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Multidrug-resistant Tuberculosis

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Description: Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis that does not respond to the two most powerful anti-TB drugs, isoniazid and rifampicin.
Type: Multidrug-resistant tuberculosis (MDR-TB) is an infectious disease caused by Mycobacterium tuberculosis strains that are resistant to at least isoniazid and rifampicin, the two most effective first-line anti-TB drugs. The genetic transmission of resistance in MDR-TB is not hereditary but rather acquired. This occurs through the selection of spontaneous genetic mutations in the bacterial DNA during inadequate or incomplete TB treatment. These mutations are then propagated during bacterial replication and can spread to other individuals primarily through airborne transmission of the resistant bacteria.
Signs And Symptoms: Multidrug-resistant tuberculosis (MDR-TB) has signs and symptoms similar to drug-susceptible TB, which include:

1. Persistent cough lasting more than three weeks
2. Chest pain
3. Coughing up blood or sputum
4. Fatigue and weakness
5. Unintentional weight loss
6. Fever and chills
7. Night sweats
8. Loss of appetite

Given that it is a form of TB resistant to at least isoniazid and rifampicin, treatment outcomes might be affected, making early diagnosis and management crucial.
Prognosis: Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis that is resistant to at least two of the most powerful first-line anti-TB drugs, isoniazid and rifampicin. The prognosis for MDR-TB can be more severe compared to drug-sensitive TB due to limited treatment options and longer treatment duration. Success rates for MDR-TB treatment are generally lower, with cure rates around 50-70% depending on various factors such as the extent of disease, timely diagnosis, individualized treatment, and patient adherence. Advanced healthcare infrastructure and new medications are gradually improving outcomes.
Onset: The onset of multidrug-resistant tuberculosis (MDR-TB) can be gradual and may initially present with nonspecific symptoms. Early signs often include a persistent cough, weight loss, night sweats, fever, and fatigue. If left untreated, these symptoms can progressively worsen.
Prevalence: Multidrug-resistant tuberculosis (MDR-TB) is a significant public health concern globally. Currently, it is estimated that approximately 3-4% of new TB cases and 18-21% of previously treated TB cases are MDR-TB. The prevalence can vary significantly by region, with higher rates often observed in countries with less effective TB control programs.
Epidemiology: Cases of MDR tuberculosis have been reported in every country surveyed. MDR-TB most commonly develops in the course of TB treatment, 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. 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). Outbreaks among non-immunocompromised healthy people do occur, but are less common.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. In Moldova, the crumbling health system has led to the rise of MDR-TB. 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.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. 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. When patients have MDR-TB, they require longer periods of treatment. 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.
Intractability: Multidrug-resistant tuberculosis (MDR-TB) is challenging to treat but not intractable. While MDR-TB requires longer, more complex, and more expensive treatment regimens compared to drug-sensitive TB, effective treatment is possible. The treatment involves a combination of second-line anti-TB drugs, tailored to the patient's specific resistance pattern. Success depends on early diagnosis, adherence to treatment, comprehensive patient support, and the use of advanced medical therapies.
Disease Severity: Multidrug-resistant tuberculosis (MDR-TB) is a severe form of tuberculosis that does not respond to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. The disease is more challenging and costly to treat than drug-susceptible TB, requiring longer and more complex therapy with second-line drugs that often have more severe side effects. MDR-TB poses significant public health challenges and has higher morbidity and mortality rates compared to drug-susceptible TB.
Healthcare Professionals: Disease Ontology ID - DOID:401
Pathophysiology: Multidrug-resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampicin, the two most potent anti-TB drugs.

### Pathophysiology:
1. **Bacterial Resistance**: MDR-TB arises due to genetic mutations in the Mycobacterium tuberculosis genome. These mutations result in altered drug targets, efflux pump overexpression, or enzyme production that deactivates the drugs.
2. **Transmission**: MDR-TB can be transmitted from person to person through airborne droplets when an infected person coughs or sneezes.
3. **Host Response**: The host immune system attempts to contain the mycobacteria by forming granulomas, which are clusters of immune cells designed to isolate the bacteria.
4. **Disease Progression**: Despite the immune response, resistant bacteria can survive and multiply within the granulomas, leading to active disease if not adequately treated. This can cause lung tissue damage and systemic symptoms such as fever, weight loss, and night sweats.

MDR-TB poses a significant treatment challenge, requiring longer, more complex, and often more toxic drug regimens compared to drug-susceptible TB.
Carrier Status: The concept of "carrier status" is not typically applied to multidrug-resistant tuberculosis (MDR-TB). Tuberculosis, including its multidrug-resistant form, is an active disease rather than a carrier state. Individuals with MDR-TB have a form of tuberculosis that is resistant to at least isoniazid and rifampin, the two most potent TB drugs. These individuals can transmit the bacteria to others, leading to potential new cases of TB, including MDR-TB, if the transmitted strain retains drug resistance. Therefore, monitoring and managing active TB cases, including MDR-TB, is crucial to prevent its spread.
Mechanism: Multidrug-resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampicin, which are two of the most effective first-line drugs.

**Mechanism:**
1. **Drug Resistance**: MDR-TB strains can survive and multiply even in the presence of these drugs. This resistance may result from improper or incomplete treatment of TB, allowing resistant bacteria to multiply.

**Molecular Mechanisms:**
1. **Isoniazid Resistance**:
- **katG Mutation**: Mutations in the katG gene reduce catalase-peroxidase activity, preventing isoniazid activation.
- **inhA Overexpression**: Mutations in the promoter region of the inhA gene lead to overproduction of the target enzyme, InhA, diminishing the drug's efficacy.

2. **Rifampicin Resistance**:
- **rpoB Mutation**: Mutations in the rpoB gene, encoding the beta subunit of RNA polymerase, alter the binding site for rifampicin, thus inhibiting drug attachment and function.

These genetic changes impede the action of the drugs, making the bacteria resistant to treatment and complicating efforts to control and eradicate TB.
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. 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 about 15% with treatment, which further 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)
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 increased mortality).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.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.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.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. 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.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).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)." 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)."
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 (now pretomanid), OPC-67683 (now delamanid), and R207910 (now bedaquiline), all of which are in Phase II of development. Pretomanid and delamanid are both in the nitroimidazole class and have mechanisms involving bioactive reductive activation. 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.When it is not possible to find five drugs from the lists above; the drugs
imipenem,co-amoxiclav,clofazimine,prochlorperazine,metronidazole have been used in desperation, though it is not certain whether they are effective at all.
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.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).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),vitamin D,Dzherelo,V5 Immunitor.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.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. The simple truth is that almost all tuberculosis deaths result from a lack of access to existing effective therapy.Treatment success rates remain unacceptably low globally with variation between regions. 2016 data published by the WHO 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.
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.
Compassionate Use Treatment: For multidrug-resistant tuberculosis (MDR-TB), compassionate use treatment, off-label, or experimental treatments may be considered in cases where standard treatments fail or are not suitable. Some of these options include:

1. **Bedaquiline** - Typically used in combination therapy for MDR-TB, sometimes employed under compassionate use schemes.
2. **Delamanid** - Another medication used for MDR-TB, its use might be off-label or experimental depending on regulatory status in different regions.
3. **Pretomanid** - Used in combination with bedaquiline and linezolid (BPaL regimen) for highly drug-resistant TB forms, including extensively drug-resistant TB (XDR-TB).
4. **Linezolid** - Frequently used off-label for MDR-TB as part of a combination therapy.
5. **Clofazimine** - Originally used to treat leprosy, often off-label for MDR-TB cases.

Clinical trials and compassionate use programs involving these drugs may provide access to new treatments for patients lacking other options.
Lifestyle Recommendations: For multidrug-resistant tuberculosis (MDR-TB), lifestyle recommendations include:

1. **Adherence to Medication**: Complete the full course of prescribed treatment without missing doses, even if symptoms improve, to prevent further resistance.

2. **Nutrition**: Maintain a balanced diet rich in vitamins and minerals to support your immune system.

3. **Avoid Alcohol and Tobacco**: Both can weaken your immune system and interact negatively with TB medication.

4. **Regular Medical Follow-Ups**: Regularly visit your healthcare provider to monitor your progress and manage side effects.

5. **Infection Control**: Practice good hygiene, cover your mouth when coughing, and wear a mask to prevent spreading the infection to others.

6. **Adequate Rest**: Ensure sufficient sleep and rest to aid recovery.

7. **Mental Health Support**: Seek psychological support if needed, as treatment can be long and stressful.

8. **Exercise**: Engage in moderate physical activities as tolerated to maintain general health.

Following these lifestyle recommendations can help manage MDR-TB more effectively and reduce the risk of complications.
Medication: Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis that is resistant to at least isoniazid and rifampin, the two most potent TB drugs. Treatment typically involves second-line medications, which may include:

1. Fluoroquinolones (e.g., levofloxacin, moxifloxacin)
2. Aminoglycosides (e.g., amikacin, kanamycin)
3. Capreomycin
4. Ethionamide or prothionamide
5. Cycloserine or terizidone
6. Linezolid
7. Bedaquiline
8. Delamanid
9. P-aminosalicylic acid

Treatment regimens may vary based on individual patient factors and local guidelines and require close medical supervision due to potential side effects and the complexity of therapy.

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Repurposable Drugs: For multidrug-resistant tuberculosis (MDR-TB), several repurposed drugs have been considered to address resistance:

1. **Linezolid**: Originally used for Gram-positive infections, it's effective against MDR-TB but has significant side effects with prolonged use.
2. **Bedaquiline**: Developed for MDR-TB, it has shown efficacy, especially in combination regimens, although it carries a risk of cardiac toxicity.
3. **Clofazimine**: Used for leprosy, it has shown activity against TB, including MDR strains.
4. **Delamanid**: Typically used in combination therapy for MDR-TB, it has good efficacy but can cause QT prolongation.
5. **Levofloxacin and Moxifloxacin**: These fluoroquinolones are often used when first-line drugs fail.

These repurposed drugs have shown promise in improving outcomes for patients with MDR-TB by providing additional treatment options beyond the standard anti-TB medications.
Metabolites: Metabolites associated with multidrug-resistant tuberculosis (MDR-TB) include various products of Mycobacterium tuberculosis metabolism that can be detected in patients. Some specific metabolites include mycobactin, which is necessary for iron acquisition by the bacteria, and lipoarabinomannan, a component of the bacterial cell wall. Detection of these metabolites can help in diagnosing and understanding the progression of MDR-TB.

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Nutraceuticals: Nutraceutical and nanotechnology approaches are emerging areas of interest in the treatment of multidrug-resistant tuberculosis (MDR-TB).

**Nutraceuticals:**
Nutraceuticals refer to food-derived products that provide health benefits beyond basic nutrition and can potentially play a role in supporting the immune system and improving overall health in patients with MDR-TB. Some examples include:
- **Vitamins:** Vitamin D, vitamin C, and vitamin E have been studied for their immune-boosting properties.
- **Minerals:** Zinc and selenium can support immune function.
- **Probiotics:** These can help in maintaining gut health, which is crucial for patients undergoing long-term antibiotic therapy.

**Nanotechnology:**
Nanotechnology offers innovative approaches to improve the delivery and efficacy of drugs used to treat MDR-TB:
- **Nanocarriers:** These can enhance the bioavailability and targeted delivery of anti-TB drugs, potentially reducing side effects and improving treatment outcomes.
- **Nanoparticles:** Engineered nanoparticles can be used to directly deliver drugs to infected cells, improving the pharmacokinetics and pharmacodynamics of anti-TB medications.
- **Liposomes:** These are lipid-based vesicles that can encapsulate TB drugs, protecting them from degradation and facilitating controlled release at the infection site.

Both nutraceuticals and nanotechnology are promising adjuncts in the management of MDR-TB, potentially enhancing the efficacy of existing therapies and improving patient outcomes. However, further research and clinical trials are necessary to validate their effectiveness and safety.
Peptides: For multidrug-resistant tuberculosis (MDR-TB), peptides and nanoparticles (nan) are emerging areas of research in treatment strategies.

**Peptides:** Antimicrobial peptides (AMPs) are being investigated for their potential to kill or inhibit Mycobacterium tuberculosis, the bacteria responsible for tuberculosis. These peptides work by disrupting bacterial cell membranes or interfering with essential bacterial processes, offering a promising alternative for treating MDR-TB.

**Nanoparticles (Nan):** Nanoparticles are being explored extensively for drug delivery in MDR-TB. They can enhance the efficacy and reduce the toxicity of existing anti-TB drugs by improving their bioavailability and targeted delivery to infected cells. Examples include liposomes, polymeric nanoparticles, and metallic nanoparticles, which can encapsulate drugs and release them in a controlled manner at the site of infection.