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impervious to being affected; "resistant to the effects of heat"; "resistant to persuasion"
infection transmitted by inhalation or ingestion of tubercle bacilli and manifested in fever and small lesions (usually in the lungs but in various other parts of the body in acute stages) (同)TB, T.B.

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結核({略}TB,T.B.) / 肺結核

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/01 12:49:12」(JST)

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Multi-drug-resistant tuberculosis (MDR-TB) is defined as a form of TB infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB drugs,^[1]^[2] isoniazid (INH) and rifampicin (RMP).^[3]

Five percent (5%) of all TB cases across the globe in 2013 were estimated to be MDR-TB cases, including 3.5% of newly diagnosed TB cases, and 20.5% of previously treated TB cases.^[2] While rates of MDR-TB infections are relatively low in North America and Western Europe, they are an increasingly serious problem worldwide, in particular in areas of the Russian Federation, the former Soviet Union and other parts of Asia.^[4]

MDR-TB infection may be classified as either primary or acquired.^[5] Primary MDR-TB occurs in patients who have not previously been infected with TB but who become infected with a strain that is resistant to treatment. Acquired MDR-TB occurs in patients during treatment with a drug regimen that is not effective at killing the particular strain of TB with which they have been infected. Rates of primary MDR-TB are low in North America and Western Europe: in the US in 2000, the rate of primary MDR-TB was 1% of all cases of TB nationally.^[5] Most cases of acquired MDR-TB are due to inappropriate treatment with a single anti-TB drug, usually INH. This can occur due to a medical provider, such as a doctor or nurse, improperly prescribing ineffective treatment, but may also be due to the patient not taking the medication correctly, which can be due to a variety of reasons, including expense or scarcity of medicines, patient forgetfulness, or patient stopping treatment early because they feel better.^[6]

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.^[6] In general, second-line drugs are less effective, more toxic and much more expensive than first-line drugs. Under ideal program conditions, MDR-TB cure rates can approach 70%.^[6]

Epidemiology

Cases of MDR tuberculosis have been reported in every country surveyed.^[7] MDR-TB most commonly develops in the course of TB treatment,^[8] and is most commonly due to doctors giving inappropriate treatment, or patients missing doses or failing to complete their treatment. Because MDR tuberculosis is an airborne pathogen, persons with active, pulmonary tuberculosis caused by a multidrug-resistant strain can transmit the disease if they are alive and coughing.^[7] TB strains are often less fit and less transmissible, and outbreaks occur more readily in people with weakened immune systems (e.g., patients with HIV).^[9]^[10]^[11]^[12]^[13] Outbreaks among non immunocompromised healthy people do occur,^[14] but are less common.^[8]

As of 2013, 3.7% of new tuberculosis cases have MDR-TB. Levels are much higher in those previously treated for tuberculosis - about 20%. WHO estimates that there were about 0.5 million new MDR-TB cases in the world in 2011. About 60% of these cases occurred in Brazil, China, India, the Russian Federation and South Africa alone.^[15] In Moldova, the crumbling health system has led to the rise of MDR-TB.^[16] In 2013, the Mexico–United States border was noted to be "a very hot region for drug resistant TB", though the number of cases remained small.^[17]

It has been known for many years that INH-resistant TB is less virulent in guinea pigs, and the epidemiological evidence is that MDR strains of TB do not dominate naturally. A study in Los Angeles, California found that only 6% of cases of MDR-TB were clustered. Likewise, the appearance of high rates of MDR-TB in New York City in the early 1990s was associated with the explosion of AIDS in that area.^[18]^[19] In New York City, a report issued by city health authorities states that fully 80 percent of all MDR-TB cases could be traced back to prisons and homeless shelters.^[20] When patients have MDR-TB, they require longer periods of treatment—about two years of multidrug regimen. Several of the less powerful second-line drugs, which are required to treat MDR-TB, are also more toxic, with side effects such as nausea, abdominal pain, and even psychosis. The Partners in Health team had treated patients in Peru who were sick with strains that were resistant to ten and even twelve drugs. Most such patients require adjuvant surgery for any hope of a cure.^[21]

MDR-TB in Russian prisons

Overview

One of the so-called “hot-spots” of drug-resistant tuberculosis is within the Russian prison system. Infectious disease researchers Nachega & Chaisson report that 10% of the one million prisoners within the system have active TB.^[22] One of their studies found that 75% of newly diagnosed inmates with TB are resistant to at least one drug; 40% of new cases are multi-drug resistant.^[22] In 1997, TB accounted for almost half of all Russian prison deaths, and as Bobrik et al. point out in their public health study, the 90% reduction in TB incidence contributed to a consequential fall in the prisoner death rate in the years following 1997.^[23] Baussano et al. articulate that concerning statistics like these are especially worrisome because spikes in TB incidence in prisons are linked to corresponding outbreaks in surrounding communities.^[24] Additionally, rising rates of incarceration, especially in Central Asian and Eastern European countries like Russia, have been correlated with higher TB rates in civilian populations.^[23] Even as the DOTS program is expanded throughout Russian prisons, researchers such as Shin et al. have noted that wide-scale interventions have not had their desired effect, especially with regard to the spread of drug-resistant strains of TB.^[25]

Contributing factors

There are several elements of the Russian prison system that enable the spread of MDR-TB and heighten its severity. Overcrowding in prisons is especially conducive to the spread of tuberculosis; an inmate in a prison hospital has (on average) 3 meters of personal space, and an inmate in a correctional colony has 2 meters.^[23] Specialized hospitals and treatment facilities within the prison system, known as TB colonies, are intended to isolate infected prisoners to prevent transmission; however, as Ruddy et al. demonstrate, there are not enough of these colonies to sufficiently protect staff and other inmates.^[26] Additionally, many cells lack adequate ventilation, which increases likelihood of transmission. Bobrik et al. have also noted food shortages within prisons, which deprive inmates of the nutrition necessary for healthy functioning.^[23]

Comorbidity of HIV within prison populations has also been shown to worsen health outcomes. Nachega & Chaisson articulate that while HIV-infected prisoners are not more susceptible MDR-TB infection, they are more likely to progress to serious clinical illness if infected.^[22] According to Stern, HIV infection is 75 times more prevalent in Russian prison populations than in the civilian population.^[27] Therefore, prison inmates are both more likely to become infected with MDR-TB initially and to experience severe symptoms because of previous exposure to HIV.

Shin et al. emphasize another factor in MDR-TB prevalence in Russian prisons: alcohol and substance use.^[25] Ruddy et al. showed that risk for MDR-TB is three times higher among recreational drug users than non-users.^[26] Shin et al.’s study demonstrated that alcohol usage was linked to poorer outcomes in MDR-TB treatment; they also noted that a majority of subjects within their study (many of whom regularly used alcohol) were nevertheless cured by their aggressive treatment regimen.^[25]

Non-compliance with treatment plans is often cited as a contributor to MDR-TB transmission and mortality. Indeed, of the 80 newly-released TB-infected inmates in Fry et al.’s study, 73.8% did not report visiting a community dispensary for further treatment.^[28] Ruddy et al. cite release from facilities as one of the main causes of interruption in prisoner’s TB treatment, in addition to non-compliance within the prison and upon reintegration into civilian life.^[26] Fry et al.’s study also listed side effects of TB treatment medications (especially in HIV positive individuals), financial worries, housing insecurities, family problems, and fear of arrest as factors that prevented some prisoners from properly adhering to TB treatment.^[28] They also note that some researchers have argued that the short-term gains TB-positive prisoners receive, such as better food or work exclusion, may dis-incentivize becoming cured.^[28] In their World Health Organization article, Gelmanova et al. posit that non-adherence to TB treatment indirectly contributes to bacterial resistance.^[29] Although ineffective or inconsistent treatment does not “create” resistant strains, mutations within the high bacterial load in non-adherent prisoners can cause resistance.

Nachega & Chaisson argue that inadequate TB control programs are the strongest driver of MDR-TB incidence.^[22] They note that prevalence of MDR-TB is 2.5 times higher in areas of poorly controlled TB.^[22] Russian-based therapy (i.e., not DOTS) has been criticized by Kimerling et al. as “inadequate” in properly controlling TB incidence and transmission.^[30] Bobrik et al. note that treatment for MDR-TB is equally inconsistent; the second-line drugs used to treat the prisoners lack specific treatment guidelines, infrastructure, training, or follow-up protocols for prisoners reentering civilian life.^[23]

Policy impacts

As Ruddy et al. note in their scholarly article, Russia’s recent penal reforms will greatly reduce the number of inmates inside prison facilities and thus increase the number of ex-convicts integrated into civilian populations.^[26] Because the incidence of MDR-TB is strongly predicted by past imprisonment, the health of Russian society will be greatly impacted by this change.^[26] Formerly incarcerated Russians will re-enter civilian life and remain within that sphere; as they live as civilians, they will infect others with the contagions they were exposed to in prison. Researcher Vivian Stern argues that the risk of transmission from prison populations to the general public calls for an integration of prison healthcare and national health services to better control both TB and MDR-TB.^[27] While second-line drugs necessary for treating MDR-TB are arguably more expensive than a typical regimen of DOTS therapy, infectious disease specialist Paul Farmer posits that the outcome of leaving infected prisoners untreated could cause a massive outbreak of MDR-TB in civilian populations, thereby inflicting a heavy toll on society.^[31] Additionally, as MDR-TB spreads, the threat of the emergence of totally-drug-resistant TB becomes increasingly apparent.

Mechanism of M. tuberculosis drug resistance

Some of the ways the tubercle bacillus acquires drug resistance are:^[32]

Cell wall: The cell wall of M. tuberculosis consists of complex lipids, and it acts as a permeability barrier from drugs.
Drug modifying & inactivating enzymes: The M. tuberculosis genome codes for certain enzymes that make it drug resistant. The enzymes usually phosphorylate, acetylate, or adenylate the drug compounds.
Drug efflux systems
Mutations: Spontaneous mutations in the M. tuberculosis genome can give rise to proteins that make the bacterium drug resistant, depending on the drug action.

Examples of mutations that make M. tuberculosis drug resistant:^[33]^[34] An example of this is the mutation in the rpoB gene, which encodes the beta subunit of the bacteria's RNA Polymerase. This mutation makes the bacillus resistant to Rifampicin. Non-resistant TB is sensitive to Rifampicin because this drug binds to the beta subunit of the RNA Polymerase, and hence disrupts transcription elongation. When the rpoB gene is mutated, the resulting beta subunit protein has different amino acids, and thus a different conformation. Rifampicin can no longer bind to the beta subunit and prevent transcription.

Other mutations make the bacterium resistant to other drugs. For example, there are many mutations that can make M. tuberculosis resistant to Isoniazid. Mutations leading to INH resistance have been identified in different gene targets including katG, inhA, ahpC and other genes that remain to be established. 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 causes the enzyme catalase peroxidase unable to convert INH to its biologically active form. Hence, INH is not able to affect M. tuberculosis.

Extensively drug-resistant TB

MDR-TB can become resistant to the major second-line drug groups: fluoroquinolones and injectable drugs. When MDR-TB is resistant to at least one drug from each group, it's defined as extensively drug-resistant tuberculosis (XDR-TB).

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.^[3] About 9% of MDR-TB cases also have resistance to two other classes of drugs, or extensively drug-resistant TB (XDR-TB).^[15]

Prevention of MDR TB

There are several ways that drug resistance to TB, and drug resistance in general, can be prevented:^[35]^[36]

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 his/her 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.
Patients with HIV/AIDS should be identified and diagnosed as soon as possible. They lack the immunity to fight the TB infection and are at great risk of developing drug resistance.
Identify contacts who could have contracted TB: i.e. 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."^[37]

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 treatment of MDR-TB in some parts of 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%.^[38]

However, TB clinicians^[who?] have expressed concern in the DOTS program administered in the Republic of Georgia because it is anchored in a 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.^[39]

Erin Koch has utilized Paul Farmer’s concept of “structural” violence as a perspective for understanding how “institutions, environment, poverty, and power reproduce, solidify, and naturalize the uneven distribution of disease and access to resources”. She has also studied the effectiveness of the DOTS protocol in the widespread disease of tuberculosis in the Georgian prison system.^[40] Unlike the DOTS passive case finding utilized for the general Georgian public, the multiple-level surveillance in the prison system has proven more successful in reducing the spread of tuberculosis while increasing rates of cure.^{[citation needed]}

Koch critically notes that because the DOTS protocol aims to change the individual’s behavior without addressing the need to change the institutional, political, and economic contexts, certain limitations arise, such as MDR tuberculosis.^{[citation needed]}

Paul Farmer believes that DOTS should be the cornerstone of tuberculosis control around the world.^{[citation needed]}

Treatment

Usually, multidrug-resistant tuberculosis can be cured with long treatments of second-line drugs, but these are more expensive than first-line drugs and have more adverse effects.^[1] The treatment and prognosis of MDR-TB are much more akin to those for cancer than to those for infection. MDR-TB has a mortality rate of up to 80%, which depends on a number of factors, including

How many drugs the organism is resistant to (the fewer the better)
How many drugs the patient is given (patients treated with five or more drugs do better)
Whether an injectable drug is given or not (it should be given for the first three months at least)
The expertise and experience of the physician responsible
How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient)
Whether the patient is HIV positive or not (HIV co-infection is associated with an increased mortality).

The majority of patients suffering from multi-drug-resistant tuberculosis do not receive treatment, as they are found in underdeveloped countries or in poverty. Denial of treatment remains a difficult human rights issue, as the high cost of second-line medications often precludes those who cannot afford therapy.^[7]

A study of cost-effective strategies for tuberculosis control supported three major policies. First, the treatment of smear-positive cases in DOTS programs must be the foundation of any tuberculosis control approach, and should be a basic practice for all control programs. Second, there is a powerful economic case for treating smear-negative and extra-pulmonary cases in DOTS programs along with treating smear-negative and extra-pulmonary cases in DOTS programs

as a new WHO “STOP TB” approach and the second global plan for tuberculosis control. Last, but not least, the study shows that significant scaling up of all interventions is needed in the next 10 years if the millennium development goal and related goals for tuberculosis control are to be achieved. If the case detection rate can be improved, this will guarantee that people who gain access to treatment facilities are covered and that coverage is widely distributed to people who do not now have access.^[41]

In general, treatment courses are measured in months to years; MDR-TB may require surgery, and death rates remain high despite optimal treatment. However, good outcomes for patients are still possible.^[42]

The treatment of MDR-TB must be undertaken by physicians experienced in the treatment of MDR-TB. Mortality and morbidity in patients treated in non-specialist centers are significantly higher to those of patients treated in specialist centers.

In addition to the obvious risks (i.e., known exposure to a patient with MDR-TB), risk factors for MDR-TB include HIV infection, previous incarceration, failed TB treatment, failure to respond to standard TB treatment, and relapse following standard TB treatment.

Treatment of MDR-TB must be done on the basis of sensitivity testing: it is impossible to treat such patients without this information. When treating a patient with suspected MDR-TB, pending the result of laboratory sensitivity testing, the patient should be started on SHREZ (Streptomycin+isonicotinyl Hydrazine+Rifampicin+Ethambutol+pyraZinamide)+moxifloxacin+cycloserine. There is evidence that previous therapy with a drug for more than a month is associated with diminished efficacy of that drug regardless of in vitro tests indicating susceptibility.^[43] Hence, a detailed knowledge of the treatment history of each patient is essential.

A gene probe for rpoB is available in some countries. This serves as a useful marker for MDR-TB, because isolated RMP resistance is rare (except when patients have a history of being treated with rifampicin alone). If the results of a gene probe (rpoB) are known to be positive, then it is reasonable to omit RMP and to use SHEZ+MXF+cycloserine. The reason for maintaining the patient on INH is that INH is so potent in treating TB that it is foolish to omit it until there is microbiological proof that it is ineffective (even though isoniazid resistance so commonly occurs with rifampicin resistance).

When sensitivities are known and the isolate is confirmed as resistant to both INH and RMP, five drugs should be chosen in the following order (based on known sensitivities):

an aminoglycoside (e.g., amikacin, kanamycin) or polypeptide antibiotic (e.g., capreomycin)
pyrazinamide
ethambutol
a fluoroquinolone (e.g., moxifloxacin (ciprofloxacin) should no longer be used^[44]);
rifabutin
cycloserine
a thioamide: prothionamide or ethionamide
PAS
a macrolide: e.g., clarithromycin
linezolid
high-dose INH (if low-level resistance)
interferon-γ
thioridazine
Ampicillin

Note: Drugs placed nearer the top of the list are more effective and less toxic; drugs placed nearer the bottom of the list are less effective or more toxic, or more difficult to obtain.

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.^[45]

There is no intermittent regimen validated for use in MDR-TB, but clinical experience is that giving injectable drugs for five days a week (because there is no-one available to give the drug at weekends) does not seem to result in inferior results. Directly observed therapy helps to improve outcomes in MDR-TB and should be considered an integral part of the treatment of MDR-TB.^[46]

Response to treatment must be obtained by repeated sputum cultures (monthly if possible). Treatment for MDR-TB must be given for a minimum of 18 months and cannot be stopped until the patient has been culture-negative for a minimum of nine months. It is not unusual for patients with MDR-TB to be on treatment for two years or more.^{[citation needed]}

Patients with MDR-TB should be isolated in negative-pressure rooms, if possible. Patients with MDR-TB should not be accommodated on the same ward as immunosuppressed patients (HIV-infected patients, or patients on immunosuppressive drugs). Careful monitoring of compliance with treatment is crucial to the management of MDR-TB (and some physicians insist on hospitalisation if only for this reason). Some physicians will insist that these patients remain isolated until their sputum is smear-negative, or even culture-negative (which may take many months, or even years). Keeping these patients in hospital for weeks (or months) on end may be a practical or physical impossibility, and the final decision depends on the clinical judgement of the physician treating that patient. The attending physician should make full use of therapeutic drug monitoring (in particular, of the aminoglycosides) both to monitor compliance and to avoid toxic effects.

Some supplements may be useful as adjuncts in the treatment of tuberculosis, but, for the purposes of counting drugs for MDR-TB, they count as zero (if four drugs are already in the regimen, it may be beneficial to add arginine or vitamin D or both, but another drug will be needed to make five).

arginine^[47] (peanuts are a good source)
vitamin D^[48]
Dzherelo^[49]
V5 Immunitor^[50]

The drugs listed below have been used in desperation, and it is uncertain as to whether they are effective at all. They are used when it is not possible to find five drugs from the list above.

imipenem^[51]
co-amoxiclav^[52]^[53]
clofazimine^[54]^[55]^[56]
prochlorperazine^[57]
metronidazole^[58]

On December 28, 2012 the U.S. Food and Drug Administration (FDA) approved bedaquiline (marketed as Sirturo by Johnson & Johnson) to treat multi-drug resistant tuberculosis, the first new treatment in 40 years. Sirturo is to be used in a combination therapy for patients who have failed standard treatment and have no other options. Sirturo is an adenosine triphosphate synthase (ATP synthase) inhibitor.^[59]^[60]

The following drugs are experimental compounds that are not commercially available, but may be obtained from the manufacturer as part of a clinical trial or on a compassionate basis. Their efficacy and safety are unknown:

pretomanid^[61] (manufactured by Novartis, developed in partnership with TB Alliance)^[62]
delamanid

In cases of extremely resistant disease, surgery to remove infection portions of the lung is, in general, the final option. The center with the largest experience in this is the National Jewish Medical and Research Center in Denver, Colorado. In 17 years of experience, they have performed 180 operations; of these, 98 were lobectomies and 82 were pneumonectomies. There is a 3.3% operative mortality, with an additional 6.8% dying following the operation; 12% experienced significant morbidity (in particular, extreme breathlessness). Of 91 patients who were culture-positive before surgery, only 4 were culture-positive after surgery.

The resurgence of tuberculosis in the United States, the advent of HIV-related tuberculosis, and the development of strains of TB resistant to the first-line therapies developed in recent decades—serve to reinforce the thesis that Mycobacterium tuberculosis, the causative organism, makes its own preferential option for the poor.^[63] The simple truth is that almost all tuberculosis deaths result from a lack of access to existing effective therapy.^[64]

References

Books

Farmer, Paul (1999). Infections and inequalities : the modern plagues. Berkeley, California, United States: University of California Press. ISBN 978-0-520-22913-6.
Farmer, Paul (2005). Pathologies of Power: health, human rights, and the new war on the poor. Berkeley, California, United States: University of California Press. ISBN 978-0-520-93147-3.
Garrett, Laurie (1994). The coming plague : newly emerging diseases in a world out of balance. New York, New York, United States: Farrar, Straus and Giroux. ISBN 978-0-374-12646-9.
Garrett, Laurie (2000). Betrayal of trust: the collapse of global public health. New York, New York, United States: Hyperion Books. ISBN 978-0-7868-6522-2.

Notes

^ ^a ^b "Scientific Facts on Drug-resistant Tuberculosis". GreenFacts Website. 2008-12-18. Retrieved 2009-03-26.
^ ^a ^b WHO MDR TB Factsheet (PDF) http://www.who.int/tb/challenges/mdr/mdr_tb_factsheet.pdf. Retrieved 9 May 2015. Missing or empty |title= (help)
^ ^a ^b Dalton, Tracy; Cegielski, Peter; Akksilp, Somsak; Asencios, Luis; Caoili, Janice Campos; Cho, Sang-Nae; Erokhin, Vladislav V; Ershova, Julia; Gler, Ma Tarcela; Kazennyy, Boris Y; Kim, Hee Jin; Kliiman, Kai; Kurbatova, Ekaterina; Kvasnovsky, Charlotte; Leimane, Vaira; Van Der Walt, Martie; Via, Laura E; Volchenkov, Grigory V; Yagui, Martin A; Kang, Hyungseok; Global Petts, Investigators; Akksilp, R; Sitti, W; Wattanaamornkiet, W; Andreevskaya, SN; Chernousova, LN; Demikhova, OV; Larionova, EE; Smirnova, TG; Vasilieva, IA (2012). "Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: A prospective cohort study". The Lancet 380 (9851): 1406–17. doi:10.1016/S0140-6736(12)60734-X. PMID 22938757.
^ WHO https://extranet.who.int/sree/Reports?op=vs&path=/WHO_HQ_Reports/G2/PROD/EXT/MDRTB_Indicators_map. Retrieved 9 May 2015. |first1= missing |last1= in Authors list (help); Missing or empty |title= (help)
^ ^a ^b Longo, Fausci; et al. (2012). Harrison's Principles of Internal Medicine (18th ed.). New York: McGraw Hill. pp. Chapter 165: Tuberculosis. Retrieved 9 May 2015.
^ ^a ^b ^c Adams and Woelke (2014). Understanding Global Health. Chapter 10: TB and HIV/AIDS (12th ed.). McGraw Hill. Retrieved 9 May 2015.
^ ^a ^b ^c Farmer, Paul (2001). "The Major Infectious Diseases in the World — to Treat or Not to Treat?". New England Journal of Medicine 345 (3): 208–10. doi:10.1056/NEJM200107193450310. PMID 11463018.
^ ^a ^b Wood, Alastair J.J.; Iseman, Michael D. (1993). "Treatment of Multidrug-Resistant Tuberculosis". New England Journal of Medicine 329 (11): 784–91. doi:10.1056/NEJM199309093291108. PMID 8350889.
^ Centers for Disease Control (CDC) (August 1991). "Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons—Florida and New York, 1988–1991". Morb Mortal Wkly Rep 40 (34): 585–91. PMID 1870559.
^ Edlin, Brian R.; Tokars, Jerome I.; Grieco, Michael H.; Crawford, Jack T.; Williams, Julie; Sordillo, Emelia M.; Ong, Kenneth R.; Kilburn, James O.; Dooley, Samuel W.; Castro, Kenneth G.; Jarvis, William R.; Holmberg, Scott D. (1992). "An Outbreak of Multidrug-Resistant Tuberculosis among Hospitalized Patients with the Acquired Immunodeficiency Syndrome". New England Journal of Medicine 326 (23): 1514–21. doi:10.1056/NEJM199206043262302. PMID 1304721.
^ Pitchenik, Arthure; Burr, Janice; Laufer, Marla; Miller, Gary; Cacciatore, Robert; Bigler, Williamj.; Witte, Johnj.; Cleary, Timothy (1990). "Outbreaks of drug-resistant tuberculosis at AIDS centre". The Lancet 336 (8712): 440–1. doi:10.1016/0140-6736(90)91987-L. PMID 1974967.
^ Centers for Disease Control (CDC) (March 1991). "Transmission of multidrug-resistant tuberculosis from an HIV-positive client in a residential substance-abuse treatment facility—Michigan". Morb Mortal Wkly Rep 40 (8): 129–31. PMID 1900098.
^ Fischl, Margaret A.; Uttamchandani, RB; Daikos, GL; Poblete, RB; Moreno, JN; Reyes, RR; Boota, AM; Thompson, LM; Cleary, TJ; Lai, S (1992). "An Outbreak of Tuberculosis Caused by Multiple-Drug-resistant Tubercle Bacilli among Patients with HIV Infection". Annals of Internal Medicine 117 (3): 177–83. doi:10.7326/0003-4819-117-3-177. PMID 1616211.
^ Centers for Disease Control (1990). "Outbreak of multidrug-resistant tuberculosis—Texas, California, and Pennsylvania". Morb Mortal Wkly Rep 39 (22): 369–72. PMID 2111434.
^ ^a ^b WHO. "Multidrug-resistant tuberculosis (MDR-TB) 2013 Update" (PDF). World Health Organization. Retrieved 14 June 2013.
^ Rochkind, David. "Moldova: Fighting a Deadly Disease". Pulitzer Center on Crisis Reporting. Retrieved 23 September 2012.
^ McKay, Betsy (March 9–10, 2013). "Risk of Deadly TB Exposure Grows Along U.S.—Mexico Border". The Wall Street Journal (paper). p. A1.
^ Frieden, Thomas R.; Sterling, Timothy; Pablos-Mendez, Ariel; Kilburn, James O.; Cauthen, George M.; Dooley, Samuel W. (1993). "The Emergence of Drug-Resistant Tuberculosis in New York City". New England Journal of Medicine 328 (8): 521–6. doi:10.1056/NEJM199302253280801. PMID 8381207.
^ Garrett 2000, p. 266ff.
^ Garrett 1994, p. 524.
^ Farmer 2005, p. 118.
^ ^a ^b ^c ^d ^e Nachega, J., & Chaisson, R. (2003). Tuberculosis Drug Resistance: A Global Threat. Clinical Infectious Diseases, 36(1), S24-S30.
^ ^a ^b ^c ^d ^e Bobrik, A., Danishevski, K., Eroshina, K., & McKee, M. (2005) Prison Health in Russia: The Larger Picture. Journal of Public Health Policy, 26(1), 30-59.
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External links

Video: Drug-Resistant TB in Russia July 24, 2007, Woodrow Wilson Center event featuring Salmaan Keshavjee and Murray Feshbach
TB Drug Resistance Mutation Database
MDR-TB : a story of Hope,Struggle & Triumph
MDR-TB (DOTS Plus) protocol followed under RNTCP in India (PDF)
The Strange, Isolated Life of a Tuberculosis Patient in the 21st Century

UpToDate Contents

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1. 薬剤耐性結核の診断、治療、および予防 diagnosis treatment and prevention of drug resistant tuberculosis
2. 薬剤耐性結核の疫学および分子メカニズム epidemiology and molecular mechanisms of drug resistant tuberculosis
3. 広範囲薬剤耐性結核の臨床症状、診断、および治療 clinical manifestations diagnosis and treatment of extensively drug resistant tuberculosis
4. 広範囲薬剤耐性結核の疫学 epidemiology of extensively drug resistant tuberculosis
5. 小児における結核 tuberculosis disease in children

English Journal

Salicylanilide pyrazinoates inhibit in vitro multidrug-resistant Mycobacterium tuberculosis strains, atypical mycobacteria and isocitrate lyase.

Krátký M1, Vinšová J2, Novotná E3, Stolaříková J4.Author information 1Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: martin.kratky@faf.cuni.cz.2Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: jarmila.vinsova@faf.cuni.cz.3Department of Biochemical Sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: eva.novotna@faf.cuni.cz.4Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 702 00 Ostrava, Czech Republic. Electronic address: jirina.stolarikova@zu.cz.AbstractThe development of antimicrobial agents represents an up-to-date topic. This study investigated in vitro antimycobacterial activity, mycobacterial isocitrate lyase inhibition and cytotoxicity of salicylanilide pyrazinoates. They may be considered being mutual prodrugs of both antimycobacterial active salicylanilides and pyrazinoic acid (POA), an active metabolite of pyrazinamide, in which these esters are likely hydrolysed without presence of pyrazinamidase/nicotinamidase. Minimum inhibitory concentrations (MICs) of the esters were within the range 0.5-8μmol/l for Mycobacterium tuberculosis and 1-32μmol/l for nontuberculous mycobacteria (Mycobacterium avium, Mycobacterium kansasii). All esters showed a weak inhibition (8-17%) of isocitrate lyase at the concentration of 10μmol/l. The most active pyrazinoates showed MICs for multidrug-resistant tuberculosis strains in the range of 0.125-2μmol/l and no cross-resistance with clinically used drugs, thus being the most in vitro efficacious salicylanilide esters with 4-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate superiority (MICs⩽0.25μmol/l). This promising activity is likely due to an additive or synergistic effect of released POA and salicylanilides. Selectivity indexes for the most active salicylanilide pyrazinoates ranged up to 64, making some derivatives being attractive candidates for the next research; 4-bromo-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate showed the most convenient toxicity profile.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.Eur J Pharm Sci.2014 Mar 12;53:1-9. doi: 10.1016/j.ejps.2013.12.001. Epub 2013 Dec 10.
The development of antimicrobial agents represents an up-to-date topic. This study investigated in vitro antimycobacterial activity, mycobacterial isocitrate lyase inhibition and cytotoxicity of salicylanilide pyrazinoates. They may be considered being mutual prodrugs of both antimycobacterial activ
PMID 24333643

Synthetic modifications of the immunomodulating peptide thymopentin to confer anti-mycobacterial activity.

Wang Y1, Ke XY2, Khara JS1, Bahety P1, Liu S2, Seow SV3, Yang YY4, Ee PL5.Author information 1Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.2Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore.3Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Rd, Singapore 119074, Singapore.4Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore. Electronic address: yyyang@ibn.a-star.edu.sg.5Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address: phaeplr@nus.edu.sg.AbstractEffective global control of tuberculosis (TB) is increasingly threatened by the convergence of multidrug-resistant TB and the human immunodeficiency virus (HIV) infection. TB/HIV coinfections exert a tremendous burden on the host's immune system, and this has prompted the clinical use of immunomodulators to enhance host defences as an alternative therapeutic strategy. In this study, we modified the clinically used synthetic immunomodulatory pentapeptide, thymopentin (TP-5, RKDVY), with six arginine residues (RR-6, RRRRRR) at the N- and C-termini to obtain the cationic peptides, RR-11 (RKDVYRRRRRR-NH2) and RY-11 (RRRRRRRKDVY-NH2), respectively. The arginine residues conferred anti-mycobacterial activity to TP-5 in the peptides as shown by effective minimum inhibitory concentrations of 125 mg/L and killing efficiencies of >99.99% against both rifampicin-susceptible and -resistant Mycobacterium smegmatis. The immunomodulatory action of the peptides remained unaffected as shown by their ability to stimulate TNF-α production in RAW 264.7 mouse macrophage cells. A distinct change in surface morphology after peptide treatment was observed in scanning electron micrographs, while confocal microscopy and dye leakage studies suggested bacterial membrane disruption by the modified peptides. The modified peptides were non-toxic and did not cause hemolysis of rat red blood cells up to a concentration of 2000 mg/L. Moreover, RY-11 showed synergism with rifampicin and reduced the effective concentration of rifampicin, while preventing the induction of rifampicin resistance. The synthetic peptides may have a potential application in both immunocompetent and immunocompromised TB patients.
Biomaterials.Biomaterials.2014 Mar;35(9):3102-9. doi: 10.1016/j.biomaterials.2013.12.049. Epub 2014 Jan 8.
Effective global control of tuberculosis (TB) is increasingly threatened by the convergence of multidrug-resistant TB and the human immunodeficiency virus (HIV) infection. TB/HIV coinfections exert a tremendous burden on the host's immune system, and this has prompted the clinical use of immunomodul
PMID 24411680

A Homogeneous Signal-On Strategy for the Detection of rpoB Genes of Mycobacterium tuberculosis Based on Electrochemiluminescent Graphene Oxide and Ferrocene Quenching.

Li F, Yu Y, Li Q, Zhou M, Cui H.Author information CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China , 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China.AbstractTuberculosis (TB) remains one of the leading causes of morbidity and mortality all over the world and multidrug resistance TB (MDR-TB) pose a serious threat to the TB control and represent an increasing public health problem. In this work, we report a homogeneous signal-on electrochemiluminescence (ECL) DNA sensor for the sensitive and specific detection of rpoB genes of MDR-TB by using ruthenium(II) complex functionalized graphene oxide (Ru-GO) as suspension sensing interface and ferrocene-labeled ssDNA (Fc-ssDNA) as ECL intensity controller. The ECL of Ru-GO could be effectively quenched by Fc-ssDNA absorbed on the Ru-GO nanosheets. The Ru-GO has good discrimination ability over ssDNA and dsDNA. Mutant ssDNA target responsible for the drug resistant tuberculosis can hybridize with Fc-ssDNA and release Fc-ssDNA from Ru-GO surface, leading to the recovery of ECL. Mutant ssDNA target can be detected in a range from 0.1 to 100 nM with a detection limit of 0.04 nM. The proposed protocol is sensitive, specific, simple, time-saving and polymerase chain reaction free without complicated immobilization, separation and washing steps, which creates a simple but valuable tool for facilitating fast and accurate detection of disease related specific sequences or gene mutations.
Analytical chemistry.Anal Chem.2014 Feb 4;86(3):1608-13. doi: 10.1021/ac403281g. Epub 2014 Jan 14.
Tuberculosis (TB) remains one of the leading causes of morbidity and mortality all over the world and multidrug resistance TB (MDR-TB) pose a serious threat to the TB control and represent an increasing public health problem. In this work, we report a homogeneous signal-on electrochemiluminescence (
PMID 24422505

Japanese Journal

Tuberculosis in and after chest surgery : A 15-patient study in a Japanese community hospital

Yoshida Junichi,Inoue Masaaki,Kanayama Masatoshi [他]
日本外科感染症学会雑誌 12(1), 1-8, 2015-02
NAID 40020386575

Memorial Lecture by Imamura Award Winner : STUDY OF TUBERCULOSIS IN PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION

NAGAI Hideaki
結核 90(1), 1-5, 2015-01
NAID 40020328617

Clinical Outcomes of Linezolid Treatment for Extensively Drug-Resistant Tuberculosis in Beijing, China: A Hospital-Based Retrospective Study

, , , , , ,
Japanese Journal of Infectious Diseases 68(3), 244-247, 2015
… Studies have shown that linezolid achieves good clinical outcomes against multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). … Of the 16 patients, 14 had received previous treatment for tuberculosis. …
NAID 130005070802