MDR-TB

HOW TO PREVENTED AND MANAGE OF MDR-TB

INTRODUCTION
Tuberculosis (TB) is a medical, social, and economic disaster of immense magnitude that is occurring the world over.[1] Strains of Mycobacterium tuberculosis that are resistant to both isoniazid and rifampicin with or without resistance to other drugs have been termed multidrug-resistant strains. Isoniazid and rifampicin are keystone drugs in the management of TB. While resistance to either isoniazid or rifampicin may be managed with other first-line drugs, multidrug-resistant TB (MDR-TB) demands treatment with second-line drugs that have limited sterilizing capacity, and are less effective and more toxic. MDR-TB is one of the most worrisome elements of the pandemic of antibiotic resistance.[2,3]


EPIDEMIOLOGY
This is the fourth report of the WHO/IUATLD Global Project on Anti-Tuberculosis Drug
Resistance Surveillance. The three previous reports were published in 1997, 2000 and 2004 and included data from 35, 58 and 77 countries, respectively. This report includes drug susceptibility test (DST) results from 91,577 patients from 93 settings in 81 countries and 2 Special Administrative Regions (SARs) of China collected between 2002 and 2006, and representing over 35% of the global total of notified new smear-positive TB cases. It includes data from 33 countries that have never previously reported. New data are available from the following high TB burden countries: India, China, Russian Federation, Indonesia, Ethiopia, Philippines, VietNam, Tanzania, Thailand, and Myanmar. Between 1994 and 2007 a total of 138 settings in 114 countries and 2 SARs of China had reported data to the Global Project [4].

The population weighted mean of MDR-TB among all TB cases from the 114 countries and 2 SARs of China that have reported to the global project is 5.3% (95% CLs, 3.9-6.6), but ranges from 0% in some western European countries to over 35% in some countries of the former Soviet Union. In terms of proportion, the countries of the former Soviet Union are facing a serious and widespread epidemic where the population weighted average of countries reporting indicates that almost half of all TB cases are resistant to at least one drug and every fifth case of TB will have MDR-TB. MDR-TB cases in this region have more extensive resistance patterns including some of the highest proportions of XDR-TB.[4].

CAUSES OF MDR_TB
“Spigots” contributing to the problem of antituberculous drug resistance
1. Incomplete or inadequate therapy selects drug-resistant mutants of M. tuberculosis
2. Prolonged infectiousness of patients due to delayed diagnosis of MDR and to the
absence of effective therapy allows ongoing transmission of drug-resistant strains to
susceptible contacts
3. Patients sick with drug-resistant TB treated with short-course chemotherapy are less
likely to be cured, diminishing the epidemiologic effect of such treatment on
transmission
4. Patients sick with drug-resistant TB exposed to short-course chemotherapy can acquire
Further resistance through inadvertent monotherapy (“the amplifier effect”)
5. HIV co-infection can shorten the period from TB infection to disease, also leading to
Lengthier periods of infectiousness

Inadequate Treatment Adherence:
Nonadherence to prescribed treatment is often underestimated by the physician and is difficult to predict. In the West, demographic factors such as age, sex, marital status, education level, and socioeconomic status have not been found to correlate with the degree of treatment adherence. On the other hand, certain factors such as psychiatric illness, alcoholism, drug addiction, and homelessness do predict non adherence to treatment.[3] The directly observed treatment, short course (DOTS) strategy, which has been endorsed by the WHO as the only effective way to control TB, has to some extent addressed these problems.[6,7]

MANAGEMENT

Principles of Management
When MDR-TB is suspected on the basis of history or epidemiologic information, the patient’s sputum must be subjected to culture and anti-TB drug-sensitivity testing. These patients may be started on WHO category II treatment [10] (under program conditions/DOTS strategy) or the regimens employing various drugs (Table 3), such as those suggested by the American Thoracic Society, the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America [9] pending sputum culture report.
Further therapy is guided by the culture and sensitivity report. These guidelines clearly mention that a single drug should never be added to a failing regimen. Furthermore, when initiating treatment, at least three previously unused drugs must be employed to which there is in vitro susceptibility.[9,10]

Need for Standard Definitions
No randomized controlled trials exist addressing the issue of the optimal management strategy for MDR-TB. As in the case with the DOTS strategy, the systematic study of the efficacy of DOTS-Plus regimens requires the standardization of definitions for MDR-TB case registration and treatment outcomes.

DOTS-Plus Strategy
DOTS is a key ingredient in the TB control strategy. In populations in which MDR-TB is endemic, the outcome of the standard short-course regimen remains uncertain.[11].
Probable reduction in level of drug-resistance after treatment outcome following DOTS implementation 10 years (1991-2000) in one-half of China’s population, were excellent and improved over time. Overall, the cure rate was 95% and 90% for new and previously treated (relapse and other retreatment) cases, respectively (Table 1). From the first to the sixth year of DOTS implementation, the cure rate for both new and previously treated cases improved, while the treatment failure rate and death rate both decreased. Roughly two-thirds of the eventual improvement in treatment outcomes took place between the first and second year of DOTS implementation. For example, the percentage of treatment failure among new cases declined from 2.8% to 0.5% over the first six to eight years of DOTS implementation, but this percentage declined from 2.8% to 1.2% during the first year alone.[12].

As a consequence, there have been calls for well-functioning DOTS programs to provide additional services in areas with high rates of MDR-TB. In order to promote the programmatic treatment of MDR-TB in low-income and middle-income countries that have adopted the DOTS strategy, the WHO and its international partners have been evolving the “DOTS-Plus for MDR-TB programs” (Table 5) since 1998.[11,13].
The WHO has also established a unique partnership known as the Green Light Committee to lower the prices of and to increase control over second-line anti-TB drugs. The DOTS-Plus strategy of identifying and treating patients with MDR-TB appears to have the
potential to be effectively implemented on a nationwide scale even in a setting with limited resources.[5].

The results from the retrospective study [14] designed to assess treatment outcomes for the first full cohort of MDR-TB patients (n _ 204), who were treated under the Latvian DOTS-Plus strategy following WHO guidelines, have been encouraging; 66% patients were cured or completed therapy, 7% died, 13% defaulted, and 14% did not respond to
treatment. Data on adverse drug reactions (ADRs) collected from five DOTS-Plus sites in Estonia,Latvia, Peru (Lima), the Philippines (Manila), and the Russian Federation (Tomsk Oblast)[15] showed that, among 818 patients enrolled for MDR-TB treatment, only 2% of patients stopped treatment and 30% required removal of the suspected drugs
from the regimen and use of alternative drugs due to ADRs. These findings indicate that ADRs are manageable in the treatment of MDR-TB even in resource-limited settings provided that standardized management strategies are followed.

Prevention of Transmission of MDR-TB
As TB poses a significant risk to health-care workers, doctors, and other patients, recommendations such as those issued by the WHO [16]65 and the CDC in Atlanta, GA,[17]66 regarding the prevention of the transmission of TB in hospitals, workplaces, and institutional settings should be implemented wherever it is feasible.


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Dr.Yusrizal Djam’an Saleh SpP.FCCP