CAPTER 1

INTRODUCTION

1.1 BACKGROUND

As recently as 10 years ago, few options for treat- ment and care were available to
those affected by multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant
tuberculosis (XDR-TB).a Later, accumulating evidence indicated that the pro- grammatic
management of M/XDR-TB was not only feasible but also cost effective. The World Health
Organization (WHO) has recognized M/XDR-TB as a major challenge to be addressed as
part of the Stop TB strategy, launched in 2006. In April 2009, WHO convened a ministerial
meeting of countries with a high burden of MDR-TB in Beijing, China, pav- ing the way in
May 2009 for the 62nd World Health Assembly to adopt resolution WHA62.15 on pre-
vention and control of MDR-TB and XDR-TB. The resolution urges Member States to take
action on multiple fronts towards achieving universal access to diagnosis and treatment of
M/XDR-TB by 2015.1,2
 CHAPTER II

THEORITICAL REVIEW

2.1 DEFENITION

MDR TB is generally taken to involve tuberculosis caused by an organism resistant to

at least isoniazid and rifampin, the cornerstones of tuberculosis theraphy. MDR TB poses
problems from both a clinical and public health perspective. It is difficult to treat and
generally requires a minimum of 18 to 24 monts of therapy. Resection of affected tissues may
be required.2,3,4

2.2 ETIOLOGY

Drug resistance is largely man-made and is a consequence of suboptimal regimens

and treatment interruptions. Clinical errors that commonly lead to the emergence of drug
resistance include: failure to provide effective treatment support and assurance of adherence;
inadequate drug regimens; adding a single new drug to a failing regimen; and failure to
recognize existing drug resistance. In addition, co-morbid conditions associated with reduced
serum levels of antituberculosis drugs (e.g., malabsorption, rapid transit diarrhea, use of
antifungal agents) and interruptions caused by adverse drug reactions may also lead to the
acquisition of drug resistance. Programmatic causes of drug resistance include drug shortages
and stock-outs, admin- istration of poor-quality drugs and lack of appropriate supervision to
prevent erratic drug intake. Transmission of drug-resistant strains of M. tuberculosis has been
well described in health care facilities, congregate settings, and in susceptible populations,
notably HIV-infected persons. However, multidrug-resistant (MDR) tuberculosis
(tuberculosis caused by organisms that are resistant to at least isoniazid and rifampicin) may
spread in the population at large as was shown in data from a number of countries, including
China, the Baltic States, and countries of the former Soviet Union.1,3,4

Drug resistance surveillance data suggest that more cases of MDR tuberculosis occur
among new cases of tuberculosis than among previously treated cases, although the pro-
portion in the previously treated group is much higher.164 In 2010, 30 countries with anti-
tuberculosis drug resistance surveillance data were each estimated to have more than 700
multidrug-resistant tuberculosis cases among their notified cases each year. Patients who had
not had previous treatment comprised a median of 54% of the MDR cases. The occurrence of
MDR TB in a new patient is an indication that MDR organisms are spreading in a
community. Although case-finding efforts for MDR tuberculosis should first prioritize
previously treated patients for drug sensitivity testing, identification of all MDR TB cases
will require screening for drug resistance in a much wider group of pat patients.1,4,5

The strongest factor associated with drug resistance is previous antituberculosis

treatment, as shown by the WHO/IUATLD Global Project on Anti-TB Drug Resistance
Surveil- lance, started in 1994. In previously treated patients, the odds of any resistance are at
least 4-fold higher, and that of MDR TB at least 10-fold higher, than in new (untreated)
patients. Patients with chronic tuberculosis (sputum-positive after re-treatment) and those
who fail treatment (sputum-positive after 5 months of treatment) are at highest risk of having
MDR tuberculosis, especially if rifampicin was used throughout the course of treatment.
Persons who are in close contact with confirmed MDR tuberculosis patients, especially
children and HIV-infected individuals, also are at high risk of being infected with MDR
strains. In some closed settings prisoners, persons staying in homeless shelters and certain
categories of immigrants and migrants are at increased risk of MDR tuberculosis. These
factors are summarized and presented in descending order of level of risk in Table.2,3

By the mid-1990s, most countries participating in the global survey of

antituberculosis drug resistance registered cases of MDR tuberculosis. Not surprisingly, in
2006, exten- sively drug-resistant (XDR) tuberculosis (defined as tuberculosis caused by M.
tuberculo- sis resistant to at least isoniazid and rifampicin, as well as to any one of the
fluoroquinolo- nes and to at least one of three injectable second-line drugs [amikacin,
capreomycin, or kanamycin]) was described and rapidly recognized as a serious emerging
threat to global public health, as well as being deadly in the initial outbreak. Subsequent
reports have identified XDR tuberculosis in all regions of the world and, to date, treatment
outcomes have been significantly worse than MDR tuberculosis outcomes. In one cohort
from KwaZulu-Natal, 98% of XDR tuberculosis patients co-infected with HIV died, with a
median time of death of only 16 days from time of specimen collection. The two strongest
risk factors for XDR tuberculosis are:

1. Failure of a tuberculosis treatment which contains second-line drugs

including an injectable agent and a fluoroquinolone.
2. Close contact with an individual with documented XDR tuberculosis or with
an indi- vidual for whom treatment with a regimen including second-line
drugs is failing or has failed.

More recently, strains of M. tuberculosis with resistance patterns beyond XDR tuberculo- sis
have been described. The available evidence suggests that treatment outcomes are worse
when resistance patterns become more complicated.1,3,4
Assessing risk for drug resistance

Multidrug-resistant 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 during the course of
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 agents (amikacin,
kanamycin and/or capreomycin). These forms of TB do not respond to the standard
six- month 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. Patient with MDR
TB remain smear- and culture- positive longer than patients with susceptible tuberculosis
even when treated with two or more effective agent. The greatest risk factor for the presence
of MDR TB is a history of prior treatment for tuberculosis. Besides those with such a history,
others who are at increased risk for drug resistance include persons from foreigh countries
and american communities where are high rates of MDR TB. in a nationwide survey of drug
resistance, 18 percent of M.tuberculosis isolates from foreigh-born persons had resistance to
at least one antituberculous medication2,4,5
2.3 DESIGNING A TREATMENT REGIMEN

This section describes the methods for designing a treatment regimen. It applies to
standardized, empirical and individualized regimens.

General principles The following are the basic principles involved in any regimen design:

Regimens should be based on the history of drugs taken by the patient.

Drugs commonly used in the country and prevalence of resistance to first- line and
second-line drugs should be taken into consideration when designing a regimen.
Regimens should consist of at least four drugs with either certain, or almost certain,
effectiveness. If the evidence about the effectiveness of a certain drug is unclear, the
drug can be part of the regimen but it should not be depended upon for success. Often,
more than four drugs may be started if the susceptibility pattern is unknown,
effectiveness is questionable for an agent(s) or if extensive, bilateral pulmonary
disease is present.
When possible, pyrazinamide, ethambutol and fluoroquinolones should be given once
per day as the high peaks attained in once-a-day dosing may be more efficacious.
Once-a-day dosing is permitted for other second-line drugs depending on patient
tolerance, however ethionamide/protionamide, cycloserine and PAS have traditionally
been given in split doses during the day to reduce adverse effects.
The drug dosage should be determined by body weight. A suggested weightbased
dosing scheme is shown in Annex 2.
Treatment of adverse drug effects should be immediate and adequate in order to
minimize the risk of treatment interruptions and prevent increased morbidity and
mortality due to serious adverse effects (see Chapter 11).
An injectable agent (an aminoglycoside or capreomycin) is used for a minimum of six
months and at least four months past culture conversion (see Section 7.9 on duration
of injectable use).
The minimum length of treatment is 18 months after culture conversion (see Section
7.10 on duration of treatment).
Each dose is given as directly observed therapy (DOT) throughout the treatment. A
treatment card is marked for each observed dose. 58
DST of drugs with high reproducibility and reliability (and from a dependable
laboratory) should be used to guide therapy. It should be noted that the reliability and
clinical value of DST of some first-line and most of the second-line antituberculosis
drugs have not been determined (see Section 7.6 and Chapter 6). DST does not predict
with 100% certainty the effectiveness or ineffectiveness of a drug (37). DST of drugs
such as ethambutol, streptomycin and Group 4 and 5 drugs does not have high
reproducibility and reliability; these guidelines strongly caution against basing
individual regimens on DST of these drugs.
Pyrazinamide can be used for the entire treatment if it is judged to be effective. Many
DR-TB patients have chronically inflamed lungs, which theoretically produce the
acidic environment in which pyrazinamide is active. Alternatively, in patients doing
 well, pyrazinamide can be stopped with the injectable phase if the patient can
continue with at least three certain, or almost certain, effective drugs.
Early DR-TB detection and prompt initiation of treatment are important factors in
determining successful outcomes.1
 CHAPTER III

CONCLUSION

3.1 CONCLUSION

Drug resistance is largely man-made and is a consequence of suboptimal regimens

and treatment interruptions. Clinical errors that commonly lead to the emergence of drug
resistance include: failure to provide effective treatment support and assurance of adherence;
inadequate drug regimens; adding a single new drug to a failing regimen; and failure to
recognize existing drug resistance. In addition, co-morbid conditions associated with reduced
serum levels of antituberculosis drugs (e.g., malabsorption, rapid transit diarrhea, use of
antifungal agents) and interruptions caused by adverse drug reactions may also lead to the
acquisition of drug resistance. Programmatic management of DR-TB is a complex health
intervention, and no one strategy will fit all situations. Programme managers need to consider
the epidemiological, financial and operational factors when deciding which strategy to use.
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extensively drug-resistant tuberculosis by 2015,Avenue Appia, CH-1211 Geneva 27,
Switzerland.2011
World Health Organization
2. Multidrug-resistant tuberculosis (MDR-TB),WHO,October 2013 Update.
3. MDR-TB INDICATORS A minimum set of indicators for the programmatic
management of MDR-TB in national tuberculosis control programmes, World Health
Organization,2010
4. International Standards For Tuberculosis Care, 3RD EDITION, 2014
5. Guidance for nationa tuberculosis programmes on the management of tuberculosis in
children,second edition,2014