 600 mg 600 mg
High-dose H (Hh) 300 mg 600 mg 900 mg 900 mg
Ethambutol (E) 400 mg 800 mg 1200 mg 1600 mg
Pyrazinamide (Z) 750 mg 1250 mg 1750 mg 2000 mg
Levofloxacin (Lfx) 250 mg 750 mg 1000 mg 1000 mg
Moxifloxacin (Mfx) 200 mg 400 mg 400 mg 400 mg
High-dose Mfx (Mfxh) 400 mg 600 mg 800 mg 800 mg
Bedaquiline (Bdq) Week 0–2: Bdq 400 mg daily
Week 3–24: Bdq 200 mg 3 times per week
Linezolid (Lzd) 300 mg 600 mg 600 mg 600 mg
Clofazimine (Cfz) 50 mg 100 mg 100 mg 200 mg
Cycloserine (Cs)† 250 mg 500 mg 750 mg 1000 mg
Delamanid (Dlm) 50 mg twice daily (100 mg) for 24 weeks in 6–11 years of age
100 mg twice daily (200 mg) for 24 weeks for ≥12 years of age
Imipenem/cilastatin (Imp/Cls)† 1000 mg imipenem/1000 mg cilastatin twice daily
Meropenem (Mpm)† 1000 mg three times daily (alternative dosing is 2000 mg twice daily)
Amikacin (Am)‡ 500 mg 750 mg 750 mg 1000 mg
Capreomycin (Am)‡ 500 mg 750 mg 750 mg 1000 mg
Kanamycin (Km)‡ 500 mg 750 mg 750 mg 1000 mg
Ethionamide (Eto) 375 mg 500 mg 750 mg 1000 mg
Na-PAS (60% weight/vol)†‖ 10 g 14 g 16 g 22 g
Amoxyclav (Amx-Clv) 875/125 mg BD 875/125 mg BD 875/12 mg 875/125 mg BD
(In child: WHO 80 mg/kg in (2 morning plus 1 evening) (2 morning plus 1 evening)
two divided doses)
Pyridoxine (Pdx) 50 mg 100 mg 100 mg 100 mg
*For H mono/poly resistant TB
†
Drugs can be given in divided doses in a day in the event of intolerance
‡
For adult more than 60 yrs of age, dose of SLI should be reduced to 10 mg/kg (max up to 750 mg)
‖
In patient of PAS with 80% weight/volume the dose will be changed to 7.5 g (16–29 kg); 10 g (30–45 kg); 12 g (46–70 kg) and 16 g (>70 kg)
Source: Guidelines on programmatic management of drug-resistant tuberculosis in India, 2019–20.

BOX 4 Criteria to decide when the shorter MDR-TB regimen may be offered

A shorter all-oral Bdq-containing regimen (4–6) Bdq (6m) Lfx Cfz E Hh Eto/(5) Lfx Cfz Z E of 9–12 months duration is recommended in eligible
patients with MDR/RR-TB in the following situations:
zz Without resistance or suspected ineffectiveness of a medicine in the shorter regimen (except H resistance)*
zz Without exposure to previous treatment with second-line medicines in the regimen for >1 month (unless DST confirms susceptibility to

these medicines)†
zz No pregnancy
zz Age >6 years
‡
zz No extensive TB disease and with no severe EPTB
zz PLHIV

*H resistance determined by mutations in either inhA or katG genes (not both) or phenotypic DST. The presence of both mutations suggests that
isoniazid at high dose and thioamides are not effective and therefore, in such patients, shorter regimen should not be used.
†
Phenotypic DST for some medicines included in the regimen (ethambutol and ethionamide) is not considered reliable and reproducible.
‡
Extensive TB disease: bilateral cavitary disease or extensive parenchymal damage on chest X-ray. In children under 15 years, advanced disease is
usually defined by the presence of cavities or bilateral disease on chest X-ray.
Bdq, bedaquiline; Cfz, clofazimine; DST, drug susceptibility testing; E, ethambutol; EPTB, extrapulmonary TB H, isoniazid; Hh, high-dose isoniazid;
Lfx, levofloxacin; MDR/RR-TB, multidrug-resistant/ Rifampicin resistant-tuberculosis; PLHIV= people living with HIV, Z, pyrazinamide
Source: WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2020.

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 National DR-TB Guidelines in 2021 CHAPTER 190 1237

TABLE 4 ATS/CDC/ERS/IDSA criteria to build an individualized treatment regimen for MDR-TB

zz Constitute a drug regimen consisting of five or more drugs to which the Mtb isolate is susceptible (or has low likelihood of resistance),
preferably with drugs that have not been used to treat the patient previously
zz Choice of drugs is contingent on capacity to appropriately monitor for significant adverse effects, patient comorbidities, and preferences/

values (choices therefore subject to program and patient safety limitations)

zz In children with TB disease who are contacts of infectious MDR-TB source cases, the source case’s isolate DST result should be used if one

is unable to obtain from the child

zz TB expert medical consultation is recommended (ungraded good practice statement). 

Step 1: Choose one of the later-generation fluoroquinolones Lfx

  Mfx
Step 2: Choose both of these prioritized drugs Bdq
  Lzd
Step 3: Choose both of these prioritized drugs Cfz
  Cs/Trd
Step 4: If a regimen can’t be assembled with five effective oral drugs, and the isolate is Am
susceptible, use one of these injectable agents* S
Step 5: If needed or if oral agents preferred over injectable agents in Step 4, use the Dlm‡
following drugs† Z
E 
Step 6: If limited options and cannot assemble a regimen of five effective drugs, consider Eto or Pto§
use of the following drugs Imp–Cln or Mpm-Cln||
  PAS¶
Hh**
The following drugs are no longer recommended for inclusion in MDR-TB regimens: Cm and Km
Amx/Clv (when used without a carbapenem)
Azithromycin and clarithromycin
* Amikacin and streptomycin should be used only when the patient’s isolate is susceptible to these drugs. Because of their toxicity, these drugs
should be reserved for when more-effective or less-toxic therapies cannot be assembled to achieve a total of five effective drugs in the intensive
phase.
† 
Patient preferences in terms of the harms and benefits associated with injectables (the use of which is no longer obligatory), the capacity to
appropriately monitor for significant adverse effects, consideration of drug–drug interactions, and patient comorbidities should be considered
in selecting Step 5 agents over injectables. Ethambutol and pyrazinamide had mixed/marginal performance on outcomes assessed in our PS-
matched IPDMA; however, some experts may prefer these drugs over injectable agents to build a regimen of at least five effective oral drugs.
Use pyrazinamide and ethambutol only when the isolate is documented as susceptible.
‡ 
Data on dosing and safety of delamanid are available in children ≥3 years of age.
§ 
Mutations in the inh A region of the Mycobacterium tuberculosis genome can confer resistance to ethionamide/prothionamide as well as to
INH. In this situation, ethionamide/prothionamide may not be a good choice unless the isolate is shown to be susceptible with in vitro testing.
|| 
Divided daily intravenous dosing limits feasibility. Optimal duration of use not defined.
¶ 
Fair/poor tolerability and low performance. Adverse effects reported to be less common in children.
** Data not reviewed in our PS-matched IPDMA (propensity score-matched individual patient data meta-analyses), but high-dose isoniazid can
be considered despite low-level isoniazid resistance but not with high-level INH resistance.
Note: pepQ mutations were associated with low-level resistance to Bdq and cross-resistance to Cfz. These mutations reduced the efficacy of both
drugs in vivo but did not lead to complete resistance to these drugs. The value of using loading doses and the optimal dosing for Cfz requires
additional research.
Am, amikacin; Amx/Clv, amoxicillin -clavulanic acid; Bdq, bedaquiline; Cfz, clofazimine; Cln, cilastatin; Cm, capreomycin; Cs, cycloserine; Dlm,
delamanid; DST, drug susceptibility testing; E, ethambutol; Hh , high-dose isoniazid; Imp, imipenem; INH, isoniazid; IPDMA, individual patient
data meta-analyses; Km, kanamycin; Lfx, levofloxacin; Lzd, linezolid; MDR, multidrug-resistant, PS: propensity score; Mfx, moxifloxacin; PAS,
p-aminosalicylic, acid; S, streptomycin; TB, tuberculosis; Trd, terizidone; Z, pyrazinamide
Source: Treatment of Drug-Resistant Tuberculosis-An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline, 2019.

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 1238 SECTION 14 Tuberculosis

TABLE 5 Sequence of using replacement drugs to modify the regimen

Regimen Sequence of using replacement drug to modify the regimen

All oral H mono/poly If SL LPA detects Lfx resistance; replace Lfx with Mfxh. LC DST should be used for detection of resistance to Mfxh
and Z
If Mfxh or Z can’t be used; substitute with Lzd. If Lzd cannot be administered, replace with Cfz. If both Lzd and
Cfz cannot be given, use Cs as replacement
If both Mfxh and Z can’t be used; add two drugs of these Lzd, Cfz, Cs, in the order of preference
Treat for 9 months in any of the above three situations; duration of the treatment can be extended to 12 months
especially in CNS-TB, spinal, miliary, bone, and lymph node TB
If R resistance; switch to appropriate regimen, i.e., MDR/RR-TB regimen
Pan-oral Bdq-containing If there is a need for stopping/replacing any drug, stop the regimen and switch to DST-guided all oral longer
shorter MDR-TB regimen regimen
Pan-oral Bdq-containing Replacement situations Proposed composition of
longer MDR-TB regimen regimen after replacement
Initial 6 months of treatment
Initiate treatment Lfx, Bdq, Lzd, Cfz, Cs
If Lfx can’t be used, replace Lfx with Mfxh if SL LPA pattern suggests Mfxh*, Bdq, Lzd, Cfz, Cs
If Mfxh can’t be used, replace it with Dlm Dlm*, Bdq, Lzd, Cfz, Cs
If Mfxh & Dlm both can’t be used, add two drugs from replacement Bdq, Lzd, Cfz, Cs plus two drugs
sequence† from replacement sequence†
If Bdq can’t be used, replace with Dlm Lfx, Dlm*, Lzd, Cfz, Cs
If Dlm can’t be used, replace with two drugs from replacement sequence† Lfx, Lzd, Cfz, Cs plus two drugs
from replacement sequence†
If one of Lzd, Cfz or Cs can’t be used, no replacement (if Bdq and Lfx/Mfxh can be given)
If two or all three of Lzd, Cfz or Cs can’t be used, replace with two or three drugs respectively from
replacement sequence†
If three out of five drugs from A & B group cannot be used, replaced with three drugs from replacement
sequence†
After 6 months of treatment
If one of the drugs from Lfx, Lzd, Cfz, Cs can’t be used; no replacement is required
If two drugs from Lfx, Lzd, Cfz, Cs cannot be used, replace with two drugs from Z*, Eto*, PAS, E in given order
to complete the four drugs regimen
*Use Dlm: if available, no history of prior use and no exclusion criteria for its use, Z: if resistance not detected, Eto: If inhA mutation not present,
Am: if SL LPA pattern suggests. DST for Bdq, Dlm, Lzd, Cfz, and Z will be considered whenever it is available. DST for E and Eto is not reliable and
reproducible
†
Replacement sequence: Dlm, Am*, Z*, Eto*, PAS, E, Imp/Cln or Mpm plus Amx/Clv
Am, amikacin; Amx/Cln, amoxicillin-clavulanic acid; Bdq, bedaquiline; Cfz, clofazimine; Cln, cilastatin; Cm, capreomycin; Cs, cycloserine; Dlm,
delamanid; DST, drug-susceptibility testing; E, ethambutol; Hh, high-dose isoniazid; Hr-TB, rifampicin sensitive but isoniazid resistant-TB; Imp,
imipenem; Km, kanamycin; Lfx, levofloxacin; Lzd, linezolid; MDR/RR-TB, multidrug-resistant/Rifampicin resistant-tuberculosis; Mfx, moxifloxacin;
Pa, pretomanid; PAS, p-aminosalicylic, acid; S, streptomycin; Z, pyrazinamide
Source: Guidelines on programmatic management of drug-resistant tuberculosis in India, 2019-20.

depending on EPTB site and the treatment duration is drugs having a low-teratogenic potential. In children with
18–20 months. Drug treatment preferably a regimen seizures Mpm is preferred over Imp.
containing FQ, Bdq, Lzd, and Cs (injectables Am/S only
if Mtb is susceptible); Cfz, Eto (provided inhA mutations Nix-TB Trial: Bedaquiline, Pretomanid, and
are absent) may be used if required. Efavirenz may be Linezolid (BPaL) Regimen for MDR-TB Treatment
replaced with nevirapine in patients with HIV/AIDS.14,16 Nix-TB is a clinical trial, conducted by TB alliance in three
Treatment of MDR/RR-TB patients with pregnancy is South African sites (April, 2015 to November, 2017) in
done with a 4-drug regimen according to the DST and with which the 3-drug pan-oral BPaL regimen, consisting of

MU-190.indd 1238 29-01-2021 15:17:56

MU-190.indd 1239
TABLE 6 Characteristics of drugs* used for DR-TB

Group Dosage Adverse events Special precautions

Group A
Include all three medicines 500–1000 mg daily I n advanced CKD, class effec t of fluoro­ Dose adjustment required in CKD
(unless they cannot be used) 400 mg daily quinolones may pose a higher risk of neuro- Cr cl 30–50 mL/min = 750–1000 mg daily
Levofloxacin (Lfx) 400 mg daily for initial 2 psychiatric adverse events and tendinopathy; <30 mL/min = 750–1000 mg thrice weekly
or weeks and subsequently QTc prolongation on ECG more with Mfx than Lfx, No dose adjustment in CKD; predominantly hepatobiliary
Moxifloxacin (Mfx) 200 mg thrice weekly for a combination of Bdq, Cfz and Lfx (rather Mfx) excretion; may increase hepatic enzymes; has good CNS
Bedaquiline (Bdq) next 22 weeks (can be preferred penetration; avoid concomitant administration of antacids,
given longer) QTc prolongation, arthralgias, hepatitis, headache, phosphate binders, calcium, iron, or aluminum containing
anorexia, nausea medications to avoid malabsorption;
Administration with meal increases bio-availability; no dose
adjustment with renal or liver disease; ECG should be done
to monitor QTc prolongation at baseline, 2,12 and 24 weeks
and stop the drug if QTc >500 ms, serum K +, Mg2+ and Ca2+
monitoring required for QTc prolongation; QTc monitoring
required when co-administered with clarithromycin, Cfz, Lfx/
Mfx
Linezolid (Lzd) 600 mg once daily; the Hematological toxicity, lactic acidosis, peripheral Main route of excretion is hepatic with some renal clearance.
dose can be decreased and optic neuropathy and serotonin syndrome. No dose adjustment is required in CKD; careful monitoring
to 300 mg after 3–6 Drug toxicity is related to dose and duration of hematological toxicity, lactic acidosis, peripheral and optic
months; linezolid should of linezolid. Hematological toxicity and lactic neuropathy (often reversible) required. Pyridoxine 100 mg daily
be discontinued in case acidosis occur early in few weeks to months while can be administered to prevent hematological toxicity. Avoid
toxicity occurs and can neurological toxicity occurs late after 3–4 months concomitant use of food items rich in tyramine and medications
be re-introduced at a (SSRIs and other medicines) known to increase serotonin
lower (300 mg daily) dose production to prevent development of serotonin syndrome
following recovery
Group B
Add both medicines (unless 100 mg daily Ichthyosis and dry skin, sun burn, pink-brownish- QTc monitoring on ECG is required when co-administered
they cannot be used) black discoloration of skin, cornea, retina and with Bdq, Lfx/Mfx and Cfz; serum potassium, magnesium and
Clofazimine (Cfz) urine; acne flare calcium monitoring required for QTc prolongation. Not to
be used in pregnancy and severe hepatic insufficiency. Skin
problems can be prevented by application of sunscreen and
lubricants
Cycloserine (Cs) 10–15 mg/kg/day in Dizziness, slurred speech, convulsions, headache, Cr cl ≥ 30 mL/min: no dose adjustment required;
OR divided dose tremor, insomnia, confusion, depression, and < 30 mL/min: 250 mg daily or 500 mg on alternate days;
Terizidone (Trd) or altered behavior, suicidal tendency, generalized therapeutic drug monitoring is recommended if facility is
250 mg morning hypersensitivity reaction or hepatitis available; avoid if possible in renal disease as the main route of
National DR-TB Guidelines in 2021

500 mg evening excretion is renal.

300 mg morning Cs (and Trd) should be avoided in patients with history of
300 mg evening epilepsy, psychiatric illness or alcoholism, to prevent minor
adverse reactions like insomnia administration of small dose of
a tranquilizer is recommended or pyridoxine 50 mg/250 mg of
administered cycloserine can be given to prevent neurotoxicity
Contd...
CHAPTER 190
1239

29-01-2021 15:17:56
 1240
Contd...

MU-190.indd 1240
Group Dosage Adverse events Special precautions
Group C
Add to complete the regimen 15–25 mg/kg/day Dose dependent optic (retrobulbar) neuropathy Cr cl ≥ 30 mL/min, no dose adjustment required;
and when medicines from (> 30 mg/kg/day or < 30 mL/min: 15–25 mg/kg thrice weekly.
SECTION 14

Group A and B cannot be used 15-25 mg/kg in CKD); generally, reverses on Patients should be monitored at baseline and regularly
Ethambutol (E) prompt discontinuation; hyperuricemia thereafter for visual acuity and red-green color discrimination
Uncommon: interstitial nephritis, cholestatic
jaundice, neutropenia and thrombocytopenia,
reversible cutaneous hypersensitivity
disappearing on desensitization
Delamanid (Dlm) 100 mg twice weekly QTc pro l o n g ati o n , n a u s e a vo mi ti n g a n d QTc monitoring at baseline, 2, 12, and 24 weeks. Stop if > QTc
for 6 months (can be abdominal pain, dizziness 500 ms; monitor serum K+, Mg2+ and Ca2+
Tuberculosis

administered longer)
Pyrazinamide (Z) 25–30 mg/kg/day GI upset, hyperuricemia, arthralgia, hepato­ Cr cl ≥ 30 mL/min: no dose adjustment required;
(1.5 g for 50 kg, toxicity (not dose related) < 30 mL/min: 25–30 mg/kg three times/week
2 g for > 50 kg)
Imipenem - cilastatin 1g IV every 12 h Dose adjustment required in CKD
(Imp-Cln) 1g every 8–12 h IV GI upset, transaminitis Dose adjustment required in CKD
OR administered with
Meropenem Amoxycillin- clavulanate (as amoxycillin
Clavulanate clavulanate 250/125 mg
(Mpm/Amx-Clv) every 8–12 h)
Amikacin (Am) 15 mg/kg-maximum 1 g; Vestibular, auditory and renal toxicities Baseline audiogram and renal functions. Dose adjustment
five to seven times weekly required in CKD; prefer to avoid if possible. Periodic monitoring
or of audiogram and renal functions every 2-4 weeks
20–25 mg/kg 2–3 times/
week
Ethionamide (Eto) 15–20 mg/kg/day Pto is generally considered to be less unpleasant Should not be administered in pregnancy (teratogenicity in
Or in divided doses. and better tolerated than Eto. However, profile of animals). Careful monitoring is required if administered in
Prothionamide (Pto) The usual dose is 250–1000 adverse events is similar. patients with diabetes mellitus, liver disease, alcoholism or
mg/day. mental instability.
Most patients should be GI disturbances, metallic taste and sulphurous No dose adjustment required in CKD.
started on 250 mg doses belching; psychotic reactions, hypoglycemia Serum TSH monitoring required periodically especially when
daily or twice daily and (especially in diabetes mellitus patients); hepatitis; co-administered with PAS
gradually increased over other rare side-effects include gynaecomastia,
several days to 750 or 1000 menstrual disturbance, impotence in males, acne,
mg total daily dose alopecia and peripheral neuropathy
p-aminosalicyclic acid (PAS) 150 mg/kg or 10–12 g daily GI disturbances (diarrhea is self-limiting), Although no dose adjustment required in CKD. However,
in 2–3 divided doses hypothyroidism (more chances if given along caution should be exercised, since main route of excretion is
with ethionamide), hypokalemia, hepatitis, renal.
thrombocytopenia, aggravation of metabolic Periodic serum TSH monitoring required especially when co-
acidosis in patients with CKD administered with ethionamide
*All are bactericidal except Cs and PAS which are bacteriostatic; Cfz and Eto are weak bactericidal
Note: Creatinine clearance (CrCl) is best calculated with estimated glomerular filtration rate (eGFR) using CKD Epidemiology Collaboration (CKD-EPI) creatinine equation.
CKD, chronic kidney disease; CKD, chronic kidney disease; Cr Cl, creatinine clearance; ECG, electrocardiogram; GI, gastrointestinal; SSRIs, selective serotonin reuptake
inhibitors; TB, tuberculosis; TSH, thyroid stimulating hormone
Source: Dheda K, Theron G, Calligaro G, Limberis J, Davids M, Esmail A et.al. Drug resistance tuberculosis. eds. Sharma and Mohan’s Textbook of Tuberculosis and
Nontuberculous Mycobacterial Diseases, 3rd ed. New Delhi. Jaypee Brothers Medical Publishers;2019. pp. 592-5.

29-01-2021 15:17:56
MU-190.indd 1241
TABLE 7 Important rug cotoxicity and drug-drug interactions in patients with HIV/DR-TB coinfection

Description Responsible ARV drugs Responsible anti-TB drugs Considerations

Renal toxicity TDF Aminoglycosides, Cm zz TDF causes renal failure with hypophosphatemia and proteinuria
zz Avoid TDF in patients receiving aminoglycosides and Cm
zz Serum creatinine should be checked before switching patients onto TDF after

completion of aminoglycoside
zz Caution is advised when administering TDF or aminoglycosides in patients

with underlying co-morbidities, such as, diabetes mellitus or in patients

who are receiving concomitant nephrotoxic agents such as NSAIDs and
amphotericin B
zz If TDF is necessary, close monitoring of serum creatinine is required

Electrolyte abnormality TDF Aminoglycosides, Cm zz Exclude exacerbating factors, such vomiting, diarrhoea, dehydration, diuretics,
etc.
Hepatitis/hepatotoxi-city NVP, EFV, PI (especially Z, Bdq, PAS, FQ zz When severe stop both ARVs and anti-TB agents, restart TB drugs first
RTV), NRTI zz Assess for other contributing factors such as alcohol abuse, viral aetiologies
and other drugs like co-trimoxazole
zz Avoid concomitant use of NVP and Z
zz The risk of NVP hepatotoxicity is highest in the first 3 months of starting

therapy with higher risk in patients with CD4+ >250/mm3, the risk of NVP
hepatotoxicity is lower if VL is suppressed
Myelosuppression AZT Lzd, H zz Stop Lzd if myelosuppression occurs. Blood transfusion is indicated if
haemoglobin falls below 8 g/dL
zz Avoid co-administration of AZT and Lzd
zz Adverse events should be managed with a combination of temporary

suspension of linezolid, dose reduction and/or symptom management

zz Reduction dose of 300 mg daily may be associated with fewer neuropathic

effects but is not supported by pharmacokinetic data

zz Consider stopping cotrimoxazole

Peripheral neuropathy ddI, d4T Lzd, Cs, H, Eto, E zz Avoid use of D4T or ddI in combination with Cs or Lzd
zz Use pyridoxine as prophylaxis in patients receiving Cs, H and Lzd
National DR-TB Guidelines in 2021

QTc prolongation Bdq, Mfx, Cfz Lfx, Ofx Close monitoring of QTc is recommended when using these agents in combination
Contd...
CHAPTER 190
1241

29-01-2021 15:17:56
 1242

MU-190.indd 1242
SECTION 14

Contd...
Description Responsible ARV drugs Responsible anti-TB drugs Considerations
Tuberculosis

Central nervous system EFV Cs, H, Eto/Pto, FQ zz EFV toxicity occurs in first 2–3 weeks of treatment
toxicity zz Concurrent use of EFV with CS needs close monitoring
Headache AZT, EFV Cs, Bdq zz Headaches may be self-limited in case of AZT, EFV and Cs
zz Advice analgesia and hydration
Nausea and vomiting RTV, d4T, NVP Eto, PAS, H, Bdq, E, Z zz Most drugs will cause some degree of nausea
zz If persistent consider drug-induced pancreatitis, hepatitis
Lactic acidosis d4T, ddI, AZT, 3TC Lzd zz High index of suspicion needed to detect hyperlactatemia to prevent overt
symptoms of lactic acidosis
Pancreatitis d4T, ddI Lzd zz Avoid co-administration where possible
zz If pancreatitis occurs discontinue the ARVs completely
Diarrhea PI, ddI PAS, FQ, Eto zz For mild diarrhea anti-motility drugs can be used
zz May be self-limited. Exclude opportunistic infections
Optic neuritis ddI E, Lzd, Eto  zz Stop all suspected agents causing optic neuritis
zz Screen patients using the Snellen chart and Ishihara chart
Hypothyroidism d4T Eto, PAS Monitor serum TSH for patients receiving these agents
Joint pain PI (Indinavir) Z, Bdq Mild symptoms can be managed with simple analgesics
ARV, anti-retroviral drugs; ARVs, anti-retroviral drugs; AZT, zidovudine; Bdq, bedaquiline; Cfz, clofazimine; Cm, capreomycin; Cs, cycloserine; d4T, stavudine; ddl, didanosine;
DR-TB, drug-resistant tuberculosis; E, ethambutol; EFV, efavirenz; Eto, ethionamide; FQ, fluoroquinolones; Gfx, gatifloxacin; H, isoniazid; HIV, human immunodeficiency
virus; Lfx, levofloxacin; Lzd, linezolid; Mfx, moxifloxacin; NRTI, nucleoside reverse transcriptase inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs; NVP, nevirapine;
Ofx, ofloxacin; PAS, para-amino salicylic acid; PI, protease inhibitor; Pto, prothionamide; RTV, ritonavir; TB, tuberculosis; TDF, tenofovir disoproxil fumarate; TSH, thyroid
stimulating hormone; VL, viral load; Z, pyrazinamide
Source: Dheda K, Theron G, Calligaro G, et al. Drug resistance tuberculosis. Sharma and Mohan’s Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases, 3rd
ed. New Delhi: Jaypee Brothers Medical Publishers; 2019. pp. 592-5.

29-01-2021 15:17:57
 National DR-TB Guidelines in 2021 CHAPTER 190 1243

Composition of pan-oral longer MDR-TB treatment reactions of the drugs and special precautions required
BOX 5 while treating MDR/RR-TB patients. 19 During treatment
regimen
of HIV DR-TB patients, clinicians should be careful and
zz 6–8 Bdq (6) Lfx Lzd Cfz Cs / 12 Lfx Lzdl Cfz Cs need to carefully monitor additive drug cotoxicities and
zz Resistance to FQ likely to be high among RR/MDR-TB
zz May need to stop Lzd due to ADRs drug-drug interactions (Table 7). Linezolid is a very
h
zz Mfx fear of high cardiac ADRs with Bdq, Cfz, Mfx
h
potent anti-TB drug and its irrational use because of
Selection of fluoroquinolones: its free availability over-the-counter for other bacterial
zz In presence of FQ class resistance by LPA, in-country data (BDQ
infections such as staphylococcus should be avoided.
CAP, NITRD, NIRT) show in ~80% patients Mfxh may be sensitive.
No such data are available for Lfx Its use in MDR-TB patients for the entire duration of
h
zz Lfx has been used in India for~8 years, while Mfx has not been treatment is desirable but its adverse events must be
h
used: concerns about efficacy of Lfx vs. Mfx . Both Lfx and Mfx monitored carefully and the dosage may be decreased
have similar efficacy
zz Lfx More likely to cause nephrotoxicity compared to Mfx
from 600 to 300 mg after 6 months. Lactic acidosis and
zz Very limited data (SALVAGE regimen, BDQ CAP): combination of hematological toxicity occurs early while peripheral and
Bdq, Cfz, Mfxh may be tolerated optic neuropathy occur late (Table 6). Optic neuropathy is
zz Systematic review (2018) also shows low incidence of cardiac
usually reversible if recognized early. Serotonin syndrome
ADRs with BDQ + other drugs
is known to occur with linezolid20,21 and can be fatal at
ADRs, adverse drug reactions; Am, amikacin; Bdq, bedaquiline; CAP,
conditional access program; Cfz, clofazimine; Cs, cycloserine; E,
times (Table 6) and a heightened awareness is required.
ethambutol; FQ, fluoroquinolones; Lfx, levofloxacin; Lzd, Linezolid; Cutaneous hyperpigmentation with clofazamine is usually
Lzdl, low dose linezolid; Mfxh, high dose moxifloxacin; NIRT, National reversible after stopping the drug (Table 6). Similar to
Institute for Research in Tuberculosis, Chennai, India; NITRD, current Indian MDR/RR-TB guidelines, the ATS/CDC/
National Institute of Tuberculosis and Respiratory Disease, New
Delhi, India ERS/IDSA guidelines3 have emphasized health education
Source: Guidelines on programmatic management of drug- regarding adverse events and serious adverse events of
resistant tuberculosis in India, 2019-20. drugs in MDR/RR-TB patients. Post-treatment, follow-up
at 6th,12th,18th and 24th months of all successfully treated
bedaquiline, pretomanid, and linezolid was administered DR-TB cases under national-TB elimination programme
in 109 XDR-TB patients.17 Patients received bedaquiline (NTEP) is recommended.
400 mg once daily for 2 weeks followed by 200 mg three
times a week for 24 weeks, plus pretomanid 200 mg Acknowledgments
daily for 26 weeks and linezolid 1,200 mg daily for up to Professor SK Sharma is sponsored by JC Bose National
26 weeks. Nix-TB data have demonstrated a successful Fellowship of the Science & Engineering Research Board
outcome in 95 (89%) of the first 107 patients after 6 months (SERB; no. SB/S2/ JCB-04/2013) of the Ministry of Science
of treatment with BPaL drug regimen and 6 months of & Technology, Govt. of India. Mr. Vishwanath Upadhyay
post-treatment follow-up. With the advantages of pan-oral is a Junior Research Fellow pursuing his PhD course in
shorter treatment duration and very low rates of adverse Jamia Hamdard Institute of Molecular Medicine at Jamia
drug reactions, in future BPaL regimen can be adopted as Hamdard (Deemed-to-be-University), Hamdard Nagar,
a standard DR-TB regimen. New Delhi. He is supported by Prof. SK Sharma through
JC Bose Fellowship of the Science & Engineering Research
Board.
Active TB Drug-safety Monitoring and
Management Conflicts of Interest
Several drugs used for the treatment of MDR-TB have Prof. SK Sharma is a member of the National Technical
additive toxicities and may cause adverse events (AEs) Expert Group (NTEG) on treatment of TB, (National
and serious adverse events (SAEs).18 Active TB Drug-Safety Tuberculosis Elimination Programme erstwhile known
Monitoring and Management (aDSM) has been strongly as Revised National Tuberculosis Control Programme)
recommended for better adherence and successful Central TB Division, Ministry of Health & Family Welfare,
treatment outcome. Table 6 details serious adverse Government of India.

MU-190.indd 1243 29-01-2021 15:17:57

 1244 SECTION 14 Tuberculosis

Conclusion Available from http://www.stoptb.org/wg/gli/assets/documents/

LPA_test_web_ready.pdf [Last accessed June 2020].
All efforts should be made to have quality laboratory 10. Nathavitharana RR, Cudahy PG, Schumacher SG, et al. Accuracy of
network with regular accreditation. Universal DST is strongly line probe assays for the diagnosis of pulmonary and multidrug-
recommended to enable individualized pan-oral long-term resistant tuberculosis: a systematic review and meta-analysis. Eur
MDR/RR-TB regimens to prevent further amplification of drug Respir J. 2017;49(1):1601075.
11. World Health Organization. WHO position statement on the use
resistance. Smear and mycobacterial cultures should be done
of delamanid for multidrug-resistant tuberculosis. Geneva: WHO;
monthly during follow-up, aDSM should be rigorously followed
2018. Available from https://www.who.int/tb/publications/2018/
to have good adherence for better treatment outcome. All
Position_Paper_Delamanid/en/ [Last accessed June 2020].
these concerted efforts will go a long way toward achieving the 12. von Groote-Bidlingmaier F, Patientia R, Sanchez E, et al. Efficacy and
goal of TB-free world. safety of delamanid in combination with an optimised background
regimen for treatment of multidrug-resistant tuberculosis: a
multicentre, randomised, double-blind, placebo-controlled,
References parallel group phase 3 trial. Lancet Respir Med. 2019;7(3):249-59.
1. Central TB Division. Guidelines on programmatic management of 13. Salhotra VS, Sachdeva KS, Kshirsagar N, et al. Effectiveness and safety
drug resistant TB (PMDT) in India. Revised national tuberculosis of bedaquiline under conditional access program for treatment of
control programme. 2019–20. Available from https://tbcindia.gov. drug-resistant tuberculosis in India: an interim analysis. Indian J
in/index1.php?lang=1&level=1&sublinkid=4571&lid=3176. Tuberc. 2020;67(1):29-37.
2. WHO consolidated guidelines on tuberculosis. Module 4: 14. Sharma SK, Dheda K. What is new in the WHO consolidated
treatment - drug-resistant tuberculosis treatment. Geneva: World guidelines on drug-resistant tuberculosis treatment? Indian J Med
Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO.Available Res. 2019;149(3):309-12.
fromhttps://www.who.int/publications/i/item/9789240007048 15. World Health Organization. Technical manual for drug susceptibility
[Last accessed December 2020]. testing of medicines used in the treatment of tuberculosis.
3. Nahid P, Mase SR, Migliori GB, et al. Treatment of Drug-Resistant Available from http://www.who.int/iris/handle/10665/275469 [Last
Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice accessed June 2020].
Guideline [published correction appears in Am J Respir Crit Care 16. World Health Organization. WHO treatment guidelines for
Med. 2020;201: Am J Respir Crit Care Med. 2019;200:e93-e142. drug-resistant tuberculosis: 2016 update. Geneva: WHO;
4. Global tuberculosis report 2020. Geneva: World Health Organization; 2016. Available from https://apps.who.int/iris/bitstream/hand
2020. Licence: CC BY-NC-SA 3.0 IGO. Available from https://www. le/10665/250125/9789241549639-eng.pdf
who.int/publications/i/item/9789240013131 [Last accessed 17. Conradie F, Diacon AH, Ngubane N, et al. Treatment of highly
December 2020]. drug-resistant pulmonary tuberculosis. N Engl J Med. 2020;382(10):
5. Sharma SK, Mohan A. Multidrug-resistant tuberculosis: a 893-902.
menace that threatens to destabilize tuberculosis control. Chest. 18. World Health Organization. Active tuberculosis drug-safety
2006;130(1):261-72. m o n i to r i n g a n d m a n a g e m e n t ( a D S M ) . Fr a m e wo r k fo r
6. Ministry of Health & Family Welfare, Government of India. Report implementation. Geneva: WHO; 2015. Available from http://apps.
of the first national anti-tuberculosis drug resistance survey: India who.int/iris/bitstream/10665/204465/1/WHO_HTM_TB_2015.28_
2014-16. Ministry of Health & Family Welfare, Government of India; eng.pdf [Last accessed June 2020].
2018. Available from https://tbcindia.gov.in/showfile.php?lid=3315 19. Dheda K, Theron G, Calligaro G, et al. Drug resistance tuberculosis. In:
[Last accessed June 2020]. Sharma and Mohan’s Textbook of Tuberculosis and Nontuberculous
7. Chatterjee S, Poonawala H, Jain Y. Drug-resistant tuberculosis: is Mycobacterial Diseases, 3rd edition. New Delhi: Jaypee Brothers
India ready for the challenge? BMJ Glob Health. 2018;3(4):e000971. Medical Publishers; 2019. pp. 592-5.
8. Steingart KR, Ng V, Henry M, et al. M. Sputum processing methods 20. Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and
to improve the sensitivity of smear microscopy for tuberculosis: a optic neuropathy, lactic acidosis, and serotonin syndrome.
systematic review. Lancet Infect Dis. 2006;6(10):664-74. Pharmacotherapy. 2007;27(8):1189-97.
9. Line probe assays for drug resistant tuberculosis detection 21. Bernard L, Stern R, Lew D, et al. Serotonin syndrome after
Interpretation and reporting guide for laboratory staff and concomitant treatment with linezolid and citalopram. Clin Infect
clinicians, global laboratory initiative (GLI) advancing TB diagnosis. Dis. 2003;36(9):1197.

MU-190.indd 1244 29-01-2021 15:17:57

 CHAPTER

191 Tuberculosis with Diabetes:

How to Tackle?
Shailendra Kumar

Abstract 
Diabetes is one of the largest causes of non-communicable morbidity and mortality worldwide and in India. Tuberculosis
is the leading infectious disease in India and some other Asian countries including china. Tuberculosis and diabetes are
frequently encountered together. About 10% of TB cases are globally linked to diabetes. Diabetes affects the presentation
and treatment outcomes of tuberculosis. On the other hand tuberculosis also affects the treatment of diabetes due to
significant drug interaction and some other factors. So, theoretically, treatment of both diseases needs to be modified. In
this context many studies have been published which indicates that TB-diabetes need special considerations in treatment.
It will help in improving the treatment outcome and preventing the emergence of drug resistance cases.

Introduction and Epidemiology active TB up to three- to fourfold. In an Indian study the

prevalence of DM among TB patients was 13.1% (known
Globally tuberculosis is the leading cause of death from
diabetic 9.1% and new diabetic 4%).5 TB and diabetes
an infectious disease and in India the incidence of
when present together affects each other in various ways:
tuberculosis in 2018 has been estimated to be 27 lakhs,
„„ Diabetics have weaker immune system so they are at
about 16% increase from previous year.1,2
higher risk of progressing latent TB to active TB.
Recent estimation of diabetic population worldwide
„„ Diabetes can lengthen the time for sputum culture
is about 463 millions. 3 The proportion of people with
conversion and thus may be potential cause for
diabetes are increasing in many countries. India has an
development of MDR-TB.
estimated 77 million people with diabetes, which makes
„„ People with TB and diabetes have four times higher
it second most affected country after China. India alone
risk of death during treatment and higher risk of
contributes to about 17% of world diabetic population.
relapse. Higher reported rate of mortality in TB patients
with diabetes may be caused by cardiovascular
TB and Diabetes Comorbidity complications rather than by TB itself.6
About 10% of TB cases globally are linked to diabetes. „„ Diabetes is complicated by the presence of infectious

The precise biological mechanism is still not very clear diseases, including TB. It is important that proper care
but it has been observed that diabetes accounts for 20% for diabetes should be provided to patient suffering
of smear-positive pulmonary TB. Recent analysis have from TB-diabetes comorbidity.
indicated that increase in diabetes prevalence in India has „„ TB is associated with worsening of glycemic control

been an important obstacle in reducing TB incidence. 4 in diabetics; good glycemic control can improve the
More recent studies suggest that DM increases the risk of outcome. Furthermore diabetics may have many other

MU-191.indd 1245 29-01-2021 15:17:46

 1246 SECTION 14 Tuberculosis

comorbidities like hypertension, dyslipidemia, and are five times more prone to develop sputum positive
needs to take many pills, so chances of developing pulmonary tuberculosis than non-diabetics. 14 These
complications due to other comorbidities and factors were analyzed in a recent Turkish study containing
unwanted drug interaction are more. 737 pulmonary tuberculosis patients hospitalized during
2000 to 2005.14 They concluded that those who are diabetic,
How Diabetes Affects Clinical Spectrum of radiologically having extensive and cavitatory lesions, take
Tuberculosis? longer sputum and culture conversion time than the other
group. Another larger study concluded that pulmonary
Clinical Presentation tuberculosis patients with diabetes had a higher bacillary
Ma j o r b i o c h e m i c a l m a n i f e s t a t i o n o f d i a b e t e s load before initiation of treatment and DM was found to be
is hyperglycemia which favors growth, viability, and an independent risk factor for more AFB on sputum smear
pathogenicity of the tubercle bacilli.7 Increased production examination.15
of glycerol, and nitrogenous substance further aids to
the growth of tubercle bacilli.8 Tuberculosis runs more Effect on Chest X-ray
aggressive course in a diabetic. In diabetic subject Comparative studies of radiological findings in TB-
increased prevalence of pulmonary TB and relatively diabetes with tuberculosis alone group have yielded
infrequent extrapulmonary form of TB have been noticed. contrasting results. In a study by Perenez-Guzman et
In a series of studies 82.6% of diabetics with TB were al. in Mexico, 192 diabetic patients were compared with
found to be above 45 years with male preponderance.9 radiological findings of tuberculosis alone.16 They found
In another Indian study it has been observed 55% of TB- that the TB-DM patients were older and have a decreased
DM group were underweight and age group was above 45 frequency of upper (17% vs. 56%), and an increased
years.10 In DM-TB group prolonged duration of illness and frequency of lower (19% vs. 7%) and increased frequency
more significant weight loss has been observed than in (64% vs. 36%) both upper and lower lung field lesions.
non-diabetic subjects.9,11 Low grade fever and productive In TB-DM group cavitatory lesions were more (82.5% vs.
cough were observed with almost equal frequencies in 59%) than control and that were more often in lower lung
both groups.12 field (29% vs. 3%). Cavities were more often multiple in the
TB-DM patients (25% vs. 2%).
Diagnosis
Sputum microscopy and X-ray chest are two most Treatment Outcome and Complications
important investigations used for the diagnosis of At the end of intensive phase treatment a slightly lower
pulmonary tuberculosis in RNTCP. Apart from that we sputum conversion rates were observed in diabetics as
have CBNAAT for detection of RR, LPA, and culture compared to non-diabetic group. Regarding treatment
sensitivity test for individual DST. Now RNTCP has a well outcome some reports suggest adverse effects of diabetes
designed program structure from national level to PHI on treatment outcome of TB patients with increased rate
level. RNTCP was launched in 1997 and achieved full of failure, death, defaults, and relapses.17 Mortality rates in
nationwide coverage by March 2006. DMC is the most these patients are reported to be several times higher than
peripheral laboratory under RNTCP. There are 13,000 the non diabetic TB patients.7 However, in contrary recent
DMCs across the country.13 HIV screening of all patients study concludes that as far as tuberculosis is concerned,
undergoing sputum examination has also been included. the survival rate and socioeconomic rehabilitation of
In 2010, an integrated National Program for Prevention adequately treated patients with diabetes and pulmonary
and Control of Cancer, Diabetes, Cardiovascular Disease, TB are the same as that of TB patients without diabetes.15
and Stroke,(NPCDCS) has been launched.
How to Tackle?
Effect of Diabetes on Sputum Examination
Sputum positivity indicates the infectivity of pulmonary Screening for Diabetes
tuberculosis and culture conversion the effectiveness Ideally WHO and International Union against Tuberculosis
of treatment. In a study it has been found that diabetics and Lung Disease recommend that all adult TB patients

MU-191.indd 1246 29-01-2021 15:17:47

 Tuberculosis with Diabetes: How to Tackle? CHAPTER 191 1247

TABLE 1 Recommended thresholds and cut-off points for diabetes and pre-DM

Blood test Diabetes mellitus Pre-diabetes

2 hrs plasma glucose after oral glucose tolerance test (OGTT) ≥11.1 mmol/L 7.8–11.0 mmol/L
≥200 mg/dL 140–199 mg/dL
Fasting plasma glucose (FPG) ≥7.0 mmol/L 6.1–6.9 mmol/L
≥126 mg/dL 110–125 mg/dL
Glycosylated hemoglobin (HbA1c) ≥6.5% 6.0–6.4%
≥48 mmol/mol 42–47 mmol/mol

should be screened for diabetes. But in country like India „„ Referral of TB patients to specialized DM treatment
where resources are tight it may be more cost effective to centre is not recommended in the early phase of
go for the targeted screening policy for high risk patients; treatment because of the risk of transmission of
above 40 years of age, those who are overweight or obese, tuberculosis.
those with family history of diabetes, those who consume
excess alcohol, those with a previous history of gestational Treatment of Tuberculosis
DM or previous pre-DM. For treating diabetic tuberculosis patients, under
When to screen a tuberculosis patient for diabetes
RNTCP a National framework for joint TB-diabetes
is very important aspect for the ease of programmatic
collaborative activities has been launched in 2017 in
management and to alleviate fallacies like stress related
co-ordination with NPCDCS (National Program for
diabetes. It has been recommended that TB patients
Cancer, Diabetes, Cardiovascular Diseases and Stroke).
should be screened for diabetes at the time of diagnosis
Currently recommended anti-tuberculosis treatment
and registration. The fasting blood glucose and HbA1c are
is similar for patients with combined TB and diabetes
the two most suitable tools in programmatic setting and
compared to those with TB only. This strategy needs
in those patients who have symptoms of diabetes—
proper evaluation because DM is associated with ATT
polyuria, polydipsia, and polyphagia. In asymptomatic
drug resistance,18 slower treatment response, higher rate
persons fasting after glucose both should be done
of toxicity, treatment failure, and recurrent TB. Points to be
(Table 1).
Treating a diabetic-tuberculosis has many challenges considered for ATT in diabetics:
„„ The length of ATT might have to be adjusted. This is
with treatment of tuberculosis as well as treatment of
diabetes. Both diseases alter each other management common practice in some countries including China.
in many ways. Medications used for their management In a retrospective cohort study in Taiwan, a 9-months
affect each other in terms of—efficacy, drug interaction, treatment regimen was associated with a lower rate of
adverse reactions. More over TB adversely affects control recurrent TB than the 6 months regimen.19
„„ Higher dose of ATT may be needed, especially
of diabetes too. Diabetics have often cardiovascular
complications and risk factors which may be worsened by rifampicin due to interaction with sulphonyl urea
tuberculosis. So there are some considerations which must derivatives. In an observational study in the USA it
be taken into account while dealing with this complex duel has been found that therapeutic drug monitoring for
problem: INH and rifampicin, after 2 weeks of treatment was
„„ Inflammation related with TB can lead to temporarily associated with significantly shorter time of sputum
elevated blood suger—“stress induced hyperglycemia,” culture conversion among patients with combined TB
sometimes quite pronounced but usually improve and DM.20
during TB treatment. „„ TB-DM should be prioritized for DST at least for RR

„„ Our initial priority should be successful initiation of TB by CBNAAT. Nowadays CBNAAT is recommended as
treatment and with optimizing blood glucose control. initial DST for all patients with high MDR/TB burden

MU-191.indd 1247 29-01-2021 15:17:47

 1248 SECTION 14 Tuberculosis

TABLE 2 Important drug interactions in TB-DM patients

Medication Refampicin Isoniazid Aminoglycosides

Metformin No clinically relevant No important interaction My worsen renal toxicity
Interaction May worsen neupatic
Drug of choice in TB-DM symptoms
Sulfonylurea (Glyburide, Glipizide, Decreased ↓ Glyburide level (39%), ↑ Sr Conc. of Glimepiride and No significant interaction
Glimepiride) Glipazide (22%), Glimepiride (30%) my cause Hypoglycemia
DPP IV inhibitor (Sitagliptin, Saxagliptin) May ↓ blood level of gliptines Not significant No significant interaction

Thiazolidinedione (Pioglitazone) ↓ Pioglitazone level (54%) No interaction No significant interaction

Insulin None None None

Source: Adopted from www.heartlandntbc.org

but on ground level this is not happening due to for the treatment of diabetes. Some important drug
resource issues. interaction should be kept in mind while adjusting the
„„ Close monitoring of ATT is needed due to risk of side dose of OHA.
effects and drug interaction particularly if more toxic „„ Refampicin, through enzyme induction, accelerates

second line drugs used for MDR-TB. the metabolism of sulphonylureas and biguanides,
„„ Close monitoring for renal, hepatic function, and reducing their plasma level and thereby leading to
neuropathic sign and symptoms because OHA and hyperglycemia.23 Isoniazid antagonizes the action of
ATT may have combined toxicity or diabetes may sulphonylureas and worsen glycemic control. Isoniazid
have impaired renal function. INH may aggravate also inhibits the release of insulin even among none
neuropathic symptoms. diabetics and causes hyperglycemia. 24 Metformin is
„„ Drug compliance needs more close observation the drug of choice having no clinically relevant drug
because of high pill burden (Table 2). interaction. It has some anti-tuberculous activity
also.25 DPPIV inhibitors causes immune paresis and
Treatment of Diabetes probably worsen treatment outcome of tuberculosis.
Treatment of diabetes itself is a vast subject but here while Thiazolidinediones efficacy may be decreased by
treating a diabetic patient with tuberculosis following enzyme inducing effect of refampicin.
„„ Insulin is the preferred agent for type 2 DM treatment
points to be considered:
„„ It should be noted that TB-diabetes form a hetero­ with TB.24 The rational for the choice of insulin includes:
—— Severe TB infection
geneous group consisting of previously diagnosed
—— Body tissue loss
(known) diabetic and “New” diabetic. In the TANDEM
—— The need for increased anabolism
cohort, around 74% of TB-DM patients have previously
—— Pancreatic hypofunction
diagnosed DM (74%), while 26% were newly detected
as a result of screening.21 The relationship between —— Interaction between OHA and ATT

tuberculosis and diabetes is bidirectional. TB is a known —— Possibility of associated liver disease which would

cause of pancreatitis and tuberculosis pancreatitis preclude the use of oral agent
might reveal itself only after the development of   So, usually in case of severe TB-DM with profound
diabetes.22 systemic sign and symptoms patient is switched over
„„ Management of diabetes should be aggressive and to insulin. After few weeks of treatment tuberculosis
optimal glycemic control results in a better patient get controlled then dose requirement of insulin falls,
outcome. If tuberculosis is not extensive or severe there patient may again be switched over to OHA. Choice of
may not be much difference for treatment of diabetes insulin should be based on safety, effectiveness, cost,
alone, i.e., it may be treated as per general guideline and patient characteristics.

MU-191.indd 1248 29-01-2021 15:17:47

 Tuberculosis with Diabetes: How to Tackle? CHAPTER 191 1249

„„ Cardiovascular risk assessment is very important in 10. Tripathy SR, Kar KP, Chakraborty DC, et al. Diabetes mellitus and
patients with TB-DM. The higher reported rate of pulmonary tuberculosis—a prospective study. Ind J Tuberc.
1984;31:122-5.
mortality in TB patients with diabetes may be caused 11. Patel JC, De Sauza, Cheryl Jigini SS. Diabetes and tuberculosis.
by these cardiovascular complications rather than TB Indian J Tuberc. 1977;24:155-8.
itself. Cohort study in Taiwan has shown that patients 12. Bakakoglu F, Basaglu OO, Cok G, et al. Pulmonary tuberculosis in
with newly diagnosed pulmonary TB have a 40% patients with diabetes mellitus. Respiration. 2000;68(6):595-600.
13. National framework for joint TB-diabetes collaborative activities.
increased risk of ACS and a 50% higher risk of ischemic
March 2017, Page 3. Available from https://tbcindia.gov.in/
stroke.26,27 WriteReadData/National%20framework%20for%20joint%20TB%20
diabetes%2023%20Aug%202017.pdf
Conclusion 14. Gular M, Unsal E, darshun B, et al. Factors influencing sputum
smear and culture conversion time among patients with new case
Our country India has very large number of tuberculosis pulmonary tuberculosis. Int J Clin Pract. 2007;61(2):231-5.
cases as well as diabetics. Clinical presentation as well as 15. Singla R, Khan N, Osman MM, et al. Influence of diabetes on
manifestation and treatment outcome of pulmonary TB patients.
treatment outcome of tuberculosis is largely affected by other
Int J Tuberc Lung Dis. 2006;10(1):74-9.
comorbidities. Diabetes is an important comorbidity which 16. Perez-Guzman C, Villarreal-Velarde H, Salazar-Lezama MA et al.
affects all aspects of tuberculosis management and vise-versa. Atypical radiological images of pulmonary tuberculosis in 192
TB-DM is a commonly encountered situation which needs diabetic patients: a comparative study. Int J Tuberc Lung Dis.
special attention in RNTCP (NTEP) to improve the treatment 2001;5(5):455-61.
outcome and prevent complications. 17. Pablos-Mendez A, Blustein J, Knirsch CA. The role of diabetes
mellitus in the higher prevalence of tuberculosis among Hispanics.
Am J Public Health. 1997;87(4):574-9.
18. Lia Q, Li W, Xue M, et al. Diabetes mellitus and the risk of multidrug
References resistant tuberculosis: a meta analysis. Sc Rep. 2017:7(1):1090.
1. WHO, Global tuberculosis report 2019, Page 7 https://www.who. 19. Wang J-Y, Lee M-C, Shu CC, et al. Optimal duration of anti TB
int/tb/publications/global_report/en/ treatment in patients with diabetes: nine or six months? Chest.
2. India TB report 2019—Central TB Division, Page 19. https://tbcindia. 2015;147(2):520-8.
gov.in/WriteReadData/India%20TB%20Report%202019.pdf 20. Alkabab Y, Kellars, Dodge D, et al. Early inter vention for
3. IDF Diabetes Atlas, Ninth edition 2019, Page 39 https://www. diabetes related tuberculosis associated with hastened sputum
diabetesatlas.org/en/ microbiological clearance in Verginia, USA. BMC Infect Dis.
4. National framework for joint TB-diabetes collaborative activities, 2017;17(1):125.
RNTCP, Ministry of Health and Family Welfare of India. 2017; Page 2. 21. Van Crevel R, Dockrel HM, Consortium T, et al. TANDEM:
Available from https://tbcindia.gov.in/WriteReadData/National%20 understanding diabetes and tuberculosis. Lancet Diabetes
framework%20for%20joint%20TB%20diabetes%2023%20Aug%20 Endocrinol. 2014;2(4):270-2.
22. Geevarghese PJ. Pancreatic Diabetes. Bombay: Popular Prakashan;
2017.pdf
1967. pp. 26-8.
5. Sharma D, Goel NK, Khaneja R, et al. Prevalence of diabetes mellitus
23. Niazi AK, Kalra S. Diabetes and tuberculosis: a review of the role of
and its predictors among tuberculosis patients currently on
optimal glycemic control. J Diabetes Metab Disord. 2012;11:28.
treatment. Indian J Com Med. 2018;43(4):302-6.
24. Lebovitz HE. Oral hypoglycamic agent. Ellenberg and Rifkin’s
6. Crevel RV, Koesoemadinata R, Hill PC, et al. Clinical management Diabetes Mellitus, 4th edition. New York,USA: Ellsevier; 1990.
of tuberculosis and diabetes. Int J Tuberc Lung Dis. 2018;22(12): 25. Padmapriyadarshini C, Bhawani PK, Singh M, et al. Evaluation
1404-10. of metformin in combination with rifampicin containing
7. Mboussa J, Monabeka H, Kombo M, et al. Course of tuberculosis in antituberculosis therapy in patients with new smear positive
diabetics. Rev Pneumol Clin. 2003;59(1):39-44. pulmonary tuberculosis. BMJ Open. 2019;9(3):eo2463.
8. Goswami R, Kochupillai N. Endocrine implications of tuberculosis. 26. Chung W-S, Lin C-L, Chu YH, et al. Tuberculosis increases the
In: Sharma SK, Mohan A (Eds). Tuberculosis. New Delhi: Jaypee subsequent risk of acute coronary syndrome: a nationwide population-
Brothers Medical Publishers (P)Ltd; 2001. p. 386. based cohort study. Int J Tuberc Lung Dis. 2014;18(1):79-83.
9. Deshmukh PA, Shaw T. Pulmonary tuberculosis and diabetes 27. Sheu J-J, Chiou H-Y, Lin HC, et al .Tuberculosis and the risk of
mellitus. Int J Tuberc. 1984;31:114-7. ischaemic stroke: a 3 year follow up study. Stroke. 2010;41(2):244-9.

MU-191.indd 1249 29-01-2021 15:17:47

 CHAPTER
Molecular Assays as Initial
192 Tests for the Diagnosis of
Tuberculosis
DP Singh, SK Ghosh, Krishna Kumar

Abstract 
Tuberculosis remains a major public health problem in developing countries like India due to undue diagnostic delay in
diagnosis, and hence treatment of TB. While diagnosis of TB has entered into an era of molecular detection of tubercle bacilli
which is faster and rapid, we are still sticking to sputum microscopy as initial test for diagnosing TB, which has comparatively less
sensitivity.1 WHO has recommended molecular assays (Gene X-pert MTB/RIF, Gene X-pert Ultra, and TrueNat) as initial tests for
diagnosis of TB and rifampicin resistance in a recent communication, which will bring a paradigm shift in to End TB program.2

Introduction „„ Pulmonary TB: Any adult patient complaining of

cough more than 2 weeks, fever more than 2 weeks,
A tribute to Robert Koch is the discovery of tubercle
significant weight loss, and any abnormality in chest
bacilli as a causative organism of tuberculosis (TB)
X-ray must be evaluated for TB.
on 24 th March, 1882, but the mystery of TB continues
„„ Pediatric TB: Children with persistent fever and/or
even today. TB attacks lungs in 80% of cases called
pulmonary tuberculosis (PTB), but it can also affect any cough more than 2 weeks, loss of weight/or no weight
extrapulmonary organ named extrapulmonary TB. Global gain, and/or contact with pulmonary TB cases must be
burden of TB is still quite high. In 2018, 10 million people investigated for TB.
„„ Extrapulmonary TB: For all patients with presumptive
contracted TB and 1.5 million died. There are more than
0.5 million new cases of multidrug resistant TB.3 Globally, EPTB, appropriate specimens from the presumed site
diagnosis of TB and drug-resistant TB remains a challenge, of involvement must be obtained for microscopy/
because a third of people with TB and two-thirds of people culture and drug sensitivity/molecular assay to
with drug-resistant TB are not being detected. Accelerated pathological examinations.
efforts to diagnose TB and drug-resistance are crucial to WHO urges countries to expand access to rapid
end the global TB epidemic. India which accounts for 1/5 mole cular tests for dete ction of TB. Mole cular
of global burden of TB needs adequate policy reforms and assay (CBNAAT) is already the preferred first diagnostic
a high-quality laboratory system which utilizes modern tool for childhood TB and TB-HIV coinfection. A
diagnostics for early and rapid diagnosis of TB and systemic review of 23 studies has shown that TB is
rifampicin (RIF) resistance. diagnosed in India after a delay of about 2 months. 5
Molecular assay as initial test will lead to early diagnosis.
Diagnosis of TB It will also promote reduction in transmission and
Standards of TB care in India (STCI)4 have laid down clear faster life-saving treatment of this deadly communicable
diagnostic criteria for different types of TB: disease.

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 Molecular Assays as Initial Tests for the Diagnosis of Tuberculosis CHAPTER 192 1251

Paradigm Shift3 —— NAAT amplifies mycobacterium specific DNA

There has to be a paradigm shift in the approach to TB sequences using a nucleic acid probe
—— It increases the rate of detection
diagnosis by using newer molecular tests in place of
—— It requires only 16–131 bacilli to give positive
conventional sputum microscopy, if we want to achieve
results in a given sample
the ambitious goal of ending TB early and accurate
—— It lessens the time of detection
diagnosis of TB and RIF resistance is a prime step in this
—— It is more accurate diagnosis with sensitivity at
direction.
„„ Sputum microscopy: It has been a diagnostic tool
least 80% in most studies and specificity 98–99%
Disadvantage: It has one disadvantage that it is not
for TB for over a century and still most conventional
able to differentiate active infections from old ones
method for diagnosing TB in India. It takes less than an
as DNA from a dead organism can be detected and
hour during the examination. At least 5–10 thousand
amplified by PCR.
tubercle bacilli per mL of sputum (limit of detection
X-pert MTB/RIF (USA) is an automated PCR test,
LOD) are needed to demonstrate bacilli in the sample.6
which detects MTB and RIF resistance within 2 hours
But this methodology lacks sensitivity and so misses
of starting the test.7
many TB cases.
X-pert Ultra is the new version of X-pert MTB/
„„ Mycobacterium culture: Culture of mycobacterium TB
RIF, which is much more sensitive than X-pert. Its
is the gold standard for diagnosis of TB. In contrast
sensitivity is comparable to liquid TB culture. Gene
to sputum microscopy only 10–100 tubercle bacilli
Ultra is an advanced version of Gene X-pert with
are needed for culture positivity. Conventional L
better TB detection capabilities and more definitive
J Media takes longer time (4–8 weeks), but liquid
identification of RS and RR bacilli. Gene Ultra can be
culture media like BACTEC or non-radiometric
used as an alternative to Gene X-pert for initial testing
MGIT (mycobacterium Growth Indicator Tube) takes
in pts with s/s of TB. It is also planned to phase out
2–3 weeks times. But this process is cumbersome
Gene X-pert to be replaced by Gene Ultra.
and time consuming. Hence, there is a dire need „„ Line Probe Assays (LPAs) are active molecular tools.
of a diagnostic tool which can provide a rapid and
LPA of TB was endorsed by WHO in 2008. Meta
confirmed diagnosis of TB. Molecular assay is most
analyses have shown that LPAs are highly accurate for
suitable to perform this role. the detection of first-line drug resistance of isoniazid
1,7
„„ Molecular assays: Science is moving from biology (INH), RIF, and other first line drugs in sample positive
to microbiology and from microbiology to molecular specimens. By using LPA it is possible to diagnose
biology. Molecular assay have ushered to a new era of MDR early and rapidly within 2 days.
rapid and early diagnosis of not only TB, but also RIF INH and RIF drug resistant strains are identified
resistance. by detecting the most common single nucleotide
Probe-based Methods/DNA Chip- based Methods: polymorphism associated with resistance.
„„ Loop-mediated isothermal amplification (LAMP):
„„ Cartridge Based Nucleic Acid Amplification Test
(CBNAAT): Gene X-pert, Gene X-pert Ultra, and LAMP is an isothermal nucleic acid amplification
TrueNat are endorsed by WHO technique. It was recommended by WHO in 2016 for
„„ Line Probe Assay (LPA) diagnosis of TB as a replacement of smear microscopy.
„„ Loop-mediated isothermal amplification (LAMP) Characteristics of TB-LAMP have been compared to
those of Gene X-pert and LPA (Table 1).
Rapid Molecular Tests:2,8-10
„„ Nucleic Acid Amplification Test (NAAT) is a molecular

system that detects pathogenic DNA (deoxyribonucleic

Evidences of Molecular Assays as Initial
Acid) of Mycobacterium tuberculosis (MTB). Test for TB Diagnosis2,11,12
Molecular assays have several advantages in their „„ X-pert TB/RIF: WHO in 2010 has approved X-pert MTB/
arms: RIF machine, which utilizes molecular technique for

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 1252 SECTION 14 Tuberculosis

TABLE 1 Characteristics of rapid molecular assays7,12,13

Test specification TB LAMP X-Pert MTB/RIF X-Pert MTB/RIF Ultra LPA

Technology LAMP R-T PCR R-T PCR Multiplex PCR
Detects MTB MTB + RIF resistance MTB + RIF resistance MTB + resistance to RIF and INH
Targets IS6110 rpoB gene rpoB gene rpoB, katG, inh genes
Time of detection <1 hour 2 hours <90 min 5 hours
LAMP, loop mediated isothermal amplification; LPA, line probe assay; R-T PCR, real-time polymerase chain reaction.

Overall sensitivity and specificity of all samples TABLE 3 Limit of detection (LOD)
TABLE 2 sputum positive (SP) and sputum negative (SN) in
Gene X-pert Diagnostic tests for TB Limit of detection
(bacilli per mL of sample)
Sensitivity (%) Specificity (%) Sputum microscopy 5,000–10,000
Non-HIV group 85 98 Mycobacterium culture 10–100
HIV group 81 98 Gene X-pert 131
Gene Ultra 16
rapid diagnosis of TB and RR.70 studies involving TrueNat 29
more than thirty thousand patients from 37 countries
have shown high diagnostic accuracy of gene X-pert in
It is as sensitive as mycobacterial culture. In other words
pulmonary TB (Table 2).
Ultra will result in greater TB case detection rate in
If a patient is rifampicin resistant (RR), can Gene X-pert
subjects with paucibacillary TB such as smear negative-
give false rifampicin sensitive (RS) results? Answer is
culture-positive TB, those with HIV coinfection,
yes and this paradox is caused by silent mutation.
pediatric TB, and those with extrapulmonary TB.
Data from JLNMCH, Bhagalpur, confirm clear-cut
High diagnostic accuracy of Gene X-pert Ultra in adults
superiority of cartridge based NAAT (CBNAAT)
with PTB: 5 studies from 12 countries (including high-
over sputum microscopy. 14 Conventional approach
burden TB countries) overall sensitivity was found to
using LED microscopy SP was 10.3% while CBNAAT
be 90%, which includes all specimens smear-positive
detected 22% positivity. An addition advantage was
and smear-negative ones. Overall specificity was 96%
19% positivity in SN samples.11,14
in both types of specimens.
„„ Molecular assays are pillars in diagnosis of EPTB:
„„ Pediatric TB: There are difficulties in obtaining sputum
Difficulties were always encountered in confirming the
specimens in children and due to this limitation various
diagnosis of EPTB because of its paucibacillary nature
non-pulmonary specimens (gastric, nasopharyngeal,
and obtaining tissues from unreachable sites. By using
and stool) are used for bacteriological confirmation.
X-pert MTB increased numbers of bacteriologically
Data from 21 countries involving more than 6,000
confirmed EPTB cases were found.
patients show.
X-pert MTB/RIF ultra: X-pert MTB/RIF-ultra is much
In pediatric TB these are variable sensitivity in
more sensitive than X-pert MTB/RIF.13 Table 3 shows
different specimens (nasopharyngeal—46%, stool—61%,
the limit of detection (LOD) of different diagnostic tests
sputum—65%, and gastric—73%) and Specificity 98–100%.
of TB.
In samples where MTB detected was very low false
RMP resistance was seen in Gene X-pert, not in
X-Pert MTB/RIF to Detect RIF Resistance
Gene Ultra. Such sample must be subjected to Gold in Pediatric TB
Standard test of TB diagnosis-culture DST. For HIV- Using Gene X-pert when RIF resistance was tested with
positive patients sensitivity of Ultra was 90% versus reference to phenotypic drug sensitivity testing it was
77%, i.e., 13% more. found to have high overall sensitivity (90%) and specificity

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 Molecular Assays as Initial Tests for the Diagnosis of Tuberculosis CHAPTER 192 1253

Sensitivity and specificity of extrapulmonary middle income countries to use TrueNat in elimination of
TABLE 4 the disease (TB).
samples by Gene X-pert15
To evaluate the performance of TrueNat assay
Samples Sensitivity (%) Specificity (%)
in comparison with Gene X-pert, 274 samples were
Lymph nodes 84.9 92.5 processed. The overall sensitivity of TrueNat and Gene
CSF 79.5 98.6 X-pert was 94.7% and 96%, respectively.
Pleural fluid 43.7 98.1
Gastric lavage 83.8 98.8 Conclusion3
zz There are robust data to support that molecular assays
(98%). Data from six studies which involved 200 patients (X-pert MTB/RIF and X-pert Ultra) should be used as initial
from four high-burden countries supported the above tests for diagnosis of pulmonary TB in adults.
zz A large number of studies support the use of X-pert
findings.
MTB/RIF and X-pert Ultra as initial diagnostic work-up of
EPTB: Similar to pediatric TB difficulties are faced
extrapulmonary TB.
in obtaining extrapulmonary specimens and in aiding
zz These molecular assays show clear superiority over
bacteriologically confirmed diagnosis in EPTB.
conventional sputum microscopy in the diagnosis of
pediatric TB.
Gene X-Pert as Initial Test for EPTB zz Both molecular assays X-pert and X-pert Ultra show high

Data was assessed from 59 studies from 26 countries, accuracy in the simultaneous detection of RIF resistance.
zz Low cost and Indian molecular assay TrueNat MTB, MTB
which used MTB/RIF in adults with extrapulmonary TB.11
Sensitivity and specificity of extrapulmonary TB varied plus, and MTB-RIF Dx show comparable accuracy with both
with specimen types (Table 4). Gene X-pert and Gene X-pert Ultra in diagnosis of TB and
RIF resistance.
Another studies group using X-pert Ultra showed high
performance of detection of RIF resistance sensitivity
96–97% and specificity 99%.8 References
1. Nurwidya F, Handayani D, Burhan E, et al. Molecular diagnosis of
TrueNat as Initial Test for Diagnosis of TB2,16 tuberculosis. Chonnam Med J. 2018;54(1):1-9.
TrueNat TB test is a new molecular assay, which is in fact 2. WHO 2020 Rapid Communication. Molecular assays as initial
a real time PCR system. It is simple and user friendly. It is tests for the diagnosis of tuberculosis and rifampicin resistance.
a point of care (POC) tool and battery operated. Therefore, Available from https://www.who.int/tb/publications/2020/rapid-
communications-molecular-assays/en/
it is suitable for diagnosis of TB and RIF resistance for poor
3. Global Tuberculosis Report 2019. Available from https://www.who.
countries like India where it can be used in rural primary int/tb/publications/global_report/en/
health centers (PHC). 4. Chopra KK, Sachdeva KS, Malik P, et al. Standards of TB care
in India: a tool for universal access to TB care. Indian J Tuberc.
WHO Endorses TrueNat Test 2015;62(4):200-6.
5. Sreeramareddy CT, Qin ZZ, Satyanarayana S, et al. Delays in
In December 2019, WHO considered the latest evidence
diagnosis and treatment of pulmonary tuberculosis in India: a
on the use of Molbio TrueNat MTB/RIF test. Multicentric systematic review. Intl J Tuberc Lung Dis. 2014;18(3):255-66.
study of TrueNat assays done in India, Peru, Ethiopia, and 6. Reid PT, Innes JA. Infections of respiratory system, tuberculosis.
Papua-New-Guinea involving 744 patients examined the Davidson’s Principles & Practice of Medicine, 22 edition. pp. 692-3.
performance of TrueNat MTB, MTB plus, and MTB RIF Dx 7. Eddabra R, Benhassou HA. Rapid molecular assays for detection of
assays, which showed comparable efficacy to X-pert MTB/ tuberculosis. Pneumonia (Nathan). 2018;10:4.
8. Alland MRD, Rowneki M, Smith L, et al. X-pert MTB/RIF Ultra: A
RIF and X-pert Ultra in TB diagnosis and RIF resistance.
New Near-Patient TB test with sensitivity equal to Culture. Seatle;
Overall sensitivity of the TrueNat MTB assay was 83%
Washington: CROI; 2015.
and that of MTB plus 89% while specificity for MTB and 9. Parida M, Sannarangaiah S, Dash PK, et al. A new generation of
MTB Plus assay was 99% and 98%, respectively. The innovative gene amplification techniques in clinical diagnosis of
endorsement of TrueNat by WHO will help the low and infection disease. Rev Med Virol. 2008;18(6):407-21.

MU-192.indd 1253 29-01-2021 15:17:43

 1254 SECTION 14 Tuberculosis

10. Lombardi G, Di Gregori V, Giromatti N, et al, Diagnosis of smear resistance to rifampicin in an assay suitable for point-of care testing.
negative TB is greatly improved by X-pert MTB/RIF. PLoS One. Mbio. 2017;8(4):e00812-e817.
2017;12(4):e176186. 14. Singh DP, Ghosh SK (Eds). Molecular assays as initial tests for the
11. Ozkutuk N, Surucuoglu S. Evaluation of the X-pert MTB/RIF assay diagnosis of tuberculosis. J Indian Med Association. 2020;118(2):
for the diagnosis of PTB and EPTB in an intermediate prevalence 30-3.
setting. Microbiyol Bul. 2014;48(2):223-32. 15. WHO policy update for X-pert MTB/RIF, 2013 Expert Group meeting
12. Cepheid, Brochure. X-pert MTB/RIF, Two-hour detection of MTB and report 2021 May, 2013.
resistance to rifampicin, 17 June 2012. 16. Nikam C, Kazi M, Rodrigues C, et al. Evaluation of the Indian
13. Chakravorty S, Simmons AM, Rownek IM, et al. The new X-pert MTB/ TrueNAT micro RT-PCR device with GeneX-pert for case detection
RIF Ultra; Improving detection of mycobacterium tuberculosis and of pulmonary tuberculosis. Int J Mycobacteriol. 2014;3:205-10.

MU-192.indd 1254 29-01-2021 15:17:44

 CHAPTER

193 Association of
Tuberculosis and COPD
SM Mishra

Abstract 
COPD and Tuberculosis are common respiratory diseases in our country. Past history of Tuberculosis is considered an important
risk factor for COPD. Chronic airflow obstruction in tuberculosis patients occurs due to tuberculosis-associated lung damage
leading to COPD. A number of factors associated with COPD may increase the progression of Tuberculosis in these patients, most
important factors are- use of inhaled/oral corticosteroids in the treatment of COPD and smoke related exposure related altered
protective response to M. tuberculosis. There is bidirectional relationship between tuberculosis and COPD. Early diagnosis and
standardized treatment of Tuberculosis and COPD is essential. Action to increase awareness regarding COPD is essential.

Introdution These diseases primarily affects lung, COPD is a non-

communicable disease, and pulmonary tuberculosis is an
Tuberculosis and chronic obstructive pulmonary disease
infective disease caused by Mycobacterium tuberculosis.
(COPD) are major causes of morbidity and mortality
As per a number of studies conducted worldwide, there
worldwide. As per recent reports the prevalence of COPD
is increasing worldwide. Past history of tuberculosis is an is bidirectional relationship between two diseases and
important risk factor of COPD. It is well known that COPD effects each other adversely.
patients have an increased risk of developing tuberculosis. Due to recent advancement in medical field incidence
Thus, there is bidirectional relationship between COPD of infective diseases are showing decreasing trend. Due
and tuberculosis. It is alarming for our country since to economic development epidemiological transition
both these diseases are prevalent in our country. These is going on globally, the incidence of infective diseases
diseases have adverse impact on each other as far are decreasing, but there is increase in the incidence of
morbidity and mortality is concerned. We are committed non-communicable diseases like COPD. But due to rapid
to eliminate TB, if we have to fulfill our commitment, urbanization, overcrowding, lack of awareness, weak
timely intervention and action for early diagnosis and health-care system in our part of world (low and middle
institution of appropriate treatment of tuberculosis is income countries), there is double burden of infective
essential. In addition to adequate steps for diagnosis diseases like tuberculosis and non-communicable
and treatment of tuberculosis, common risk factors for diseases like COPD.1
tuberculosis and COPD must be addressed properly to We are committed to eliminate tuberculosis, from
prevent development of both these diseases in future, India by 2025, 5 years ahead of global target, if we have
otherwise we cannot achieve the target of TB elimination. to achieve the target we must take steps to control both
COPD and pulmonary tuberculosis are two very COPD and tuberculosis simultaneously. Early diagnosis
important disease of respiratory system, worldwide. and proper and standardized treatment of tuberculosis

MU-193.indd 1255 29-01-2021 15:17:39

 1256 SECTION 14 Tuberculosis

is mandatory to reduce the future burden of COPD and Fig. 1: Common risk factors for COPD and tuberculosis
tuberculosis both. Similarly, steps must be taken to reduce
air pollution and other common risk factors, which may
help in prevention of these diseases. Fortunately a number
of programs are going on in our country, so we can expect
favorable results in near future.

Current Global Burden of Tuberculosis

As per global TB report (2019), this is one of the top 10
causes of death worldwide and the leading cause of death
from a single infectious agent. About a quarter of the world’s
population is infected with Mycobacterium tuberculosis
and thus at risk of developing TB disease.2 Globally, an
estimated 10 million people fell ill with TB in 2018, and
there were about 1.5 million death due to this disease. With
timely diagnosis and treatment, most people who develop
TB can be cured and transmission of infection reduced in
the society, thus decreasing mortality and morbidity.

Current Global Burden of COPD

COPD is a major public health problem worldwide, due to countries.7,8 This relationship of TB and COPD is dangerous
its high prevalence, morbidity and mortality.3,4 Mortality for our country since the prevalence of both diseases
due to COPD is showing an increasing trend. At present are high in our country. The pathological process due to
it is the third leading cause of death globally.5 Chronic tuberculosis leads structural changes in the lungs. These
obstructive disease is a progressive disease, treatment structural damage of the lungs increases with increasing
can relieve symptoms and thus, improve quality of life number of episodes and they persists despite anti-
and reduce the risk of death.6 Air pollution and smoking tubercular chemotherapy.
both active and passive is very important risk factor. Use The structural damage leads to air flow obstruction
of conventional fuel is prevalent in our country, this is also and impairment of lung function. Impairment in
an important risk factor. By risk reduction measures we airflow can occur during active phase of tuberculosis
can reduce the burden and socioeconomic consequences. or may be detected after the treatment. Patients usually
Fortunately, a number of initiatives have been taken in our develop maximum loss of lung function within 6 months
country, this may have a positive impact and reduce the of diagnosis of tuberculosis and generally stabilize
burden of COPD in our country. about 18 months after the completion of treatment. 9,10
Antitubercular treatment leads to improvement in lung
Tuberculosis and COPD Different function, but the residual lung function impairment
depends on both pre- and post-treatment radiological
Aspects of Association extent of disease. Delay in initiation of treatment lead
COPD and Tuberculosis Shared Risk Factors to more extensive disease and more structural damage
leading to more impairment of lung function.
There are some common risk factors for COPD and
Tuberculosis, that is, they share some of the risk factors
and these are shown in Figure 1.
Mechanism of Airflow Obstruction
Due to Tuberculosis
Tuberculosis as the Risk Factor for COPD The sequence of pathological process leading to chronic
Past history of tuberculosis is well recognized as risk factor airflow obstruction in post-tuberculosis patient is not
for development of COPD, particularly in developing clear, following mechanisms have been proposed:

MU-193.indd 1256 29-01-2021 15:17:39

 Association of Tuberculosis and COPD CHAPTER 193 1257

„„ Role of macrophages: Macrophages are one of the Flowchart 1: Pathological process leading to chronic airflow
key cells concerned in the pathological process of obstruction in post-TB patients
tuberculosis, these cells play an important role in wound
healing and resolution, they may cause remodeling of
airways, leading to chronic airflow obstruction.
„„ Small airway involvement: The pathological process

undergoing in lungs in tuberculosis may involve

the small airways leading to airflow obstruction.
The observation of Allwood et al. during their study
supports this concept, they observed that patients
with chronic airflow obstruction with definite previous
TB had higher gas trapping, fibrosis, and emphysema
score than subjects with no previous tuberculosis.
The diffusion capacity was also significantly lower in
patients with definite previous TB.11
„„ Bronchiectasis: Post-tuberculosis bronchiectasis is

very common finding and probably most common

cause of Bronchiectasis in our country. Endobronchial
obstruction or peribronchial fibrosis or obstruction by
enlarged lymph nodes found in tuberculosis, may lead
to bronchiectasis and chronic airflow obstruction.12
study observed that COPD is an independent risk factor
„„ Accelerated parenchymal destruction: Lung paren­
for tuberculosis.15
chymal inflammation occurs in tuberculosis, this leads
Exact mechanism or the factors which leads to increased
to destruction of pulmonary extra-cellular matrix
risk is not well known, inhaled and oral corticosteroids
(ECM). As described earlier remodeling occurs in the
are used for the treatment of COPD. Corticosteroids
lung due to ongoing pathological and healing process,
Matrix metalloproteinases (MMP) are considered to are known to produce immune-suppression; this may
mediate tissue remodeling in tuberculosis. MMPs increase the risk of tuberculosis.16
are a family of calcium dependent zinc containing Use of corticosteroids is not the only factor responsible
endopeptidases. There are different kinds of MMPs. for immune impairment in COPD and tuberculosis, but
Different MMPs plays different role in Mycobacterial other factors also involved in immune impairment in
infection. MMP-9 is concerned in the formation of these cases are:
„„ Cigarette smoke exposure: According to study
stable granuloma, thus containing the infection.
Reactivation of latent TB leads to MMP-1 secretion, conducted by patients Shang et al., the cigarette
which causes alveolar destruction and is responsible smoke exposure alters the protective response to M.
for cavitation in tuberculosis.13 Type II pneumocyte tuberculosis.17
„„ High levels of cytokines: High levels of some of cytokines
makes MMP-1.14 MMPs lead to degradation of ECM and
thus involved in the pathogenesis of both tuberculosis like sIL-2R, IL-6, TNF-alpha, IFN-y are found in COPD
and COPD, the scaffold of alveolar wall. patients. These cytokines by producing an exuberant
The pathological process in tuberculosis leading to inflammatory response may cause progression of
chronic airflow obstruction maybe summarized in the tuberculosis in COPD patients.18
Flowchart 1. „„ Dysfunction of alveolar macrophages: In patients

suffering from COPD, dysfunction of alveolar

Impact of COPD on Tuberculosis macrophages develops, which is considere d
It is well known that patients suffering COPD have independent of steroids, this leads to an additional risk
increased risk of developing tuberculosis. Lee et al. in his of developing tuberculosis.19,20

MU-193.indd 1257 29-01-2021 15:17:40

 1258 SECTION 14 Tuberculosis

Conclusion 5. Lozano R, Naghavi M, Foreman K, et al. Global and regional

mortality from 235 causes of death for 20 age groups in 1990 and
COPD and tuberculosis are most common respiratory problem 2010: a systematic analysis for the Global Burden of Disease study
in our country. As per different studies conducted, past history 2010. Lancet. 2012;380(9859):2095-128.
of tuberculosis is considered an important risk factor for 6. Global burden of disease study. Available from https://www.who.
COPD. Chronic airflow obstruction in tuberculosis patients int/healthinfo/global_burden_disease/about/en/
7. ZGeng G, Sun B, Zhong N. Non-smoking related chronic obstructive
occurs due to tuberculosis associated lung damage leading
pulmonary disease: a neglected entity. Respirology. 2012;17(6):
to COPD. A number of factors related to COPD may increase
908-12.
the risk of progression of tuberculosis in these patients— 8. Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non
use of inhaled and oral corticosteroids in the treatment of smokers. Lancet. 2009;374(9691):733-43.
COPD, may increases the risk of progression of tuberculosis 9. Plit ML, Anderson R, Van Rensburg CE, et al. Influence of antmicrbial
by causing immune suppression. Other factors are—smoke chemotherapy on spirometric paraeters and pro-inflamatory
exposure related altered protective response to M. tuberculosis, indices in severe pulmonary tuberculosis. E Respir J. 1998;12(2):
high levels of some of the cytokines and dysfunction of 351-6.
alveolar macrophages observed in COPD patients, which is 10. Chung KP, Chen JY, Vu HD, et al. Trends and predictors of changes
independent of steroids. Thus, above mentioned facts indicates in pulmonary function after treatment for pulmonary tuberculosis.
that there is bidirectional relationship between two diseases. Clinics. 2011;66(4):549-56.
11. Allwood BW, Gillespie R, Gaperin-Aizenberg M, et al. Mechanism
Early diagnosis and timely initiation of standardized and
of airflow obstruction in tuberculosis-associated obstructive
complete of treatment of tuberculosis and COPD is essential.
pulmonar y disease ( TOPD). Am J Respir Crit Care Med.
Government of India under ‘National Tuberculosis Elimination’ 2014;189:A5832.
has increased facility for early diagnosis and proper treatment of 12. Lopez-Campos JL, Calero C. Infectious causes of chronic obstructive
tuberculosis, definitely this will have a positive impact. Diagnosis pulmonary disease: ‘TB or not TB’ that is the question. Respiration.
of COPD is based on clinical suspicion, confirmed by respiratory 2013;86(1):15-6.
function tests , it is essential to increase general awareness 13. Elkington P, Shiomi T, Breen R, et al MMP-1 drives immunopathology
regarding this disease and improvement in facility for diagnosis in human tuberculosis and transgenic mice. J Clin Invest.
of COPD. Action to reduce shared risk factors for COPD and 2011;121(5):1827-33.
tuberculosis is the prerequisite to reduce the burden of both 14. Imai K, Dalal SS, Chen ES, et al. Human collagenase (matrix
tuberculosis and COPD in our country. These steps may improve metalloproteinase-1) expression in lungs of patients with
emphysema. Am J Respir Crit Care Med. 2001;163:786-91.
the quality of life, morbidity, and mortality due to these diseases.
15. Lee CH, Lee MC, Shu CC, et al. Risk factors for pulmonary in patients
with chronic obstructive airway disease in Taiwan: a nationwide
cohort study. BMC Infect Dis. 2013;13:194.
References 16. S e g a l B H , S n e l l e r M C . I n f e c t i o u s c o m p l i c a t i o n s o f
1. Bygbjerg IC. Double burden of noncommunicable and infectious immunosuppressive therapy in patients with rheumatic diseases.
diseases in developing countries. Science. 2012;337(6101): Rheum Dis Clin North Am. 1997;23(2):219-37.
1499-501. 17. Shang S, Ordway D, Henao-Tamayo M, et al. Cigarette smoke
2. Global TB Report. 2019. Executive Summary. Available from https:// increases susceptibility to tuberculosis evidence from in vivo and in
www.who.int/tb/publications/global_report/en/ vitro models. J Infect Dis. 2011;203:1240-8.
3. Adeloye D, Chua S, Lee C, et al. Global and regional estimates of 18. Tang S, Cui H, Yao L, et al. Increased cytokines response in patients
COPD prevalence; systematic review and meta-analysis. Global with tuberculosis complicated with chronic obstructive pulmonary
Health Epidemiology. Reference Group (GHERG). J Global Health. disease. PLoS One. 2013;8(4):e62385.
2015;5(2):020415. 19. Taylor AE, Finney-Hayward TK, Quint JK, et al. Defective macrophage
4. World Health Organization .Chronic obstructive pulmonary disease phagocytosis of bacteria in COPD. Eur Respir J. 2010;35(5):1039-107.
(COPD). Available from https://www.who.int/news-room/fact- 20. Hiemstra PS. Altered macrophage function in chronic obstructive
sheets/detail/chronic-obstructive-pulmonary-disease-(copd) pulmonary disease. Ann Am Thoracic Soc. 2013;10 (Suppl):S180-5.

MU-193.indd 1258 29-01-2021 15:17:40

 CHAPTER

194 Exudative Pleural Effusion—

Diagnostic Approach
Sanjay Kumar

Abstract 
The exudative pleural effusion caused either by infections like tuberculosis or due to other diseases like cancer, is
associated with a lot of complications and even mortality. The proper history and pleural fluid examination is the first
step in differential diagnosis of exudative pleural effusion, but sometimes other investigation techniques like imaging,
closed pleural biopsies, and pleuroscopy or video associated thoracoscopy are needed to clinch the diagnosis and proper
management.

Introduction The other common causes are pneumonic, malignancy

(primary or secondary) and pulmonary embolus with
Pleural effusion is a common condition in day to day
infarction. The less common causes are—rheumatoid
practice. It develops when more fluid enters the pleural
arthritis, other connective tissue diseases, pancreatitis,
fluid than is removed. The first step in the evaluation of
esophageal rupture, post coronary artery bypass surgery,
pleural effusion is to determine whether it is exudate or
etc.
transudate. In cases of exudative effusion the stepwise
approach to find out the etiology is needed. Thoracentesis
and pleural fluid examination are useful in differential Initial Evaluation
diagnosis of such cases. Other tests like CT scan, The careful history, including the occupational history &
Pleuroscopy, etc. may help in reaching an etiological history of past illness, symptoms, and signs on physical
diagnosis. examination are the first vital measure in guiding the
Pleural effusion may be caused by variety of diseases. evaluation of pleural effusion.
Traditionally to simplify the diagnostic approach the Pleuritic chest pain, cough, and dyspnea are three
pleural effusion is first dichotomized as transudative basic symptoms of exudative pleural effusion besides
or exudative. Exudative effusion usually develops due other symptoms like fever may be present. Pleuritic chest
to inflammatory or malignant disorders. The basic pain is due to inflammation of parietal pleurae and it likely
pathophysiological mechanism of exudative pleural indicates some infectious cause, while dull aching chest
effusion is increased capillary permeability, which leads pain is very much suggestive of pleural malignancy. Non-
to accumulation of large molecular weight compounds in productive cough is also a common symptom. Although
the pleural space. the exact mechanism of cough is not clear, but pleural
There are numerous causes of exudative pleural inflammation is again implicated as possible cause.
effusion. The most common cause of this in areas where The third symptom dyspnea is basically due to space
tuberculosis is endemic is secondary to pleural TB.1 occupying process in the thoracic cavity and reappearance

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 1260 SECTION 14 Tuberculosis

of fluid quickly after therapeutic thoracentesis is most in patients with parapneumonic effusion is indicative of
likely due to malignant involvement of pleura. drainage of the fluid.4
In the unavailability of pH value determination, a
Thoracentesis and Examination pleural fluid glucose concentration of less than 60 mg%
helps in detecting complicated parapneumonic effusion.4
of Pleural Fluid
The enzyme ADA plays a very important role in
After the initial evaluation, the next step is diagnostic
lymphoid cell differentiation. Pleural fluid ADA level
thoracentesis and examination of pleural fluid. It not only
greater than 40 U/L is highly sensitive and specific marker
settles the issue of transudative versus exudative effusion,
for the diagnosis of tuberculous pleural effusion. The
but also diagnoses the cause of exudative effusion in most
sensitivity varies between 90% and 100%, while specificity
cases.
is as high as 85% and 95%.5
The usual tests that should be performed on fluid
Pleural fluid culture for both aerobic and anaerobic
obtained during diagnostic thoracentesis are—cell counts
bacteria may identify the culprit microorganism in almost
and differentials, glucose, adenosine deaminase (ADA)
40% of parapneumonic effusion.2
estimation, and cytologic analysis. The pH measurement
Pleural fluid smears for mycobacterium are positive
and bacterial cultures should be done when acute
infection is suspected. The routine pleural fluid tests are very rarely found in about 5% of cases2 and about one third
summarized in Table 1. of patients with tuberculous pleural effusion have negative
For proper total white blood cell count and differential tuberculin skin test.6
cell count, it is necessary to send the pleural fluid in Pleural fluid cytology is very important to diagnose
anti-coagulated tube. Otherwise the fluid is likely to clot malignant pleural effusion. Cytology positivity is almost
leading to an inaccurate count.3 60% in malignant pleural effusion.7
The main WBC cell type is determined by the The test result negativity are related to different factors
mechanism of pleural injury and the time interval between such as type of tumor (usually negative in mesothelioma,
the onset of pleural pathology and thoracentesis. So, sarcoma, and lymphoma), the tumor burden in pleural
the neutrophil-rich fluid is highly suggestive of an acute space and the expertise of the person performing the
process like parapneumonic effusion, while lymphocyte job. An amount of 10 mL of pleural fluid is adequate for
predominant fluid profile is indicative of chronic process cytologic processing. Additional pleural taps increase the
like tuberculosis or malignancy. diagnostic yield further.
A low pH value of fluid has important therapeutic A second thoracentesis may be considered in suspected
and prognostic implications with parapneumonic and malignant effusion and the initial pleural fluid cytology
malignant pleural effusion. Low pH value less than 7.20 examination is negative for malignancy.

TABLE 1 Routine pleural fluid tests for pleural effusion

Test Test value Suggested diagnosis

ADA >40 U/L Tuberculosis (>90%), Empyema (60%) complicated parapneumonic effusion
(30%), malignancy (5%), Rheumatoid arthritis2
Cytology Atypical cells/Malignant cells Malignancy (primary or secondary)
Glucose <60 mg/dL Acute infection like parapneumonic effusion, tuberculosis, malignancy,
rheumatoid arthritis2
RBC count >100×106/L Malignancy, trauma, parapneumonic effusion, pulmonary embolism
9
WBC count & differential 10×10 /L Infection, empyema, etc.
Lymphocytes >50% Tuberculosis-most likely, malignancy, and post-CABG
Neutrophils >50% Parapneumonic effusion, pulmonary embolism, abdominal diseases

MU-194.indd 1260 29-01-2021 15:17:33

 Exudative Pleural Effusion—Diagnostic Approach CHAPTER 194 1261

Flowchart 1: Exudative pleural effusion

Other Diagnostic Modalities of image guided biopsy is much higher than closed
biopsy. Histological examination associated with
There are occasions when we need to further investigate
culture of pleural biopsy tissue confirms the diagnosis
the case in order to get a cause of exudative pleural
effusion. The further work up includes: of tuberculosis in 90% of patients.5
„„ Imaging techniques: High resolution helical CT scan
„„ Pleuroscopy: Pleuroscopy, usually referred to as
is the investigation that is used as first line modality medical thoracoscopy, is gradually gaining importance
for delineating pulmonary circulation in patients and now recognized as procedure of choice both for
suspected to have pulmonary embolism. CT can diagnosing and treating exudative pleural effusion,
distinguish malignant from benign pleural disease also which eludes diagnosis after thoracentesis. It is
as it detects nicely pleural nodules or nodular pleural diagnostic in more than 90% of patients with pleural
thickening. The detection and differentiation of benign malignancy where cytology is negative.9 Pleuroscopy
and malignant pleural disease is further enhanced offers the additional benefit of effective pleurodesis
using positron emission tomography scan.8 during the procedure.
„„ Bronchoscopy: Endobronchial malignancy may lead

to exudative pleural effusion also. Whenever this is Conclusion

suspected in chest radiography or CT scan images,
or patient has symptoms of hemoptysis or there is The careful stepwise approaches starting from proper history
massive pleural effusion or shift of mediastinum to the taking, evaluation of symptoms & signs, and diagnostic tests
side of pleural effusion, bronchoscopy is useful. help in finding out the exact cause of exudative pleural effusion
„„ Closed pleural biopsy: In cases of undiagnosed
in majority of cases. Despite the best of efforts, approximately
15% of patients of pleural effusion remain undiagnosed.10
exudative pleural effusion, percutaneous closed
The suggested algorithm for the investigation of exudative
pleural biopsy (CPB) is recommended. Image guided
pleural effusion is shown in Flowchart 1.
biopsy is superior to blind closed biopsy. The sensitivity

MU-194.indd 1261 29-01-2021 15:17:34

 1262 SECTION 14 Tuberculosis

References 5. Light RW. Pleural Disease, 4th edition. Philadelphia: Lippincot

Wilkins; 2002. p. 311.
1. Thomas M, Ibrahim WH, Raza T, et al. Medical thoracoscopy for 6. Porcel JM, Vives M. Differentiating tuberculous from malignant
exudative pleural effusion, an eight year experience from a country pleural effusion: a scoring model. Med Sci Monit. 2003;9(5):175-80.
with young population. BMC Pulm Med. 2017;17(1):151. 7. Maskell NA, Butland RJ. Pleural Diseases Group, Standards of care
2. Porcel JM, Light RW. Thoracentesis, PIER, American College of committee, BTS. BTS guidelines for the investigation of a unilateral
Physicians, 2004. (Online access) Available from http://pcer. pleural effusion in adults. Thorax. 2003;58(2):8-17.
acponline.org 8. Dusynix B, Nguyen D, Louis R, et al. Evaluation of pleural disease
3. Conner BD, Lee YC, Branca P, et al. Variations in pleural fluid WBC with 18-flurodeoxyglucose position emission tomography
count and differential counts with different sample containers and imaging. Chest. 2004;125(2):489-93.
different methods. Chest. 2003:123(4):1181-7. 9. Antony VB, Loddenkemper R, Astoul P, et al. Management of
4. Coliece GL, Cursh A, Deslauriers J, et al. Medical and surgical malignant pleural effusions. Eur Respir J. 2001;18:402-19.
treatment of parapneumonic effusion: an evidence based 10. Light RW. Clinical practice pleural effusion. NEJM. 2002;346:
guideline. Chest. 2000;118:1158-71. 1971-7.

MU-194.indd 1262 29-01-2021 15:17:34

 CHAPTER

195 Tubercular Lymphadenitis—

Challenges in Treatment
Deependra Kumar Rai

Abstract 
Tubercular lymphadenitis is most common form of extrapulmonary tuberculosis. The most common Lymph node involved
is cervical followed by Supraclavicular, Axillary, submandibular and, Inguinal region. Majority of patient presented as
isolated chronic nontender lymphadenopathy. The regimen and duration of tuberculosis is same as pulmonary tuberculosis.
Treatment is complicated by paradoxical reaction in almost 1/5th of patients, which does not require change in treatment
and most of the patient subside by its own.

Introduction during primary infection or may occur due reactivation

of previous infection. In NTM lymphadenitis, the bacilli
We are living in the second-most populous country after
enter through oropharyngeal mucosa, salivary glands,
China in the world and one-fourth of the global incident
tonsil, or conjunctiva.
tuberculosis (TB) cases occur in India annually as per
the WHO Global TB Report.1 Extrapulmonary TB (EPTB) There are five stages of lymph node TB described by
is defined as occurrence of TB other than lung is more Jones and Campbell:4
„„ Stage 1: Enlarged, firm mobile discrete lymph nodes
common in immunocompromised individual with HIV
infection. Lymph node TB was found as most common showing non-specific reactive hyperplasia
„„ Stag e 2: Large rubber y lymph nodes fixed to
EPTB (37.14%) found in 517 EPTB cases. 2 Cervical
lymphadenitis is also known as scrofula. 3 Tubercular surrounding tissue due to periadenitis
„„ Stage 3: Central softening due to abscess formation
lymphadenitis also caused mainly mycobacterium TB,
„„ Stage 4: Collar stud abscess formation
rarely by nontuberculous mycobacteria (NTM), especially
„„ Stage 5: Sinus tract formation
in children or patient who immunocompromised.

Pathogenesis Clinical Presentation

Tubercular lymphadenitis is considered as local Most common clinical presentation as slowly enlarging
manifestation of systemic disease while lymphadenopathy lymph node. Constitutional symptoms like fever, weight
due to NTM is purely a localized disease. Tubercular bacilli loss, anorexia, and fatigue rarely found. We found 5
generally enter the body via respiratory tract and undergo almost one-fourth of study patients (25.38%) having a
hematogenous and lymphatic dissemination. Hilar and symptom for more than 1 year before getting diagnosed
mediastinal lymph node are first lymphoid organ involved as tubercular lymphadenitis before putting on anti-
when spread from lung parenchyma occur. This can occur tubercular treatment. Cervical lymph node is the most

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 1264 SECTION 14 Tuberculosis

commonly involved followed by axillary and inguinal in the setting of HIV infection and in regions where the
lymph node. Fever has been reported in 20–50% of cases prevalence of TB is high. Specimens should be subjected
in HIV-negative patients and 60–80% in HIV-positive for microscopy, culture, cytology, and polymerase chain
patients.3 Our study5 showed fever, anorexia, and weight reaction/GeneXpert testing. Excisional lymph node
loss in 72.30%, 50.76%, and 41.53%, respectively. More than biopsy is indicated when FNA is not diagnostic. The
half of study patients (55.38%) received homoeopathic or finding of caseating granulomas on histopathology is
ayurvedic treatment before putting on anti-tubercular highly suggestive of TB but it is not confirmatory because
treatment that could be one of the causes of delayed other disease like sarcoidosis and fungal infection may
presentation. Physical examination finding depends upon have granuloma. Multiplicity, matting and causation are
stage of disease. Enlarged lymph node may be firm, discrete three features which help in differentiating TB from other
mass or matted nodes fixed to surrounding structures; the differential. In our study among 130 study patients, 62
overlying skin may be indurated.6 The lymph nodes are (47.69%) were classified as having confirmed TB based on
usually non tender unless secondary bacterial infection AFB positivity in FNAC sample. The remaining 68 (52.30%)
has occurred. Sometimes, lymph node abscess ruptured patients had probable TB.
leading to non-healing sinus formation. The typical TB
sinus appears thin, bluish, undermined edges with watery Treatment
discharge. There is various complication occur especially Treatment options for tubercular lymphadenitis are
due to mediastinal TB. These include dysphagia due to surgical excision of involved node and/or anti-tubercular
pressure on esophagus, esophagomediastinal fistula and treatment. It is generally agreed that anti-tubercular
tracheoesophageal fistula. Node may cause thoracic duct treatment is sufficient for majority of cases and surgical
obstruction presenting as chylothorax, chylous ascites, or treatment required in selected cases. INDEX TB guideline
chyluria. recommends 6-month therapy with first-line anti-
We found5 almost one-fourth of study patients (25.38%) tubercular drug of isoniazid, rifampicin, ethambutol, and
having a symptom for more than 1 year before getting pyrazinamide.7 The studies evaluated 6–9 months regimen
diagnosed as tubercular lymphadenitis before putting on and found no difference as far as cure rates (89–94%) or
anti-tubercular treatment. relapse rates (3%) are concern.8 Anti-tubercular treatment
may be complicated by paradoxical reaction or increase
Differential Diagnosis in size of primary lymph node and/or appearance of
new lymph nodes in up to 20% of patients during or
„„ Hodgkin lymphoma and non-Hodgkin lymphoma
even after cessation of treatment. These nodes may show
„„ Reactive lymphadenitis (secondary to bacterial or viral
histopathological features characteristics of TB but sterile
infections)
on culture. These phenomena are transient and nodes
„„ NTM infection
ultimately regress in size. We did a study 5 to identify
„„ Cat scratch disease
incidence of paradoxical reaction and residual lymph node
„„ Fungal infection
at the end of 6 months of treatment. Forty-six (35.38%)
„„ Sarcoidosis
patients out of 130 developed paradoxical reaction, and
„„ Kikuchi disease (idiopathic histiocytic necrotizing
most of this occurred in the first 2 months of the initiation
lymphadenitis)
of anti-tubercular treatment. Fifty-eight patients (44.61%)
had a residual lymph node of size more than 1 cm after 6
Diagnosis months of treatment. Only 9 patients out of 54 patients had
Diagnosis of tuberculous lymphadenitis is confirmed significant reduction in the size of the lymph node with
by histopathology showing caseating granuloma and/or extended 9 months of treatment (Flowcharts 1 and 2). So,
bacteriological evidence in form of smear positive for acid- presence of residual lymph node at the end of treatment
fast bacilli (AFB), molecular test, or culture positivity. Fine does not require extended duration of treatment rather
needle aspiration (FNA) is appropriate for initial evaluation just close observation required but if there is increase in
of cervical lymphadenopathy to evaluate for tuberculous size of lymph node, send sample for histopathological
lymphadenitis. The yield of FNA appears to be highest examination, GeneXpert, and AFB culture.

MU-195.indd 1264 29-01-2021 15:17:30

 Tubercular Lymphadenitis—Challenges in Treatment CHAPTER 195 1265

Flowchart 1: Treatment outcome of standard 6 months and

extended 9 months of lymph node tuberculosis patients
References
1. World Health Organization. Report on Global Tuberculosis
Control: Epidemiology, Strategy, Financing. Geneva, Switzerland:
World Health Organization; 2015. pp. 1-9. Available from https://
www.who.int/tb/publications/global_report/gtbr15_main_text.
pdf?ua=1
2. Rai DK, Pandey S. A hospital-based cross-sectional study on clinico-
demographic characteristic of extrapulmonary tuberculosis cases
coming to a tertiary hospital of Bihar. Indian J Community Med.
2018;43(2):122-3.
3. Fontanilla JM, Barnes A, von Reyn CF. Current diagnosis and
management of peripheral tuberculous lymphadenitis. Clin Infect
Dis. 2011;53(6):555-62.
4. Jones PG, Campbell PE. Tuberculous lymphadenitis in childhood:
the significance of anonymous mycobacteria. Br J Surg. 1962;50:
302-14.
5. Rai DK, Kumar R, Ahmad S. Clinical characteristics and treatment
outcome in tubercular lymphadenitis patients—a prospective
Flowchart 2: Characteristics of paradoxical reactions (number in observational study. Indian J Tuberculosis. 2020. Available
bracket showing number of patients) from https://www.sciencedirect.com/science/article/abs/pii/
S0019570720300925.
6. Alvarez S, McCabe WR. Extrapulmonary tuberculosis revisited: a
review of experience at Boston City and other hospitals. Medicine.
1984;63(1):25-55.
7. Sharma SK, Ryan H, Khaparde S, et al. Index-TB guidelines:
Guidelines on extrapulmonary tuberculosis for India. Indian J Med
Res. 2017;145(4):448-63.
8. van Loenhout-Rooyackers JH, Laheij RJ, Richter C, et al. Shortening
the duration of treatment for cervical tuberculous lymphadenitis.
Eur Respir J. 2000;15(1):192-5.

Conclusion
Lymph node TB is the most common forms of EPTB and
is different from pulmonary TB in terms of diagnosis and
treatment. Treatment regimen and duration is similar to
pulmonary TB, but complicated by paradoxical reaction or
residual lymph node at the end of treatment. So, patient might
be given multidrug-resistant (MDR) treatment for paradoxical
reaction and extended the duration of treatment for residual
lymph node. Sample should always be processed for molecular
test like GeneXpert and culture in all worsening lymph node
with treatment to differentiate paradoxical reaction from drug
resistance.

MU-195.indd 1265 29-01-2021 15:17:30

 CHAPTER

196 Gastric Tuberculosis:

An Often Unrecognized Entity
Piyush Manoria, Vishal Yadav

Abstract 
Tuberculosis of stomach is a very rare manifestation of mycobacterium tuberculosis and presents as a diagnostic challenge
to physicians. Gastrointestinal tuberculosis is the sixth most common cause of extrapulmonary tuberculosis, and stomach is
the sixth most common site of it. It mostly occurs as a part of disseminated tuberculosis or in an immunocompromised state
and presents as non-healing gastric ulcer or gastric outlet obstruction. It’s mostly diagnosed after surgical intervention as
yield of endoscopic biopsies is low due to submucosal location of granulomas. It’s treated with conventional antitubercular
therapy, and surgery is only needed when it presents with complications.

Introduction proximally and distally from ileocecal region. Stomach

is the sixth most common cause of gastrointestinal
Tuberculosis is endemic and a major health problem
tuberculosis and it accounts for 0.5–3% of its all cases.3
in India. Gastric tuberculosis is a rare manifestation
The various sites of tuberculosis have been shown in
of gastrointestinal tuberculosis and usually occurs
in association with pulmonary tuberculosis or in Flowchart 1. It occurs mostly between ages of 15–62 years
immunocompromised states. It mostly presents as a with a male preponderance.4
diagnostic dilemma and often masquerades as peptic
ulcer disease or gastric malignancy. Pathogenesis
Gastric tuberculosis usually occurs as a part of disseminated
Epidemiology disease or in immunocompromised states. Isolated gastric
Pu l m o na r y t u b e rc u l o s i s a c c o u nt s f o r 8 5 % a n d tuberculosis in immunocompetent person is very rare
extrapulmonary tuberculosis accounts for 15% of all and only few case reports are published till date. We
cases of tuberculosis in an immunocompetent person. have published a case of isolated gastric tuberculosis in
Gastrointestinal tuberculosis is the sixth most common a healthy female presenting as non-healing gastric ulcer5
cause of extrapulmonary tuberculosis after lymph node, (Figs. 1A to C). Stomach as a site for tuberculosis is very
genitourinary, bone and joints, miliary, and meningeal rare due to bactericidal properties of gastric acid, absence
tuberculosis. 1 Tuberculosis can involve any part of of lymphoid tissue, and rapid transit of food in stomach
gastrointestinal tract but it most commonly involves the due to its continuous motor activity.6 The possible routes
ileocecal region followed by ascending colon, jejunum, of infection in stomach are: direct infection of mucosa
appendix, duodenum, stomach sigmoid colon, and due to swallowing of sputum, direct infection from
rectum.2 The incidence of tuberculosis reduces as we move neighboring tubercular lesion, hematogenous spread or

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 Gastric Tuberculosis: An Often Unrecognized Entity CHAPTER 196 1267

Flowchart 1: Various sites of tuberculosis in an immunocompetent person

retrograde lymphatic spread.7 Most commonly it occurs Granulomas in tuberculosis are more in number, larger in
from neighboring celiac lymph nodes.8 size, and confluent compared to Crohn’s disease.11

Pathology Clinical Features

Gastric tuberculosis can present as an ulcer, hypertrophic Clinical presentation of gastric tuberculosis is nonspecific.
mass, or ulcerohypertrophic lesion in the stomach.9 It Its most common symptom is abdominal pain followed
most commonly presents with non-healing gastric ulcer. by vomiting. Constitutional symptoms of tuberculosis like
Hypertrophic lesions mimic gastric carcinoma and fatigue, evening rise of temperature, loss of weight and
present with gastric outlet obstruction. It mostly involves appetite, etc. can also be present in some patients. Due to
the antrum or prepyloric region in the lesser curvature.10 delay in its diagnosis it can also present with its sequelae
The granulomatous lesions can involve the mucosa, like:
submucosa, or serosa but most commonly it involves „„ Gastric outlet obstruction, which presents with

the submucosa. Granulomas in stomach can be caused postprandial vomiting, pain, and distension of
by various disorders like tuberculosis, Crohn’s disease, abdomen
sarcoidosis, fungal and parasitic infection, Whipple’s „„ Gastrointestinal bleed in the form of hematemesis and

disease, xanthogranulomatous gastritis, lymphoma, melena

Churg-Strauss syndrome, exposure to beryllium and „„ Perforation peritonitis and rarely

silicates and syphilis, but most commonly it is caused by „„ Gastrocolic and gastrobronchial fistula.

tuberculosis and Crohn’s disease. Granulomas are more Gastric tuberculosis most commonly presents as a case
common in gastrointestinal tuberculosis compared to of non-healing gastric ulcer, which is resistant to proton
Crohn’s disease. Caseation is present in around 40% cases. pump inhibitor and negative for helicobacter pylori or as

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 1268 SECTION 14 Tuberculosis

A B

Figs. 1A to C: Isolated gastric tuberculosis in an immunocompetent

female.* (A) Endoscopic image showing large gastric ulcer; (B)
Endoscopic biopsy showing granuloma with multinucleate giant
cell; (C) Endoscopic image showing healing of ulcer after 2 months
of antitubercular treatment
*Reprinted from Manoria P, Gulwani HV. Gastric tuberculosis presenting as
non healing ulcer: a case report. Indian J Tuberc. 2019;66:502-4, Copyright
C 2020, with permission from Elsevier.

a case of a gastric outlet obstruction mimicking gastric „„ submucosal lesion with normal overlying mucosa.
malignancy but negative in histopathology. In both these Endoscopic biopsies have a low yield for granuloma
clinical scenarios we should be highly suspicious of its as majority of lesions are submucosal in location. 4 So
diagnosis. it’s advisable to take multiple deeper biopsies during
endoscopy to increase the yield. Helicobacter pylori
Diagnosis should always be ruled out in tissue biopsy and by doing
Diagnosis of gastric tuberculosis is difficult and often rapid urease test. Colonoscopy should always be done in
delayed and it’s mostly diagnosed after surgical suspected cases as ileocecal tuberculosis can coexist with
intervention. The gold standard for its diagnosis is it.
presence of acid fast bacilli in the histopathology specimen Endoscopic ultrasonography (EUS) is very helpful and
which is very rare. should be performed when it presents with submucosal
Upper gastrointestinal endoscopy is the most mass or if there are associated adjacent lymph nodes.
important initial investigation. It can detect EUS guided fine needle aspiration cytology (FNAC) and
„„ solitary or multiple ulcers in prepyloric region in lesser biopsies should be taken from submucosal lesions and
curvature lymphnodes as it has a high yield for its diagnosis.
„„ ulceroproliferative mass in antrum causing gastric Imaging modalities like ultrasonography (USG) and
outlet obstruction, or contrast enhanced computed tomography (CECT) of

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 Gastric Tuberculosis: An Often Unrecognized Entity CHAPTER 196 1269

abdomen is not much useful in diagnosis as their findings initial treatment for it. For unresponsive cases surgery
are non-specific. They can show gastric wall thickening, in the form of gastric resection with gastrojejunal
hypodense lesion in antrum, multiple enlarge lymph anastomosis is usually done.
nodes, peritoneal thickening, ascites, etc. CT or USG „„ Patient presenting with gastrointestinal bleeding should
guided FNAC from enlarged lymph nodes should be done be initially managed with endoscopic hemostatic
if they are accessible for making diagnosis. X-ray chest procedures like adrenaline spray, adrenaline injection,
should always be done in any suspected patient as 25% hemoclipping, etc. Non-responsive cases are treated
of patients will have coexisting pulmonary tuberculosis.12 surgically with partial gastrectomy.
The yield of mycobacterial culture is from 0–69% in
gastrointestinal tuberculosis in various studies. Bhargava Conclusion
et al. has suggested to do routine culture of biopsy
specimen to increase the diagnostic yield.13 The sensitivity Tuberculosis can involve any part of gut even in immuno­
and specificity of polymerase chain reaction (PCR) in competent person. Gastric tuberculosis though rare should be
endoscopic biopsies for gastrointestinal tuberculosis is kept as one of the differential diagnosis in any case of chronic
infiltrative lesion of stomach like non-healing ulcers and gastric
44% and 95%, respectively.14 Kim et al. has suggested to do
outlet obstruction. The yield of endoscopic biopsies is low for
PCR testing as it also helps in ruling out Crohn’s disease.15
granuloma due to submucosal location of the lesion so deeper
So, in any suspected cases of gastric tuberculosis, culture and repeated biopsies are advisable for making early diagnosis
and PCR testing of biopsy should also be done to increase and avoiding surgical interventions. If diagnosed early, it
the yield of diagnosis. responds very well to standard ATT.
Tuberculin test is non-specific test and is not done
routinely for its diagnosis. There is no specific biochemical
or hematological test for it. References
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