Tuberculosis

Samah Selim Abd El-Naiem, MD

Professor of Pulmonology
Faculty of Medicine
Cairo University
November, 2022
Updated , 2023
Agenda

• Tuberculosis history.
• Epidemiology.
• Latent TB.
• Clinical presentation.
• Imaging of tuberculosis.
• Treatment of drug sensitive TB.
• Drug resistance TB.
• Complications of pulmonary TB
• Surgery in TB.
• TB in special conditions.
• Tuberculosis (TB) is an old disease.
• Its cause remained unknown until 24 March 1882, when

• Discovery of the bacillus responsible, Dr Robert Koch

• Subsequently named Mycobacterium tuberculosis

 TB Transmission

• Air-born.
Infectivity of the source
• Other modes (Smear positive)
Radiological evidence of a cavity
of transmission…

Environmental
Host susceptibility
factors

Virulence of
TB bacilli

Duration of exposure
 Tuberculosis
Healed primary
infection (majority)

Primary Progressive primary

infection infection (5%)

Haematogenous
spread
Miliary TB/ Extra-

Post pulmonary TB

primary Re-infection

infection Or
Re-activation
International Journal of Infectious Diseases
DOI: (10.1016/[Link].2022.02.047
 (Latent) TB Infection(LTBI)

Definition
LTBI is defined by WHO as a state of persistent

immune response to stimulation by M. tuberculosis

antigens (Infection) with no evidence of clinically

manifest active TB.

 (Latent) TB Infection

• The aim of testing for LTBI is to identify those who will benefit

from prophylactic therapy.

• Patients with LTBI have a 4%–6% lifetime risk of developing TB

disease

• Although, Both IGRA and TST testing provide evidence for

infection with Mtb, they cannot distinguish active from latent

tuberculosis.

• Therefore, the diagnosis of active TB must be excluded prior to

treatment for LTBI. ( clinical/ radiological / bacteriological

How to diagnose LTBI?
 Tuberculin Skin Testing

• TST is the standard method for testing LTBI.

• TST detects cell-mediated immunity to Mtb through a delayed-type
hypersensitivity reaction .
• It uses protein precipitate of heat-inactivated tubercle bacilli (purified
protein derivative [PPD]–tuberculin).
• Intradermal injection of 0.1 mL of PPD (5 TU) into the forearm (Mantoux
method) to produce a transient wheal. The test is interpreted at 48–72
hours by measuring the transverse diameter of the palpable induration.
Tuberculin Skin Testing
 Tuberculin Skin Testing
Interpretation

A reaction of ≥10 mm
A reaction of 5 mm or
Immune competent , high TB greater
incidence countries
Immune suppressed, HIV
Occupational exposure
TNF blocker/ steroids
medical risk factors that
Close contact
increase the probability of
Previous TB
progression from LTBI to TB

A reaction of 15 mm or greater:
BCG vaccinated, Age less than 5 years
 Tuberculin Skin Testing

Benefits Limitations
• Simple. • Trained personnel.

• Low cost. • Variability in interpretation.

• Return visit to have the test read
• No need for phlebotomy.
• False-positive results: due to the
• Detect LTBI and guide the
cross-reactivity of the antigens
use of prophylactic therapy.
within the PPD to both BCG and
• Serial testing to detect non-tuberculous mycobacteria.
tuberculin conversion in • False-negative results.
contact screening.
 TB antigen-based skin tests

• They use Mtb specific antigens (ESAT6 and CFP10) .

• They are as sensitive as TST and IGRA, making them suitable alternatives

• Compared with TST: They are more specific , specially in BCG vaccinated

patients and , more reliable ; specially in children and HIV.

• Similar specificity to IGRA.

 Interferon-Gamma Release Assays

• The IGRAs diagnose infection with Mtb, in vitro.

• T cell–based assays that measure interferon gamma (IFN-γ) release by
sensitized T cells in response to highly specific Mtb antigens:

*Early secretory antigen (ESAT-6) *Culture filtrate protein (CFP-

10) .

• Both antigens are absent from all attenuated strains of M. bovis (BCG
strains) and most non-tuberculous mycobacteria with the important
exceptions of Mycobacterium kansasii, Mycobacterium
szulgai, Mycobacterium marinum, and Mycobacterium leprae.
Interferon-Gamma Release Assays

• The Quantiferone TB Gold in tube (QFT-GIT) measures IFN-γ

plasma concentration using an enzyme-linked immuno-sorbent
assay (ELISA), while the T-SPOT assay enumerates T cells
releasing IFN-γ using an enzyme-linked immuno-spot (ELI-SPOT)
assay.
• Discordance between TST and IGRA testing is common.
Interferon-Gamma Release Assays

Benefits Limitations
• The use of antigens that are • The need for phlebotomy.

largely specific for Mtb. • Cost .

• Specimen collection, long
delays in specimen processing,
or technical errors.
• The lack of reproducibility of
results particularly the setting
of serial testing.
 Preventive treatment
2ry prevention
1ry prevention
LTBI
Vaccination
Identification
BCG
and treatment
 TB primary prevention : BCG

• BCG is an attenuated M. bovis that was found to protect a

variety of animal species against TB. It was first used in humans
in 1921.

• In infants, (Compulsory vaccination):

BCG has been demonstrated to reduce both the
frequency and severity of disseminated TB and TB
meningitis.
 TB primary prevention : BCG

• In adults,

The results of BCG vaccination are less clear; in

controlled clinical trials of BCG vaccination
against pulmonary TB in adults, protection has
ranged from 0–77%.
WHY?
• Host genetic factors, Variations in pathogenicity of tubercle
bacilli,
• Variations in potency of the strains of BCG used, administration
 TB primary prevention : BCG

• As an attenuated live vaccine,

BCG should not be given to immune-compromised

persons, including those with HIV infection, or to
pregnant women .

New TB vaccines are in development and in clinical

trials
 TB 2ndry prevention: LTBI treatment

• Provided that :

TB infection is identified by TST and/or IGRAs and

active tuberculosis disease is excluded.
 Whom will benefit from 2ndry
preventive treatment?
• Contacts of an infectious Preventive treatment
tuberculosis patient,
• HIV-infection,
• 6-month isoniazid, or
• Anti-tumour necrosis factor
• 9-month isoniazid, or
(TNF) treatment, Steroids,
• Renal dialysis, • 3–4-month isoniazid plus

• Organ or haematological rifampicin, or

transplantation, • 3–4-month rifampicin
• Silicosis alone
Clinical picture of Pulmonary TB
Disease

Symptoms
History? • Cough
• Constitutional manifestations
• Haemoptysis
• Chest pain
• Extra-pulmonary: According
to the site
 Testing for TB disease

• Microbiological diagnosis:
Sampling:

• Sputum,

(Sputum induction, bronchoscopy/bronchoalveolar lavage and

gastric lavage in children).
• Sample from extra-pulmonary sites.
 Testing for TB disease

• Microbiological diagnosis:
• Z. N stain: 3 samples ( increased sensitivity) , volume : 5-10 ml, fluorescence
microscopy is preferred, Induced sputum, bronchoscpic sample.

Ziehl Nelsen stain Auramine phenol stain

• Sputum culture for tuberculosis (Differentiate between alive and dead bacilli).

• Nucleic acid amplification Test (NAAT): the Gene Xpert and the line probe

• whole-genome sequencing (WGS): (tuberculosis outbreaks/ HIV).

 Microbiological diagnosis
One day Acid fast bacilli microscopy detection

Growth detection
weeks 2 Liquid culture (BACTEC TB-460/ MGIT 960)
weeks 3-4 Solid culture (Lowenstein jensen / Middlebrook)

One day Identification of mycobacteria by DNA probe

One day Nucleic acid amplification test, detection( NAAT-TB)

days 1-2 Nucleic acid amplification test , resistance markers

(NAAT-R)
weeks 1-2 First line drug susceptibility testing (liquid medium)

Second line and novel drug susceptibility testing

weeks 1-2 Liquid media
weeks 3-4 Solid media
GeneXpert MTB/RIF

It is an automated molecular testing for :

• Detection of M. tuberculosis and

• Rifampicin resistance by targeting specific mutations in the rpoB

gene.

• It is performed directly on sputum other body fluids (except

blood) and tissue samples.

• Results should be available within 2 hours in the laboratory but

available in health facilities within 48 hours.

Line Probe Assay:

• Direct testing on smear positive

specimens and on isolates from solid

and liquid culture.

• It simultaneously detects MTB

complex and specific mutations in: the

rpoB gene conferring rifampicin

resistance and katG gene, and inhA

gene mutations which is

 Drug susceptibility testing (DST)

• In vitro testing using either:

molecular genotypic techniques to

detect resistance-conferring mutations, or

phenotypic methods to determine

susceptibility to a medicine
 Drug susceptibility testing (DST)

• Rapid molecular drug susceptibility testing (DST) for

rifampicin with or without isoniazid using the respiratory

specimens of persons who are meet one of the following

criteria:

• Previous treatment of tuberculosis.

• Patients who were born in or have lived for at least 1 year in a

foreign country with at least a moderate tuberculosis incidence

(≥20 per 100 000) or a high primary multidrug-resistant

tuberculosis prevalence (≥2%),

• The diagnosis of Culture negative pulmonary
tuberculosis:
 All bacteriological tests are negative (including direct sputum
smear examinations, cultures and rapid molecular testing);
 Clinical and Chest radiographic findings compatible with
tuberculosis; and
 Lack of response to a trial of broad spectrum antimicrobial
agents

• ?......Course of anti tuberculosis treatment is

allowed .
 The diagnosis of extra-pulmonary tuberculosis:
Specimen:…
Bacteriological Clinical
diagnosis presentatio
n (Site)
(Pauci-bacillary)

Imagi Biopsy/ Fine

ng needle
Extra- aspiration
pulmona
ry TB

Fluid
aspiratio TB granuloma
n IGRA
Analysis/
ADA
 Testing for TB disease

• HIV testing:

All patients should be tested.

 Imaging
of
pulmonary TB
• Primary TB ( Right hilar lymphadenopathy and lower infilterate)
• Right upper lobe cavitary TB • Miliary TB
Bilateral upper lobe
• Left upper lobe cavity • Cavity with fungal ball
Anti-Tuberculosis
treatment
 What are the principles of anti-TB chemotherapy?

• Combined treatment. DOT

• Duration.

Intensive phase
Continuation phase
(2 months)
(4months / may be 7 , 10
Rifampicin
months)
INH
Rifampicin
Ethambutol
INH
Pyrazinamide

• Monitoring for side effects/ drug interactions.

 Drug susceptible TB (DS-TB)

• A bacteriologically confirmed or
clinically diagnosed case of TB,
without
evidence of infection with strains resistant
to rifampicin and isoniazid.
 Drug susceptible TB (DS-TB)
Side effects Dose Drug
Hepato-toxicity Adult: 5mg/kg (300mg) INH
Peripheral neuropathy… Oral tablet (50-100-300)
(pyridoxine (25–50 IV, IM
mg/day vitamin B6)
supplementation)
Hepato-toxicity Adult: 10mg/kg (600 mg) Rifampicin
Thrombo-cytopenia Oral tablet, IV
.Drug-drug interactions
mg/kg intermittent 10-20 Rifapentin
dose
Hepato-toxicity Less than 40Kg: 30-40 Pyrazinamid
Hyper-uricaemia mg/kg e
arthralgia kg: 1000mg 40-55
kg: 1500 mg 56-75
kg: 2000 mg 76-90
 Two
New
recommendations
for
DS-TB
( W H O, 2 0 2 2 )
CDC recommends:
The 4-month rifapentine / moxifloxacin
regimen
(INH, Rifapentine, moxifloxacin,
• Age ≥ 12 years.
Pyrazinamide: 2HPMZ/2HPM)
• Body weight ≥ 40 kg
• As an option for treating
• HIV with CD4 counts at or above 100
pulmonary TB disease
cells/μL, who start efavirenz as part
caused by organisms that of their antiretroviral therapy in the
are not known or absence of drug interactions.

suspected to be drug- • No contraindications to this regimen

(low K, pregnancy, prolonged QT).

resistant who are:
…………………………………………………..

• Smear, culture negative pulmonary

TB.
 4-month treatment regimen (2HRZ(E)/2HR)

• In children and adolescents aged between 3

months and 16 years with non-severe TB.
(without suspicion or evidence of drug resistance)
(Ethambutol should added in High prevalence of INH
resistance or HIV).
(Strong
Non recommendation,
Severe pulmonary TB: moderate certainty of evidence)
• Intrathoracic lymph node TB without airway obstruction; or
• Pulmonary TB confined to one lobe with no cavities and no miliary
pattern; or
• Uncomplicated pleural effusion (without pneumothorax or empyema).
• Corticosteroids?

As an adjuvant therapy with dexamethasone or prednisone during

the first 6–8 weeks:
 TB meningitis
 Tuberculous
 TB pericarditis (to prevent constrictive pericarditis) pleural
effusion..
 spinal TB (if evidence of spinal cord compression)
 Growth pattern Of TB-
Mycobacteria
And
Principles of Anti-TB drugs
 4 growth modalities of TB
mycobacteria

1. Metabolically active and under conditions of

continuous growth.
2. Bacilli in the acid-inhibition phase.
3. Bacilli in the sporadic multiplication phase.
4. Persistent or totally dormant populations.
 Metabolically active and under conditions of
continuous growth.
 They are present in cavitary wall, located extracellular .
 responsible for treatment failure and resistance if not
homogeneously eradicated.
 Eradicated by bactericidal drugs, mainly INH, then less by
streptomycin & Rifampicin.
 Bacilli in the acid-inhibition phase.

• They are scanty population (103-105 bacilli). Growth inhibited by the acidic

medium in the necrotic tissue (for extra-cellular bacilli), or in the phagocytes

(for intracellular bacilli). Their growth is also inhibited by the deficient

oxygen.

• These can‟t be eradicated by the drugs as they lack metabolic activity. They

represent the main cause of relapse.

• Most active drug against them is Pyrazinamide. This action of

(Pyrazinamide is referred to as sterilizing effect).

 Bacilli in the sporadic multiplication phase.
 Often located in solid caseum where the PH is neutral.

 They show long dormant periods, with occasional & brief metabolic activity

periods (for hours).

 They are also responsible for relapse. The limited and occasional activity of

these bacteria prevents them from developing resistances.

 Rifampicin is the drug of choice to eradicate these population during their brief

metabolic action because of the rapid onset of its sterilizing action (15-20

minutes, versus 24 hours as in the case of isoniazid).

 Persistent or totally dormant populations.

• Bacteria lack metabolic activity. Treatment is not effective against

them.
• Probably only the individual host defense mechanisms are able to
have some effect on this population.
• May be responsible for relapse in patients with severe
immunodeficiency.
Treatment
Monitoring
 How to monitor TB- treatment?

• Follow up:
• Clinical: Side effects of
drugs
• Laboratory: ?
Inflammatory markers, Others.
• Radiological

Follow up smear microscopy or culture at least at the

completion of the intensive phase and further DST should
be performed when positive culture remains
 Clinical monitoring

• Weight
• Symptoms Laboratory monitoring
• Inflammatory markers: ESR,
CRP,
• Liver function tests (at
baseline, every month) /
Kidney functions /CBC, others.
Radiological monitoring

Chest radiograph:
• At baseline,
• after the second month
of treatment
• At the end of treatment, Other imaging
techniques: when
When clinical needs
indicated
 Bacteriological monitoring
Response to treatment in pulmonary TB patients is monitored by bacteriological sputum smear
examination and culture.

For pulmonary DS-TB, the most important evidence of improvement is

conversion of the sputum culture to negative…(although culture conversion does not mean cure)

For MDR-TB: sputum culture and DST are important

Sputum smear/
Positive smear
culture: remains,
When ? means?
Positive smear
remains,
means?

Patient Bacilli
•Not compliant • Dead bacilli
Treatment •Malabsorption (Do Culture)
prescription
• Not adequate •Comorbidity: • Drug
• Not supervised HIV, DM, resistance (Do
concomitant Culture and
fungal infection DST)
 Bacteriological monitoring
 Rapid molecular testing Xpert MTB/RIF or Xpert Ultra at
baseline (recommended) to ensure rapid diagnosis and
exclude DR-TB. These tests cannot be used for treatment
monitoring.

 DST Undertaken where possible. It should be repeated for

patients who do not improve clinically and radiologically,
remain sputum smear and culture positive, or revert to
positive after having converted.
• Where sputum smears and cultures are persistently
positive for acid-fast bacilli, it is also necessary to assess
for:

?
non-TB
Treatment
mycobacteria
failure (NTM)
 Treatment
Outcomes
WHO definitions
 • WHO, 2022;
• Cure: (old):
Patient with bacteriological
A patient whose sputum smear
or culture was positive at the
evidence of TB at the

beginning of the treatment beginning of treatment

but who was smear-or who completed the course
culture-negative in the last with evidence of
month of treatment and on
bacteriological response
at least one previous
occasion.
with no evidence of
failure .
Treatment completed : A patient
who completed treatment but who
does not have a negative sputum
smear or culture result in the last
month of treatment and on at least
one previous occasion.
Treatment success: A sum of cured
and completed treatment.
 Treatment failure:
Old Definition:
• A patient whose sputum
WHO,2022
smear or culture is A patient whose
positive at 5 months or treatment regimen
later during treatment. needed to be
• Also patients with terminated or
multidrug resistant permanently
(MDR) strain at any point
changed to a new
of time during the
treatment, whether they regimen or
are smear-negative or treatment strategy.
positive.
 Treatment failure:
Bacteriological response:
Reasons for the
bacteriological conversion
change include:
with no reversion:
• No clinical response or no
Bacteriologically confirmed TB where at least
bacteriological response, or
two consecutive cultures (for DR-TB
both and DS-TB) or smears (for DS-TB only)

• Adverse drug reaction; or taken on different occasions at least

7 days apart are negative.

• Evidence of additional

drug-resistance.
:Lost to follow up (Default)
A patient who did not start treatment or

whose treatment was interrupted for 2 consecutive

.months or more
 New: Patients have never had treatment for TB, or have
.taken anti-TB drugs for less than 1 month

Previously treated: Patients have received 1 month or

more of anti-TB drugs in the past, may have positive or
negative bacteriology and may have disease at any
.anatomical site
Transfer out: A patient who has been transferred to
another recording and reporting unit and whose
treatment outcome is unknown

Patient death
Sustained treatment success: An
individual assessed at 6 months (for DS-TB and DR-
TB) and at 12 months (for DR-TB only) after
successful TB treatment, who is alive and free of
TB.

(NEW, WHO,2022)
TB-Drug resistance
 WHO: five categories to classify cases
of DR-TB

• Isoniazid-Resistant TB.

• Rifampicin R-TB .

• MDR-TB: TB resistant to at least both INH and Rifampicin .

• Pre XDR-TB: TB resistant to Rifampicin , INH, and … any Fluoroquinolone or to

Rifampicin , INH, and to an injectable class of second-line anti-TB drug; Amikacin,

Kanamycin, Capreomycin.

• XDR-TB (Extensively drug-resistant TB): TB that is resistant to Rifampicin, INH plus

any Fluoroquinolone, plus at least one of the drugs Bedaquiline and/or Linezolid.
 What is MDR-TB?

• Tuberculosis caused by mycobacteria that

have become resistant to at least the two the
most effective anti-TB drugs; Isoniazid and
Rifampicin.

• The treatment is longer, more expensive

and more difficult.
Why MDR-
TB?
Mechanism of resistance:

Bacillus
genetic Inappropri
mutation ate drug
s prescriptio COVID19
n pandemic
( immunity
Treatment )
interruptio
n
HIV
 How to prevent?
• Treat the primary case, Patient isolation (Isolation should be in
rooms with negative pressure ventilation). (prevent the
transmission).
• Detection using drug susceptibility testing (DST) [early, when
possible].
• Combined treatment.

• Supervised treatment and observe for side effects.

 Patient-
centered
case
managemen
How to treat? Referral
t

• Drug sensitivity testing should be done.

• No drug should be administered to a patient with documented resistance.
• The individualized regimen should include at least five effective TB
medicines during the intensive phase, including pyrazinamide and four
core second-line TB medicines.
• Total treatment duration ranges from 20 to 24 months, with the
recommended intensive phase being 8 months.
• (No intensive phase if new longer oral MDR/RR regimen is used).
 How to treat? Referral

• Old WHO classifications of MDR anti-

tuberculous drugs
 How to Treat?
• The old recommended treatment combines:
 All first-line drugs to which the strain is still sensitive,
 A fluoroquinolone,
 An injectable second line drug (Amikacin, capreomycin, Kanamycin)
 One of several second-line drugs, including ethionamide, linezolid,
clofazimin, cycloserine or PAS (p-aminosalicylic acid) and pyrazinamide.
 New drugs such as bedaquiline and delamanid may also be used.

• Treatment can last up to 2 years.

• Side-effects.
• Cost.
 Second line anti-Tuberculosis drugs
Important Side effects Drug
Renal failure, hearing loss Aminoglycosides
.QT prolongation, hepatotoxicity Bedaquline
QT prolongation, skin hyperpigmentation Clofazimine

Neurological side effects Cycloserine

Mild QT prolongation Delamanid

QT prolongation, Achilis tendon rupture Levofloxacin

Bone marrow suppression, peripheral Linezolid

neuropathy, optic neuritis
QT prolongation, Achilis tendon rupture Moxifloxacin

Nausea, vomiting, diarrhea, hypothyroidism Para-aminosalicylic acid

Hepatotoxicity, hyperuricaemia Pyrazinamide

 WHO
recommendatio
n 2022
 Contraindications Indications Regimen

•Pregnancy/ •MDR/RR-TB patients

The 6- )1
breastfeeding
aged ≥15 years,
(Pretomanid)
irrespective of HIV
month BPaLM
•Cardiac (QT)
status. regimen
•Extra pulmonary: CNS,
• No prior exposure to
Milliary, osteoarticular.
the three drugs for ≥30

days.

•BPaL,in pre-XDR-TB

patients when
 The 6-month BPaLM regimen

• Bedaquiline: 200mg for 2m then • DST

100mg or 400 mg once daily for 2 • Drug interactions
weeks followed by 200 mg three • Side effects
times per week.
• Pretomanid: 200mg/day

• Linezolid: 600mg /day…reduced to

300mg/day
(if myelosuppression, neuropathy)
• Moxifloxacin: 400 mg /day
 Contraindications Indications Regimen

i) previous exposure to • in all patients (adults

2) The shorter,
and children more than
second-line treatment

(including BDQ) for

6 years) affected by all-oral, BDQ-
MDR/RR-TB.
more than 1 month; containing,
• Non pregnant
ii) Resistance to drugs
regimens, 9-
in the regimen/ FQ

resistance 12 month
iii) extensive pulmonary

TB disease

iv) severe
 2) The shorter, all-oral, BDQ-containing, 9-12 month, regimens
Initial phase: 4–6 Bdq(6 m)-Lfx-Cfz-Z-E-Hh-Eto
Continuation phase: 5 Lfx-Cfz-Z-E

Composition: Seven drugs:

Bedaquiline (used for 6 months), in combination with

levofloxacin/moxifloxacin, ethionamide, ethambutol, isoniazid (high-dose),

pyrazinamide and clofazimine (for 4 months, with the possibility of extending to 6

months if the patient remains sputum smear positive at the end of 4 months),

followed by treatment with levofloxacin/ moxifloxacin, clofazimine, ethambutol

and pyrazinamide (for 5 months).

[Ethionamide can be replaced by 2 months of linezolid (600 mg daily)].

 2) The shorter, all-oral, BDQ-containing, 9-12 month, regimens

• All medicines were taken once a day on all days of the week, except for

bedaquiline, which was taken every day for the first 2 weeks, followed

by three times a week in the remaining 22 weeks.

• Prothionamide may be used instead of ethionamide.

• Moxifloxacin may be used instead of levofloxacin.

• If a patient is started on the shorter all-oral bedaquiline-containing

MDR/RR-TB regimen but is later found to be ineligible because of

development of resistance……..Do DST and start longer regimen.

 2) The shorter, all-oral, BDQ-containing, 9-12 month,
regimens

DST:
• (MTBDRplus) can
• Isoniazid has been
shown to be a key determine mutations
component of shorter
regimens, despite the in the inhA promoter
presence of resistance to the
drug. (low resistance) or

This may reflect residual in vivo katG regions (high

effectiveness of the agent, even
in the presence of low-level resistance).
isoniazid resistance,
when the agent is used at a higher
dose(15–20 mg/kg)
 2) The shorter, all-oral, BDQ-containing, 9-12 month,
regimens

DST:

• INH:
• Mutations at the inhA promoter are also associated with

resistance to ethionamide and prothionamide.

• The presence of both mutations (i.e. inhA promoter and katG)

suggests that isoniazid at high dose and ethionamides are not

effective, and that the shorter regimen may therefore not be

used .
 2) The shorter, all-oral, BDQ-containing, 9-12 month,
regimens

DST:
• Pyrazinamide and ethambutol:
DST for pyrazinamide and ethambutol is not carried out routinely

in most settings . These do not affect eligibility for the 9-month

all-oral regimen.

• Clofazimine, linezolid and bedaquiline

There are no rapid methods to detect M. tuberculosis resistance to

…… Use MGIT
 Contraindications Indications Regimen

safety of bedaquiline i) those with extensive The )3

and delamanid in
forms of drug-
regimen
pregnancy and during
resistant-TB (e.g., XDR-
previously
? breastfeeding known as the
TB);
longer
ii) those who are not
regimen (≥18
eligible for the
,months)
regimens described

above, which is

iii) those who have individualized and

Groups of Anti-TB drugs for Longer regimen MDR/RR-TB

Group A:
•Levofloxacin or moxifloxacin
Include all three medicines:
•Bedaquiline

•Linezolid

Group B:
•Clofazimine
Add one or both medicines:
•Cycloserine or terizidone
Groups of Anti-TB drugs for Longer regimen MDR/RR-TB

•Ethambutol

•Delamanid

•Pyrazinamide
Group C:
•Imipenem–cilastatin
Add to complete the regimen
or meropenemg
and when medicines from
•Amikacin (or streptomycin)
Groups A and B cannot be

used:
•Ethionamide or

prothionamide (only if….)

 3) The oral longer regimen (≥18 months)

Composition: start at least four TB agents.

• at least three agents are included for the rest of the treatment if
bedaquiline is stopped.

All three Group A plus at least one Group B

If only one or two Group A agents are used, both Group B agents are to

be included.
If the regimen cannot be composed with agents from Groups A and B
alone, Group C agents are added to complete it.
 3) The oral longer regimen (≥18 months)

• Total treatment duration of: 18-20months is suggested for most patients; the
duration may be modified according to the patient‟s response to therapy.

• Treatment duration of 15–17 months after culture conversion is suggested for most
patients.

• Factors to be considered: DST, Preference of treatment, co morbidity, Drug side

effects, Drug interactions.
 Regimen for rifampicin-susceptible, isoniazid-resistant TB
(Hr-TB)
6(H) REZ-Lfx

⃝ Rifampicin, ethambutol, pyrazinamide and levofloxacin is

recommended for a duration of 6 months.

⃝ It is not recommended to add streptomycin or other injectable

agents to the treatment regimen.
Complications
 Complications of pulmonary TB

• The colonization of cavities by fungus, e.g. Aspergilloma

• Bronchiectasis
• Arterial Pseudo aneurysm: Bronchial artery pseudo-aneurysm /
Rasmussen aneurysm
• Haemoptysis

• TB- Empyema

• Fibrothorax
• Bronchopleural fistula
 Extra-pulmonary
• CNS
TB
• Bone and joint
• Pleural, pericardial, peritoneal, Intestinal

• Lymph Nodes (common)

 Extra-pulmonary TB

CNS TB Treatment: duration:9-12 months

• Intensive phase: 2 months

• TB meningitis.  INH, RIF, PZA, and EMB or :
• Tuberculoma:  INH, RIF, PZA, and ethionamide
Hydrocephalus, Paraplegia or an aminoglycoside (in place
• TB cerebral abscess. of EMB),
• Continuation phase: 7 to 10
months of INH and RIF.
Another option: 6 month
Intensive regimen: H, R, Z ,
Ethionamide.
CNS TB Treatment
Steroids
• Adults (>14 years):
Dexamethasone: 0.4 mg/kg/24 hr. 6 -
8 weeks .
• Children (<14 years):
prednisolone 4 mg/kg/24 hr or
equivalent dose of dexamethasone:
0.6 mg/kg/24 hr) for 4 weeks,
followed by a reducing course over
2 - 4 weeks.
Bone and joint TB Treatment: duration: 9-12 months

• Anti TB treatment.
• Surgery: when:
 there is poor response to
chemotherapy with evidence
of ongoing infection or
clinical deterioration,
 relief of cord compression.
 there is instability of the
spine.
Pleural TB
• Tuberculous effusion: • Diagnostic tapping
(lymphocytic, increased ADA, • Thoracoscopic pleural biopsy
paucibacillary). • Drainage.
• Haematogenous pleural • AMT.
deposits
(pleural biopsy is diagnostic)
• TB empyema:

(positive bacteriology).
Pericardial TB Treatment
• AMT
• Constrictive pericarditis
• Steroids? cautious
• Pericardial effusion
TB Lymph nodes Treatment : 6 months
• AMT.
• TB lymphadinitis. • Paradoxical lymph-node
• Cold abscess. enlargement: consider steroids
• Drainage or fine-needle
aspirate may be obtained for
culture and to ensure drug
susceptibility.
Tuberculosis
in
special
situations
 TB in special situations

• Liver disease
• Renal disease
• HIV
• TB in children
• TB in pregnancy
 Liver Disease

TB………..Liver

• TB hepatitis. • Elevated liver enzymes

• Tuberculoma in the liver. • Jaundice

• State of liver disease:
 Liver Disease

Problem of drug induced hepatitis?

• Treatment without PZA: INH/ • For severe hepatic disease:

RIF for 9 months with EMB EMB combined with a
given for the first 2 months fluoroquinolone, cycloserine,
• Treatment without INH and and second-line injectable

PZA: RIF/ EMB with a for 18 to 24 months (similar

fluoroquinolone (injectable), to an MDR-TB regimen)

or cycloserine for 12 to 18 • Avoid aminoglycosides

months. (severe) renal insufficiency or
bleeding from the site of
injection.
 Renal Disease

• Problem of drug • RIF/INH safe.

elimination with renal • PZA and EMB maintaining the

dosage of but decreasing the
impairment.
frequency of administration (i.e.,

Monitor: creatinine changing from daily to three

level, Electrolytes times weekly).
• Post dialysis administration of
AMT.
• ECG monitoring in case of
moxifloxacin use ( prolonged QT).
 HIV: All patients should be tested.

• 6-month isoniazid, or
• LTBI should have
• 9-month isoniazid, or
preventive therapy.
• 3-month regimen of weekly
rifapentine plus isoniazid, or
• 3–4-month isoniazid plus
rifampicin, or
• 3–4-month rifampicin alone.
 HIV: All patients should be tested.

• WHO treatment guidelines suggest

• TB disease should be
a delay between the initiation of TB
treated. therapy and the start of
• The principles of treatment of TB in antiretroviral treatment of at least
patients living with HIV and 14 days to reduce the risk of
receiving antiretroviral therapy are paradoxical reactions due to
similar to those in patients who are immune reconstitution syndrome
HIV negative. However treatment • Drug resistance.
duration extended to 7 months/ 10
• Drug interactions are common.
months continuation phase.
• Drug toxicity increased.

• Problems
 HIV: Immune reconstitution Inflammatory syndrome (IRIS)

• IRIS in association with TB treatment: is the worsening of

symptoms in a patient receiving appropriate treatment :
Intravenous
 High fevers, Steroids
 Worsening respiratory symptoms,
 Increase in size and inflammation of involved lymph nodes, new
lymphadenopathy,
 Expanding CNS lesions,
 Worsening of pulmonary parenchymal infiltrations, new or
increasing pleural effusions, and
 Development of intra-abdominal or retroperitoneal abscesses.
 TB in children

• Pulmonary TB • Pauci-bacillary.
• Extra-pulmonary TB: common; TB • Problem of Sampling: sputum
meningitis/ Lymph nodes
induction, gastric lavage,
• MDR/RR .HIV bronchoscopy, tissue sample.
LTBI:
Children over 2 years of age
can be treated for LTBI with
once-weekly isoniazid-
Ethambutol ? Visual
rifapentine for 12 weeks. acuity
Alternative: 4 months rifampin
or
9 months
 TB in Pregnancy

• Untreated active TB poses a far greater hazard to a pregnant woman and

her fetus than does treatment for the disease.
• Although anti tuberculosis drugs cross the placenta, they do not appear
to have teratogenic effects in humans. Congenital TB is rare.
Risk of transmission of
• Breast feeding can be maintained.
infection (precaution).
…………………………………………………………………………………………………………
• LTBI: Testing can be done safe. Treatment of LTBI can be delayed in the
first 3 months, Imaging, CXR , CAN BE DONE with abdominal shield.
• Drug sensitive TB: 9 Months duration.
• Drug resistant TB / HIV :
 TB in Pregnancy

• Pyrazinamide use is controverse , however its administration is advisable.

• Contraindicated drugs, in pregnant women:

• Streptomycin
• Kanamycin
Safety of
• Amikacin bedaquiline?

• Capreomycin
• Fluoroquinolones
 Surgery in TB

• Surgery may be needed in selected cases.

• It should be under cover of anti-tuberculous treatment.

 References
• Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease

Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and

ChildrenClinical Infectious Diseases® 2017;64(2):e1–e33

• ERS/ECDC Statement: European Union standards for tuberculosis care, 2017 update. Eur Respir

J 2018; 51: 1702678

• [Link]/tb

• European Respiratory Review . Tuberculosis

• [Link] WHO drug-resistant TB guidelines 2022: what is new?

• WHO/TB, 2022.
THANK
YOU