ELECTIVE STUDY

MULTI DRUG RESISTANT TUBERCULOSIS

By Brigitta Marcia Budihardja

NIM 1302005172

Supervised by
dr. I Nyoman Semadi, Sp.B, Sp.BTKV

FACULTY OF MEDICINE
UDAYANA UNIVERSITY
2014

FOREWORD
Praise to God Almighty whose blessings has made the accomplishment of
this paper possible. I want to express my biggest gratitude to my supervisor, dr. I
Nyoman Semadi, Sp.B, Sp.BTKV who has guided me pleasantly in the process of
writing this paper. I also want to thank my fellow students who has helped and
motivated me in the process of writing this paper.
This paper is titled Drug-resistant Tuberculosis. This paper is written
through literature review. This paper explains MDR-TB (Multi Drug Resistant
Tuberculosis) as an emerging condition that needs immediate response to prevent
further development of the condition. The aim of this paper is to gain knowledge
about this condition as the result of the writing process. Hopefully, this paper can
be also be used by other fellow students as a source of new knowledge and
information. The benefit of this paper is also to put this problem in the spotlight.
There are still a lot of mistakes and flaws in this paper due to the lack of
experience of the writer. Constructive criticism and suggestions are more than
welcomed in hope of gaining more experience for future writing.
Lastly, I sincerely hope that this paper can be helpful for the readers.
Thank you for reading this papers.

Denpasar, August 23rd 2014

Writer

CONTENT LIST
Foreword
Content List...
I. INTRODUCTION
1.1 Background
1.2 Problem Identification...
1.3 Aims..
1.4 Benefits.
II. CONTENT
2.1 Definition..
2.2 Classification
2.3 Epidemiology
2.4 Diagnostics
2.5 Surgical Treatment
III. CONCLUSION
3.1 Conclusion
3.2 Recommendation
References
Appendix

I.

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INTRODUCTION

1.1 Background
For decades, Tuberculosis (TB) has been a major global health problem. It
has been the top cause of death compared to other treatable infectious diseases.
More than one third of world population has been infected by tuberculosis [1].
Tuberculosis occurs worldwide and it has remained as an important cause of
morbidity and mortality in many countries. World Health Organization (WHO)
reported that there were an estimated 9.4 million new cases of TB and 14.0
million prevalent cases causing death to 1.3 million people in 2009 [2]. In
3

Indonesia, TB is a huge problem. TB is the number one cause of death among

communicable diseases and also ranked as the top third cause of death in
Indonesia [3].
Lately, multi-drug resistant Tuberculosis (MDR-TB) has emerged as a new
and serious problem resulting from inappropriate treatment of TB. Although the
history of anti-tuberculosis drug resistance is fairly recent, emerging just over 60
years ago [4], the incidence and degree of TB drug resistance are increasing
worldwide [5]. Every year, approximately 500.000 new cases of MDR-TB are
diagnosed [6]. Globally, more than 50,000 cases of XDR-TB emerge every year as
a result of poor management of both drug-susceptible and drug-resistant TB [2].
World Health Organization has estimated a worldwide prevalence of 150,000
MDR-TB related deaths annually [7]. Out of all TB cases, about 3,6% has turned
into MDR-TB [1]. Mycobacterium tuberculosis resistance to antibiotics has
developed as one of the most challenging problems to disease control all around
the world [8].
In reality, MDR-TB is a manmade problem. MDR-TB is generated by poor
clinical practices and also poor control strategies in new TB patients.
Mismanagement of MDR-TB with inconsistent use of second-line drugs may lead
to development of XDR-TB [2].

1.2 Problem Identification

What is Multi-Drug-Resistant Tuberculosis?

How is the role of surgery as a possible treatment of Multi-Drug-Resistant
Tuberculosis?

1.3 Aims
Aim of this paper is to elaborate multi drug resistant Tuberculosis as an
emerging global health problem. This paper aim to explain this disease and also
present a possible treatment for this condition. The writer hopes that with writing
this paper, a clear general understanding of drug-resistant Tuberculosis can be
gained as a result.
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I.4 Benefits
Benefit from this paper is to spread the knowledge and concern for multi drug
resistant Tuberculosis as a public health challenge worldwide. This paper is
expected to put attention to MDR-TB as an important issue that needs special
attention from health workers, especially in countries where Tuberculosis is a big
burden, such as Indonesia. Hopefully, this paper can be used as a way to share
knowledge of drug-resistant Tuberculosis to fellow medical students.

II. CONTENT
2.1 Definition
Tuberculosis is an infectious
disease that is caused by infection of
Mycobacterium

tuberculosis

[9].

Compared to any other single microbial

agent, Mycobacterium tuberculosis has
caused more deaths. Mycobacterium
tuberculosis is transmitted from one
person to another by respiratory aerosol.
Its initial site of infection is the lung
[10]. Tuberculosis is a result from tissue
hypersensitivity that leads to granuloma
formation
lymphocytic

with

organization

predominant

of

cellular

Figure 1. Chest Radiograph showing

consolidation in superior portion of upper
right lobe, a typical site of Tuberculosis
associated
pulmonary
abnormalities.
Adapted
from
http://web.stanford.edu/group/parasites/Pa
raSites2006/TB_Diagnosis/Current
%20Diagnostic%20Techniques.html

proliferation with Langhan cell giant

cells fibroblasts and capillaries [9].
Tuberculosis, when not properly treated, can lead to drug-resistant TB.
Patients with drug-resistant TB carry strains that are resistant to certain antituberculosis drugs [4]. Drug resistant TB is a result of inappropriate treatment of
TB, whether due to prescribing error or to patients poor compliance with therapy.
There are a lot of factors that contributed in the emergence of MDR-TB. Both
social and medical factors underlie the emergence of multi-drug resistant TB
(MDR-TB) [08]. The main risk factor for the development of resistance among
TB cases is incorrect TB treatment. It is usually linked with irregular drug use,
errors in medical prescription, poor patient obedience with the therapy, and low
quality of TB drugs [8].
Patients motivation is also one of the risk factors for MDR-TB. A patient
who is less motivated has 4,2 higher risk to have MDR-TB compared to other
patient who is highly motivated [3]. Some social determinants also contributed as
risk factors for MDR-TB. Unemployment, alcohol abuse, and smoking were
6

additional risk factors for resistance for second-line drugs of TB. HIV infection,
age less than 35 years, history of imprisonment are also risk factors for drugresistant TB [8]. Public health system also contributed in MDR-TB. The
incompetent utilization of resources, specifically the available treatment
strategies, has led to alarming levels of MDR-TB in many parts of the world.
Most of MDR-TB factors are somehow related to poor functioning of National
Tuberculosis Programs (NTPs), such as the DOTS strategy that has not been
implemented properly [4]. Low number of visit to the Primary Health Center is
also included as one of the risk factors of MDR-TB [1].
MDR-TB is far more difficult to treat compared to drug-susceptible TB.
The drugs used to treat MDR-TB are highly toxic, cost a lot more than the one
used for drug-susceptible TB. Treatment duration is also longer. These treatments
often lead to disappointing outcomes [5]. The treatment is also more complex and
has higher relapse rates and a lower likelihood of treatment success when
compared to drug-susceptible TB [6].
2.2 Classification
Multi-drug resistant Tuberculosis (MDR-TB) indicates bacillary resistance
to at least isoniazid and rifampicin [11]. Isoniazid and rifampicin are the two most
effective first-line drugs for TB. Pre-extensively drug resistant TB (Pre-XDR-TB)
refers to MDR-TB resistant to one of the following; second-line injectable drug or
a fluoroquinolone [6]. Extensively drug-resistant (XDR) TB is MDR-TB with
additional bacillary resistance to any fluoroquinolone and at least one of the three
second-line injectable drugs (SLID), which are kanamycin, amikacin and
capreomycin [11].
2.3 Epidemiology
World Health Organization has estimated a worldwide prevalence of
150,000 MDR-TB related deaths annually [7]. In 2012, the estimated global
burden of MDR-TB was 450,000, including 300,000 incident MDR-TB cases.
This means that the growth of MDR-TB is rapid. But, number of MDR-TB cases
that were reported to the WHO in 2012 was just 94,000 MDR-TB cases, which is
7

less than a third of the estimated cases. The gap between number of reported and
estimated cases is caused by limited access to drug-susceptibility testing [8].
MDR-TB is currently under-diagnosed and not treated adequately. Globally, less
than 2% of new cases and 6% of previously treated cases were tested for MDRTB. Also, only 16% of MDR-TB cases notified in 2010 were given treatment [11].
By the end of 2012, 92 countries had reported cases of XDR-TB. Among MDRTB cases, the average percentage of XDR-TB cases was 9.6% (95% CI: 8.1%
11%) [8].
2.4 Diagnostics
2.4.1 Signs and symptoms
For tuberculosis in general, signs and symptoms include fever, fatigue,
weight loss, night sweats, and a productive cough [12]. Fever is the most common
symptom of TB. It occurs in approximately 70% of patients with TB. Other
symptoms are pleuritic and nonpleuritic chest pain [9]. The sign and symptoms of
drug-resistant TB are similar to drug-susceptible TB. To correctly diagnose drugresistant TB, a laboratory diagnosis is needed.
2.4.2 Laboratory testing
To diagnose drug-resistant TB, culture-based test called drug-susceptibility
testing (DST) is performed. Conventional DST includes the demonstration of the
presence of Mycobacterium tuberculosis growth in the presence of specific anti
tuberculosis drugs. The golden standard of DR-TB is solid agar methods. But
there are also some other alternatives, which are liquid culture methods. This
method has been proved to have equivalent performance with the solid agar
method. But, in many developing countries, access to DST is very limited due to
the lack of laboratory infrastructure.
Another major weakness of culture-based methods is the long delay in
obtaining DST results. It can take several weeks to get the result [6]. One possible
way to reduce the time delay is to use liquid culture. The expected time for MDRTB detection can be shorten to 35 weeks by using liquid culture [11].

New nucleic acid amplification tests (NAATs) provided an alternative with

reduced interval between sample acquisition and susceptibility result from weeks
to hours. By providing rapid DST results, this test has the potential to bring
changes to drug resistant TB epidemic in high burden countries. With faster
diagnosis, correct treatment can be started immediately and the treatment can have
better outcomes [6].
2.5 Surgical Treatment
To treat MDR-TB, a few alternatives are available. MDR-TB can be
treated with new drugs, such as bedaquiline or delamanid [11]. One of the
possible alternatives that will be explored in this paper is surgical treatment.
Surgery plays a decisive role in the overall management of MDR-TB. Surgical
treatment for MDR-TB has shown better mortality and morbidity [13].

lesions,
penetrated

Figure 2. Gross pathology of resected lung lesion.

The inside of the cavity shows caseous necrosis.
Adapted from [14]

Tuberculosis
which

are

poorly by anti

tuberculosis drugs, contain huge amount of Mycobacterium tuberculosis,

harboring actively replicating bacilli. Cavities act as huge reservoirs of
Mycobacterium tuberculosis infection and also as the likely site of the
development of drug resistance. Since the infection site cannot be reached by the
drugs, to cure the disease completely, it is vitally important to resect the cavitary
lesion and damaged lung tissue [13]. The removal of infected area of lungs by
surgery can reduce the overall organism burden in the lung [6]. By removing the
9

main area of infection, it may be possible to prevent further disease spread. This
surgical treatment can also allow medical therapy to work better [7]. Resection of
cavitary lesions, or destructive of a lobe or lung, would decrease the bacilli count,
which can improve the efficiency of medical treatment [13]. Surgery should be
done as soon as chemotherapy is felt to be not sufficient to cure the disease.
Delaying surgery and persisting with ineffective chemotherapy may enable
progression of disease, and further promote the development of drug resistance
[6].
One study has explained a case of a 26-year-old patient with XDR-TB
refractory to medical therapy. Drug susceptibility testing (DST) to first-line antiTB drugs, utilizing the agar proportion method, was performed. The result from
this test demonstrated resistance to all first-line drugs including rifampin,
isoniazid, pyrazinamide, ethambutol, and streptomycin. Another DST was
performed to test resistance to second-line anti-TB drugs. The result stated that
there were also resistances to ethionamide, kanamycin, capreomycin, ofloxacin.
After a series of treatment regimen, there was no radiological improvement.
Considering the lack of improvement and also high degree of resistance,
physicians who are in charge for this patient felt that it was unlikely that this
patient would be cured with chemotherapy alone and referred the patient for
evaluation for adjunctive surgical therapy. The patient was considered a good
operative candidate, taking into account his young adult age and no co-morbid
illnesses. Surgical resection of the patients solitary cavitary lesion was performed
as adjunctive treatment. After the surgery, the patient was continued on the same
anti-TB treatment regimen. The patient was declared cured from TB a year after
the surgery. With combination of surgery and medical therapy, a successful
outcome was achieved [14].
2.5.1 Pre-operative work up
Before the surgery, a chest CT scan should be done to evaluate the extent
of disease. A pulmonary function testing should also be done to guide surgical
resection. Ventilation perfusion scan should be done to ensure adequate
pulmonary reserve to tolerate surgery. Bronchoscopy is needed to rule out
10

endobronchial

tuberculosis,

contralateral

disease,

and

malignancy

[14].

Bronchoscopy is also needed to visualize airway [7]. Echocardiogram should be

done to rule out heart failure and pulmonary hypertension. Nutritional assessment
is also needed to ensure patient can tolerate and recover from surgery [14].

Figure 3 (left). Chest radiography

(A) Preoperative image showing left
lower lobe infiltrate (arrows). (B) One
month postoperative image, showing
clear lung fields.
Figure 4 (above). Pre-operative CT
Scan
of the
Lung
Adapted
from
[14]
Cross-sectional view showing 3x5 cm
left lung cavitary lesion.
Adapted from [14]

2.5.2 Indications for surgery

Surgery for patient with MDR-TB should be considered for patients who
have persistently positive AFB smear or sputum culture despite aggressive
chemotherapy [14]. Adjunctive lung resection may be considered for patients with
MDR-TB if the patients meet a certain criteria. The criteria include a high
probability of failure or relapse with medical therapy alone, sufficiently localized
disease for resection with adequate postoperative cardiopulmonary capacity, and
sufficient drug activity for facilitating postoperative healing of bronchial stump
[11]. The presence of complications of tuberculosis including bronchiectasis,
empyema, and hemoptysis should also be considered as an indication for surgery
[14].
2.5.3 Methods
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As has been shown by large cohort studies, the best outcomes in MDR-TB
are achieved by the use of fluoroquinolones and adjunctive surgery [13]. The most
common approach for surgical resection was through a muscle sparing
posterolateral thoracotomy [14]. The median approach has also been studied, but
offers limited exposure for left-sided resections [6]. The type of resection was
based on the extent of the pulmonary lesion [7]. The balance of removing all
affected lung and desire to preserve pulmonary function was used to determine
which type of resection was done [14]. The different types of resections
performed

included

pneumonectomy, lobectomy, segmentectomy, wedge

resection, and some combination of these procedures. Pneumonectomy is a

surgical procedure in which an entire lung is removed. Lobectomy is a surgical
procedure that removes one lobe of the lung, while removal of 2 lobes is called
bilobectomy. A wedge resection is a surgical procedure during which the surgeon
removes a small, wedge-shaped portion of the lung. This procedure can be
performed by minimally-invasive video-assisted thoracoscopic surgery (VATS) or
a thoracotomy (open chest surgery). Segmentectomy is a surgical procedure that
removes a larger portion of the lung lobe than a wedge resection, but does not
remove the whole lobe [16].
2.5.4 Post-Operative Work Ups
Postoperative individualized chemotherapy is required for MDR-TB
patients even after the removal of the most grossly involved lesions, to ensure
long-term cure [15]. Antibiotic therapy is recommended for approximately 2 years
[13]. Postoperatively, the pleural space was routinely drained with a chest tube.
Occasionally, if resection created a large residual space, a thoracoplasty can be
used to reduce the open space to help prevent further complications [14].
2.5.5 Complication
Few complications can occur after surgery in MDR-TB patients. Possible
complications are postoperative intrathoracic bleeding, bronchopleural fistula, and
empyema [15]. Wound complication is also included as one of the possible

12

complications, although minor [6]. The most common complication is

bronchopleural fistula [7].
2.5.6 Outcomes
Many studies have reported favorable outcomes of surgery for MDR-TB.
One study has found a significant association between surgical intervention and
successful outcome when compared to non-surgical treatment alone (OR 2.24,
95% CI: 1.68-2.97) [6]. Another study suggested that pulmonary resection is
curative, reported 100% conversion rate and 92,3% cure rate. But, this study also
stated that ways must be found to reduce the morbidity, which was found to be
23% [13]. Another study reported that sputum negativity was achieved in 93% of
patients [15].
Patients with MDR-TB seem to have better outcomes compared to patients
with XDR-TB. One study reported that favorable outcomes were achieved in 82%
patients, including 90% in those with MDR-TB and 67% in XDR-TB patients [7].

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III.

CONCLUSION

III.1 Conclusion
Tuberculosis has been a major global health problem for decades. Now,
the problem has grown. Inappropriate treatment of TB has lead to multi-drug
resistant Tuberculosis (MDR-TB). MDR-TB indicates a resistance to at least 2 of
most effective antituberculous drugs, which are isoniazid and rifampicin. A more
extreme type of MDR-TB is called extensively drug-resistant (XDR) TB. Not
only isoniazid and rifampicin, patients with XDR-TB are also resistant to any
fluoroquinolone and at least one of the three second-line injectable drugs. Both
MDR-TB and XDR-TB has shown rapid growth in global population.
One of the challenges in the fight against drug resistant TB is diagnostic
method. Drug-susceptibility testing (DST) is the main diagnostic laboratory
testing for drug resistant TB. However, this method has some weaknesses, such as
the limited access to this test in developing countries and long delay in obtaining
results. Alternatives that offer better diagnostic testing are using liquid culture
instead of solid or using a newly developed nucleic acid amplification test.
MDR-TB can be treated by surgical treatment to remove infected lung
areas. Surgery is done to remove tuberculosis lesions that contain huge amount of
Mycobacterium tuberculosis and cannot be penetrated by the drugs. Resection of
lesions would decrease the bacilli count, which can improve the efficiency of
medical treatment. Many studies have shown a good outcome resulting from
combination of chemotherapy and surgical treatment.
III.2 Recommendation
Drug-resistant Tuberculosis is a serious problem that needs to be put as a
priority. Development in diagnostic methods is really essential to make better
treatment possible. A diagnostic method that is easy to perform, accessible by
many, and able to provide result in short amount of time, is really needed.
Adjunctive surgery for MDR-TB should be considered as a possible
treatment. Studies have shown that surgery can bring good outcomes for patient
with MDR-TB. A good combination of surgery and medication should be
developed further to achieve best treatment regimen for patients with MDR-TB.
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