(SEMINAR) DRUG RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS

ABSTRACT

This study reviewed drug resistance in mycobacterium tuberculosis. Tuberculosis (TB) is a serious public health problem worldwide. Its situation is worsened by the presence of multidrug resistant (MDR) strains of Mycobacterium tuberculosis, the causative agent of the disease. In recent years, even more serious forms of drug resistance have been reported. A better knowledge of the mechanisms of drug resistance of M. tuberculosis and the relevant molecular mechanisms involved will improve the available techniques for rapid drug resistance detection and will help to explore new targets for drug activity and development.Tuberculosis (TB) remains to be a serious health problem worldwide.

There is an increased transmission of Mycobacterium tuberculosis strains with drug resistance, hence complicating TB control. The deciphering of the M. tuberculosis genome, together with the implementation of new molecular biology tools, has allowed the identification of changes in nucleic acid sequences with a functional impact. These mutations have become important in the design of early”diagnostic kits to identify the resistance profile of M. tuberculosis. Since the conventional methods to determine the identity of M. tuberculosis strains based in cultures are laborious, time”consuming and performed by specialized technicians, the result is generated until 4 months after receiving the samples.

During this time, patients with TB are not adequately treated, and resistant strains may be transmitted to the rest of the population. In this chapter, we describe the most relevant mutations in genes associated with drug resistance in M. tuberculosis, the analysis of gene expression to identify new markers of drug resistance strains, and the development of new antituberculosis drugs against drug”resistant strains.

CHAPTER ONE

Introduction

1.1 Background of the study

The discovery of anti-tuberculosis drugs in the 1940s followed by combination chemotherapy made tuberculosis a curable disease. In the developed countries, effective treatment and surveillance reduced tuberculosis dramatically with high hopes of total eradication (Raviglioneet al., 1992; Raviglioneet al., 1995). However, in the 1980s, it was realized that tuberculosis had not only ceased to decline in the developed countries, notably the USA, but was actually increasing, particularly in major cities (Raviglioneet al., 1995). It was also soon realized that the disease was out of control and increasing at an alarming rate across most of the poorest regions of the world especially Africa due to HIV/AIDS (Raviglioneet al., 1992; WHO, 2009).

Despite aggressive international efforts, tuberculosis remains a leading infectious cause of death, with an estimated 8.6 million incident cases per year. In 2012, an estimated 1.3 million people died from the disease. These death rates, however, only partially depict the global TB threat; more than 80% of TB patients are in the economically productive age of 15 to 49 years (WHO, 2013).

Global tuberculosis control efforts have been threatened by the emergence of multidrug resistant tuberculosis (MDR-TB). MDR-TB is defined as strains of Mycobacterium tuberculosis which show high level resistance to both isoniazid and rifampicin, with or without resistance to other anti TB drugs (WHO, 2013). MDR-TB is estimated to cause 4% of new tuberculosis cases in the developing world. Patients infected with MDR strains are not only difficult to cure but also more likely to remain sources of infection for a longer period of time than those with drug susceptible organisms. MDR-TB requires longer duration of treatment (up to 2 years) to achieve cure, in comparison with 6 month treatment for drug susceptible TB, lower cure rates and even higher default rates.

The cost of drugs to treat an MDR-TB case can be up to 100 times more expensive than the cost of treating a drug susceptible TB case (Leimane and Leimans, 2006). Because of its increasing prevalence MDR-TB is now subdivided into basic MDR-TB, with resistance only to rifampicin and isoniazid, and extensively drug resistant TB (XDR-TB), with a similar resistance pattern but with resistance to one or more additional first and/or second line drugs.Various perturbations in the individual drug target genes are responsible for the genesis of anti-TB drugs resistance. Rifampicin resistance has been shown to be caused by a change in the β-subunit of DNA dependent RNA polymerase, which is encoded by the rpoβ gene. More than 95% of rifampicin resistant strains are associated with mutations within an 81-base pair region of the rpoβ gene, which is termed rifampicin resistance determinant region (Telentiet al., 1993; Traoreet al., 2000; Sharma and Mohan, 2006).

On the contrary, resistance to isoniazid is due to mutations at one of two main sites, in either the katGor inhAgenes (Zhang et al.,1992; Piateket al., 2000). These mutations are not directly connected, and so separate mutations are required for organisms to change from a drug susceptible isolate to MDR-TB. Furthermore, rifampicin resistance has been considered to be a surrogate marker for checking multidrug resistance in clinical isolates of M. tuberculosis since rifampicin resistance is often accompanied by resistance to isoniazid (Traoreet al., 2000; Sharma and Mohan, 2006).

Drug resistance in M. tuberculosis occurs by random, single step, spontaneous mutation at a low but predictable frequency, in large bacterial populations. The accurate diagnosis of MDR-TB requires a positive culture of M. tuberculosis and drug susceptibility testing. Previous drug treatment is the largest single risk factor for the presence of MDR-TB. There is a strong suspicion of drug resistance, including MDR-TB, in persons with a history of prior treatment or in treatment failure cases.

The emergence of drug resistance in M. tuberculosis has been associated with a variety of management, health provider and patient related factors. These include

Deficient or deteriorating TB control programmes resulting in inadequate administration of effective treatment;
Poor case holding, administration of sub-standard drugs, inadequate or irregular drug supply and lack of supervision; (iii) ignorance of health care workers in epidemiology, treatment and control;
Improper prescription of regimens; (v) interruption of chemotherapy due to side effects;
Non-adherence of patients to the prescribed drug therapy;
Availability of anti-TB drugs across the counter, without prescription;
Massive bacillary load;
Illiteracy and low socio economic status of the patients;
The epidemic of HIV infection;
Laboratory delays in identification and susceptibility testing of M. tuberculosis isolates;
Use of nonstandardized laboratory techniques, poor quality drug powders and lack of quality control measures; and
Use of anti-TB drugs for indications other than tuberculosis (Paramasivanand Venkataraman, 2004).

Although some individuals who have not had previous TB treatment are infected by MDR-TB, this is not the case for most patients. Many new cases of MDR-TB are created each year by a combination of physician error and poor patient compliance with treatment, which turn fully susceptible organisms, or those with less complex resistance patterns, into MDR-TB.

1.2 Statement of the problem

The global burden of TB remains enormous. In 2012, there were an estimated 8.6 million incident cases of TB and 1.3 million people died from the disease. Among these deaths there were an estimated 170,000 from MDR-TB. General problem of MDR-TB with an estimated 450,000 incidence cases worldwide annually has been recognized since the first World Health Organization (WHO) global survey on drug resistance in the late 1990s (WHO, 2013). MDR-TB has reached alarming levels worldwide with the emergence of strains that are virtually untreatable with the existing drugs. Drug-resistant strains, along with HIV/AIDS, are causing the biggest challenge to efficient management and control of TB. The report of an outbreak of extensively drug resistant TB (XDR-TB) in South Africa (Gandhi et al., 2006), with its extremely high case fatality rate, has drawn wide attention.

It has been indicated that MDR-TB is likely to be more prevalent in Africa than previous reports indicated. The latest WHO global report on anti-tuberculosis drug resistance in the world was produced in 2008 and published in a 2010 WHO report on MDR-TB epidemic. A systematic literature review of evidence about mortality associated with MDR-TB was commissioned by WHO in 2013. The results have been used to produce global estimates of MDR-TB incidence and mortality in 2012. The estimate of mortality due to MDR-TB is slightly higher than before, while the incidence is similar to the previous estimate (WHO, 2013).

1.3 Justification of the study

Five of 13 countries with the highest incidence rates of TB per capita are in Africa. According to the WHO global report on anti-tuberculosis drug resistance in the world, MDR-TB strains have emerged in all regions of the world (WHO, 2013). The overwhelming burden of MDR-TB is in high burden resource poor countries. The diagnosis depends on confirming the drug susceptibility pattern of isolated organisms, which is often only possible in resource rich settings. Lack of comprehensive national DRS data from all countries in Africa is a barrier to understanding the magnitude of prevalence and incidence of MDR-TB.

WHO (2013) reported Nigeria as the thirteenth in the list of the 22 highest incidence countries on the basis of numbers of new cases of TB. Also, Nigeria is considered as having moderate rate of MDR-TB. According to the National drug resistance survey in 2012, the prevalence rate of MDR-TB in Nigeria is about 2.9%. However, MDR-TB in Africa, including in Nigeria, is more prevalent than previously reported.

Given the limited health care funding and substantial incidence of HIV in Nigeria, even a relatively low but increasing tide of MDR-TB can lead to disastrous consequences for the country. The availability of drugs on the open market and a private sector that delivers drugs to the population in an unregulated fashion in Nigeria could also be factors that might favour development of MDR-TB. There is very little information on the prevalence of MDR-TB in Nigeria.

1.4 Objectives of the study

The objectives of the study are:

To provide an overview of tuberculosis
To review drug resistant in mycobacterium tuberculosis

…

CHAPTER TWO

2.0 Literature Review

2.1 Introduction

The review of relevant literature is the main topic of this chapter. A literature review covers theoretical and methodological contributions to a certain issue in addition to the state of knowledge at the time of writing. It provides information about the state of the art in relation to the subject you are writing about. It examines the body of work on the chosen subject. The literature evaluation in this study comprises the …

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Preliminary Pages,
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TABLE OF CONTENTS
PRELIMINARY PAGES

Title page
Approval page
Dedication
Acknowledgement
Table of Contents
Abstract
CHAPTER ONE
1.0 Introduction
1.1 Background of the study
1.2 Statement of the problem
1.3 Justification of the study
1.4 Objectives of the study
CHAPTER TWO
2.0 Literature Review
2.1 History of Tuberculosis
2.2 The genus Mycobacterium
2.2.1 Nutritional requirements and growth
2.2.2 Susceptibility to physical and chemical agents
2.2.3 Habitats
2.3 The Mycobacterium tuberculosis complex (MTBC)
2.4 Pathogenesis and clinical presentations of TB
2.5 Global TB burden
2.6 Drug resistant tuberculosis
CHAPTER THREE
3.0 Conclusion And Recommendations
3.1 Conclusion
3.2 Recommendations
REFERENCES

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