Multidrug-resistant tuberculosis

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.^[12] 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.^[5][8]

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.^[13] Globally, most MDR-TB cases occur in South America, Southern Africa, India, China, and the former Soviet Union.^[14]

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.^[9] Under ideal program conditions, MDR-TB cure rates can approach 70%.^[9]

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.^[15] 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.^[16]

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:^[17]

1. 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.
2. 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.
3. Drug efflux
   systems: The TB cell contains molecular systems that actively pump drug molecules out of the cell.
4. Mutations: Spontaneous mutations in the TB genome can alter proteins which are the target of drugs, making the bacteria drug-resistant.^[18]

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.^[19]

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.^[20][21] The discovery of new molecular targets is essential to overcome drug-resistance problems.^[22]

In some TB bacteria, the acquisition of these mutations can be explained by other mutations in the DNA recombination, recognition and repair machinery.^[23] Mutations in these genes allow the bacteria to have a higher overall mutation rate and to accumulate mutations that cause drug resistance more quickly.^[24][25]

Extensively drug-resistant TB

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).^[8]

WHO has revised the definitions of pre-XDR-TB and XDR-TB in 2021 as following:^[26]

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.^[27] About 9% of MDR-TB cases are resistant to a drug from both classes and classified as XDR-TB.^[1][28]

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.^[29][30][31] 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.^[30]

There have been reports of totally drug-resistant tuberculosis, but such strains of TB are not recognized by the WHO.^[32]

Prevention

There are several ways that drug resistance to TB, and drug resistance in general, can be prevented:^[33][34]

1. 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.
2. 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.
3. 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.
4. Identifying contacts who could have contracted TB: family members, people in close contact, etc.
5. 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 ^[35]

DOTS-Plus

Community-based treatment programs such as DOTS-Plus, a MDR-TB-specialized treatment using the popular

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.^[37]

Treatment

Usually, multidrug-resistant tuberculosis can be cured with long treatments of second-line drugs, but these are more expensive than

The majority of patients with multidrug-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.^[40]

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 a 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 than those of patients treated in specialist centers. 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 could be started on SHREZ (Streptomycin+ isonicotinyl Hydrazine+ Rifampicin+Ethambutol+ pyraZinamide) and moxifloxacin with 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. 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.^{[citation needed]}

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).^{[citation needed]}

For treatment of RR- and MDT-TB, WHO treatment guidelines are as follows: "a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines – one chosen from Group A, one from Group B, and at least two from Group C3 (conditional recommendation, very low certainty in the evidence). If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five. It is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation, very low certainty in the evidence)."^[44] Medicines recommended are the following:

• Group A: Fluoroquinolones (levofloxacin, moxifloxicin), linezolid, bedaquiline
• Group B: Clofazimine, cycloserine/terizidone
• Group C: Other core second-line agents (ethambutol, delamanid, pyrazinamide, imipenem-cilastatin/meropenem, amikacin/streptomycin, ethionamide/prothionamide, p-aminosalicylic acid)

For patients with RR-TB or MDR-TB, "not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead of the longer regimens (conditional recommendation, very low certainty in the evidence)."^[45]

The factual accuracy of parts of this article (those related to Pretomanid, delamanid, bedaquiline approval & current clinical experience (if any)) may be compromised due to out-of-date information. Please help update this article to reflect recent events or newly available information. (November 2023)

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.^[46] 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.^[16] 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 (now pretomanid), OPC-67683 (now delamanid), and R207910 (now bedaquiline), all of which are in Phase II of development.^[16] Pretomanid and delamanid are both in the nitroimidazole class and have mechanisms involving bioactive reductive activation.^{[47][failed verification]} Bedaquiline is 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.^[48]

When it is not possible to find five drugs from the lists above; the drugs imipenem,^[49]

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.^[57]

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. Response to treatment must be obtained by repeated sputum cultures (monthly if possible).^[58]

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). Supplements include: arginine (peanuts are a good source),^[59] vitamin D,^[60] Dzherelo,^[61] V5 Immunitor.^[62]

On 28 December 2012, the U.S. Food and Drug Administration (FDA) approved bedaquiline (marketed as Sirturo by Johnson & Johnson) to treat multidrug-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.^[63][64]

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.^[65] The simple truth is that almost all tuberculosis deaths result from a lack of access to existing effective therapy.^[66]

Treatment success rates remain unacceptably low globally with variation between regions. 2016 data published by the WHO^[67] reported treatment success rates of multidrug-resistant TB globally. For those started on treatment for multidrug-resistant TB 56% successfully completed treatment, either treatment course completion or eradication of disease; 15% of those died while in treatment; 15% were lost to follow-up; 8% had treatment failure and there was no data on the remaining 6%. Treatment success rate was highest in the World Health Organization Mediterranean region at 65%. Treatment success rates were lower than 50% in the Ukraine, Mozambique, Indonesia and India. Areas with poor TB surveillance infrastructure had higher rates of loss to follow-up of treatment.^[67]

57 countries reported outcomes for patients started on extreme-drug resistant TB, this included 9258 patients. 39% completed treatment successfully, 26% of patients died and treatment failed for 18%. 84% of the extreme drug resistant cohort was made up of only three countries; India, Russian Federation and Ukraine. Shorter treatment regimes for MDR-TB have been found to be beneficial having higher treatment success rates.^[67]

Surgery

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.^[68] 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.^[68] As of 2016, surgery is typically performed after 6–8 months of unsuccessful anti-TB treatment by other means.^[69] 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.^[69] 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.^[68][69]

Epidemiology

Cases of MDR tuberculosis have been reported in every country surveyed.^[40] MDR-TB most commonly develops in the course of TB treatment,^[5] 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.^[40] 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).^{[70][71][72][73][74]} Outbreaks among non-immunocompromised healthy people do occur,^[75] but are less common.^[5]

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.^[28] In Moldova, the crumbling health system has led to the rise of MDR-TB.^[76] 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.^[77]

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

MDR-TB is widespread in Somalia, where 8.7% of newly discovered TB cases are resistant to Rifampicin and Isoniazid, in patients which were treated previously the share was 47%.[82]

Refugees from Somalia brought an until then unknown variant of MDR tuberculosis with them to Europe. A few number of cases in four different countries were considered by the European Centre for Disease Prevention and Control to pose no risk to the native population.^[82]

Russian prisons

One of the so-called "hot-spots" of drug-resistant tuberculosis is within the

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.[84] 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.^[87] 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.^[84]

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.^[83] According to Stern, HIV infection is 75 times more prevalent in Russian prison populations than in the civilian population.^[88] 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.^{[citation needed]}

Shin et al. emphasize another factor in MDR-TB prevalence in Russian prisons: alcohol and substance use.^[86] Ruddy et al. showed that risk for MDR-TB is three times higher among recreational drug users than non-users.^[87] 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.^[86]

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.^[89] 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.^[87] 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.^[89] 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.^[89] In their World Health Organization article, Gelmanova et al. posit that non-adherence to TB treatment indirectly contributes to bacterial resistance.^[90] 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.^[83] They note that prevalence of MDR-TB is 2.5 times higher in areas of poorly controlled TB.^[83] Russian-based therapy (i.e., not DOTS) has been criticized by Kimerling et al. as "inadequate" in properly controlling TB incidence and transmission.^[91] 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.^[84]

Policy impacts

As Ruddy et al. note, Russia's early 2000s penal reforms could greatly reduce the number of inmates inside prison facilities and thus increase the number of ex-convicts integrated into civilian populations.

• 2007 tuberculosis scare
• Drug resistance
• MRSA
• Vancomycin-resistant enterococcus
  (VRE)
• Totally drug-resistant tuberculosis (TDR-TB)
• Medicines Patent Pool

References