MULTIDRUG-RESISTANT

TUBERCULOSIS (MDR-TB)
Presenter: Mesay Assefa (MD, R1)
Moderator: Professor Samuel Yoo (Internist, pulmonologist)

JUMC, Department of Internal Medicine (April 2021G.C)

Outline

• Introduction

• Epidemiology

• Mechanisms of drug resistance

• Diagnosis
INTRODUCTION
◦Tuberculosis (TB) is one of the top 10 causes of death
worldwide.

◦10 million people fell ill with TB in 2019.

◦There were 1.2 million TB deaths among
HIV-negative people and an additional
208 000 deaths among HIV-positive people.
◦about 1.7 billion people are known to be latently infected with
Mtb, with about 10% of them reactivating to active TB in their
lifetime.
◦2RHZE/4RH
◦To prevent reactivation of latent TB, a long treatment is also used,
consisting of at least
6 months of INH, or 3 to 4 months of RIF plus INH [1,2].
◦Despite the recent progress of global control efforts,
tuberculosis (TB) remains a major public health threat,
worldwide.
◦Drug-resistant TB continues to be a public health threat.

◦0.5 million people developed MDR/RR.TB in 2019.

◦Medicine resistant TB can be primary or secondary
(acquired).
Types of TB resistance

◦Mono-resistance
◦Poly-resistance
◦Multidrug-resistance (MDR)-TB
◦Extensive drug-resistance (XDR-TB):
◦pre–XDR-TB
◦Total drug-resistance (TDR-TB): resistance to all anti
TB medicines.
◦New cases - patients never treated
with anti-TB medicines, or treated for < 1 month;
◦Previously treated cases - patients treated for ≥ 1
month in the past.
EPIDEMIOLOGY OF DRUG
RESISTANT TB
Worldwide

◦ Globally in 2019, there were an estimated 465,000 (484

000, in 2018) incident cases of MDR/RR TB cases,
including about 362,000 MDR-TB cases(78%) and182,000
(214,000 in 2018) deaths.
◦ This is slightly lower than the 484 000 estimated incident
cases of MDR/RR TB cases, including about 378,000 MDR-TB
cases (78%) and 214,000 deaths for 2018.
8%

14%
27%
◦Globally in 2019, an estimated 13.1% of new cases and
17.4% of previously treated cases had isoniazid resistance.

In other words, 11% of all incident cases of TB had isoniazid-resistant

and rifampicin-susceptible TB.
◦Globally, 105 countries have representative data from the
past 15 years on resistance to fluoroquinolones.
◦Among 105 countries, the proportion of MDR/RR-TB
cases with resistance to any fluoroquinolone for which
testing was done was 20.1%.
Ethiopia
DRUG RESISTANCE
MECHANISMS IN TB
◦ Standard 2RHZE/4RH regimens can cure TB in >90% of patients.
◦ There is no cross resistance among the commonly used classes of drugs.
◦ The chance that an organism in a population is resistant to two drugs
classes is the product of the probabilities
of resistance to each drug and thus is low (roughly 1 in 10(14)).
◦ The resistance developed by Mtb to any antimicrobial agent is not due
to a single mechanism, but to the interplay of biological, clinical and

microbiological reasons, including

◦ 1. Nonadherence of patients and/or errors of physicians in the
therapy management (human errors), that increases the risk of
developing genetically drug resistant bacilli;

◦ 2. Complexity and poor vascularization of granulomatous

lesions, further leading to suboptimal drug concentration and
the development of phenotypic and genetic resistance;

◦ 3. Naturally occurring high levels of antibiotic resistance in

tubercle bacilli (intrinsic resistance);

◦ 4. Formation of non-replicating (NR) drug-tolerant bacilli

inside the granulomas (phenotypic resistance) ;

◦ 5. Development of genetically resistant bacilli by chromosomal

mutations (acquired resistance).
 They were: (i) Inappropriate treatment by health care
providers (inappropriate or absent guidelines, poor
training of physicians and nurses, sub-optimal
education of patients, poor management of adverse
drug reactions, no monitoring of treatment, poorly
◦ Human errors may contribute to or
organized thefunded
development of drug-resistance
TB control programs); because
of the improper use of anti-TB drugs.

 the failure of the health care provider to prescribe at least two

drugs to which tubercle bacilli are susceptible;

 the failure of the patient to absorb or take properly prescribed

therapy; or

 the failure of poor-quality drugs to be adequately

bioavailable.
◦ Human errors may contribute to the development of drug-resistance because
of the improper use of anti-TB drugs.
(iii) Inadequate drug intake or treatment
response by patients (lack of information on
treatment
 the failure of the health adherence,toadverse
care provider effects,
prescribe at least two
drugs to which tuberclemalabsorption)
bacilli are susceptible;

 the failure of the patient to absorb or take properly prescribed

1% of TB patients with perfect
therapy; or adherence may develop MDR-
TB due to pharmacokinetic
variability alone.
 the failure of poor-quality drugs to be adequately
bioavailable.
◦ Human errors may contribute to the development of drug-resistance because
of the improper use of anti-TB drugs.

 the failure of the health care provider to prescribe at least two

drugs to which tubercle bacilli (ii)
areInadequate drug supply (poor quality
susceptible;
medicines, stock-outs, poor storage
conditions, wrong dose or combination)
 the failure of the patient to absorb or take properly prescribed
therapy; or

 the failure of poor-quality drugs to be adequately

bioavailable.
 Creation of drug-resistant TB can be prevented
by adherence to the principles
of sound treatment:
 inclusion of at least two quality-assured,
bactericidal drugs to which the organism is
Common clinicalsusceptible;
errors in MDR-TB management, particularly in
 use of
developing countries, FDC products;
include
 supervision of treatment with patient
support; and verification that patients
◦ The addition of a single drug to a failing regimen,
complete the prescribed course.
◦ Failure to recognize existing of
Transmission drug resistance, strains can be
drug-resistant
prevented
◦ Failure to provide DOT and to manage nonadherence,
 By implementation of respiratory infection-
◦ Suboptimal dosages of second-line drugs to decrease side effects,
control measures (see
◦ Drug treatment based on clinical
below) and facts while waiting for DST results.
 by early detection of people with active TB
followed by immediate initiation of
treatment with an effective regimen.
Acquired Drug-Resistance of Mtb (MOLECULAR BASIS)

◦ Our understanding of the molecular basis for drug resistance in M.

tuberculosis is improving.
◦ This knowledge is important for new drug design, new therapeutic
strategies against MDR-TB, and development of probes for detection of
mutations associated with resistance.
◦ Each molecule binds to one or more target, thus inhibiting their
functions.
◦ The continuous drug exposure during lengthy treatments and the
noncompliance of patients to drug regimens, pushes Mtb to select for
mutations in genes encoding drug targets.
 DIAGNOSIS OF DRUG
RESISTANT TUBERCULOSIS
DIAGNOSIS  

◦ The clinical manifestations and radiographic features of

DR-TB are comparable to those of drug-susceptible
disease.
 
◦ A careful history for clues that drug resistance may be
an issue of concern.

◦ Sputum should be collected.

◦ Rapid testing is an increasingly utilized tool.

Clinical history
 Clinical evidence of failure can include
persistence or recurrence of symptoms.
 An unchanged or worsening cough.
 Lack of sputum conversion
 Continued fever and/or night sweats and
 Failure to gain weight
Clues for RR/MDR-TB
History of prior therapy (most powerful
predictor)
History of non-adherence, lost to followup
Residence in an MDR-endemic area
Exposure to known or suspected MDR-TB
case
HIV infection (in some settings)
Laboratory methods

◦ AFB MICROSCOPY
Fails to distinguish drug-susceptible from DR-TB.
Main uses for DR-TB are limited to monitoring of Rx response, along
with culture and to assess infectiousness of patients.
Microscopic observation drug susceptibility (MODS) is
test in which drug-free and drug-containing media (liquid
for MODS) are inoculated with patient specimens and
cultures are microscopically examined for early growth.
MODS is faster than automated liquid culture (results
can be available in as little as seven days) and can be
used in smear-positive and smear-negative cases.
MYCOBACTERIAL CULTURE AND SENSITIVITY

◦ Susceptibility testing may be conducted on solid (4–8 weeks) or liquid

medium (10 days to 2–3 weeks).

◦ Commercial liquid-culture systems such as the mycobacterial growth

indicator tube (MGIT) system are recommended by the WHO as the
reference standard for culture.
A, Solid culture media (Löwenstien-Jensen)
Advantages
• ease of preparation
• low cost, and
• low contamination rate.
Results may not be available for ≥8 weeks, thus the
use of this technique is less often.

41
B, Liquid culture media
Results are obtained rapidly, with an average
reporting time of 3 weeks.

However, the method is prone to higher

contamination rate and high cost.
culture
Advantage
◦ Detects small numbers of
organisms (as few as10 bacilli)
◦ More sensitive than AFB
microscopy to diagnosis of TB
◦ Allows species identification and
DST.
Limitations
◦ Slow growth of MTB (weeks to
months) especially for solid
culture media
◦ High installation and maintenance
cost
Nucleic acid amplification technology

◦ Molecular methods for the rapid identification of genetic mutations in

gene regions known to be associated
with resistance.

◦ Xpert MTB/RIF assay and molecular line probe assays.

 GeneXpert MTB/RI
F ASSAY
 The first-line diagnostic
test
 sensitivity of 98% among
AFB-positive cases and
~70% among AFB-
negative/culture positive
specimens.
 specificity (99%)for
detection of TB infection
 Rifampicin resistance
detection sensitivity of 95%
specificity of 98%
 Xpert® MTB/RIF Ultra
assay (Ultra)
Line Probe Assay (LPA)

◦ LPAs are WHO-approved tests for

rapid detection of drug resistance
to first- and second-line agents.
◦ After extraction of DNA from M.
tuberculosis isolates or from
clinical specimens,
the resistance gene regions are
amplified by PCR, and labeled
and probe-hybridized PCR
products are detected by
colorimetric development.
 LPA
FL-LPA
◦performed in two ways:
Directly from sputum, if sample is
Smear Positive.
•test result can be produced in two days’
time.
From the isolates which initially has
grown on culture medium, preferably
on liquid culture medium, if smear
microscopy was negative for AFB.
•takes few weeks to produce the test result.
SL-LPA
◦are used to screen resistance
to quinolones and injectables,
◦Unlike First line LPA Second-
line LPA test, is recommended
to perform directly on sputum
specimen without considering
the positivity on AFB
microscopy.
 Molecular tests

GeneXpert MTB/RIF ASSAY LPA

◦ Advantages: Advantages of LPA:

◦ detection of both M. TB and rifampicin resistance
• Rapid test and gives results into 2 days
◦ More sensitive to detect MTB even in smear time when performed on sputum
negative cases
 Disadvantages of LPA:
◦ Useful to confirm dx. Of TB and RR-TB from
extrapulmonary sites • Requires a well-trained staffs
◦ Produce results in two hours • Requires at least three rooms
◦ Does not require sophisticated bio-safety • Infection control precautions requires
precautions. sophisticated biosafety level.
◦ Limitations:
• Not suitable for peripheral laboratories
◦ Requires continuous electrical supply.
◦ It’s not designed to inform susceptibility to INH
TUBERCULOSIS AND COVID-19
Dual burden of TB and COVID-19

◦Finding and treating people with TB remain the

fundamental pillars of TB prevention and care.

◦Substantial reductions in TB notification sustained over

successive months have been observed in 2020.

◦During this exceptional period it is important that TB

prevention and care continue uninterruptedly.
Modelling work suggests that;

if the COVID-19 pandemic led to

a global reduction of 25% in
expected TB detection for 6
months then we could expect a
26% increase in TB deaths,
bringing us back to the levels of
TB mortality that we had in 2012.
Are people with TB likely to be at increased risk of
COVID-19 infection, illness and death?

◦ It is anticipated that people ill with both TB and COVID-19 may have
poorer treatment outcomes, especially if Tb treatment is interrupted.

◦ Both diseases have similar symptoms such as cough, fever and

difficulty breathing.

◦ TB, however, has a longer incubation period with a slower onset of

disease.
Should all people being evaluated for TB also be tested
for COVID-19 and vice-versa?

◦It is advised to adopt diagnostic algorithms for testing for TB or COVID-19 based on the
clinical features and history of a patient and local TB burden.

◦A positive result for COVID-19 infection does not exclude the possibility of concomitant TB.

◦Healthcare workers need to consider the possibility of TB in a patient with COVID-19 if the
course of the illness after the first weeks suggests so, e.g. progression to haemoptysis,
persistent fever, night sweats or weight loss.

◦A careful history of exposure to TB or even a past episode of TB in the same patient or in the
family may clinch the diagnosis.

◦Chest radiography or imagery may help differentiate TB from other pathologies.