Extensively drug-resistant tuberculosis
Extensively drug-resistant tuberculosis (XDR-TB) is a form of tuberculosis caused by bacteria that are resistant to some of the most effective anti-TB drugs. XDR-TB strains have arisen after the mismanagement of individuals with multidrug-resistant TB (MDR-TB).
One in three people in the world is infected with TB bacteria. 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 (i.e., isoniazid, rifampin and any fluoroquinolone). If these drugs are misused or mismanaged, multidrug-resistant TB (MDR-TB) can develop. MDR-TB takes longer to treat with second-line drugs (i.e., amikacin, kanamycin, or capreomycin), 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 had confirmed cases of XDR-TB. By 2013, that number had risen to 84.
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. 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, is no longer used, but may be referred to in older publications.
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. XDR-TB cannot be spread by kissing, sharing food or drinks and by shaking someone’s hand. The bacterium has the ability to stay in the air for several hours. 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 with 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. To reduce the time needed for diagnosis, new tools for rapid TB diagnosis are urgently needed.
The original method used to test for MDR-TB and XDR-TB was the Drug Susceptibility Testing (DST). DST is capable of determining how well four primary antitubercular drugs inhibit the growth of Mycobacterium Tuberculosis. The four primary antitubercular drugs are Isoniazid, Rifampin, Ethambutol and Pyrazinamide. Drug Susceptibility testing is done by making a Lowenstein-Jensen medium plate and spreading the bacteria on the plate. Disks containing one of the four primary drugs are added to the plate. After weeks of allowing the bacteria to grow the plate is checked for clear areas around the disk. If there is a clear area, the drug has killed the bacteria and most likely the bacteria is not resistant to that drug.
As the Mycobacterium Tuberculosis evolved new strains of resistant bacteria were being found such as XDR-TB. The problem was that primary DST was not suitable for testing bacteria strains that were extensively drug resistant. This problem was starting to be fixed when drug susceptibility tests started including not just the four primary drugs, but secondary drugs. This secondary test is known as Bactec MGIT 960 System. Although Bactec MGIT 960 System was accurate it was still slow at determining the level of resistance.
In recent years drug resistant tuberculosis testing has shown a lot of progress. Some studies have found an in-house assay that could rapidly detect resistance to drugs involved in the definition of XDR-TB directly from smear-positive specimens. The assay is called Reverse Line Blot Hybridization Assay also known as RLBH. The study showed that the results of RLBH were as accurate as other drug susceptibility tests, but at the same time didn`t take weeks to get results. RLBH testing only took 3 days to determine how resistant the strain of bacteria was.
The current research has shown progress in the testing of drug resistance. A recent study found that a research technique known as direct nitrate reductase assay (D-NRA) showed efficient accuracy for the rapid and simultaneous detection of resistance to isoniazid (INH), rifampicin (RIF), kanamycin (KAN) and ofloxacin (OFL). D-NRA results were obtained in 16.9 days, comparably less than other drug susceptibility testing. At the same time the study mentioned how D-NRA is a low-cost technology, easy to set up in clinical laboratories and suitable to be used for DST of M. tuberculosis in all smear-positive samples.
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, hallucinations, and deafness. Patients are often hospitalized 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. 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.
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 of 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. 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.
Carriers who refuse to wear a mask in public have been indefinitely involuntarily committed to regular jails, and cut off from contacting the world. Some have run away from the USA, complaining of abuse.
Studies have found that men have a higher risk of getting XDR-TB than women. One study showed that the male to female ratio was more than threefold, with statistical relevance (P<0.05) Studies done on the effect of age and XDR-TB have revealed that individuals who are 65 and up are less likely to get XDR-TB. A study in Japan found that XDR-TB patients are more likely to be younger.
XDR-TB and HIV/AIDS
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 for TB and are taking treatment should inform their clinician or nurse.
South African epidemic
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. 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. 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, 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. 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. It is now clear that the problem has been around for much longer than health department officials have suggested, and is far more extensive.
- Tuberculosis treatment
- Multi-drug-resistant tuberculosis (MDR-TB)
- Totally drug-resistant tuberculosis (TDR-TB)
- World Health Organization (2007). “Fact Sheet No. 104: Tuberculosis”
- World Health Organization (2008). “Countries with XDR-TB confirmed cases as of June 2008” 
- WHO. "Multidrug-resistant tuberculosis (MDR-TB) 2013 Update". World Health Organization. Retrieved 14 June 2013.
- World Health Organisation (2006). Press release: "WHO Global Task Force outlines measures to combat XDR-TB worldwide" 
- Center for Disease Control (2006). "Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drug—Worldwide, 2000–2004". MMWR Weekly 55 (11): 301–305.
- Centers for Disease Control and Prevention (2006). "Notice to Readers: Revised Definition of Extensively Drug-Resistant Tuberculosis". JAMA: the Journal of the American Medical Association (American Medical Association) 296 (23): 2792. doi:10.1001/jama.296.23.2792-a. Retrieved 2009-05-30.
- "Tuberculosis (TB)." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 18 Jan. 2013. Web. 28 Jan. 2014. <http://www.cdc.gov/tb/publications/factsh
- World Health Organization (2006). “Frequently asked questions – XDR-TB” 
- Richter, Elvira, Sabine Rüsch-Gerdes, and Doris Hillemann. (2009) "Drug-susceptibility Testing In TB: Current Status And Future Prospects." Expert Review of Respiratory Medicine 3.5: 497-510.
- "Missouri Department of Health & Senior Services." Drug Susceptibility Testing (DST). N.p., n.d. Jan. 2014. <http://health.mo.gov/lab/dst.php>
- Rodrigues, C. et al. (2008)"Drug susceptibility testing of Mycobacterium tuberculosis against second-line drugs using the Bactec MGIT 960 System." Int J Tuberc Lung Dis. 12.12:1449-1455.
- Kanchan, A. et al. ( 2011) "Rapid Diagnosis of Extensively Drug-Resistant Tuberculosis by Use of a Reverse Line Blot Hybridization Assay." J Clin Microbiol 49.7: 2546-2551.
- Imperiale, BR, NS Morcillo, JC Palomino, P Vandamme, and A Martin. (2014). "Predictive value of direct nitrate reductase assay and its clinical performance in the detection of multi and extensively drug resistant tuberculosis." J Med Microbiol
- Jason Beaubien (June 4, 2013). "Moldova Grapples With Whether To Isolate TB Patients". Special Series: Tuberculosis Returns With A Deadly Twist. NPR. Retrieved January 29, 2015.
- Keshavjee, S; Gelmanova, I; Farmer, P; Mishustin, S; Strelis, A; Andreev, Y; Pasechnikov, A; Atwood, S et al. (2008). "Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study". The Lancet 372 (9647): 1403. doi:10.1016/S0140-6736(08)61204-0.
- Aeras Global Vaccine Foundation. “Need for New TB Vaccines”. Retrieved 2008-09-12. 
- "Man Isolated with Deadly Tuberculosis Strain". NPR.
- "Drug-proof TB strain poses ethical bind - Health - Infectious diseases _ NBC News.htm".
- "TB Patient Flees U.S. "Abuse" For Russia".
- ( Flor de Lima, B, and M Tavares. "Risk factors for extensively drug-resistant tuberculosis: a review." The Clinical Respiratory Journal 8.1 (2013): 11-23.)
- ( Velayati AA, Masjedi MR, Farnia P, Tabarsi P, Ghanavi J, Ziazarifi AH, Hoffner SE. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest. 2009;136(2): 420–425.
- (Shah NS, Pratt R, Armstrong L, Robison V, Castro K, Cegielski JP. Extensively drug-resistant tuberculosis in the United States, 1993–2007. JAMA. 2008;300(18): 2153–2160.)
- (Murase Y, Maeda S, Yamada H, Ohkado A, Chikamatsu K, Mizuno K, Kato S, Mitarai S. Clonal expansion of multidrug-resistant and extensively drug-resistant tuberculosis, Japan. Emerg Infect Dis. 2010;16(6): 948–954.)
- Gandhi, NR; Moll, A; Sturm, AW; Pawinski, Robert; Govender, Thiloshini; Lalloo, Umesh; Zeller, Kimberly; Andrews, Jason; Friedland, Gerald (2006). "Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa". The Lancet 368 (9547): 1575–80. doi:10.1016/S0140-6736(06)69573-1. PMID 17084757.
- Shah NS, Wright A, Drobniewski F, et al.. (2005). "Extreme drug resistance in tuberculosis (XDR-TB): global survey of supranational reference laboratories for _Mycobacterium tuberculosis_ with resistance to second-line drugs". Int J Tuberc Lung Dis 9(Suppl 1): S77.
- Centers; Control, Diseases (2006). "Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs-worldwide, 2000-2004". Morb Mort Wkly Rep 55: 301–5.
- Angela Quintal. "314 XDR-TB cases reported in SA". Cape Times. Retrieved on 2007-04-04.
- Migliori, GB; Ortmann, J; Girardi, E. "et al". (2007). "Extensively drug-resistant tuberculosis, Italy and Germany" 13: 5.
- Sidley, P. (2006). "South Africa acts to curb spread of lethal strain of TB". Brit Med J 333 (7573): 825. doi:10.1136/bmj.333.7573.825-a. PMC 1618468. PMID 17053232.
- World Health Organization Stop TB Department
- Stop TB Partnership
- The Global Plan to Stop TB
- Advocacy to Control TB Internationally - ACTION
- International Standards of TB Care
- Video: Drug-Resistant TB in Russia July 24, 2007, Woodrow Wilson Center event featuring Salmaan Keshavjee and Murray Feshbach
- XDRTB.org: Spread the Story. Stop the Disease. (photo documentary of XDR-TB by James Nachtwey)
- TB Drug Resistance Mutation Database
- British Red Cross helps combat TB
- Drug Resistant TB, a Nagging Challenge
- The Strange, Isolated Life of a Tuberculosis Patient in the 21st Century