New - PPT - VINAYAK

CURRENT TRENDS IN MANAGEMENT
AND TREATMENT OF TUBERCULOSIS
DR. ANIMESH ARYA

SR. CONSULTANT CHEST PHYSICIAN
HEAD
DEPARTMENT OF PULMONARY MEDICINE,
SHRI BALAJI ACTION MEDICAL INSTITUTE AND
CENTRE FOR CHEST DIDSEASES , ALLERGY AND
SLEEP DISORDERS
NEW DELHI
Wednesday, June 24, 2 Dr.Animesh Arya 1

020
A Tribute of Robert
Koch

020
Discovery of Mycobacteria
24 MARCH CELEBRATED AS WORLD TB

DAY
Mycobacterium tuberculosis is a pathogenic bacterial
species in the family Mycobacteriaceae
and the causative agent of most cases of tuberculosis.
First discovered in 1882 by Robert Koch,

M. tuberculosis has an unusual, waxy coating on its cell
surface (primarily due to the presence of mycolic acid),
which makes the cells impervious to Gram staining
The Ziehl-Neelsen stain, or acid-fast stain, is used instead.
GLOBAL BURDEN OF
•
TB
2 billion infected, i.e. 1 in 3 of global population
• In 2012, 8.6 million people fell ill with TB and 1.3 million died98% in low-
income countries
• In 2012, an estimated 530 000 children became ill with TB and 74 000
HIV-negative children died of TB
• 80% in 22 high-burden countries
• 4 m new sm+ve PTB (61/lakh).
• MDR-TB -prevalence in new cases around 3.6%.
 Tuberculosis accounts for one-third of AIDS deaths
 it is among the top three causes of death for women aged 15 to 44.
 Global incidence of TB has peaked in 2004 and is declining

 The TB death rate dropped 45% between 1990 and 2012.
 An estimated 22 million lives saved through use of DOTS and the Stop
TB Strategy recommended by WHO.
Wednesday, June 24, 2 Dr.Animesh Arya Ref: WHO Global Report, 2006
4
020
INDIA
• India accounts for ¼ of the 8.6 million cases of TB that occur
worldwide.
– India also accounts for a third of the ‘missing 3 million TB cases’
that do not get diagnosed or notified.
– 75 new smear positive PTB cases/1lakh population per year
– 330,000 deaths due to TB each year
– Over 1000 deaths a day
– 2 deaths every 3 minutes
• Not only is TB not going away, we are now seeing severe

forms of multi-drug resistant TB (MDR-TB).
• About 450 000 people developed MDR-TB in the world in
2012. More than 15%these cases were in India
• It is estimated that about 9.6% of MDR-TB cases had XDR-TB
• It constitutes a huge burden

020
TB – A MULTI-SYSTEM
INFECTION

020
Tb problem in India
80% of the time only radiological
investigation is asked for diagnosing
the TB and decision is taken.
BIG GAP
Only 20% of the time Microbiological

investigations are asked.
Pulmonary vs Extra pulmonary
positive cases
Detecting EPTB
Clinical suspicion
Right sample – from site of the disease

Options: need to use a combination
Smears [likely to be neg]
NAAT [Xpert looks very promising, but

sens is still an issue for fluids]
Culture [helpful but 2 – 3 weeks TAT]

Biopsy [very helpful]
If nothing works, empiric TB Rx

No role for blood tests
Best Diagnostic Practises
• Internationally accepted, best practices for
the diagnosis of
• Active TB
• Drug resistant TB
• Latent TB infection
• Based on WHO policies and International
Standards of TB Care
Diagnostic options
• Diagnostic options
• See the bugs [microscopy]
• Multiply the bugs [NAATs]
• Grow the bugs [cultures]
Microscopy
• What should be the sample?
• Timing
• Difficult sites
• Children
• HIV positive subjects
• Rewards Pulmonary vs Extrapulmnary
The slow road to microscopy diagnosis of TB
 “The starting-point in the fight against all contagious diseases is the obligation to report
because without this most cases of the disease remain unknown.” Nobel lecture by Robert Koch,
1905
 A new POC TB Diagnostic tool could save up to 400,000 lives per year. Nature
Microscopy
 Auramine Screen
 Ziehl Neelsen(ZN) Stain
 Spot Samples -2
 Role of automated microscopy
Images of ZN & Auramine STAINED slides
ZN stained slides
AFB bacilli
Auramine stained
M.tuberculosis
AFB culture specimen vice
positivity
Molecular Diagnostics
GenExpert results snapshot
Xpert for EPTB WHO expert
group meeting in May 2013
Xpert for EPTB WHO expert group meeting in May 2013
Systematic review of 20+ studies
Xpert had good sensitivity compared with culture in lymph
node tissues or aspirates
gastric fluid
CSF
other tissue samples
Xpert had poor sensitivity in pleural fluid
Xpert should not be ordered for BLOOD, STOOL & URINE.

Integrated automated NAAT: Cepheid
Xpert MTB/RIF Assay

Major advantages in workflow
fully automated with 1-step external

sample preparation
 time-to-result 2 h (walk away test)
 throughput: up to 4 tests / module
no bio-safety cabinet
 closed system (no contamination risk)
Performance
 specific for MTB

 sensitivity similar to solid culture
 detection of rif-resistance via rpoB cartridge
MTB
gene
IGRAs ≠ Serologic Antibody
tests
IGRAs measures cell mediated immunity, NOT antibody!

FIRST THINGS FIRST:
TST and IGRAs are diagnostic aids
Our current tools measure the immune response to TB

antigens and not the bug itself…..
 No gold standard for LTBI
 Clinical and programmatic use of Interferon gamma
release assays (IGRAs) are the same as for the
Mantoux test (TST)
The difference is in its accuracy…..more on that later

IGRA
Interferon
Gamma
Release
Assay
• THEORY: A person’s T-cells that previously
were sensitized to TB antigen produce high
levels of IFN-gamma when re-exposed to the
same mycobacterial antigen.
LIMITATIONS of QFT are the same as the TST …..
 CANNOT distinguish between active and

latent TB
 CANNOT distinguish between recent and

old infection
 SHOULD NOT be used to determine

efficacy of treatment
Interferon Gamma Release Assays
vs. Tuberculin Skin Test
IGRA TST
 In vitro  In vivo
 Specific TB antigens (ESAT 6,  Antigen soup
CFP10, TB7.7)
 Automated results  Manual reading and entry
 Not affected by BCG & most  BCG & NTM confounds results
NTM
 Result with one patient visit  Two patient visits required for result
 Minimal inter-reader variability  Significant inter-reader variability
 Outstanding surveillance tool if
results electronic  Poor surveillance tool
 Results confidential  Results not confidential
IGRA Performance compared to TST
Performance TST QFT-Gold IT

Characteristics
Est. sensitivity 67-72%* 78-83%*
Est. specificity 59% (+BCG)** 98-100%*
Correlates with Often no Yes

exposure
*Diel, Chest published online 12/09 **Pai et al 2008

Can IGRAs be supportive evidence in the
diagnosis of pediatric and extrapulmonary TB?
Yes when….
Disease is paucibacillary
When tissue specimens

are unavailable or to
dangerous to obtain
When maximum
diagnostic power is
needed 3 yr old contact: +QFT with
cough, runny nose and fever for
a few days but otherwise
healthy – normal exam
Key message: TST and IGRAs
should be restricted for latent
infection screening of high
risk groups
If used for persons with suspected
active TB, these tests will be positive in
a large proportion (since 40% of Indians
have latent infection)
This can result in serious over-treatment

with 4-drug TB Rx with economic and
health consequences for patients
Antibiotic abuse is a big concern already

in India and we are seeing MDR, XDR
and ‘TDR’ strains
Clinical problem case 1
 Sample given for 3 consecutive days for
microscopy
 Day- positive
 Day2- -negative
 Day3-positive
What to do?
 Sample sent for XPERT test comes
negative but Tb –PCR is positive for
MOTT?
 What is right?
All investigations negative except TB Gold?
What to do?
Management of Tuberculosis
NATURAL HISTORY OF TB INFECTION
Exposure to TB
No infection Infection
(70-90%) (10-30%)
Latent TB Active TB
(90%) (10%)
Never develop
Active disease Untreated Treated
Die within 2 years Survive

Die Cured
020
Diagnostic algorithm for pulmonary
tuberculosis

020
Case definitions of TB patients
Type of patient Case definition
New A patient who has never had treatment for TB, or has been on anti-TB
treatment for less than four weeks.
Relapse A patient who has been declared cured or treatment completed for any
form of TB in the past, but who reports back to the health service and is
found to be sputum smear-positive or culture positive.
Treatment after previous A patient who, while on treatment remained sputum smear-positive or
treatment failure became sputum smear-positive at the end of thefour months or more,
after commencing treatment.
Treatment after default (did A patient who had previously been recorded as defaulted from treatment
not complete previous and returns to the health service with smear-positive sputum.
treatment)
Transfer in A patient who is transferred from another district to continue treatment.
Other A patient who does not fit into any of the above categories.
Chronic case A patient who is still sputum smear-positive at the completion of a re-
treatment regimen.

020
Table 14.2 Treatment category by type of patient.
Treatment Type of patient

category
I Sputum smear-positive; new

Sputum smear-negative; seriously ill, new
EPTB; seriously ill, new
Others (e.g. TB with HIV infection)
II Sputum smear-positive; relapse

Sputum smear-positive; failure
Sputum smear-positive; return after default
PTB patients who become smear-positive after two months of treatment (case definition
= other)
Return after default from re-treatment
Relapses after re-treatment
III Sputum smear-negative, not seriously ill, new

EPTB, not seriously ill, new
IV Chronic and drug resistant-TB cases (still sputum positive after supervised re-
treatment)

020
TB Chemotherapy : The Effective TB Control
• Drugs used to treat TB:
(a) Front-line Drugs:

isoniazid (INH)
rifampicin (RMP),
pyrazinamide (PZA),
streptomycin,
ethambutol.
(b) Second-line Drugs: PAS, kanamycin, cycloserine,
ethionamide, thiacetazone, ciprofloxacin/ofloxacin,
rifapentine, amikacin, viomycin, capreomycin.
Grouping of Anti TB Agents
Grouping Drugs
Group 1: Isoniazid (H); Rifampicin (R); Ethambutol (E);
First-line oral anti-TB Pirazinamide (Z)
agents
Group 2: Streptomycin (S); Kanamycin (Km); Amikacin
Injectable anti-TB agents (Am); Capreomycin (Cm); Viomycin (Vm).
Group 3: Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin
Flouroquinolones (Lvx); Moxifloxacin (Mfx); Gatifloxacin (Gfx)
Group 4: Ethionamide (Eto); Prothionamide (Pto);
Oral second-line anti-TB Cycloserine (Cs); Terizadone (Trd);
agents para-aminosalycilic acid (PAS);
Group 5: Clofazimine(cfz); Clarithromycin(Clr)
Agents with Unclear role Amoxacillin/Clavulanate(amx/clv);
in Treatment of DR TB Thioacetazone(Thz); High Dose INH;
Imipenem/Cilastatin(Ipm/Cln); Linezolide(lzd);
Drug action on TB bacillary population
INH RIF
RIF
Extra-cellular Extra-cellular
SM slowly
rapidly
multiplying 108 multiplying <105
EMB
PAS
PZA
Intra- and extra-

cellular, acidic
Dormant No drugs environment
<105
INDIA

020
Tuberculosis Management
• Standard/Conventional Chemotherapy
• Supervised Chemotherapy
• Short course Chemotherapy
• RNTCP based on DOTS
• Directly Observed Treatment Short course
• Stop TB Strategy
• DOTS Plus strategy and ISTC
• STCI
Intensive Phase
• Aims for a rapid killing of bacilli

• A state of non-infectiousness within 2/52
• Quick relief of symptoms
• Smear negativity by 2/12
• Prevent development of drug resistance
 multi-drug regimens and DOT
Continuation Phase
• Aims to eliminate remaining bacilli

• Killing of “persisters” prevents relapses
• Multi-drug regimens and DOT necessary
(unless R not used) even though risk of
emergence of drug resistance is less as
fewer bacilli remain
020
DIRECTLY OBSERVED TREATMENT,
SHORT-COURSE STRATEGY (DOTS),
1994
1. Government commitment to TB control
2. Diagnosis by smear microscopy mostly on self-reporting symptomatic patients
3. Standardised short course chemotherapy (SCC) with direct observation of treatment (DOT)
4. Efficient system of drug supply
5. Efficient recording and reporting system with assessment of treatment result
6. Five components were expanded in 2002
7. Since 1995,over 21 million patients have been diagnosed and treated in DOTS
programes
8. Of 2.5 million new smear positive patients registered in 2006, 85% were successfully
treated under DOTS

020
Dosage and abbreviation of
essential antituberculosis drugs
Drug (abbreviation) Recommended dosage
(dose range) in md/kg
Daily 3 times weekly
Isoniasid (H) 5 10
(4-6) (8-12)
Rifampicin (R) 10 10
(8-12) (8-12)
Pyrasinamide (Z) 25 35
(20-30) (30-40)
Streptomycin (S) 15 15
(12-18) (12-18)
Ethambutol (E) 15 30
(15-20) (20-35)
020
Table 14.2 Treatment category by type of patient.
Treatment Type of patient

category
I Sputum smear-positive; new

Sputum smear-negative; seriously ill, new
EPTB; seriously ill, new
Others (e.g. TB with HIV infection)
II Sputum smear-positive; relapse

Sputum smear-positive; failure
Sputum smear-positive; return after default
PTB patients who become smear-positive after two months of treatment (case definition
= other)
Return after default from re-treatment
Relapses after re-treatment
III Sputum smear-negative, not seriously ill, new

EPTB, not seriously ill, new
IV Chronic and drug resistant-TB cases (still sputum positive after supervised re-
treatment)
020
Basic treatment regimens
Diagnostic TB patients Treatment regimenI
category
Initial phase Continual phase
I New smear-positive Preferred Preferred

patients; new smear- 2 HRZEI 4 HR- 4HRE
negative PTB with 4 (HR)3
extensive parenchymal Optional or Optional
involvement; concomitant 2 (HRZE)3 4 (HR)3 –4HRE
HIV disease or severe or
or
forms of extrapulmonary 6 HEV
2 HRZEIV
TB
II Previously treated sputum Preferred Preferred
smearpositive 2 HRZES / 1 HRZEVI 5 HREVI
PTB: Optional Optional
- relapse; 2(HRZES) /1HRZE3 5 (HRE)3
- treatment
Wednesday, June 24, 2 after defaultDr.Animesh Arya 3 56
020
Basic treatment regimens
(continued)
Diagnostic TB patients Treatment regimenI
category Initial phase Continual phase
III New smear-negative PTB Preferred Preferred

(other than in category I) 2 HRZEVIII 4 HR
and less severe forms of Optional Optional
extra-pulmonary TB 2 (HRZE)3 4 (HR)3
or
6 HE
IV Chronic (still sputum- Specially designed standardized or
positive after supervised individualized regimens
re-treatment); proven or
suspected MDR TB cases.
WHO/CDS/TB/2003.313 Treatment of tuberculosis:guidelines

Wednesday, June 24, 2 for national
Dr.Animesh Arya programmes, third edition.
57
020
Revision approved by STAG, June 2004
Drug Resistant
Tuberculosis
• MDR-TB caused by strains of
Mycobacterium Tuberculosis resistant
both Rifampicin and Isoniazid with or
without resistance to other drugs.
• Single Isoniazid or Rifampicin
resistance is not MDR - TB
• MDR TB is a laboratory diagnosis

020
When to suspect MDR TB?
• Re-treatment patients who’s sputum
smear remains positive after three months’
of intensive therapy Cat II
• Treatment failure and interruption cases
• Sputum positive patients who are contacts
of a known MDR TB patient
• Positive diagnoses with;

TB culture and susceptibility testing
020
Causes MDR TB
• MDR-TB is a man made phenomenon
 Poor drugs
 Poor treatment
 Poor adherenceInadequate drug delivery
is main cause of secondary drug
resistance
• ”Amplifier effect of Short Course
Therapy”
 Use of DOTS in MDR-TB pts-More
resistance to the drugs-
 Uncontrolled use of 2nd line drugs
020
Are we Returning to a
Pre-antibiotic Era ???
Drug
susceptible MDR-TB XDR-TB Total DR
TB 1990 2006 ?
*or limited Resistance Resistance Resistance to

resistance to H&R – to 2nd line all available
manageable drugs – drugs –
with 4 drug Treatable
Treatment
with 2nd
regimen -
line drugs
options No
DOTS seriously treatment
restricted
Wednesday, June 24, 2 Dr.Animesh Arya options 62
020
DIAGNOSIS OF TB: Drug Resistance
TB
MONO & POLY
RR TB
MDR TB
DR TB
MDR TB Plus
XDR TB
XDR TB Plus
NTM ??
How to evaluate MDR TB ?
MDR TB is only a laboratory proved

HR resistance
Clinical suspicion should be
followed by lab. Confirmation
 Laboratories should be quality controlled
020
Treatment outcome of XDR-TB, Global
Total 1,269 XDR TB patients from 40 countries for whom outcomes were reported in 2013.
Can XDR-TB be cured or
• Yes, in some cases.
treated?
• Several countries with good TB control programmes have
shown that cure is possible for up to 30% of affected people.
• But successful outcomes depend on the extent of the drug
resistance,
• Severity of the disease
• Patient’s immune system
• Access to laboratories that can provide early and accurate
diagnosis so that effective treatment is provided as soon as
possible.
• All classes of second-line drugs are available to clinicians
who have special expertise in treating such cases.

020
020
Hepatotoxicity (Hepatitis)
• Clinical Presentation
[Hepatotoxicity is very uncommon in children]
• Symptoms: nausea, vomiting, abdominal
tenderness, discomfort near the ribs on the right
upper abdomen, jaundice
• Signs: hepatic enlargement, increased LFTs
• Causative Agents
• INH + rifampin > INH alone >> pyrazinamide*
alone > rifampin alone > ethionamide
• Among the second-line drugs, ethionamide,
protionamide and PAS can also be hepatotoxic,
But less than any of the first-line drugs.
• Wednesday,
Patients June with
24, 2 chronic Dr.Animesh
liver disease
Arya should not 72
receive pyrazinamide.
020
Hepatotoxicity (Hepatitis)
Management in Adults
•Hold all drugs and obtain LFTs
•If LFTs are within the normal ranges, Manage Nausea/Vomiting
•If LFTs are elevated, hold drugs until symptoms resolve and the
transaminases decreases to < 2x normal
•1)E and S should be started if drug therapy can not be held secondary to
the patient’s clinical condition
•2) Rechallenge the patient after resolution of signs and symptoms by
adding drugs to the regimen every 4 days:
•a) INH for 3 days, if patients remains asymptomatic then add
•b) Rifampin for 3 days, if patients remains asymptomatic then add
•c) Pyrazinamide (15-20mg/kg/d) for 3 days
•3) If signs and symptoms recur with rechallenge, discontinue the
responsible drug and modify the regimen and/or duration of therapy as
required

020
EPTB -Overview
EPTB constitutes about:
15-20 % of all TB cases in immunocompetent pts
>50 % of TB cases in immunosuppressed pts
M.C. sites of involvement :
LN > Pl eff> Others
S/S depend on area inv –often nonspecific
Dx often delayed:
Atypical clinical presentation
No pathognomonicradiographic signs for any site
Poor diagnostic yield of conventional methods
Tissue samples for Dx often difficult to obtain

020
EPTB usually responds to std
ATT

020
MDR EPTB –Mimickers
Paradoxical response
•Enlargement of old lesions or appearance of new
lesions during apparently adequate ATT:
•TB LNE Appearance of new LN or ↑in size of
original LN
•EPTB Development of new pul infiltrates
•PTB Development of PE & progression of pul
infiltrates
•1°TB (children) 􀃆↑in size of LN & pul infiltration
•PE Development of C/L PE & ↑in amount of I/L PE
& even appearance of new pul lesions
020
CONCLUSION
• TB patients need a complete solution to their
problem, regardless of whether they seek care in
the public or the private sector. Therefore, it is
important for the private sector to work hand in
hand with the RNTCP, and improve the overall
quality of TB care, help control TB, but also save
lives.
• Private providers should be encouraged to

disseminate best practices, Standards of TB Care
in India (recently brought out by the government),
and encourage strict compliance with the
Government of India’s ban on serology and
mandatory notification of cases.

020
THANK YOU
REFINED APPROACH
Newer Diagnostics
• CXR (Digital; Computer Aided Detection for
TB)
Newer Diagnostics
• Sputum smear microscopy (LED FM)
• Automated staining tool and slide processors
(RAL STAINER)
• Automated slide reader

(TBDx system)
• Automated slide reader
Newer Diagnostics
• Fluorescence in situ hybridization (FISH)
• Liquid culture plateforms (MGIT 960, BacT/Alert

3D 120, VersaTREK 528)
Case finding strategy
• Proactive case finding approach
 Widespread awareness with community engagement in
identifying presumptive TB case and referring them to
diagnostic centres
 Community mobilization with support of local self-government
 Active TB case finding among high risk groups

• Urban slum, PLHIV, DM, malnutrition, high risk health care settings,
patient contacts, migrants
Management of TB: First Line therapy
- Intensive Phase: 3 HERZ ( Extension of 1 month if
require)
Continuous Phase: 6 HER
RIETT Panel (Redefining Indian Expertise based

Tuberculosis Treatment 2006)
-
Initial phase : Two months of HERZ &
Continuation phase consist of three HER at least four months.
The duration of continuation phase may be extended by three to six

months in special situations like Bone & Joint TB, Spinal TB with
neurological involvement and neuro-tuberculosis.
(Standard of TB Care in India WHO 2014)

Management of TB: First Line therapy
All patients should be given daily regimen under direct
observation.
However, the country programme may consider daily or

intermittent regimen for treatment of TB depending on the
available resources
and operational considerations as both are effective
provided all doses are directly observed
All paediatric TB patients and HIV associated TB patients

should be given daily regimen under direct observation.
(Standard of TB Care in India WHO 2014)
Management of Tuberculosis
• Patients with mono-resistant TB and patients
with poly-resistant TB other than MDR-TB.
• Mono-resistance refers to resistance to a

single first-line drug, (without Rifampicin)
• Poly-resistance refers to resistance to two or

more first-line drugs. (without Rifampicin)
Suggested regimen for Mono & Poly Drug
Resistance TB (WHO 2008)
Pattern of Suggested Minimum For extensive disease
drug resistant regimen duration
(months)
H ( S) RZE 6-9 FQ strengthen regimen
HZ REFQ 9-12 Longer duration of

treatment
HE RZFQ 9-12 Longer duration of
treatment
HEZ ( S) RFQ+oral 18 Longer duration (6
SLD+inj for months) of injectables
2-3 months
DRUG RESISTANCE PATTERN
Monodrug resistant TB Polydrug resistant TB
 INH Resistance- By LPA Basic regimen-

Inj SLD + FQ + Rifampicin + any 2
FLD (from H,E,Z). If 2 FLDs cannot
 S, H, E or Z monoresistance by Liquid be used, select from WHO Group 4
Culture drugs -Ethionamide, Cycloserine or
PAS to make a total of 5 given
Basic regimen- 5 drugs DAILY
Inj SLD + FQ + Rifampicin+ 2 out of the
remaining three first line drugs to
which the patient is sensitive (from H,E
& Z) to make a total of 5 effective drugs
given DAILY
The regimens for every DR TB Patient will be decided by the DR TB

Centre committee and the patient will be sent back to the DTO for
further management
National Workshop on Drug Susceptibility Testing (DST) Guided Treatment for

Drug Resistant Tuberculosis patients in India,at Mumbai on 26-28 August 2014
To have a National Guidelines for
DST guided Treatment Regimen
for MDR TB and XDR TB
Rifampicin Resistance/MDR TB
STARTS REGIMEN FOR MDR TB STR-

KM/E/Z/ETO/CS/LFX/H
LC DST results of E,Z,KM, AM, CM,LFX, MFX received after 6-8

weeks
ADDL RESISTANCE PATTERN
FLUOROQUI SL MIXED FLDS

FLDS ONLY
NOLONES INJECTABLES AND SLDS
Further modification on the regimen to be decided by DR-TB centre

MDR TB (With or without Additional Resistance)
Additional Drug Treatment Additional
Resistance Recommendation recommendation
None Regimen for STR of continue STR
MDR,
Ethambutol Ethambutol to be Less reliability of
removed Ethambutol sensitivity
Pyrazinamide Omit Pyrazinamide in Good Reliability of PZA by
STR LC
Levofloxacin or Use FQ to which patient
Moxifloxacin is sensitive
Resistance to Replace FQ in regimen
both Levofloxacin with PAS + Clofa + LNZ
or Moxifloxacin in IP and continue in
CP
MDR TB (With or without Additional Resistance)
Additional Drug Treatment Recommendation Additional
Resistance recommendation
Resistance to any Use one Injectable as per Kanamycin

S.L. DST & in following order: vs.Amikacin to be
INJECTABLE decided by CTD later
1.Kanamycin
(AM,KM,CM)
2.Amikacin
3.Caperomycin
All SL injectables Replace Injectable with PAS

+ Clofa + LNZ in IP and
continue in CP also

MDR with mixed pattern of resistance
Resistance Treatment Additional
Pattern Recommendation recommendation &
Justification
Mixed Basic regimen : Cat IV regimen & if Injectable SLD &
modify based on resistance pattern:
resistance FQ are included:
pattern any USE ANY INJECTABLE and FQ as
per recommendation discussed earlier Minimum 6 Drugs in
FLD/Inj IP and 4 Drugs in CP
CONSIDER OTHER ORAL DRUGS
SLD/FQ /
as per DST pattern and in following if Injectable SLD
Ethionamide, Sequence of preference :-
PAS, LZ, CF PYRAZINAMIDE (if sensitive),
and /or FQ are not
ETHAMBUTOL, ETHIONAMIDE, included:
(including XDR- CYCLOSERINE, PAS,
TB) CLOFAZIMINE,LINEZOLID,
Minimum 8-9 drugs
COAMOXYCLAV, HIGH DOSE INH & are to be given in IP
CLARITHROMYCIN and 7-8 drugs in CP

Special Considerations
• Extension of services to Pediatric group and

EPTB
• All MDR & XDR TB Patients: evaluate for
surgery
• Management of terminally ill patients without any
appropriate regimen available
• Salvage Regimen for XDR-TB Plus, newer
drugs
• Infection control measures
• Management of contacts of MDR/XDR TB
Need for Newer Molecules
There is an urgent need to improve treatment
either enhancing the application of existing agents
or introducing new drugs.
Potential new agents should
reduce treatment duration,
have an acceptable tolerability profile,
active against MDR/XDR TB,
useful in HIV-infected patients with TB, and be
active against latent TB
Challenge in TB drug development
• In phase II clinical trials, culture conversion after 2 months of treatment -
surrogate marker for relapse rate,
value of surrogate marker is controversial,
Several other surrogate markers are under evaluation
• The phase of clinical testing of new anti-TB drugs

time-consuming,
“gold standard” to assess efficacy of anti-TB regimens in phase III
clinical trials, relapse rate 2 years after completing treatment.
• Large sample sizes needed in phase III clinical trials

to compare the effective standard regimen to a new regimen,
even in trials that use a non inferiority design.
Contributes to length TB drug development process
• Scarcity of trial sites with sufficient research capacity.

• Trials should be performed in countries where the TB burden is highest,
Global TB Drug Pipeline
Discovery1 Preclinical Development Clinical Development
Diarylquinoline CPZEN-45 BTZ043 AZD5847 Delamanid (OPC-67683)

DprE Inhibitors DC-159a TBA-354 Bedaquiline (TMC-207) Gatifloxacin
GyrB inhibitors Q201 Linezolid Moxifloxacin
InhA Inhibitors SQ609 Novel Regimens2 Rifapentine
LeuRS Inhibitors SQ641 PA-824
MGyrX1 inhibitors 4 Repurposed Rifapentine
Mycobacterial Gyrase Drugs SQ-109
Inhibitors 6 New Drugs Sutezolid (PNU-100480)
Pyrazinamide Analogs
Riminophenazines
3 New Classes
Ruthenium (II) complexes Drugs currently in the regulatory
Spectinamides
review process
Translocase-1 Inhibitors
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone

1
Ongoing projects without a lead compound series can be viewed at http://www.newtbdrugs.org/pipeline-discovery.php.
2
Combination regimens: first clinical trial (NC001) of a novel TB drug regimen testing the three drug combination of PA-824,
moxifloxacin, and pyrazinamide was initiated November 2010 and completed in 2011 with promising results. The second
clinical trial (NC002) of this regimen was launched in March 2012 and will test the efficacy of the regimen in drug-sensitive www.newtbdrugs.org
and multidrug-resistant patients. The third clinical trial (NC003) will evaluate PA-824, TMC-207, pyrazinamide and Updated: June 18, 2013
clofazimine in combinations and is scheduled to begin September 2012.
Global TB Vaccine Pipeline
Phase I Phase II Phase IIb Phase III
AdAg85A VPM 1002 MVA85A/ M. Vaccae

McMaster, CanSino Max Planck, VPM, AERAS-485 Anhui Longcom
TBVI, Serum Institute Oxford, Aeras,
MTBVAC EDCTP
TBVI, Zaragoza, Biofabri H1+IC31
SSI, TBVI, EDCTP, M72+AS01
Intercell GSK, Aeras
ID93+GLA-SE
Infectious Disease
Research Institute (IDRI),
RUTI
Aeras
Archivel Farma, S.L.
Crucell Ad35/MVA85A
Crucell, Oxford, Aeras
H56/AERAS-456
+IC31
SSI, Aeras, Intercell
H4/AERAS-404
+IC31
Prime SSI, sanofi-pasteur,
Aeras, Intercell
Boost TB Vaccine Types
Post-infection Crucell Viral-vectored: MVA85A, AERAS-402, AdAg85A
Ad35/AERAS-402 Protein/adjuvant: M72, Hybrid-1, Hyvac 4, H56, ID93
Immunotherapy Crucell, Aeras rBCG: VPM 1002
Killed WC or Extract: Mw, RUTI
June 2013
Extreme Drug resistant Tuberculosis
(XDR-TB) and AIDS
• It can also be contracted without a patient
receiving any previous treatment for TB
• Mostly associated with HIV positive patients
• HIV has the potential to fast tracking XDR-TB
into an uncontrollable epidemic
• Average survival period for patients infected with
XDR-TB is 16 days.

020
Drug susceptibility testing (DST)
• DST is recommended for all new cases for all
first line drugs with specimens taken before
initiating treatment.?
• Accuracy is more important than speed
within 1-2 days
• Early identification of mycobacterial growth as M.
tuberculosis complex and the identification of rifampicin
resistance should be the first priority as rifampicin
resistance invalidates standard 6 month short-course
chemotherapy and is a useful marker in most countries
for MDR-TB.

020
INTERPRETATION OF DST
RESULTS
- CAUTION
• Drug susceptibility test results of
 Pyrazinamide, streptomycin, and ethambutol
are poorly reproducibile
 2nd line anti-TB drugs should be interpreted

with great caution due to limited capacity of
laboratories, absence of quality-assurance,
and lack of standardized methodology.

020
CDC Updates Guidelines for Nucleic Acid
Amplification Techniques to Diagnose Tuberculosis
• NAAT results should be interpreted

in conjunction with the AFB smear
results.
• NAAT and smear positive: start Rx
despite pending culture results.
PPV 95%
• Smear negative, NAAT positive:
use clinical judgment to either treat
or await culture
020
Alternative method of grouping anti tuberculosis drugs
GROUPING DRUGS (ABBREVIATION)
Group 1 – First-line oral Isoniazid (H); Rifampicin (R);

antituberculosis agents Ethambutol (E); Pyrazinamide (Z)
Group 2 – Injectable Streptomycin (S); Kanamycin (Km);

antituberculosis agents Amikacin (Am); Capreomycin (Cm);
Viomycin (Vi)
Group 3 Ciprofloxacin (Cfx); Ofloxacin (Ofx);
Fluoroquinolones Levofloxacin, (Lfx); Moxifloxacin (Mfx);
Gatifloxacin (Gfx)
Group 4 – Ethionamide (Eto); Protionamide (Pto);
Oral bacteriostatic agents Cycloserine (Cs); Terizidone (Trd)a; P-
aminosalicylic acid (PAS);
Thioacetazone (Th)
Group 5 – Antituberculosis agents Clofazimine (Cfz);
with unclear efficacy (not Amoxicillin/Clavulanate (Amx/ Clv); -
recommended by WHO for routine use Clarithromycin (Clr); Linezolid (Lzd)
in MDR-TB
Wednesday, patients)
June 24, 2 Dr.Animesh Arya 106
020
Drugs in M/XDR TB Management
*Guidelines for Programmatic management of Drug Resistant Tuberculosis, WHO 2008
1st line drugs: Most efficacious and best tolerated (G 1)

(HR)ZE
Injectable: S, Km, Am, Bactericidal (G 2)
Cm
Fluoroquinolone: Mfx, Lfx, Bactericidal (G 3)
Ofx
Less efficacious and Other bacteriostatic drugs: Pto/Eto, Cs,
poorly tolerated (GP 4)
PAS, Cfz, Amx/clv, Linezolid, imipenam / cilastatin,
Drugs with thiocetazone, clarithromycin, High dose INH
unclear efficacy
020 (Gp 5)
Dosage and Weight band recommendations
Drugs 16-25Kg 26-45 Kg > 45-70 Kg

Kanamycin 500 500 mg 750 mg
Levofloxacin 250 750 1000
Ethionamide 375 500 mg 750 mg
Ethambutol 400 800 mg 1200mg
Pyrazinamide 500 1250 mg 1500 mg
Cycloserine 250 500 mg 750 mg
*Na PAS 5gm 10 gm 12 gm
Pt >70 Kg: kana, Ethio, Cycl:1gm; Etm:1.6gm; PZA:2gm
020 * Na PAS is to be used as a substitute drug
Basic Principles-1
Use at least 4 drugs certain or highly
likely to be effective depending on
following factors
• DST results show susceptibility.
• No previous history of treatment failure
with the drug.
• No known close contacts with resistance
to the drug.
• Drug resistance survey indicates
resistance is rare in similar patients.
• The drug is not commonly used in the area.
If at least 4 drugs are not certain to be
effective, use 5–7 drugs depending on the
specific
Wednesday, June 24, 2drugs and levelAryaof uncertainty. 109
Dr.Animesh
020
Basic Principles-2
Do not use drugs for which resistance
crosses over
• All rifamycins (rifampicin, rifabutin,
rifapentene, rifalazil) have high levels of
cross-resistance.
• Fluoroquinolones : that some higher-
generation fluoroquinolones remain
susceptible when lower-generation
fluoroquinolones are resistant.
• Not all aminoglycosides and polypeptides
cross-resist; in general, only kanamycin and
amikacin fully cross-resist.
020
Basic Principles-3
Include drugs from Groups 1–5 in a hierarchical
order
 Use any Group 1 (oral first-line) drugs that are
likely to be effective
Use an effective aminoglycoside (Group 2 drugs).
Use a fluoroquinolone (Group 3).Moxifloxacin
preferred
Use the remaining Group 4 drugs to make a regimen
of at least 4 effective drugs. For regimens with ≤4
effective drugs, add second-line drugs most likely
to be effective, to give up to 5–7 drugs in total, on
the basis that at least 4 are highly likely to be
effective. The number of drugs will depend on the
degree of uncertainty.
• Use Group 5 drugs as needed so that at least 4
drugs are likely to be effective.
020
Basic principle -5
• Injection 6 days, oral 7 days

• Daily DOT; Sundays: self administration
• All drugs in single dose
• Ethionamide, cycloserine, PAS may be
split if not tolerated
• PAS as substitute drug
• Dose ↑ if >5 Kg gain & weight band cross
020
Cat V Regimen
• Cat V treatment: 7 drugs with 2 reserve

drugs
– 7 drugs: capreomycin, moxifloxacin, PAS,
high dose INH, linezolid, clofazimine,
amoxy-clauvulanate
– Reserve drugs: clarithromycin,
thiacetazone
• Intensive phase: 6-12 months
• Continuation phase: 18 months
020
TB and HIV treatment sequence

020
Spl . situations
• Pregnancy[2HRZ+4HR]
• Breast feeding women- INH prophy., BCG

020
Breastfeeding
• Encourage breast feeding if negative
• Chemotherapy is the best way to prevent
transmission of tubercle bacilli to baby.
• Most antituberculosis drugs will be found
in the breast milk
• It is recommended to provide infant
formula options

020
Contraception
• A woman receiving rifampicin treatment
may choose between
• Oral contraceptive pill containing a higher
dose of estrogen (50 μg);
• Or use of another form of contraception.

020
Pregnancy
• Not much experience with MDR TB & pregnancy
• All women on MDR TB-Birth control measures
• Risk/Benifits discussed with pt.
• Tt started ii/iii trimester unless life threatening
• Avoid AG-May be added after delivery
• Aim-Achieve sputum conversion before delivery
• Pregnancy is not a contraindication for treatment
of active drug-resistant TB
• Avoid injectable agents- Capreomycin used if
unavoidable
• Avoid ethionamide.-Nausea, TERATOGENIC

020
Diabetes mellitus
• With MDR-TB are at risk for poor
outcomes.
• Diabetes mellitus may potentiate the
adverse effects of drugs,-renal
dysfunction and peripheral neuropathy
• Use of ethionamide or protionamide may
make it more difficult to control insulin
levels.

020
Renal insufficiency
• Discontinue suspected agent.

• Adjustment of antituberculosis medication in renal
insufficiency
• Dose and/or the interval between dosing should
be adjusted
• Consider using capreomycin if an aminoglycoside
had been the prior injectable in regimen.
• Consider dosing 2 to 3 times a week if drug is
essential to the regimen and patient can tolerate
• Adjust all TB medications according to the
creatinine clearance.

020
Renal impairment and dose/interval adjustment
Drug Mod GFRml/mt

ifica >50 10-50 <10
tion
Km, D,I 7.5-15mg/kg/24h 4-7.5mg 3/kg/48

E I 20mg/kg/24h 20mg/kg/ 20/kg/48
24-36h
Z D 30mg/kg/24h 30mg/kg/ 15-
24h 30/kg/24
Ofx D 100% 50-75% 50%
Eto D 100% 100% 50%
Cs D 100% 50-100% 50%
PAS D 100% 50-75% 50%

020
Is MDR-TB a real threat in India?
State Proportion of MDR Proportion of MDR
amongst new TB cases amongst re-treatment TB
cases
Gujarat 2.4% 17.4%
Maharashtra 2.7% 14%
Andhra Pradesh 1.8% 11.8%
National DRS – (7 sites) co-ord. by AIIMS, patients of Medical colleges, DTC & PHC
7 sites
(unpublished)
7.8% 29.8%
Community survey of TB prevalence- MDR out of TB
Gujarat 7.8% 17.1%

>30% of Tuberculosis cases amongst the contacts of MDR TB are found
to be MDR-TB
Primary transmission ?
Is XDR TB a real threat in India?
High XDR / pre-XDR levels out of XDR suspects undergoing

Second-line Drug Susceptibility Testing at NRLs
Source: National TB Institute, Bangalore

The case of Mumbai and the
“TDR-TB outbreak” – Jan 2012
March 2012 - WHO convened 40 experts meet

•Such cases pose a formidable challenge to clinicians
and public health authorities
•No reliable definition beyond XDR-TB
•Improvements in the accuracy of drug susceptibility
testing to certain drugs
•Release of innovative new drugs will, however, change
this position in future.
•India turned this crisis into opportunities for
improvements in Mumbai and country wide
Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin Infect Dis. 2012 Feb 15;54(4):579–81.
RNTCP Category IV Regimen
RNTCP is using a Standardised Treatment Regimen (STR) for the treatment of

MDR-TB cases under the programme.
REGIMEN:
- 6 (9) Km Lvx Eto Cs Z E /
- 18 Lvx Eto Cs E
• All drugs to be given daily under direct observation with Inj KM.
• On Sundays, Inj KM is omitted and oral drugs are given un-observed
• Na PAS is a reserve drug to be used instead on any one drug
RNTCP Category V Regimen
RNTCP is using a Standardised Treatment Regimen

(STR) for the treatment of XDR-TB cases under the
programme by daily DOT.
REGIMEN:
6 (12) Cm Mfx PAS, High Dose H, Cfz, Lzd,Amx-Clv./
18 Mfx PAS, High Dose H, Cfz, Lzd,Amx-Clv
Clr. & TZN are substitute drugs for any one drug
in case of intolerance or ADRs
DR-TB – Ambulatory Care
• After completion of in patient Care, patient has to

receive Ambulatory daily DOT services
• Hence need to create DR-TB DOT provider network for
MDR-TB patients
• Follow-up smear and culture examinations at months 3,
4, 5, 6, 7, 9, 12, 15, 18, 21, and 24
• Outcome will be based on culture results
• Treatment outcome report submitted 31-33 months after
patients in the respective cohort registered for treatment
Regimen for XDR TB
Moxifloxacin (Mfx)
High dose INH (High dose-H)
Clofazimine (Cfz)
Linezolid (Lzd)
Inj. Capreomycin (Cm)
Amoxyclav(Amx/Clv)
Pyridoxine PAS
Type-A
Type-B
RNTCP Challenges
• Diagnosis reliant on age old low sensitivity tools and case
finding strategies
• Multi drug resistance
– HIV/AIDS infection and other comorbid conditions
• Barriers to DOTS
– Practical challenges in rural conditions
– patients cultural beliefs
– human rights
• Insufficient infrastructure
– Lack of motivated personnel
• No regulation over private providers
• Need for stronger national policy
• Funding gaps
EVOLUTION OF TB CONTROL IN
INDIA
• 1950s-60s Important TB research at TRC and NTI
• 1962 National TB Programme (NTP)
• 1992 Programme Review
• only 30% of patients diagnosed;
• of these, only 30% treated successfully
• 1993 RNTCP pilot began

• 1998 RNTCP scale-up
• 2001 450 million population covered
• 2004 >80% of country covered
• 2006 Entire country covered by RNTCP
020

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CURRENT TRENDS IN MANAGEMENT

AND TREATMENT OF TUBERCULOSIS

DR. ANIMESH ARYA

Wednesday, June 24, 2 Dr.Animesh Arya 1

Wednesday, June 24, 2 Dr.Animesh Arya 2

24 MARCH CELEBRATED AS WORLD TB

First discovered in 1882 by Robert Koch,

 Global incidence of TB has peaked in 2004 and is declining

• Not only is TB not going away, we are now seeing severe

Wednesday, June 24, 2 Dr.Animesh Arya 5

Wednesday, June 24, 2 Dr.Animesh Arya 6

Only 20% of the time Microbiological

Right sample – from site of the disease

NAAT [Xpert looks very promising, but

Culture [helpful but 2 – 3 weeks TAT]

If nothing works, empiric TB Rx

 Ziehl Neelsen(ZN) Stain

Xpert had poor sensitivity in pleural fluid

Xpert should not be ordered for BLOOD, STOOL & URINE.

Xpert MTB/RIF Assay

fully automated with 1-step external

 specific for MTB

IGRAs measures cell mediated immunity, NOT antibody!

Our current tools measure the immune response to TB

The difference is in its accuracy…..more on that later

 CANNOT distinguish between active and

 CANNOT distinguish between recent and

 SHOULD NOT be used to determine

Performance TST QFT-Gold IT

Est. sensitivity 67-72%* 78-83%*

Est. specificity 59% (+BCG)** 98-100%*

Correlates with Often no Yes

*Diel, Chest published online 12/09 **Pai et al 2008

When tissue specimens

This can result in serious over-treatment

Antibiotic abuse is a big concern already

Die within 2 years Survive

Wednesday, June 24, 2 Dr.Animesh Arya 42

Type of patient Case definition

Transfer in A patient who is transferred from another district to continue treatment.

Wednesday, June 24, 2 Dr.Animesh Arya 43

Treatment Type of patient

I Sputum smear-positive; new

II Sputum smear-positive; relapse

III Sputum smear-negative, not seriously ill, new

Wednesday, June 24, 2 Dr.Animesh Arya 44

• Drugs used to treat TB:

(a) Front-line Drugs:

Intra- and extra-

Wednesday, June 24, 2 Dr.Animesh Arya 48

• Aims for a rapid killing of bacilli

• Aims to eliminate remaining bacilli

Wednesday, June 24, 2 Dr.Animesh Arya 53

Treatment Type of patient

I Sputum smear-positive; new

II Sputum smear-positive; relapse

III Sputum smear-negative, not seriously ill, new

I New smear-positive Preferred Preferred

III New smear-negative PTB Preferred Preferred

WHO/CDS/TB/2003.313 Treatment of tuberculosis:guidelines

Wednesday, June 24, 2 Dr.Animesh Arya 59

• Positive diagnoses with;

*or limited Resistance Resistance Resistance to