Multi-drug resistant TB (MDR-TB) is a situation when a strain of TB is resistant to INH and RMP. The resistance develops from random mutation of bacterial chromosome, which occurs spontaneously in wild type strains even before contact with an anti tuberculosis drug. These mutations occur at a low rate, which varies depending on the drug. If large numbers of TB bacilli are present and the patient is treated with one drug, it eliminates the organism susceptible to that drug but organisms resistant to that drug remain unaffected. Eventually resistant bacilli make up a substantial proportion of bacterial population and clinical drug resistance occurs.

Until 50 years ago, there were no medicines to cure TB. Now, strains that are resistant to a single drug have been documented in every country surveyed; what is more, strains of TB resistant to all major anti-TB drugs have emerged. Drug-resistant TB is caused by inconsistent or partial treatment, when patients do not take all their medicines regularly for the required period because they start to feel better, because doctors and health workers prescribe the wrong treatment regimens, or because the drug supply is unreliable. A particularly dangerous form of drug-resistant TB is multidrug-resistant TB (MDR-TB), which is defined as the disease caused by TB bacilli resistant to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. Rates of MDR-TB are high in some countries, especially in the former Soviet Union, and threaten TB control efforts.

From a public health perspective, poorly supervised or incomplete treatment of TB is worse than no treatment at all. When people fail to complete standard treatment regimens, or are given the wrong treatment regimen, they may remain infectious. The bacilli in their lungs may develop resistance to anti-TB medicines. People they infect will have the same drug-resistant strain. While drug-resistant TB is generally treatable, it requires extensive chemotherapy (up to two years of treatment) that is often prohibitively expensive (often more than 100 times more expensive than treatment of drug-susceptible TB), and is also more toxic to patients.

WHO and its international partners have formed the DOTS-Plus Working Group, which develops global policy on the management of MDR-TB, and facilitates access to second-line anti-TB drugs for approved projects.

A standard and inexpensive tuberculosis treatment regimen cut the overall TB rate in half and lowered the rate of drug-resistant cases even more dramatically in a remote Mexican health district with a high prevalence of the disease. “This shows what basic TB control can accomplish,” said Maria de Lourdes García García, a Howard Hughes Medical Institute international research scholar who led the Mexican study.

To learn more about TB transmission in less developed countries, García García and colleagues from the National Institutes of Mexico and Stanford University launched a five-year study in the Orizaba Health Jurisdiction, four hours by bus southeast of Mexico City. The district, which has a higher rate of TB than Mexico as a whole, encompasses five mostly urban communities in an industrialized valley and surrounding rural mountains.

What is the difference between the management of drug-resistant TB and drug-susceptible TB?
In areas of minimal or no MDR-TB, DOTS achieves cure rates of up to 95%; rates high enough to dramatically reduce the TB burden while preventing the emergence of drug-resistant TB. However, an effective strategy, the management of drug-resistant TB is still in pilot stage. While drug-susceptible TB can be cured within six months, forms of drug-resistant TB (such as MDR-TB) require extensive chemotherapy (with drugs which have more side effects) for up to two years.

How do we measure drug-resistant TB globally?
In 1994, WHO, the International Union Against TB and Lung Disease, and other partners began the Global Project on Drug Resistance Surveillance in order to standardize the sampling and laboratory methodologies used to measure drug resistant tuberculosis. Today, areas representing almost one-third of global TB cases have been surveyed.

Are TB and drug-resistant TB real threats to everyone?
Presently, TB is the second greatest contributor among infectious diseases to adult mortality causing approximately two million deaths a year worldwide. WHO estimates that one-third of the world's population is infected with Mycobacterium tuberculosis. The WHO/IUATLD Global Project on Drug Resistance Surveillance has found MDR-TB (prevalence > 4% among new TB cases) in Eastern Europe, Latin America, Africa, and Asia.

Given the increasing trend toward globalisation, trans-national migration, and tourism, all countries are potential targets for outbreaks of MDR-TB.

How is WHO addressing the problem of drug resistance?
In 1998 WHO and several partners around the world conceived DOTS-Plus, a strategy currently under continuous development and testing for the management of MDR-TB. In 1999, WHO established the Working Group on DOTS-Plus for MDR-TB. The aims of the working group are to approve, conduct, and oversee pilot projects based on the Guidelines for Establishing DOTS-Plus Pilot Projects for the Management of MDR-TB prepared by the Scientific Panel of the Working Group. In addition, the Working Group aims to improve access to second-line anti-TB drugs for DOTS-Plus pilot projects via mechanisms such as the Green Light Committee.

Multidrug-Resistant Tuberculosis Fact Sheet

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 anit-TB drugs and among second-line drugs, is resistant to any fluoroquinolone and at least one of three injectable drugs.

Resistance to one or several forms of treatment occurs when the bacteria develops the ability to withstand antibiotic attack and relay that ability to newly produced bacteria.  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-restistant TB is difficult and costly to treat and can be fatal.

• In 2005, the CDC reported that 7.8 percent of tuberculosis cases in the U.S. were resistant to isoniazid, the first line drug used to treat TB.
• The CDC also reported that 1.2 percent of tuberculosis cases in the U.S. were resistant to both isoniazid and rifampin.   Rifampin is the drug most commonly used with isoniazid.
• Overall, 124 cases of MDR-TB cases were reported in 2005, which remained constant from the previous year.
• Only 27 percent of primary MDR-TB cases were in U.S. born persons. The percentage of U.S. born persons with MDR-TB has remained stable at approximately 0.6 percent since 2000.  The proportion of MDR-TB cases continued to disproportionately affect foreign-born persons in the United States. Among this group, MDR-TB cases has increased from 26 percent in 1993 to 81.5 percent of cases in 2005.
• The World Health Organization estimates that up to 50 million persons worldwide may be infected with drug resistant strains of TB. Also, 300,000 new cases of MDR-TB are diagnosed around the world each year and 79 percent of the MDR-TB cases now show resistance to three or more drugs.
• 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.
• Once a strain of MDR TB develops it can be transmitted to others just like a normal drug-susceptible 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 co infected with HIV.
• 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 HIV-infected individuals are:
  
  
• Delayed diagnosis and delayed determination of drug susceptibility, which may take several weeks
• 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
• Inadequate respiratory isolation procedures and other environmental safety conditions, especially in confined areas such as prisons
• Noncompliance or intermittent compliance with antituberculosis drug therapy.
  
  
• 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.
• 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.
• 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.
• 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.
• 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.
• In June 1998, the U.S. Food and Drug Administration approved the first new drug for pulmonary tuberculosis in 25 years. The drug, rifapentine (Priftin), has been approved for use with other drugs to fight TB. One potential advantage of rifapentine is that it can be taken less often in the final four months of treatment --once a week compared with twice a week for the standard regimen.
• In 2006, a study in Africa revealed the presence not only of 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.

The growing problem of multidrug-resistant (MDR) tuberculosis threatens to derail TB control efforts unless there is greater investment in control and diagnosis, TB experts warned this week in the run-up to the 38th World Lung Health conference, which opens tomorrow in Cape Town, South Africa.

This year’s conference is taking place in South Africa in order to highlight the growing challenge of drug-resistant tuberculosis in the regions of the world most seriously affected by HIV.

Last year’s discovery of an outbreak of extensively drug-resistant TB among HIV-positive patients in the rural KwaZulu Natal town of Tugela Ferry rocked the worlds of TB and HIV treatment, and highlighted the need for greater integration of TB and HIV care.

“XDR TB is a wake-up call to ensure a better future of HIV treatment by strengthening TB control,” said Dr Haileyesus Getahun of the World Health Organization Stop TB department, speaking at a workshop on XDR and MDR-TB in the context of HIV, organised by the Treatment Action Group and the Stop TB Partnership.

The XDR outbreak has now spread to every province in South Africa, and two cases have been identified in Mozambique, Dr Lindewe Mvusi, TB director of the South African department of health, reported at the International Union Against Tuberculosis and Lung Disease African regional meeting on Wednesday.

Four hundred and eighty-one cases have now been identified in South Africa, 188 in KwaZulu Natal, 157 in Eastern Cape and 64 in the Western Cape, with 281 deaths to date. Two hundred and thirty-five patients are currently receiving treatment in hospital, while 18 patients have been discharged to receive directly observed therapy in the community following conversion to a smear-negative state.

Although extensively drug-resistant tuberculosis has been spotted before, notably in China, India and the Russian Federation, this is the first time it has emerged in a region where HIV prevalence is high. The consequences have been particularly bleak in people with HIV, said Dr Neel Gandhi, part of the research team that identified the Tugela Ferry outbreak.

Almost all HIV-positive patients died within weeks of being examined for suspected tuberculosis, often before the results of sputum tests could confirm tuberculosis, and XDR-TB was confirmed retrospectively in many patients.

The Church of Scotland hospital in Tugela Ferry has seen little improvement in survival rates since the initial outbreak was identified in April 2006, Dr Gandhi said this week.
Where has the XDR-TB outbreak come from? Although there’s little doubt that the current outbreak is due in large part to transmission from person to person, particularly in health care settings, and that proper implementation of infection control measures could greatly reduce the incidence, the initial XDR case must have developed as a result of the evolution of drug resistance in persons receiving first and second-line TB treatment.

Molecular analysis of the XDR-TB strains present in Tugela Ferry patients has been able to uncover the gradual accumulation of resistance to more and more drugs. The road to XDR-TB in KwaZulu Natal began around 1994, when patients first began to develop strains resistant to all first-line drugs. As the decade went on, these drug-resistant strains, circulating in the community, began to accumulate resistance to additional drugs used in second-line TB treatment, until by 2001 the first strain classified as extensively drug resistant is now known to have been present in a patient in KwaZulu Natal.

But at the time no one knew just how much drug resistance was already present in some TB patients due to the lack of drug sensitivity testing.

The critical step appears to have been presumptive treatment of patients who had failed first-line TB therapy, using a standard regimen of second-line drugs.

Why should it have emerged in KwaZulu Natal? Probably because the province has consistently had the lowest TB cure rate in South Africa; just 45% of patients who commenced TB treatment were pronounced cured in 2006, compared with just over 70% in the Western Cape province.

A national drug sensitivity survey carried out in 2001/2002 showed that although the highest prevalence of MDR-TB per capita occurred in the northern provinces of Mpumalanga and Limpopo, the largest numbers of cases of multi-drug resistance were found in KwaZulu Natal and the Western Cape.

In addition, KwaZulu Natal has the highest HIV prevalence in South Africa, in excess of 30% in many communities, compared with levels closer to 10% in the Western Cape. HIV-positive people are particularly vulnerable to TB, and likely to have a faster and more virulent course of MDR-TB.

All these factors explain why KZN was the site of emergence, but what’s still unclear is whether the outbreak spread across the country from the province, or whether greater vigilance coupled with drug sensitivity testing uncovered a phenomenon that was emerging simultaneously in every province of South Africa.

Other countries in Africa have reason to be concerned about the potential for home-grown outbreaks of XDR-TB. The World Health Organization estimates that alongside South Africa, Nigeria and Ethiopia are the hotspots for MDR-TB in Africa, followed by Tanzania, Malawi, Zambia, Rwanda, Mozambique and the Democratic Republic of Congo.

Countries in southern and central Africa are currently investigating whether XDR-TB is present, but surveillance will be hampered by the severe shortage of drug sensitivity testing. Few laboratories are equipped to do it, the equipment is expensive and trained staff are thin on the ground.

For most countries, the likelihood that XDR-TB is present will be present is governed by the extent to which patients already have access to second-line TB treatment.

Second-line TB treatment is expensive ($1500 - $4000 for a course of treatment), it’s hugely labour intensive and requires hospital beds to be set aside for six to eight months until the patients achieves conversion to smear-negative. Just under 40% of TB programmes in Africa and Asia currently include MDR TB treatment as part of their routine activities, says Dr Haileyesus Getahun of WHO.

The WHO and Stop TB Partnership has set a target for the expansion of MDR-TB treatment from 30,000 patients worldwide in 2007 to 1.6 million in 2015. The target is based on the estimated number of patients who fail TB treatment and develop drug resistance to components of the first-line regimen.

Unless efforts to control MDR-TB succeed, said Dr Mario Raviglione, director of WHO’s Stop TB department, “MDR-TB will replace the drug-susceptible strain as the dominant strain. There are countries in the former Soviet Union already approaching 15 – 20% [of new TB cases MDR] today.”

But, says Dr Rhehab Chimzizi of Malawi’s National TB Programme, “What is slowing us [in MDR response] is laboratory capacity. We have one lab to do drug sensitivity testing and sputum culture for a country of 12.8 million people!”

Until countries can carry out drug sensitivity testing, their requests for free or subsidised second-line drugs are likely to be turned down by WHO’s Green Light Committee, which approves requests for second-line TB drugs based on the capacity of a country to preserve the efficacy of those drugs.

Currently, drug sensitivity testing is not only expensive but slow. It can take five to six weeks to establish whether a TB isolate is resistant to rifampicin or isoniazid, or both, often leading to presumptive treatment with an inappropriate combination of drugs that can serve to increase the level of drug resistance.

Tests of a new method of diagnosing isoniazid and rifampicin resistance without the need for culturing TB bacteria are currently underway in southern Africa, and if successful, could lead to the approval of a new diagnostic method by WHO within a year.

This would have the potential to speed up MDR treatment, if the investment in laboratory standards takes place now.

But, as Dr Mario Raviglione points out, unless donors begin to invest in combating the MDR-TB crisis now, we will fall further and further behind in the fight against MDR-TB. Earlier this year WHO and the Stop TB Partnership issued a call for $2.15 billion to back an extensive plan to combat MDR and XDR TB. So far, he says, there is a funding gap of close to half a billion dollars in 2007, despite the fact that more than 400,000 MDR-TB cases are expected to be diagnosed this year alone.