Extensively drug-resistant tuberculosis (XDR-TB) is a form of TB caused by bacteria that are resistant to the most effective anti-TB drugs. Some contend that XDR-TB strains have emerged from the mismanagement of multidrug-resistant TB (MDR-TB) and once created, can spread from one person to another. The exact nature of this mismanagement is not yet known, but origin of XDR-TB may coincide with the institution of new policies to promote drug compliance, such as DOTS.[1]
One in three people in the world is infected with TB bacteria.[2] Only when the bacteria become active do people become ill with TB. Bacteria become active as a result of anything that can reduce the person’s immunity, such as HIV, advancing age, or some medical conditions. TB can usually be treated with a course of four standard, or first-line, anti-TB drugs. If these drugs are misused or mismanaged, multidrug-resistant TB (MDR-TB) can develop. MDR-TB takes longer to treat with second-line drugs, which are more expensive and have more side-effects. XDR-TB can develop when these second-line drugs are also misused or mismanaged and therefore also become ineffective.
XDR-TB raises concerns of a future TB epidemic with restricted treatment options, and jeopardizes the major gains made in TB control and progress on reducing TB deaths among people living with HIV/AIDS. It is therefore vital that TB control be managed properly and new tools developed to prevent, treat and diagnose the disease.
The true scale of XDR-TB is unknown as many countries lack the necessary equipment and capacity to accurately diagnose it. It is estimated however that there are around 40,000 cases per year. As of June 2008, 49 countries have confirmed cases of XDR-TB.[3] By 2010, that number had risen to 58.[4]
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XDR-TB is defined as TB that has developed resistance to at least rifampicin and isoniazid (resistance to these first line anti-TB drugs defines Multi-drug-resistant tuberculosis, or MDR-TB), as well as to any member of the quinolone family and at least one of the following second-line anti-TB injectable drugs: kanamycin, capreomycin, or amikacin.[5] This definition of XDR-TB was agreed by the WHO Global Task Force on XDR-TB in October 2006. The earlier definition of XDR-TB as MDR-TB that is also resistant to three or more of the six classes of second-line drugs,[6] is no longer used, but may be referred to in older publications.[7]
Like other forms of TB, XDR-TB is spread through the air. When a person with infectious TB coughs, sneezes, talks or spits, they propel TB germs, known as bacilli, into the air. A person needs only to inhale a small number of these to be infected. People infected with TB bacilli will not necessarily become sick with the disease. The immune system "walls off" the TB bacilli which, protected by a thick waxy coat, can lie dormant for years.
The spread of TB bacteria depends on factors such as the number and concentration of infectious people in any one place together with the presence of people with a higher risk of being infected (such as those with HIV/AIDS). The risk of becoming infected increases the longer the time that a previously uninfected person spends in the same room as the infectious case. The risk of spread increases where there is a high concentration of TB bacteria, such as can occur in closed environments like overcrowded houses, hospitals or prisons. The risk will be further increased if ventilation is poor. The risk of spread will be reduced and eventually eliminated if infectious patients receive proper treatment.
Successful diagnosis of XDR-TB depends on the patient’s access to quality health-care services. If TB bacteria are found in the sputum, the diagnosis of TB can be made in a day or two, but this finding will not be able to distinguish between drug-susceptible and drug-resistant TB. To evaluate drug susceptibility, the bacteria need to be cultivated and tested in a suitable laboratory. Final diagnosis in this way for TB, and especially for XDR-TB, may take from 6 to 16 weeks.[8] To reduce the time needed for diagnosis, new tools for rapid TB diagnosis are urgently needed.
The principles of treatment for MDR-TB and for XDR-TB are the same. Treatment requires extensive chemotherapy for up to two years. Second-line drugs are more toxic than the standard anti-TB regimen and can cause a range of serious side-effects including hepatitis, depression and hallucinations. Patients are often hospitalised for long periods, in isolation. In addition, second-line drugs are extremely expensive compared with the cost of drugs for standard TB treatment.
XDR-TB is associated with a much higher mortality rate than MDR-TB, because of a reduced number of effective treatment options.[6] Despite early fears that this strain of TB was untreatable, recent studies have shown that XDR-TB can be treated through the use of aggressive regimens. A study in the Tomsk oblast of Russia, reported that 14 out of 29 (48.3%) patients with XDR-TB successfully completed treatment.[9]
Successful outcomes depend on a number of factors including the extent of the drug resistance, the severity of the disease and whether the patient’s immune system is compromised. It also depends on access to laboratories that can provide early and accurate diagnosis so that effective treatment is provided as soon as possible. Effective treatment requires that all six classes of second-line drugs be available to clinicians who have special expertise in treating such cases.
Countries aim to prevent XDR-TB by ensuring that the work of their national TB control programmes, and all practitioners working with people with TB, is carried out according to the International Standards for TB Care. These emphasize providing proper diagnosis and treatment to all TB patients, including those with drug-resistant TB; assuring regular, timely supplies of all anti-TB drugs; proper management of anti-TB drugs and providing support to patients to maximize adherence to prescribed regimens; caring for XDR-TB cases in a centre with proper ventilation, and minimizing contact with other patients, particularly those with HIV, especially in the early stages before treatment has had a chance to reduce the infectiousness. Also an effective disease control infrastructure is necessary for the prevention of XDR tuberculosis. Increased funding for research, and strengthened laboratory facilities are much required. Immediate detection through drug susceptibility testing's are vital, when trying to stop the spread of XDR tuberculosis.
The BCG vaccine prevents severe forms of TB in children, such as TB meningitis. It would be expected that BCG would have the same effect in preventing severe forms of TB in children, even if they were exposed to XDR-TB, but it may be less effective in preventing pulmonary TB in adults, the most common and most infectious form of TB.[10] The effect of BCG against XDR-TB would therefore likely be very limited. New vaccines are urgently needed, and WHO and members of the Stop TB Partnership are actively working on new vaccines.
TB is one of the most common infections in people living with HIV/AIDS. In places where XDR-TB is most common, people living with HIV are at greater risk of becoming infected with XDR-TB, compared with people without HIV, because of their weakened immunity. If there are a lot of HIV-infected people in these places, then there will be a strong link between XDR-TB and HIV. Fortunately, in most of the places with high rates of HIV, XDR-TB is not yet widespread. For this reason, the majority of people with HIV who develop TB will have drug-susceptible or ordinary TB, and can be treated with standard first-line anti-TB drugs. For those with HIV infection, treatment with antiretroviral drugs will likely reduce the risk of becoming infected with XDR-TB, just as it does with ordinary TB.
A research study titled "TB Prevalence Survey and Evaluation of Access to TB Care in HIV-Infected and Uninfected TB Patients in Asembo and Gem, Western Kenya," says that HIV/AIDS is fueling large increases in TB incidence in Africa, and a large proportion of cases are not diagnosed.
Symptoms of XDR-TB are no different from ordinary or drug-susceptible TB: a cough with thick, cloudy mucus (or sputum), sometimes with blood, for more than 2 weeks; fever, chills, and night sweats; fatigue and muscle weakness; weight loss; and in some cases shortness of breath and chest pain. A person with these symptoms does not necessarily have XDR-TB, but they should see a physician for diagnosis and a treatment plan. TB patients whose symptoms do not improve after a few weeks of treatment with TB and are taking treatment should inform their clinician or nurse.[8]
XDR-TB was first widely publicised following the report of an outbreak in South Africa in 2006. 53 patients in a rural hospital in Tugela Ferry were found to have XDR-TB of whom 52 died.[11] The median survival from sputum specimen collection to death was only 16 days and that the majority of patients had never previously received treatment for tuberculosis suggesting that they had been newly infected by XDR-TB strains, and that resistance did not develop during treatment.[11] This was the first epidemic for which the acronym XDR-TB was used, and although TB strains that fulfill the current definition have been identified retrospectively,[12][13] this was the largest group of linked cases ever found. Since the initial report in September 2006, cases have now been reported in most provinces in South Africa. As of 16 March 2007, there were 314 cases reported, with 215 deaths.[14] It is clear that the spread of this strain of TB is closely associated with a high prevalence of HIV and poor infection control; in other countries where XDR-TB strains have arisen, drug resistance has arisen from mismanagement of cases or poor patient compliance with drug treatment instead of being transmitted from person to person.[15] It is now clear that the problem has been around for much longer than health department officials have suggested, and is far more extensive.[16]
Dr. Jeremiah Chakaya, one of Kenya's leading chest specialist and researcher with the Kenya Medical Research Institute, argues that, although XDR-TB is not yet common in Africa, it is bad news. "XDR-TB is very difficult to treat and some people consider it untreatable. If we generate a lot of this form of TB we will have pushed ourselves back to the pre-antibiotic days of the last century," says Chakaya. Africa, according to him, will end up with a disease that is killing people and cannot be treated, just like it was at the beginning of the last century. In Kenya the most recent figures gathered in 2005 indicate that about 1 percent of new, not previously treated patients have MDR-TB. The country may have one or two cases of XDR-TB. "This is the situation in most other countries of Africa," pointed out Chakaya. "But in Southern Africa, the rate of MDR-TB in new patients may be more than 3 percent," said Chakaya. Chakaya explained that the side effects and the hassle of taking fifteen to twenty pills a day for six months means that many patients might stop taking medicines as soon as they feel better. This is especially true in Africa where keeping patients on therapy for such a long time is extremely difficult.[17]