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

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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

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CONTENT LIST

Foreword…………………………………………………………………… i

Content List………………………………………………………………... ii

I. INTRODUCTION

1.1 Background……………………………………………………… 1

1.2 Problem Identification…………………………………………... 2

1.3 Aims…………………………………………………………….. 2

1.4 Benefits…………………………………………………………. 2

II. CONTENT

2.1 Definition……………………………………………………….. 3

2.2 Classification…………………………………………………… 4

2.3 Epidemiology…………………………………………………… 4

2.4 Diagnostics……………………………………………………… 5

2.5 Surgical Treatment……………………………………………… 6

III. CONCLUSION

3.1 Conclusion……………………………………………………… 11

3.2 Recommendation………………………………………………… 11

References 12

Appendix 14

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I. 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

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].

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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.

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.

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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 with organization of

lymphocytic predominant cellular

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 anti-

tuberculosis drugs [4]. Drug resistant TB is a result of inappropriate treatment of

TB, whether due to prescribing error or to patient’s 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].

Patient’s 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

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/ParaSites2006/TB_Diagnosis/Current%20Diagnostic%20Techniques.html

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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 drug-

resistant 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

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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 MDR-

TB. 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

MDR-TB 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 drug-

resistant 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 MDR-

TB detection can be shorten to 3–5 weeks by using liquid culture [11].

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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].

Tuberculosis

lesions, which are

penetrated 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

Figure 2. Gross pathology of resected lung lesion.The inside of the cavity shows caseous necrosis.Adapted from [14]

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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 anti-

TB 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 patient’s 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

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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].

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

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

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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

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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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