multidrug-resistant tuberculosis multidrug-resistant tuberculosis 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 rifampin. some forms of tb are also resistant to second-line medications, and are called extensively drug-resistant tb (xdr-tb). multidrug-resistance tuberculosismycobacterium tuberculosis bacteria seen by microscopespecialtyinfectious disease 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, rifampin, 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.) 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), or 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 two years, compared to the six 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%. 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-resistant 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 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. 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 main article: extensively drug-resistant tuberculosis mdr-tb can become resistant to the major second-line tb drug groups: fluoroquinolones (moxifloxacin, ofloxacin) and injectable aminoglycoside or polypeptide drugs (amikacin, capreomycin, kanamycin). when mdr-tb is resistant to at least one drug from each group, it is classified as extensively drug-resistant tuberculosis (xdr-tb). who has revised the definitions of pre-xdr-tb and xdr-tb in 2021 as following: pre-xdr-tb: tb caused by mycobacterium tuberculosis (m. tuberculosis) strains that fulfill the definition of mdr/rr-tb and which are also resistant to any fluoroquinolone. xdr-tb: tb caused by mycobacterium tuberculosis (m. tuberculosis) strains that fulfill the definition of mdr/rr-tb and which are also resistant to any fluoroquinolone and at least one additional group a drug. the group a drugs are currently levofloxacin or moxifloxacin, bedaquiline and linezolid, therefore xdr-tb is mdr/rr-tb that is resistant to a fluoroquinolone and at least one of bedaquiline or linezolid (or both). in a study of mdr-tb patients from 2005 to 2008 in various countries, 43.7% had resistance to at least one second-line drug. about 9% of mdr-tb cases are resistant to a drug from both classes and classified as xdr-tb. in the past 10 years tb strains have emerged in italy, iran, india, and south africa which are resistant to all available first and second line tb drugs, classified as totally drug-resistant tuberculosis, though there is some controversy over this term. increasing levels of resistance in tb strains threaten to complicate the current global public health approaches to tb control. new drugs are being developed to treat extensively resistant forms but major improvements in detection, diagnosis, and treatment will be needed. there have been reports of totally drug-resistant tuberculosis, but such strains of tb are not recognized by the who. prevention there are several ways that drug resistance to tb, and drug resistance in general, can be prevented: rapid diagnosis & treatment of tb: one of the greatest risk factors for drug-resistant tb is problems in treatment and diagnosis, especially in developing countries. if tb is identified and treated soon, drug resistance can be avoided. completion of treatment: previous treatment of tb is an indicator of mdr tb. if the patient does not complete their antibiotic treatment, or if the physician does not prescribe the proper antibiotic regimen, resistance can develop. also, drugs that are of poor quality or less in quantity, especially in developing countries, contribute to mdr tb. identifying and diagnosing patients with hiv/aids as soon as possible. they lack the immunity to fight the tb infection and are at great risk of developing drug resistance. identifying contacts who could have contracted tb: family members, people in close contact, etc. research: much research and funding is needed in the diagnosis, prevention and treatment of tb and mdr tb. "opponents of a universal tuberculosis treatment, reasoning from misguided notions of cost-effectiveness, fail to acknowledge that mdrtb is not a disease of poor people in distant places. the disease is infectious and airborne. treating only one group of patients looks inexpensive in the short run, but will prove disastrous for all in the long run." paul farmer dots-plus community-based treatment programs such as dots-plus, a mdr-tb-specialized treatment using the popular directly observed therapy – short course (dots) initiative, have shown considerable success in the world. in these locales, these programs have proven to be a good option for proper treatment of mdr-tb in poor, rural areas. a successful example has been in lima, peru, where the program has seen cure rates of over 80%. however, the dots program administered in the republic of georgia uses passive case finding. this means that the system depends on patients coming to health care providers, without conducting compulsory screenings. as medical anthropologists like erin koch have shown, this form of implementation does not suit all cultural structures. they urge that the dots protocol be constantly reformed in the context of local practices, forms of knowledge and everyday life. treatment