CHAPTER I

INTRODUCTION

1.1 Background

Tuberculosis (TB) is a disease caused by bacteria (Mycobacterium

tuberculosis) that most often affect the lungs and spread from person to person
through the air. When people with lung TB cough, sneeze or spit, they propel the
TB germs into the air and to become infected, it just needs to inhale only a few of
these germs.1

There are several names for TB. It was called phthisis in ancient Greece,
tabes in ancient Rome, and schachepheth in ancient Hebrew. On 1882, Dr. Robert
Koch discovered Mycobacterium tuberculosis, the bacteria that causes TB. During
this time, TB killed one out of every seven people living in the United States and
Europe.2

TB is one of the top 10 causes of death worldwide and a leading killer of

HIV-positive people. In 2017, 10 million people fell ill with TB, 1.6 million died
from the disease, 1 million children became ill with TB and 230 000 children died
of TB. TB occurs in every part of the world. The largest number of new TB cases
occurred in the South-East Asia, Western Pacific regions and African region.
Eighty seven percent of new TB cases occurred in the 30 high TB burden
countries, such as India, China, Indonesia, Philippine, Pakistan, Nigeria,
Bangladesh and South Africa. Over 95% of cases and deaths are in developing
countries.1

In active TB disease, the symptoms may be mild for many months.

Common symptoms of active lung TB are cough with sputum and blood at times,
chest pains, weakness, weight loss, fever and night sweats. TB mostly affects
adults in their most productive years. However, all age groups are at risk. People
who are infected with HIV are 20 to 30 times more likely to develop active TB.
The risk of active TB is also greater in persons suffering from other conditions
that impair the immune system.1

1
 TB is a treatable and curable disease. Active, drug-susceptible TB disease
is treated with a standard 6 month course of 4 antimicrobial drugs. Anti-TB
medicines have been used for decades and strains that are resistant to 1 or more of
the medicines have been documented in every country surveyed.1

Drug resistance emerges when anti-TB medicines are used inappropriately,

through incorrect prescription by health care providers, poor quality drugs, and
patients stopping treatment prematurely. Multidrug-resistant tuberculosis (MDR-
TB) is a form of TB caused by bacteria that do not respond to isoniazid and
rifampicin, the 2 most powerful, first-line anti-TB drugs. MDR-TB is treatable
and curable by using second-line drugs. However, second-line treatment options
are limited and require extensive chemotherapy (up to 2 years of treatment) with
medicines that are expensive and toxic.1

1.2 Problem Statement

1.2.1. What is Tuberculosis?

1.2.2. What is the etiopathogenesis of Tuberculosis?
1.2.3. How is the management of Tuberculosis?
1.2.4. What is Multidrug-resistant tuberculosis (MDR-TB)?
1.2.5. How is the epidemiology of Multidrug-resistant tuberculosis
(MDR-TB)?
1.2.6. What is the etiopathogenesis of Multidrug-resistant
tuberculosis (MDR-TB)?
1.2.7. What are the clinical manifestation of Multidrug-resistant
tuberculosis (MDR-TB)?
1.2.8. How to diagnosis Multidrug-resistant tuberculosis (MDR-TB)?
1.2.9. What are the differential diagnosis of Multidrug-resistant
tuberculosis (MDR-TB)?
1.2.10. How is the management of Multidrug-resistant tuberculosis
(MDR-TB)?
1.2.11. How is the prognosis of Multidrug-resistant tuberculosis
(MDR-TB)?

2
 1.2.12. What are the complications of Multidrug-resistant tuberculosis
(MDR-TB)?

1.3 Objective of Study

1.3.1. To know what Tuberculosis is
1.3.2. To know what the etiopathogenesis of Tuberculosis is
1.3.3. To know how the management of Tuberculosis is
1.3.4. To know what Multidrug-resistant tuberculosis (MDR-TB) is
1.3.5. To know how the epidemiology of Multidrug-resistant
tuberculosis (MDR-TB) is
1.3.6. To know what the etiopathogenesis of Multidrug-resistant
tuberculosis (MDR-TB) is
1.3.7. To know what the clinical manifestation of Multidrug-resistant
tuberculosis (MDR-TB) are
1.3.8. To know how to diagnose Multidrug-resistant tuberculosis
(MDR-TB)
1.3.9. To know what the differential diagnosis of Multidrug-resistant
tuberculosis (MDR-TB) are
1.3.10. To know how the management of Multidrug-resistant
tuberculosis (MDR-TB) is
1.3.11. To know how the prognosis of Multidrug-resistant tuberculosis
(MDR-TB) is
1.3.12. To know what the complications of Multidrug-resistant
tuberculosis (MDR-TB) are

1.4 Significance of Study

Get a better understanding about Multi-Drug Resistance Tuberculosis.

3
 CHAPTER II
CONTENT

2.1 Definition of Tuberculosis

Tuberculosis (TB) is an infectious disease caused by slightly bent, thin,

aerobic, non motile, non spore forming beaded rods belonging to the family
Mycobcteriaceae and to the order Actinomycetales, of the patogenic species
belonging to Mycobacterium tuberculosis. Generally tuberculosis affects the lungs
and also other parts of the body. Infections such latent tuberculosis do not have
any symptoms which cause about 10% of it progress to active disease that which
can lead to death if left untreated.3

Based on Crofton's Clinical Tuberculosis, tuberculosis is an infectious

disease, spread mainly through cough. If a patient has any of the following,
consider him or her a 'tuberculosis suspect' cough for 3 or more weeks,coughing
up blood-stained sputum or in serious cases blood, pain in the chest for 3 or more
weeks ,fever for 3 or more weeks. All these can be due to other diseases, but
sputum must be tested if any of these symptoms are present.4

2.2 Etiophatogenesis of Tuberculosis

Mycobacterium tuberculosis infection begins when a person inhaled a

droplet nuclei containing viable microorganisms that propelled into the air by
infectious patients. Most bacilli are trapped in the mucus secreting goblet cells
parts.5 Bacteria that bypass the mucociliary system reach the alveoli and quickly
engulfed by alveolar macrophages.6 Mycobacterial lipoarabinomannan is a key for
a macrophage receptor and activate the complement system to phagocyte the
bacteria. When the bacteria is engulfed they become dormant, the mycobacteria
continue to multiply slowly with bacterial cell division occurring every 25 to 32
hours.7 Initial development involve production of proteolytic enzymes and
cytokines by macrophages in an attempt to degrade the bacteria. The released
cytokines attract T lymphocytes to the site this immune process continues for 2 to

4
12 weeks.8 For persons with intact cell-mediated immunity, the next defensive
step is formation of granulomas from accumulation of activated T lymphocytes
and macrophages. This environment destroys macrophages and produces solid
necrosis at the center of the lesion.9 By 2 or 3 weeks the necrotic environment
resembles soft cheese, often called caseous necrosis, and characterized by low
oxygen levels, low pH, and limited nutrients. For less immunocompetent persons,
granuloma formation is initiated yet ultimately is unsuccessful in containing the
bacilli. The necrotic tissue undergoes liquefaction, and the fibrous wall loses
structural integrity. The semiliquid necrotic can drain into bronchus or nearby
blood vessel, leaving an air-filled cavity at the original site. If goes to bronchus
the person becomes infectious, if goes to blood vessel the occurrence of
extrapulmonary tuberculosis is likely.10

2.3 Management of Tuberculosis

If the patient of tuberculosis is diagnosed early on it is possible to cure any

patient of tuberculosis. This can be achieved if the disease treated properly and the
bacteria causing the TB is not resistant to drugs. Patient with resistant TB bacteria
is more difficult to cure. In cases of patient wih HIV and TB, it is important to pay
attention to efficiency of the treatment.

Treatment of anti tuberculosis is one of the most efficient means of

preventing the spread of tuberculosis micro organisms. There are some
requirement for adequate treatment:

 Apropriate combination of antituberculosis drugs, intially to prevent

development of resistance to those drugs
 Prescibed on one correct dosage
 Taken regularly by patient
 Sufficient period of treatment to prevent relapse of disease
Treatment should not be applied until a firm diagnosis has been made.
Treatment should be given as soon as positive smear in suspect patient. If the
clinical appearance is incosistent with the diagnosis of tuberculosis, treatment may

5
start only if a second positive result is made or the patient have been referred to an
experienced medical officer. If the patient has been treated for more than a month
with anti tuberculosis drugs previously, such patient require very careful follow
up and a different treatment compared to those who has never been treated before.
There are 2 phases of medication; intensive phase which is the first 1-2 months of
adequate dose of drugs and continuous phase which is the next months with less
dosage to ensure the microbacteria has been eradicted form the patient.11
There are only limited numbers of drugs currently available for the
treatment of TB. For that reason, medical staffs should be very cautious to
prescribe these drugs to prevent resistance. According to WHO, anti TB drugs can
be classified into five groups based on the efficacy, experience of use, safety, and
drug class (Table 1)

Table 1. Classification of Anti-TB drugs.12,13

Groups Drugs

Group 1: First-Line Oral Anti-Tuberculosis Isoniazid (H);

- Most potent and best-tolerated, thus if Rifampicin (R);

laboratory evidence and clinical history
Ethambutol (E);
indicates that a drug from this group is
effective, it should be used. Pyrazinamide (Z).

- If drug used in a previous regimen failed, its

efficacy should be questioned despite of
Drugs Susceptibility Test (DST) results
suggesting susceptibility.
Group 2: Injectable Anti-Tuberculosis Streptomycin (S);
Agents
Kanamycin (Km);
- Are given if susceptibility is suspected.
Amikacin (Am);
- Km or Am is the first choice of an
injectable agent, given the high rates of Capreomycin (Cm);
streptomycin resistance. Vincomycin (Vi).
- If an isolate seemed to be resistant to both

6
 streptomycin and kanamycin, or is DRS
data show high rates of resistance to
amikacin and kanamycin, Cm should be
used.
Group 3: Fluoroquinolones Ciprofloxacin (Cfx);

- Are given if the isolate is susceptible or if Ofloxacin (Ofx);

the agent is thought to have efficacy.
Levofloxacin (Lfx);
- Lfx or Mfx is the fluoroquinolone of choice.
Cfx is no longer recommended. Moxifloxacin (Mfx);

Gatifloxacin (Gfx).

Group 4: Oral Second-line Anti- Ethionamide (Eto);

Tuberculosis Agents
Prothionamide (Pto);
- Eto (or Pto) is often added to the treatment
Cycloserine (Cs);
regimen because it cost less.
- If cost is not a constraint, PAS may be Terizidone (Trd);
added frist, because the enteric-coated Para-aminosalicylic acid
formulas are relatively well-tolerated and (PAS);
there is no cross-resistance to other agents
Thioacetazone (Th)
- When 2 agents are needed, Cs or Terizidone
can be added

Group 5: Agents with Unclear Role in Clofamizine (Cfz);

Treatment of Drug-Resistant Tuberculosis
Linezolid (Lzd);
- Are not recommended by WHO for routine
Amoxicillin/ Clavulanae
use in drug-resistant TB treatment because
(Amx/ Clv);
their efficacy remains unclear.
- Can be used in cases where group 1-4 Thioacetazone (Thz);
cannot possibly make an adequate regimen. Imipenem/ Cilastatin (Lpm/
Cln);

High-dose Isoniazid (high

7
 dose H);

Clarithromycin (Clr)

The choices of the first line treatment regimen for patients who has never
been treated for as much as one month are as follwing; rifampicin plus isoniazid
are given daily for six months. During the intensive phase, the durgs are
strengthened with pyrazinamide plus ethambutol. (see figure 1) As for patients
who have been exposed to first line of anti TB drugs for more than one month,
including patients who relapses ( become smear positive again after declared
cured or treatment compleated), treatment after failure ( while on treatment, smear
positive for more than 5 months), and treatment after default (return to treatment
and are smear positive after having interrupted treatment for more than 2 months).
The treatment recommended for these patients are of 8 months duration with
rifampicin and isoniazid and is added with pyrazinamide, ethambutol,
streptomycin during the first 2 months (see figure 2). Keep in mind that patients
who are proven to have multidrugs resistant TB should require different
treatments.11

Figure 1. Number of tablets taken daily for adults on treatment according to

body weight and the content of the tablets for patient who are never
previously treated11

8
Figure 2. Number of tablets taken daily for adults on treatment according to
body weight and the content of the tablets for patients given treatment for
TB before11

Side effect of anti TB drugs (figure 3) can lower life quality of the
patients, therefore, it should be important to know some of the inications to stop
or continue the medications as instructed below.

Indications for the drug to be stopped without further considerations are11 :

 Generealized reactions; shock, purpura, fever. Commonly induced by

rifampicin, pyrazinamide or streptomicin
 Impairment of vision in a patient who consumes ethambutol or rarely
because of isoniazid
 Pregnant patients
Indications for the drug to be stopped while the cause is investigated are:
 Jaundice or severe abdominal discomfort, which may be suspected as
hepatitis. Usually because of rifampicin, or could be any of the anti TB
drugs given.
 Skin rash, commonly caused by isoniazid, streptomycin or pyrazinamide.
 Dizziness may be caused by injectable drugs, usually happen to older
patients.
Reactions that do not require interruptions are:

9
  Numbness or tingling caused by isoniazid, can be cured with vitamin B6 at
dose of 50mg daily
 Joint symptoms, usually caused by pyrazinamide, can be cured with
acetylsalicylic acid
 Red/orange body fluids, caused by rifampicin

Table 2. Side effects of anti TB drugs14

2.4 Definition of Multidrug-Resistance Tuberculosis

Multidrug-resistance TB (MDR-TB) is caused by bacteria that are resistant

to at least isoniazid and rifampicin, the most effective anti-TB drugs. MDR-TB
results from either primary infection with resistant bacteria or may develop in the
course of a patient’s treatment. Extensively drug-resistant TB (XDR-TB) is a form
of TB caused by bacteria that are resistant to isoniazid and rifampicin (i.e. MDR-
TB) as well as any fluoroquinolone and any of the second-line anti-TB injectable
drugs (amikacin, kanamycin or capreomycin). These forms of TB do not respond
to the standard sixmonth treatment with first-line anti-TB drugs and can take up to
two years or more to treat with drugs that are less potent, more toxic and much
more expensive.15

10
2.5 Epidemiology of Multidrug-Resistance Tuberculosis

Almost every country has reported cases of multidrug resistance

tuberculosis (MDR-TB). MDR-TB usually develops during the period of TB
treatment and it is commonly due to doctors giving inappropriate treatment,
patients skipping their medications or not completing their treatments properly.
MDR-TB is an airborne pathogen and can be transmitted if the patient is
coughing.16
In 2013, 3.7% of TB cases have been reported to be MDR-TB. WHO
estimates that in 2011, there were about 0.5 million cases of MDR-TB and 60% of
it were in Brazil, China, India, Russia and South Africa. In 2016, about 19% of
previously treated TB cases were MDR-TB. About 6.2% of MDR-TB cases in
2016 had additional drug resistance, also known as extensively drug resistance TB
which has decreased throughout the years. In 2016, MDR-TB has caused about
240,000 deaths.17
When patients have MDR-TB, they need longer periods of treatment
which is about two years of multidrug regimen. Some of the less effective second-
line drugs, which are required to treat MDR-TB, are also more toxic, with side
effects such as nausea, abdominal pain, and even psychosis. The Partners in
Health team had treated patients in Peru who were sick with strains that were
resistant to ten and even twelve drugs. Patients like them require adjuvant surgery
for any hope of a cure.16

2.6 Etiophatogenesis of Multidrug-Resistance Tuberculosis

Bacteria have a remarkable genetic plasticity that allows them to respond a

wide array of environmental threats, including the presence of antibiotic
molecules that may interfere their existence.18 Most of the molecular mechanisms
of acquiring resistance to drugs have been described, and by now people have
started to realize the truth behind the development of drug resistant strains of
MTB.19,20

Multidrug resistant tuberculosis refers to tuberculosis that is resistant to

both rifampicin and isoniazid.21 This classification is important because treatment

11
outcomes for this group of patients are far worse than for patients with fully drug
susceptible or lesser forms of drug resistant tuberculosis. Multidrug resistant
tuberculosis with additional resistance to any fluoroquinolone (such as ofloxacin
or moxifloxacin), also any one of the three second line injectable agents
(amikacin, capreomycin, kanamycin) is designated as extensively drug resistant
tuberculosis (XDR-TB). Accumulations of mutations in individual drug target
genes involved in generation of MDR-TB are listed as below.20, 22

Table 3. Pathogenesis of Multidrug-Resistance Tuberculosis

Drugs Genes

RIF rpoB (RNA polymerase subunit B)

INH katG (Catalase-peroxidase)

oxyR (Oxydative stress regulator)

ahpC (Alkyl hydroperoxide reductase)

INH-ETH inhA (Enoyl acyl carrier protein reductase)

Streptomycin rpsL (Ribosomal protein subunit 12)

rrs (16 ribosomal RNA)

Fluoroquinolone gyrA (DNA gyrase A)

PZA pncA (Pyrazinamidase)

EMB embCAB (Arbinosyl transferase)

Resistance to INH, the most important first line anti-TB drug, can be
mediated by several genetic mutations involving ndh, kasA, inhA, ahcP, and katG.
INH is a pro-drug that requires activation by the catalase/peroxidase enzyme
encoded by katG, but it is reported that katG-activated INH inhibits inhA (the
target for INH), inhibits the NADH-dependent enoyl-acyl carrier protein reductase
to interfere with mycolic acid (indispensable element of its cell wall) synthesis.
Therefore, any mutation that reduces the activity of either inhA or katG, will result

12
in resistance to INH. The most common mutations of inhA is hugely targeted in
the promoter region. In addition, mutation in the inhA gene can cause resistance to
a second line drug, ETH. It was probably due to the structural similarity of ETH
with INH.20, 22

RIF resistance caused by the mutation of β-subunit of the

RNApolymerase. It hinders the elongation of the mRNA, priorly interfering with
the binding of RIF. This drug counteracts to the aggressively multiplying
pathogen, which are at the same time metabolizing bacterial in a very slow period.
The resistance is produced by the conformational changes, a downstream event to
the mutation of rpoB, which determine a low affinity for the drug resulting in
resistance.20, 22

Other than two mechanisms explained above, there are also several
mechanisms related to drug pharmacokinetics and pharmacodynamics that
probably cause antibiotic resistance in MDR-TB, such as: role of non-adherence
period, pharmacokinetic variability of the drug, and the role of efflux pumps.
Those mechanisms explained as below.23, 24

a. During periods of non-adherence, the drugs with shorter half-lives

disappear so that M. tuberculosis bacilli are exposed to monotherapy with
the drug that has the longer half-life for periods of their growth, leading to
resistance to that drug.
b. In the relation to pharmacokinetic variability, differential rapid elimination
of some drugs in the regimen, leading to prolonged monotherapy with the
drug that is not rapidly or extensively metabolized over tens to hundreds of
rounds of bacterial replication. Pharmacokinetic variability at the level of
drug penetration into tuberculosis lesions, depends on the architecture of
the tuberculosis lung cavity. The lung cavity and surrounding fibrosis,
depending on the size, will create a physicochemical barrier to drug entry,
leading to anatomical site-based monotherapy.
c. In the theory of efflux pump, as part of the bacterial stress reaction to the
suboptimal antibiotic concentrations, and to effective monotherapy, efflux
pumps in the bacilli are upregulated within hours. This efflux pump-

13
 dependent low-level resistance process, allows the bacteria time to
undergo multiple rounds of replication under suboptimal antibiotic
pressure or monotherapy, allowing for development of mutations in the
canonical drug resistance genes, in efflux pump genes, or in negative
regulators of efflux pumps.

2.7 Clinical Manifestation of Multidrug-Resistance Tuberculosis

Tuberculosis can be divided into two stages; latent and active. Latent stage
shows no clinical symptoms. Meanwhile, the active stage shows several clinical
manifestations based on the sites of infection mainly pulmonary and
extrapulmonary.25 Development of tuberculosis among patients may vary due to
immune status and various cellular processes.26 Each stage of tuberculosis has
different clinical manifestations.

a. Latent Tuberculosis
At this stage, there are no clinical symptoms found as well as radiological
or microbiological evidence of the disease.27 This stage occurs when the pathogen
resides and stay dormant inside the host’s body. However, it may progress and
become active during the lifetime of individual if immune system becomes
compromised.

b. Primary Disease
From the latent stage, the pathogen may become active yet often
asymptomatic with some self-limiting clinical findings.26 As an example, pleural
effusion may occur due to bacterial infiltration of pleural space and cause
symptoms such as chest pain, fever, and dyspnea.

c. Primary Progressive Tuberculosis

The growth and multiplication of bacteria in the host is referred as active
disease, due to the failure of immune system to contain the infection. According
to CDC, pulmonary TB may cause symptoms such as persistent bad cough (3
weeks) with sputum or blood (hemoptysis) and also pain in the chest. 28 Other
symptoms include weakness or fatigue, weight loss, loss of appetite, chills, fever,
and sweating at night.

14
d. Extrapulmonary Tuberculosis
Extrapulmonary tuberculosis (EPTB) is defined as any site of infection in
the body other than the lung parenchyma. This results from the hematogenous and
lymphatic spread of the pathogen.29 The most common form of EPTB and occurs
due to infection of lymph nodes is lymph node tuberculosis. 30 This type of EPTB
mainly affects children and young adults presenting with enlarged lymph nodes
and are usually asymptomatic. The most common location is cervical lymph
nodes, followed by supraclavicular, axillary, thoracic, and abdominal nodes.31

Another common type is pleural tuberculosis, also called as tuberculous

pleurisy. The symptoms manifest as chest pain, cough, acute illness with fever,
and pleural effusion. Genitourinary tuberculosis commonly affects kidneys and
also genitals that may lead to infertility. This type of tuberculosis shows non-
specific symptoms with serious complications such as kidney failure.25

A study in Brazil mentioned that MDR-TB may present with symptoms

such as productive cough without fever, fatigue, and weight loss.32

2.8 Diagnosis of Multidrug-Resistance Tuberculosis

Diagnosing MDR-TB are considerably more difficult than for drug-
susceptible tuberculosis (TB) because of the absence of effective and affordable
rapid diagnostic techniques for drug sensitivity and higher level infrastructure and
proficiency from laboratory specialists and clinicians. WHO-recommended rapid
diagnostics and universal drug susceptibility testing (DST) for all persons with
signs and symptoms of TB. There are a number of laboratory tools available for
diagnosis of MDR-TB, including phenotypic culture-based DST as well as
molecular methods that have been explored to develop rapid, reliable and accurate
methods for the rapid detection of MDR in M tuberculosis.33
1. Phenotypic (Culture-Based) Method
1.1. Conventional Method
A standardized DST procedure with conventional methods is required
for the definitive diagnosis of MDR-TB. M. tuberculosis is isolated
from patient sputum and then tested for growth in the presence of anti-

15
 TB drugs antibiotics to distinguish between susceptible and resistant
strains on solid media. While relatively inexpensive and undemanding
of sophisticated equipment, results usually take up to 8 weeks and this
is challenging. Delayed identification of drug resistance results in
inadequate treatment, which may generate additional drug resistance.34
1.2. Liquid Culture-Based Methods
Automated liquid culture systems are more sensitive than solid media
cultures, and they significantly reduce the time. However, even with
liquid cultures, two to four weeks are still needed to obtain results, and
their substantially higher cost is an issue for resource-limited
countries.34
1.3. Novel, Rapid Phenotypic Methods
Microcolony method is one of the novel and rapid methods that
relatively low cost. It has been adapted for the rapid detection of drug
resistance directly from sputum samples, and has been shown in early
studies to be accurate for the detection of MDR-TB compared with the
methods mentioned before, with results available in one week. Newly
developed phenotypic tests are usually cheaper but not always simple
to perform, with some requiring high standards of biosafety and
quality control.34
Though consume more time than molecular DST, phenotypic DST for first-
line agents (isoniazid (H) and rifampicin(R)) and selected second-line anti-
TB drugs (kanamycin, amikacin, ofloxacin, levofloxacin) are generally
reliable.33
2. Molecular (Genotypic) Methods (Line Probe Assay [LPA] and Xpert MTB)
Molecular methods have considerable advantages for programmatic
management of DR-TB, in particular with regard to their speed, the
standardization of testing, their potentially high throughput and the reduced
requirements for laboratory biosafety. Molecular tools are based on
polymerase chain reaction techniques to detect the genetic mutations that are
known to resistance to drugs. Molecular tests for detecting drug resistance

16
 to rifampicin (R) alone or in combination with isoniazid (H) have been
recommended for use by WHO since 2008. 33,35
Specifically, a positive molecular test for rifampicin (R) resistance can be
considered diagnostic for MDR-TB, because in most countries, greater than 90%
of rifampicin-resistant strains are also resistant to isoniazid (H). All patients
diagnosed with resistance to rifampicin (R) and/or isoniazid (H) should be tested
further, includes testing for resistance to the three second-line injectable drugs
(SLID) such as levofloxacin, amikacin, and capreomycin, and at least one
fluoroquinolone (FQ). Standard phenotypic tests must also be performed; while
these take longer and support the treatment decision, they can resolve any
discrepancies between the methods.35

2.9 Differential Diagnosis of Multidrug-Resistance Tuberculosis

Mycobacteria are commonly characterized by positive acid-fast staining.
Most mycobacterial species belong to the nontuberculous mycobacteria (NTM),
excluding species in the Mycobacterium tuberculosis complex and M. leprae.
Both M. tuberculosis and NTM can induce pulmonary infection with similar
symptoms. These similarities have led to difficulty in distinguishing these
infections clinically. The majority of these patients present with positive smear for
Acid Fast Bacilli (ADB) and no response to first line anti-TB treatment, so
sputum culture and PCR are necessary, especially in NTM. As in many
developing countries, the acid-fast stain is the only bacteriologic basis for
diagnosing TB, where facilities are limited for M. tuberculosis culture, strain
identification, and drug resistance detection. Thus, NTM is easily misdiagnosed
as M. tuberculosis, and MDR-TB is unable to be accurately identified.36

2.10 Management of Multidrug-Resistance Tuberculosis

Treatment of MDR-TB is more complex, difficult, and expensive as

patients are infected with strains resistant to both isoniazid and rifampicin, first-
line to TB therapy, yet the second-line TB drugs are mostly weak and toxic.
Because of their weak sterilizing activity, MDR-TB treatment generally takes 18-

17
24 months with the reported global cure rate by WHO accounted for 48% - lower
than the number of those considered best (60-80%).37

Assessment of history of treatment as well as meticulous laboratory

parameters to characterize the susceptibility of the specific strain are necessary in
the initiation of drug therapy in patients with MDR-TB. Irregular, incomplete, and
inadequate treatment and poor compliance often lead to the acquisition of drug
resistance.37

2.10.1 General Principles in Designing an MDR-TB Treatment Regimen

The general principle for selecting an empirical or standard MDR-TB

regimen is shown in the Table 1. Treatment regimens should consist of at least
four drugs which are likely to be effective. When the effectiveness of a certain
drug is unclear, the drug can be part of the regimen but it should not be depended
upon to. Often, more than four drugs may be started if the susceptibility pattern is
unknown or the effectiveness of one or more agents is questionable.39

One of the most important steps in designing an MDR-TB regimen is

taking a detailed history of past TB treatment. As a general rule, any drug that has
been used in a regimen that did not cure the patient should be considered
ineffective, despite of a recent DST indicating patient’s strain is still susceptible.
For example, if the patient previously used ethambutol or pyrazinamide as part of
a failed first-line regimen, neither of these drugs should be considered likely to be
still effective.

As for another general rule, the possibility of further acquired resistance

developing during the previous treatment must be considered. If a drug is used for
more than 1 month with persistently positive cultures, the strain should be
considered as “probably resistant” to that drug, even if DST results indicate that it
is susceptible. Thus, that drug should not be counted as one of the four drugs in
the core regimen (but can be used as an adjunctive agent).38,39

Susceptibility testing for isoniazid, rifampicin, the fluoroquinolones, and

the injectable agents is fairly reliable. However, it is less reliable for other agents,
thus, basing the treatment on DST for other agents should be avoided.39

18
Figure 3. General principles in designing an MDR-TB treatment regimen.39

2.10.2 Designing a Regimen Therapy for MDR-TB

At least four second-line anti-TB drugs with either certain, or almost

certain, effectiveness. All regimens should include a later generation
fluoroquinolone such as levofloxacin or moxifloxacin (a second-line injectable
drug, and other oral second-line drugs). Pyrazinamide may also be included unless
contraindicated (history of drug allergy or evidence of ineffectiveness against the
patient’s strain).38

19
 Dosing of anti-TB drugs is based on the weight of the patient. Even though
anti-TB are generally given once a day to improve peak-dependent killing, many
of those second-line anti-TB drugs have severe side effects that can be reduced by
twice-daily divided dosing.38

If an injectable drug is still likely to be effective, many clinicians will try

to use it for longer duration, such as 12 months or even the entire duration of the
treatment.

Figure 4. Designing an MDR-TB regimen.38

20
2.10.3. Monitoring and Duration of the Treatment

Timely and intensive monitoring for, and management of, adverse effects
caused by second-line drugs are important for MDR-TB. To assess treatment
response, sputum smears and cultures should be performed monthly until smear

21
and culture conversion (two consecutive negative smears and cultures taken 30
days apart). After a conversion, the minimum frequency recommended for
bacteriological monitoring is monthly for smears and quarterly for cultures. Each
patient’s weight should be assessed monthly.39

The optimal duration of MDR-TB treatment remains controversial. One

study that a 9-month treatment regimen was sufficient to affect cure in a small
cohort patients in Bangladesh.2 The injectable agents should be continued for at
least 6 months, and for 4 months after the patient becomes culture-negative.
Clinicians may use an individualized approach by reviewing the cultures, smears,
x-rays, and clinical status to decide how long to continue the injectable to decide
whether or not to continue an injectable agent longer than recommended.39

2.10.4. Management of Side Effects

Second-line drugs have more side effects compared to the firs-line anti-
TB. Mismanagement of side effects is the major reason why patients do not
adhere or continue to take MDR-TB treatment, thus it is the responsibility of the
clinician to diagnose and manage them. Patient should be screened for side-effects
of medications. Clinical and laboratory services can help detecting side-effects,
and medications to treat adverse effects when they occur.38,39

Mild side effects are common, and can be managed symptomatically with
ancillary drugs without altering the treatment the treatment regimen. Side effects
often diminish over time, allowing patients to finish their treatment.38

A poorly tolerated drug may be temporarily suspended unless the patient’s

strain is highly resistant since a satisfactory replacement drug may not be
available. The decision to suspend any drug should be made by weighing the risk
of continued side effects against the chances of curing a deadly disease.38

Side effects vary and are listed in Table 2.38

Table 4. Common side effects of anti-TB drugs.38

Side Effects Causes Management

Gastrointestinal distress PAS & Ethionamide Improve over time with

22
 supportive therapy

Nephrotoxicity Aminoglycosides & Creatinine monitoring;

Capreomycin Eldelry patient or a
patient with a history of
renal disease (including
comorbidities such as
HIV and diabetes) should
be monitored more
closely.

Electrolyte wasting Any injectable drugs Electrolyte replacement

(similar to Fanconi’s therapy; serum potassium
Syndrome) monitoring

Hypothyroidism Prolonged exposure to All patients should be

PAS or Ethionamide/ screened for
Prothionamide hypothyroidism after the
third month of MDR-TB
therapy

Neurotoxic effects Cycloserine Screen patients for

abnormal behaviour and
symptoms of depression,
anxiety, and agitation on
regular basis

Ototoxicity Injectable drugs Hearing loss is

irreversible even if the
drug is discontinued;
Assess for hearing and
balance monthly

2.11 Prognosis of Multidrug Resistance-Tuberculosis

23
 The treatment success rate in patients with non MDR TB Infections was
higher than MDR-TB infections.40 Treating patients with multidrug-resistant
tuberculosis (MDR-TB) strains is more complicated, complex, toxic, expensive,
than treating patients with suspectable TB strains. Previous use of second- line
drugs have been documented as significant risk factors for poor treatment
outcome due to the development of more drug resistance. 41 People who has HIV-
Positive, male gender, smoking, diabetes history, alcoholic, lower education has
higher risk factors for poor outcome and increase of death in populations, but
good outcome will be reached if the patient use MDR TB therapy at least 18
months, directly observed therapy throughout treatment,no previous treatment and
being educated about their situations.42,43

2.12 Complication of Multidrug Resistance-Tuberculosis

In patients with highly resistant TB, a satisfactory replacement drug may

not be available. In such cases, permanent discontinuation of the drug should be
avoided if possible. The decision to suspend any drug should be made by
weighing the risk of continued side effects against the chances of curing a deadly
disease.

In multidrugs resistant tuberculosis (MDR-TB) patients several

complications can occur, either before treatment or after treatment is complete.
Some of the complications that may arise are coughing up blood, pneumothorax,
pulmonary pulses, respiratory failure, heart failure, pleural effusion.
Gastrointestinal distress is a common side effect of MDR-TB treatment, caused by
PAS and ethionamide. Nausea and vomiting are common in early weeks of
therapy but usually improve over time and with supportive therapy.
Nephrotoxicity is a known complication of the aminoglycosides and capreomycin.
Because symptoms of acute renal failure can be nonspecific, serum creatinine
monitoring is recommended. Patients with advanced age or a history of renal
disease (including comorbidities such as HIV and diabetes) should be monitored
more closely, particularly at the start of treatment. Electrolyte wasting with
similar characteristics to Fanconi’s Syndrome can be induced by all of the

24
injectable drugs. It is reversible once the injectable is suspended, but it may take
weeks or months to be resolved completely. Because electrolyte wasting is
generally managed with electrolyte replacement therapy, serum potassium should
be checked at least monthly in all patients during the initial injectable phase.
Hypothyroidism can be induced by prolonged exposure to PAS or
ethionamide/prothionamide. The exact incidence of hypothyroidism during MDR-
TB treatment is unknown, but rates of up to 80% have been reported in some
patient populations. Because symptoms are nonspecific, all patients should be
screened for hypothyroidism starting after the third month of MDR-TB treatment.
Neurotoxic effects such as psychosis or depression can be caused by cycloserine.
Clinicians should screen patients for abnormal behavior and symptoms of
depression, anxiety, and agitation on a regular basis. Ototoxicity can be caused by
the injectables, which can cause damage to cranial nerve VIII. This may result in
hearing loss, tinnitus (ringing in the ear), or other vestibular symptoms such as
nystagmus, ataxia, and disequilibrium. Hearing loss is generally not reversible on
discontinuation of therapy. Hearing and balance should be assessed at least
monthly while the patient is receiving the injectable. Where available, audiometry
should be performed monthly and is an excellent way of detecting early hearing
loss.44,45

The patient's skin and eyes appear yellow, Hearing is reduced or the ears
are buzzing, Hearing voices, hallucinations, delusions, Severe allergic reactions
namely anaphylactic shock and angionerotic edema, must be immediately handled
by the clinic doctor according to standard shock management before being
referred to the referral hospital MDR-TB, Another severe allergic reaction in the
form of redness of the mucosa (mucous membrane) such as the mouth, eyes and
can affect the entire body in the form of exfoliation (Steven Johnsons
Syndrome).46

CHAPTER III

25
 CONCLUSION

Tuberculosis (TB) is an infectious disease caused by slightly bent, thin,

aerobic, non-motile, non-spore forming beaded rods belonging to the family
Mycobcteriaceae and to the order Actinomycetales, of the patogenic species
belonging to Mycobacterium tuberculosis. Mycobacterium tuberculosis infection
begins when a person inhaled a droplet nuclei containing viable microorganisms
that propelled into the air by infectious patients. Treatment of anti-tuberculosis is
one of the most efficient means of preventing the spread of tuberculosis. There are
some requirement for adequate treatment:

 Apropriate combination of anti-tuberculosis drugs, intially to prevent

development of resistance to those drugs
 Prescibed on one correct dosage
 Taken regularly by patient
 Sufficient period of treatment to prevent relapse of disease

In the other hand, multidrug-resistance TB (MDR-TB) is caused by

tuberculosis bacteria that are resistant to at least isoniazid and rifampicin, the most
effective anti-TB drugs. MDR-TB results from either primary infection with
resistant bacteria or may develop in the course of a patient’s treatment. Almost
every country has reported cases of multidrug resistance tuberculosis (MDR-TB).
MDR-TB usually develops during the period of TB treatment and it is commonly
due to doctors giving inappropriate treatment, patients skipping their medications
or not completing their treatments properly.

Treatment for MDR-TB at least four second-line anti-TB drugs with either
certain, or almost certain, effectiveness. All regimens should include a later
generation fluoroquinolone such as levofloxacin or moxifloxacin (a second-line
injectable drug, and other oral second-line drugs). Pyrazinamide may also be
included unless contraindicated (history of drug allergy or evidence of
ineffectiveness against the patient’s strain). Timely and intensive monitoring for,

26
and management of, adverse effects caused by second-line drugs are important for
MDR-TB.

27
 REFERENCE

1. Tuberculosis (TB). World Health Organization. 2018 [cited 6 November

2018]. Available from:
http://www.who.int/news-room/fact-sheets/detail/tuberculosis
2. Tuberculosis (TB). Cdc.gov. 2018 [cited 6 November 2018]. Available
from: https://www.cdc.gov/tb/worldtbday/history.htm
3. Mandell, G., Bennett, J. and Dolin, R. (2010). Mandell, Douglas, and
Bennett's principles and practice of infectious diseases. Philadelphia, PA:
Churchill Livingstone/Elsevier, p.250.
4. Rieder, H., Chiang, C., Gie, R., Enarson, D. and Crofton, J.
(2009). Crofton's clinical tuberculosis. 3rd ed. pp.4-5.
5. Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis.
Lancet.2003;362: 887-899.
6. Jensen PA, Lambert LA, Iademarco MF, Ridzon R; Centers for Disease
Control and Prevention. Guidelines for preventing the transmission of
Mycobacterium tuberculosis in health-care settings, 2005. MMWR
Recomm Rep.2005;54(RR-17):1-141.
7. Porth CM. Alterations in respiratory function: respiratory tract infections,
neoplasms, and childhood disorders. In: Porth CM, Kunert MP.
Pathophysiology: Concepts of Altered Health States.Philadelphia, PA:
Lippincott Williams & Wilkins; 2002:615-619.
8. Van Crevel R, Ottenhoff THM, van der Meer JWM. Innate immunity to
Mycobacterium tuberculosis. Clin Microbiol Rev.2002;15: 294-309.
9. Dheda, K, Booth H, Huggett JF, et al. Lung remodeling in pulmonary
tuberculosis. J Infect Dis.2005;192:1201-1210.
10. Dheda, K, Booth H, Huggett JF, et al. Lung remodeling in pulmonary
tuberculosis. J Infect Dis.2005;192:1201-1210.
11. Ait-Kahed N, Alacron E, Armengol R, Bissell K, Boillot F, Caminero J A,
Chiang C-Y, Clebenbergh P, Dlodlo R, Enarson D A, Enarson P, Fujiwara
P I, Harries A D, Heldal E, Hinderaker S G, Lienhardt C, Monedero I,
Rieder HL, Rusen I D, Trebucq A, Van Deun A, Wilson N. Management

28
 of Tuberculosis: a guide to the essentials of good practice. Paris, France:
International Union Agaunst Tuberculosis and Lung Disease. 2010. pp.27-
38
12. Seung KJ, Keshavjee S, Rich ML. Drug-Resistant Tuberculosis. Cold
Spring Harb Perspect Med. 2015.
13. WHO. Treatment of Tuberculosis Guidelines 4th Edition. 2009.
14. Health Department Republic of South Africa. National Tuberculosis
Mangement Guidelines . 2014 .pp.43
15. WHO. (2010). Multidrug and extensively drug-resistant TB (M/XDR-TB).
Geneva, Switzerland: World Health Organization.
16. Tbfacts.org. (2018). Multi Drug Resistant TB - What is MDR, statistics,
treatment. [online] Available at: https://www.tbfacts.org/multi-drug-
resistant-tb/ [Accessed 8 Nov. 2018].
17. Dodd, P., Sismanidis, C. and Seddon, J. (2018). Global burden of drug-
resistant tuberculosis in children: a mathematical modelling study.
18. Munita J M, Arias C A. Mechanisms of Antibiotic Resistance. Microbiol
Spectr. 2016;4(2):10.1128/microbiolspec.VMBF-0016-2015.
19. Bhunia S, Sarkar M, Banerjee A, Giri B. An update on pathogenesis and
management of tuberculosis with special reference to drug resistance.
Asian Pacific Journal of Tropical Disease. 2015;5(9):673-686.
20. Davies J, Davies D. Origins and evolution of antibiotic
resistance. Microbiol Mol Biol Rev. 2010;74(3):417-33.
21. Millard J, Ugarte-Gil C, Moore D. Multidrug resistant tuberculosis. BMJ.
2015;350(feb26 10):h882-h882. doi:10.1136/bmj.h882
22. Raviglione M. Tuberculosis. New York: Informa Healthcare; 2010.
23. Dheda K, Gumbo T, Maartens G et al. The epidemiology, pathogenesis,
transmission, diagnosis, and management of multidrug-resistant,
extensively drug-resistant, and incurable tuberculosis. The Lancet
Respiratory Medicine. 2017;5(4):291-360. doi:10.1016/s2213-
2600(17)30079-6
24. Valafar F. Pathogenesis of multi drug-resistant and extensively drug-
resistant tuberculosis as a determinant of future treatment success. Int J

29
 Mycobacteriol. 2016;5:S64-S65. doi:10.1016/j.ijmyco.2016.11.017
25. Joon D, Nimesh N, Nimesh M. Clinical manifestations of tuberculosis.
Voyager. 2017 Jun;8(1):37-46.
26. Knechel NA. Tuberculosis: pathophysiology, clinical features, and
diagnosis. Critical Care Nurse. 2009 April;29(2):34-43.
27. Lee SH. Diagnosis and treatment of latent tuberculosis infection. Tuberc
Respir Dis (Seoul). 2015 Apr;78(2):56-63.
28. CDC. Basic tb facts: signs & symptoms [Online]. CDC; 2016 [updated
2016 Mar 17; cited 2018 Nov 6]. Available from:
https://www.cdc.gov/tb/topic/basics/signsandsymptoms.htm
29. Polena H, Boudou F, Tilleul S, Dubois-Colas N, Lecointe C,
Rakotosamimanana N, et al. Mycobacterium tuberculosis exploits the
formation of new blood vessels for its dissemination. Sci Rep [Internet].
2016 Sep;6:33162. Available from:
https://www.ncbi.nlm.nih.gov/pubmed/27616470 DOI: 10.1038/srep33162
30. Fontanilla JM, Barnes A, von Reyn CF. Current diagnosis and
management of peripheral tuberculous lymphadenitis. Clin Infect Dis
[Internet]. 2011 Sep;53(6):555-62. Availbable from:
https://www.ncbi.nlm.nih.gov/pubmed/21865192 DOI: 10.1093/cid/cir454
31. Peto HM, Pratt RH, Harrington TA, LoBue PA, Armstrong LR.
Epidemiology of extrapulmonary tuberculosis in the united states, 1993-
2006. Clin Infect Dis [Internet]. 2009 Nov;49(9):1350-7. Available from:
https://www.ncbi.nlm.nih.gov/pubmed/19793000 DOI: 10.1086/605559
32. Micheletti VCD, Kritski AL, Braga JU. Clinical features and treatment
outcomes of patients with drug-resistant and drug-sensitive tuberculosis: a
historical cohort study in porto alegre, brazil. PLoS ONE [Internet]. 2016
Aug;11(8):e0160109. Available from: DOI:
10.1371/journal.pone.0160109
33. Gilpin C, Korobitsyn A, Weyer K. Current tools available for the
diagnosis of drug-resistant tuberculosis [Internet]. 2016 [cited 4 November
2018]. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5375090/

30
34. Migliori GB, Matteelli A, Cirillo D. Diagnosis of mutrigrug-resistant
tuberculosis and extensive drug-resistant tuberculosis: Current standards
and challenges [Internet]. 2008 [cited 4 November 2018]. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605858/
35. Seung KJ, Keshavjee S, Rich ML. Multidrug-Resistant Tuberculosis and
Extensively Drug-Resistant Tuberculosis [Internet]. 2015 [cited 4
November 2018]. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561400/
36. Kaijin W, Sheng B, Zhongkang J. Distinguishing Nontuberculous
Mycobacteria from Multidrug-Resistant Mycobacterium tuberculosis,
China [Internet]. 2014 [cited 4 November 2018]. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036753/
37. Chhabra N, Aseri ML, Dixit R, Gaur S. Pharmacotherapy for multidrug
resistant tuberculosis. J Pharmacol Pharmacother. 2012;3(2).
doi:10.4103/0976-500X.95502.
38. Seung KJ, Keshavjee S, Rich ML. Drug-Resistant Tuberculosis. Cold
Spring Harb Perspect Med. 2015.
39. WHO. Treatment of Tuberculosis Guidelines 4th Edition. 2009.
40. Elmi O, Hasan H, Abdullah S, Mat Jeab M, BA Z, Naing N. Treatment
Outcomes of Patients with Multidrug-Resistant Tuberculosis (MDR- TB)
Compared with Non-MDR-TB Infections in Peninsular Malaysia.
Malaysian Journal of Medical Sciences. 2016;23(4):17-25.
41. Gadallah M, Mokhtar A, Rady M, El-Moghazy E, Fawzy M, Kandil S.
Prognostic factors of treatment among patients with multidrug-resistant
tuberculosis in Egypt. Journal of the Formosan Medical Association.
2016;115(11):997-1003.
42. Oliveira O, Gaio R, Villar M, Duarte R. Predictors of treatment outcome
in multidrug-resistant tuberculosis in Portugal: Table 1–. European
Respiratory Journal. 2013;42(6):1747-1749.
43. Chung-Delgado K, Guillen-Bravo S, Revilla-Montag A, Bernabe-Ortiz A.
Mortality among MDR-TB Cases: Comparison with Drug-Susceptible
Tuberculosis and Associated Factors. PLOS ONE. 2015;10(3):e0119332.

31
44. Keshavjee S, Farmer PE. 2012. Tuberculosis, drug resistance, and the
history of modern medicine. New Engl J Med 367: 931–936. 
45. Pomerantz BJ, Cleveland JC, Olson JK, Pomerantz M. 2001. Pulmonary
resection for multi-drug resistant tuberculosis. J Thorac Cardiovasc
Surg 121: 448–453.
46. Riyanto BS, Wilhan. 2006. Management of MDR TB Current and Future
dalam Buku Program dan Naskah Lengkap Konferensi Kerja Pertemuan
Ilmiah Berkala. PERPARI.

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