Multidrug-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 rifampicin. 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 bacterium 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, rifampicin, pyrazinamide and ethambutol). 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). 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), or not taking medication consistently or for the full treatment period (treatment is required for several months). Treatment of MDR-TB requires treatment with 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 regimes can run for two years, compared to the six months of first-line drug treatment. If these second-line drugs are prescribed or taken incorrectly, further resistance can develop leading to XDR-TB. 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.
Origin Researchers hypothesize that an ancestor of Mycobacterium tuberculosis first originated in the East African region approximately 3 million years ago, with modern strains mutating and arising 20,000 years ago. As migration out of East Africa increased, so did the spread of the disease, starting in Asia and then spreading towards the West and South America. Multidrug-resistant tuberculosis has a variety of causes, but resistance is usually due to treatment failure, drug combinations, coinfections, prior use of anti-TB medications, inadequate absorption of medication, underlying disease, and noncompliance with anti-TB drugs.
Mechanism of drug resistance The TB bacterium has natural defenses against some drugs, and can acquire drug resistance through genetic mutations. The bacterium does not have the ability to transfer genes for resistance between organisms through plasmids (see horizontal transfer). Some mechanisms of drug resistance include:
Cell wall: The cell wall of M. tuberculosis (TB) contains complex lipid molecules which act as a barrier to stop drugs from entering the cell. In order to lessen its vulnerability, M. tuberculosis can also stop medications from penetrating its cells. RIF resistance is linked to numerous genes and proteins that are involved in the formation of cell walls. Maintaining the M. tuberculosis cell wall is a major function of the PE11 protein. It is hypothesized that upregulating the production of PE11 protein can decrease the quantity of antibiotics that enter M. tuberculosis. The expression of M. tuberculosis PE11 protein in M. smegmatis can generate raised resistance levels to several antibiotics, including RIF. Drug modifying & inactivating enzymes: The TB genome codes for enzymes (proteins) that inactivate drug molecules. These enzymes are usually phosphorylate, acetylate, or adenylate drug compounds. Drug efflux systems: The TB cell contains molecular systems that actively pump drug molecules out of the cell. Mutations: Spontaneous mutations in the TB genome can alter proteins which are the target of drugs, making the bacteria drug-resistant. One example is a mutation in the rpoB gene, which encodes the beta subunit of the bacterium's RNA polymerase enzyme. In non-resistant TB, rifampin binds the beta subunit of RNA polymerase and disrupts transcription elongation. Mutation in the rpoB gene changes the sequence of amino acids and eventual conformation, or arrangement, of the beta subunit. In this case, rifampin can no longer bind or prevent transcription, and the bacterium is resistant. Other mutations make the bacterium resistant to other drugs. For example, there are many mutations that confer resistance to isoniazid (INH), including in the genes katG, inhA, ahpC and others. Amino acid replacements in the NADH binding site of InhA apparently result in INH resistance by preventing the inhibition of mycolic acid biosynthesis, which the bacterium uses in its cell wall. Mutations in the katG gene make the enzyme catalase peroxidase unable to convert INH to its biologically active form. Hence, INH is ineffective and the bacterium is resistant. The discovery of new molecular targets is essential to overcome drug-resistance problems. In some TB bacteria, the acquisition of these mutations can be explained by other mutations in the DNA recombination, recognition and repair machinery. Mutations in these genes allow the bacteria to have a higher overall mutation rate and to accumulate mutations that cause drug resistance more quickly.
Extensively drug-resistant TB
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