Mechanisms of Resistance

Multi-drug-resistant tuberculosis (MDR-TB) is a type of tuberculosis that often develops in patients who do not adhere to or complete the proper treatment for regular TB. This can occur when a physician does not prescribe a proper treatment regimen, or when a patient is unable to stick to the lengthy therapy. Once a strain of MDR-TB develops, it can be spread to other people just like "normal" TB.

Drug resistance is more common in people who:

• have spent time with someone with drug-resistant TB disease
• do not take their medicine regularly
• do not take all of their prescribed medicine
• develop TB disease again, after having taken TB medicine in the past
• come from areas where drug-resistant TB is common ( Russia , former USSR , Southeast Asia , Latin America , Haiti , Dominican Republic , and the Philippines )

 The emergence and spread of multidrug-resistant (MDR) Mycobacterium tuberculosis (MT) represents a worldwide health care problem because of the difficulty in treating these infections. Development of drug resistance in MT arises mainly by mutation of chromosomal genes. Various strategies and programmes are carried out on mass to educate and implementation of full treatment on TB so that to avoid MDR such as DOTS. 

MDR-TB and the Mechanisms of Resistance

The current mechanism for the emergence of multiresistants stains, which is a major health problem in our days, is not due to new mechanisms of resistance, but related to mechanisms that we already know (for M. tuberculosis), i.e., mutations on target genes for the antibiotics. The resistance to isoniazid (the most common resistance to first line drugs[get the link to chaitanyas]) is most commonly related to a change on the kat G gene (catalase/peroxidase), and is also responsible for resistance to ethionamide. Resistance to rifampicin is associated to mutation on rpo B gene, and to streptomycin to the genes rps L and rrs. Resistance to rifampicin is most found in association to resistance to isoniazid.

source: Canetti, G. et alli. Bull. WHO, 1969

Problem of multi drug resistant tuberculosis (MDR-TB)

One of the classical threats of the tuberculosis epidemic has been the MDR-TB. Drug resistance arises in Mycobacterium tuberculosis (MTB) generally by mutation of chromosomal genes, but despite combined drug therapy the spread of multi-drug-resistant (MDR) strains is alarmingly increasing.

Use, and often abuse or misuse, of antimicrobial agents has encouraged the evolution of bacteria toward resistance, resulting often in therapeutic failure. There are evidences that bacteria have the ability to adapt to this deficit and recover fitness on serial passage1. Resistance to antituberculosis drugs has been a problem since the era of chemotherapy began. After dramatic outbreaks of MDR-TB in the early 1990s, resistance became recognized as a global problem. MDR-TB now threatens the inhabitants of countries in Europe, Asia, Africa, and the Americas too.

An understanding of the molecular basis of drug resistance may contribute to the development of new drugs. Management of MDR-TB relies on prompt recognition and treatment with at least 3 drugs to which an isolate is susceptible. The roles of drug containing environments, and the immunological status of the host and bacterial molecular mechanisms of development of drug resistance to M. tuberculosis have been examined and results are helpful in implementation of modified drug regimens in tuberculosis control programmes.

Multidrug resistant strains of M. tuberculosis seriously threaten tuberculosis control and prevention efforts. Molecular studies of the mechanism of action of antitubercular drugs have elucidated the genetic basis of drug resistance. Drug resistance in M. tuberculosis has been primarily attributed to the mutations in the drug target genes, however, the presence of efflux pumps in clinical MDR isolates cannot be ruled out. These mutations lead either to an altered target or to a change in titration of the drug.

A diverse array of strategies is already available to assist in rapid detection of drug resistance-associated gene mutations. In spite of remarkable advances in this area, much remains to be learned about the molecular genetic basis of drug resistance in M. tuberculosis.

During the last decade, there has been a marked increase in the number and gravity of tuberculosis cases both in developing countries and in industrialized nations. One of the more insidious consequences of this resurgence has been the recent emergence of nosocomial transmission of multi drug resistant strains of M. tuberculosis, thus creating untreatable forms of the disease and these strains may become widespread. That the various clinical isolates of M. tuberculosis are geographically partitioned at the global level.

ABOUT XDR(Extreme Drug Resistance)

XDR –TB is been defined as strains that are not resistant to the frontline drugs ,but also there are more of the six classes of second line drugs.Resistance to the first line drug(link to chaitanya) is stated as MDR, while reistanc to the second line drugs(llink to chaitanya) emerging has made the matter worse.

When multidrug resistant TB arises when the bacteria causing TB is resistant to atleast isoniazid and rifampcin,the treatment with second line drugs makes it possible but that is not the case with extremely drg resistant TB.

But there is some good news that the mutations responsible for XDR-TB are specific for resistance to certain drugs rather than reflecting a fundamental change in the organisms behaviour.

“XDR-TB has been identified in all regions of the world but is most frequent in the countries of the former Soviet Union and in Asia.In the US four percent of MDR-TB cases met the criteria for XDR-TB”,noted WHO.This was based on the survey carried by Centre for Disease Control and Prevention(CDC)in Atlanta .

The STRAIN

XDR-TB has been found to be very virulent too.The outbreak was seen recently in the KwaZula-Natal province in South Africa.Of the 53 who tested positive for XDR-TB,52 died within 25 days ,many of whom were HIV positive.

The combination is thus deadly for the virulent nature of the bacteria no medicines are currently available to fight them the drugs to fight can be expected only after 6 yrs.

PROBLEM OF XDR TB

Treatment cost for MDR is still possible through the cost is prohibitive .The treatment of XDR-TB can be 40 times required than for the MDR-TB.