Multi-drug-resistant tuberculosis

Multi-drug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs), isoniazid and rifampin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB). Tuberculosis is caused by infection with the bacteria Mycobacterium tuberculosis. Almost one in four people in the world are 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, diabetes or other immunocompromising illnesses. TB can usually be treated with a course of four standard, or first-line, anti-TB drugs (i.e., isoniazid, rifampin and any fluoroquinolone). However, beginning with the first antibiotic treatment for TB in 1943, some strains of the TB bacteria developed resistance to the standard drugs through genetic changes (see mechanisms.) Currently the majority of multidrug-resistant cases of TB are due to one strain of TB bacteria called the Beijing lineage. This process accelerates if incorrect or inadequate treatments are used, leading to the development and spread of multidrug-resistant TB (MDR-TB). Incorrect or inadequate treatment may be due to use of the wrong medications, use of only one medication (standard treatment is at least two drugs), not taking medication consistently or for the full treatment period (treatment is required for several months). Treatment of MDR-TB requires second-line drugs (i.e., fluoroquinolones, aminoglycosides, and others), which in general are less effective, more toxic and much more expensive than first-line drugs. Treatment schedules for MDR-TB involving fluoroquinolones and aminoglycosides can run for 2 years, compared to the 6 months of first-line drug treatment, and cost over US$100,000. If these second-line drugs are prescribed or taken incorrectly, further resistance can develop leading to XDR-TB. Resistant strains of TB are already present in the population, so MDR-TB can be directly transmitted from an infected person to an uninfected person. In this case a previously untreated person develops a new case of MDR-TB. This is known as primary MDR-TB, and is responsible for up to 75% of cases. Acquired MDR-TB develops when a person with a non-resistant strain of TB is treated inadequately, resulting in the development of antibiotic resistance in the TB bacteria infecting them. These people can in turn infect other people with MDR-TB. MDR-TB caused an estimated 600,000 new TB cases and 240,000 deaths in 2016 and MDR-TB accounts for 4.1% of all new TB cases and 19% of previously treated cases worldwide. Globally, most MDR-TB cases occur in South America, Southern Africa, India, China, and the former Soviet Union. Treatment of MDR-TB requires treatment with second-line drugs, usually four or more anti-TB drugs for a minimum of 6 months, and possibly extending for 18–24 months if rifampin resistance has been identified in the specific strain of TB with which the patient has been infected. Under ideal program conditions, MDR-TB cure rates can approach 70%. The TB bacteria has natural defenses against some drugs, and can acquire drug resistance through genetic mutations. The bacteria does not have the ability to transfer genes for resistance between organisms through plasmids (see horizontal transfer). Some mechanisms of drug resistance include: One example is a mutation in the rpoB gene, which encodes the beta subunit of the bacteria's RNA polymerase. In non-resistant TB, rifampin binds the beta subunit of RNA polymerase and disrupt transcription elongation. Mutation in the rpoB gene changes the sequence of amino acids and eventual conformation of the beta subunit. In this case rifampin can no longer bind or prevent transcription, and the bacteria is resistant.