User:Hannahah01/Multidrug-resistant tuberculosis

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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; Archaeologists confirmed this with skeletal analysis of Egyptian remains. 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-resistent tuberculosis has a variety of causes, but resistance 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
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.

Prevention
However, the DOTS program administered in the Republic of Georgia is anchored in passive case finding.

Treatment
In cases of extremely resistant disease, surgery to remove infection portions of the lung is, in general, the final option. Early surgical treatments beginning in the 19th century include inducing lung collapse, as standing tissue heals faster than tissue in use, called artificial pneumothorax. Shrinking the lung cavity, thoracoplasty, to fill void space caused by tuberculosis damage was done by either removing ribs, raising the diaphragm, or implanting fluids or solid materials into lung cavity as a less invasive alternative to artificial pneumothorax. These treatments fell out of favor with the invention anti-tuberculosis drugs in the mid-20th century and have not seen a revival with MDR-TB, except for thoracoplasty done with implanted muscle tissue. Surgically removing portions of the lung, called lung resectioning, was a mostly theoretical possibility until the improved surgical tools and techniques of the mid-20th century. As of 2016, surgery is typically preformed after 6-8 months of unsuccessful anti-TB treatment by other means. Surgical treatment has a high success rate, upwards of 80%, but a similarly high failure rate of upwards of 10% including the risk of death. Surgery is first focused on stabilizing cavities, or "destroyed lung", caused by the disease, followed by the removal of tuberculomas, and then the removal of fluid and pus build up. Tuberculosis and lung cancer can coexist in patients as a possible complication, however the surgical therapies are similar as lung cancer surgery has its roots in aforementioned tuberculosis treatments.

In general, resistance to one drug within a class means resistance to all drugs within that class, but a notable exception is rifabutin: Rifampicin-resistance does not always mean rifabutin-resistance, and the laboratory should be asked to test for it. It is possible to use only one drug within each drug class. If it is difficult finding five drugs to treat then the clinician can request that high-level INH-resistance be looked for. If the strain has only low-level INH-resistance (resistance at 0.2 mg/L INH, but sensitive at 1.0 mg/L INH), then high dose INH can be used as part of the regimen. When counting drugs, PZA and interferon count as zero; that is to say, when adding PZA to a four-drug regimen, another drug must be chosen to make five. It is not possible to use more than one injectable (STM, capreomycin or amikacin), because the toxic effect of these drugs is additive: If possible, the aminoglycoside should be given daily for a minimum of three months (and perhaps thrice weekly thereafter). Ciprofloxacin should not be used in the treatment of tuberculosis if other fluoroquinolones are available. As of 2008, Cochrane reports that trials of other fluoroquinolones are ongoing. While Rifampin is an effective drug, lack of adherence has led to relapse. This is why the use of various first-line drugs, along with developing new drugs that are specific towards drug-resistant strains, is essential. There are a number of new anti-TB medications that are currently in the developmental stage that are directed to treat drug resistant strains; a few of these drugs are PA-824, OPC-67683, and R207910, all of which are in Phase II of development. PA-825 and OPC-6783 are both in the nitroimidazole class and have mechanisms involving bioactive reductive activation, but target different proteins in the strains. R207910 his a diarylquinoline that has a different mechanism; this drug directly inhibits energy production, so this drug may be a better option because it may not require as long of a treatment course as other drugs.