Defining MDR- and XDR-TB

Multidrug-resistant tuberculosis (MDR-TB) is defined as TB that is resistant to both isoniazid [INH] and rifampicin [RMP], two of the first-line drugs used in treating smearpositive pulmonary tuberculosis. Extensively drug-resistant tuberculosis (XDR-TB) is defined by the WHO as MDR-TB with additional resistance to any fluoroquinolone (FQ) and to at least one of three injectable second-line anti-tuberculosis drugs used in treatment (capreomycin [CPM], kanamycin [KM] or amikacin [AMK]).

Some 440,000 cases of multidrug-resistant tuberculosis (MDR-TB) are identified each year, causing at least 150,000 deaths from a disease that should be curable. Extensively drugresistant TB, which has an even higher fatality rate, has now been reported in more than 65 countries.

Drug-resistant TB is the end result of a number of different failures, each of which, on its own, is solvable with existing tools. The Union offers technical assistance in MDR-TB in the field to more than 15 countries yearly and has developed a package, including this technical assistance, training and research to support countries in implementing and developing an MDR-TB project. To address all of the issues and stop the spread of this disease requires a comprehensive, multi-pronged strategy, such as The Union has developed.

When TB is misdiagnosed or the treatment is poorly managed, the doors open to drug resistance.
Consequently training for people at every level of the health care system is central to The Union's approach. More than 300 people including physicians from 35 countries participated in MDR-TB training offered by The Union in 2010. These international and national courses in English, French or Spanish train clinicians to manage MDR-TB cases and cover questions ranging from logistics and procurement to ethics and human rights.

Patients who do not correctly take the medicines required to complete their TB treatment are at high risk for developing drug-resistant tuberculosis and passing on these new strains.
Strong programmes for case detection, diagnosis and patient monitoring are all critical to avoid this scenario. At the request of an NTP, The Union helps review plans, procedures, policies and systems and makes suggestions for improvement. In recognition of the pivotal role of laboratories in diagnosing and monitoring drug-resistant strains of the disease, The Union has also helped develop an international network of TB reference laboratories.

Use of poor quality medicines and drug shortages are also leading causes of drug-resistant TB.

If the quality of first-line TB drugs is not assured or the supply is not adequate to meet the needs of those in treatment patients will not be cured and may develop MDR-TB. They will then require treatment with the more expensive second-line drugs (SLD). The Union works closely with NTPs to support them in the implementation of best practices for ordering, storing and distributing medicines, as well as to assure the quality of the medicines selected for national procurement and to monitor their quality.

Treating drug-resistant TB is much more expensive and can take up to two years creating a strain on both patients and health systems.
Through its operational research and clinical trials programmes, The Union continually seeks new solutions to issues of prevention, treatment and control. The Union also collaborates with international working groups, such as the Green Light Committee, and publishes recommendations on these issues.

Multidrug-Resistant Tuberculosis (MDR TB) Fact Sheet

February 2010 Multidrug-resistant tuberculosis (MDR TB) is a form of tuberculosis that is resistant to two or more of the primary drugs (isoniazied and rifampin) used for the treatment of tuberculosis. Extensively drug-resistant TB (XDR TB) is TB resistant to at least isoniazied and rifampin among the first-line anti-TB drugs and is resistant to any fluoroquinolone and at least one of the three second-line injectable drugs.1 Resistance to one or several forms of treatment occurs when the bacteria develops the ability to withstand antibiotic attack and relays that ability to its offspring. Since that entire strain of bacteria inherits this capacity to resist the effects of the various treatments, resistance can spread from one person to another. On an individual basis, however, inadequate treatment or improper use of the anti-tuberculosis medications remains an important cause of drug-resistant tuberculosis. Drug-resistant TB is difficult and costly to treat and can be fatal.

In 2008, the CDC reported that 8.2 percent of tuberculosis cases in the U.S. were resistant to isoniazid, the first-line drug used to treat TB.2 The CDC also reported that 1.0 percent of tuberculosis cases in the U.S. were resistant to both isoniazid and rifampin.3 Rifampin is the drug most commonly used with isoniazid. Overall, 125 cases of MDR TB cases were reported in 2007, which was an increase from the 116 cases reported in 2006.4 Only 18.4 percent of primary MDR TB cases were in U.S. born persons in 2007. The proportion of MDR TB cases continues to disproportionately affect foreign-born persons in the United States. This group accounted for 26 percent of MDR TB cases in 1993, but 81.6 percent of such cases in 2007.5 The World Health Organization estimates that there were half a million cases of MDR TB worldwide in 2007, the highest ever reported. These cases are not spread proportionately across the globe, as only 27 countries account for 85 percent of all MDR TB cases. Unfortunately, only a small portion of MDR TB cases are treated properly each year; about 1 percent (3,700) in 2007.6 A strain of MDR TB originally develops when a case of drug-susceptible tuberculosis is improperly or incompletely treated. This occurs when a physician does not prescribe proper treatment regimens or when a patient is unable to adhere to therapy. Improper treatment

allows individual TB bacilli that have natural resistance to a drug to multiply. Eventually the majority of bacilli in the body are resistant.7 Once a strain of MDR TB develops it can be transmitted to others just like a normal drugsusceptible strain. Airborne transmission has been the cause of several well-publicized cases of nosocomial (hospital-based) outbreaks of MDR TB in New York City and Florida. These outbreaks were responsible for the deaths of several patients and health care workers, a majority of whom were coinfected with HIV.8 MDR TB has been a particular concern among HIV-infected persons. Some of the factors that have contributed to the number of cases of MDR TB, both in general and among HIVinfected individuals are: 1. Delayed diagnosis and delayed determination of drug susceptibility, which may take several weeks 2. Susceptibility of immunosuppressed individuals for not only acquiring MDR TB but for rapid disease progression, which may result in rapid transmission of the disease to other immunosuppressed patients 3. Inadequate respiratory isolation procedures and other environmental safety conditions, especially in confined areas such as prisons 4. Noncompliance or intermittent compliance with antituberculosis drug therapy.9 MDR TB is more difficult to treat than drug-susceptible strains of TB. The success of treatment depends upon how quickly a case of TB is identified as drug resistant and whether an effective drug therapy is available. The second-line drugs used in cases of MDR TB are often less effective and more likely to cause side effects.10 Tests to determine the resistance of a particular strain to various drugs usually take several weeks to complete. During the delay, the patient may be treated with a drug regimen that is ineffective. Once a strain's drug resistance is known, an effective drug regimen must be identified and begun. Some strains of MDR TB are resistant to seven or more drugs, making the identification of effective drugs difficult. To deal with this problem, it is recommended that newly discovered cases of TB in populations at high risk for MDR TB be treated with four drugs rather than the standard three as part of initial treatment.11 Treatment for MDR TB involves drug therapy over many months or years. Despite the longer course of treatment, the cure rate decreases from over 90 percent for nonresistant strains of TB to 50 percent or less for MDR TB.12 Because it is difficult for some people to successfully complete their tuberculosis treatment, several innovations have been developed. One of these is the use of incentives and enablers, which may be transportation, tokens or food coupons that are given to patients each time they appear at the clinic or doctor's office for treatment. Incentives and enablers are combined with the use of directly observed therapy (DOT). DOT is a system of treatment in which the patient is administered his or her medication by a nurse or other health worker and observed taking the medication.13 FDA has approved Rifater, a medication that combines the three main drugs (isoniazid, rifampin, and pyrazinamide) used to treat tuberculosis into one pill. This reduces the number of pills a patient has to take each day and makes it impossible for the patient to take only one of the three medications, a common path to the development of MDR TB.14 In 2006, a study in Africa revealed the presence of not only multidrug-resistant (MDR) tuberculosis but also what is now known as extensively drug-resistant (XDR) tuberculosis in patients infected with HIV. The Centers for Disease Control and Prevention and the World Health Organization reported the existence of XDR TB in 17 countries, including 4 percent of cases here in the United States.15

For more information on tuberculosis, please review the Tuberculosis Morbidity and Mortality Trend Report in the Data and Statistics section of our website at www.lung.org or call the American Lung Association at 1-800-LUNG-USA (1-800-586-4872).