Multi-drug-resistant tuberculosis
Encyclopedia
Multi-drug-resistant tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

(MDR-TB) is defined as TB that is resistant at least to isoniazid (INH)
Isoniazid
Isoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...

 and rifampicin (RMP)
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...

, the two most powerful first-line anti-TB drugs. Isolates that are multiply resistant to any other combination of anti-TB drugs but not to INH and RMP are not classed as MDR-TB.

MDR-TB develops during treatment of fully sensitive TB when the course of antibiotics is interrupted and the levels of drug in the body are insufficient to kill 100% of bacteria. This can happen for a number of reasons: Patients may feel better and halt their antibiotic course, drug supplies may run out or become scarce, or patients may forget to take their medication from time to time. MDR-TB is spread from person to person as readily as drug-sensitive TB and in the same manner.

Epidemiology

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. MDR-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
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

). Outbreaks among non immunocompromised healthy people do occur, but are less common. A 1997 survey of 35 countries found rates above 2% in about a third of the countries surveyed. The highest rates were in the former USSR, the Baltic states, Argentina, India, and China, and was associated with poor or failing national tuberculosis control programmes.

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
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...

 in that area.

Treatment of MDR-TB

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 that for cancer than to that for infection. It has a mortality rate of up to 80%, which depends on a number of factors, including
  1. How many drugs the organism is resistant to (the fewer the better)
  2. How many drugs the patient is given (patients treated with five or more drugs do better)
  3. Whether an injectable drug is given or not (it should be given for the first three months at least)
  4. The expertise and experience of the physician responsible
  5. How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient)
  6. 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 tend to live in underdeveloped countries or in a state of poverty. Denial of treatment remains a difficult human rights issue, as the high cost of second-line medications often precludes individuals unable to afford therapy.

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 the patient are still possible.

The treatment of MDR-TB must be undertaken by a physician experienced in the treatment of MDR-TB. Mortality and morbidity in patients treated in non-specialist centers are significantly inferior 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. If treating a patient with suspected MDR-TB, the patient should be started on SHREZ (Streptomycin
Streptomycin
Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...

+isonicotinyl Hydrazine+Rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...

+Ethambutol
Ethambutol
Ethambutol is a bacteriostatic antimycobacterial drug prescribed to treat tuberculosis. It is usually given in combination with other tuberculosis drugs, such as isoniazid, rifampicin and pyrazinamide....

+pyraZinamide
Pyrazinamide
Pyrazinamide is a drug used to treat tuberculosis. The drug is largely bacteriostatic, but can be bacteriocidal on actively replicating tuberculosis bacteria.-Abbreviations:...

)+MXF
Moxifloxacin
Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG . It is marketed worldwide under the brand names Avelox, Avalox, and Avelon for oral treatment. In most countries, the drug is also available in parenteral form for intravenous infusion...

+cycloserine
Cycloserine
Cycloserine is an antibiotic effective against Mycobacterium tuberculosis. For the treatment of tuberculosis, it is classified as a second line drug, i.e...

 pending the result of laboratory sensitivity testing. There is evidence that previous therapy with a drug for more than a month was associated with diminished efficacy of that drug regardless of in vitro tests indicating susceptibility, so, detailed knowledge of the treatment history of that patient is essential.

A gene probe for rpoB
RpoB
rpoB is a bacterial gene that codes for part of an enzyme which synthesises RNA. Specifically, rpoB is the β subunit of the bacterial RNA polymerase. It is the subunit which possesses the polymerase activity, that is, it catalyzes the synthesis of RNA...

is available in some countries, which 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
Moxifloxacin
Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG . It is marketed worldwide under the brand names Avelox, Avalox, and Avelon for oral treatment. In most countries, the drug is also available in parenteral form for intravenous infusion...

+cycloserine
Cycloserine
Cycloserine is an antibiotic effective against Mycobacterium tuberculosis. For the treatment of tuberculosis, it is classified as a second line drug, i.e...

. 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
    Aminoglycoside
    An aminoglycoside is a molecule or a portion of a molecule composed of amino-modifiedsugars.Several aminoglycosides function as antibiotics that are effective against certain types of bacteria...

     (e.g., amikacin
    Amikacin
    Amikacin is an aminoglycoside antibiotic used to treat different types of bacterial infections. Amikacin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.-Administration:Amikacin may be...

    , kanamycin
    Kanamycin
    Kanamycin sulfate is an aminoglycoside antibiotic, available in oral, intravenous, and intramuscular forms, and used to treat a wide variety of infections. Kanamycin is isolated from Streptomyces kanamyceticus.-Mechanism:...

    ) or polypeptide antibiotic (e.g., capreomycin
    Capreomycin
    Capreomycin is a peptide antibiotic, commonly grouped with the aminoglycosides, which is given in combination with other antibiotics for tuberculosis...

    )
  • PZA
    Pyrazinamide
    Pyrazinamide is a drug used to treat tuberculosis. The drug is largely bacteriostatic, but can be bacteriocidal on actively replicating tuberculosis bacteria.-Abbreviations:...

  • EMB
    Ethambutol
    Ethambutol is a bacteriostatic antimycobacterial drug prescribed to treat tuberculosis. It is usually given in combination with other tuberculosis drugs, such as isoniazid, rifampicin and pyrazinamide....

  • a fluoroquinolone: e.g., moxifloxacin
    Moxifloxacin
    Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG . It is marketed worldwide under the brand names Avelox, Avalox, and Avelon for oral treatment. In most countries, the drug is also available in parenteral form for intravenous infusion...

     (ciprofloxacin
    Ciprofloxacin
    Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...

     should no longer be used);
  • rifabutin
    Rifabutin
    Rifabutin is a bactericidal antibiotic drug primarily used in the treatment of tuberculosis. The drug is a semi-synthetic derivative of rifamycin S. Its effect is based on blocking the DNA-dependent RNA-polymerase of the bacteria. It is effective against Gram-positive and some Gram-negative...

  • cycloserine
    Cycloserine
    Cycloserine is an antibiotic effective against Mycobacterium tuberculosis. For the treatment of tuberculosis, it is classified as a second line drug, i.e...

  • a thioamide
    Thioamide
    Thioamide is a functional group with the general structure R-CS-NR'R, where R, R', and R are organic groups. They are analogous to amides but they exhibit greater multiple bond character along the C-N bond, resulting in a larger rotational barrier...

    : prothionamide or ethionamide
    Ethionamide
    Ethionamide is an antibiotic used in the treatment of tuberculosis.It is a prodrug.It has been proposed for use in combination with gatifloxacin.The action may be through disruption of mycolic acid.-Synthesis:...

  • PAS
    Aminosalicylic acid
    4-aminosalicylic acid, commonly known as PAS, is an antibiotic used to treat tuberculosis. This organic compound has been use since the 1940s for the treatment of inflammatory bowel diseases , where it has shown greater potency in ulcerative colitis and Crohn's disease. It is thought to act via...

  • a macrolide
    Macrolide
    The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...

    : e.g., clarithromycin
    Clarithromycin
    Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...

  • linezolid
    Linezolid
    Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics...

  • high-dose INH
    Isoniazid
    Isoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...

     (if low-level resistance)
  • interferon-γ
  • thioridazine
    Thioridazine
    Thioridazine is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis...

  • Ampicillin


Drugs are placed nearer the top of the list because they are more effective and less toxic; drugs are placed nearer the bottom of the list because they 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 only to use 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.

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.

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.

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
    Arginine
    Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

     (peanuts are a good source)
  • Vitamin D
    Vitamin D
    Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....

  • Immunoxel/Dzherelo
  • V5 Immunitor


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
    Imipenem
    Imipenem is an intravenous β-lactam antibiotic developed in 1980. It has an extremely broad spectrum of activity.Imipenem belongs to the subgroup of carbapenems. It is derived from a compound called thienamycin, which is produced by the bacterium Streptomyces cattleya...

  • co-amoxiclav
    Co-amoxiclav
    Amoxicillin/clavulanic acid or co-amoxiclav is a combination antibiotic consisting of amoxicillin trihydrate, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor...

  • clofazimine
    Clofazimine
    Clofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients and...

  • prochlorperazine
    Prochlorperazine
    Prochlorperazine is a dopamine receptor antagonist that belongs to the phenothiazine class of antipsychotic agents that are used for the antiemetic treatment of nausea and vertigo. It is also a highly-potent typical antipsychotic, 10-20x more potent than chlorpromazine...

  • metronidazole
    Metronidazole
    Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....



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:
  • PA-824 (manufactured by PathoGenesis Corporation, Seattle, Washington)
  • R207910
    R207910
    R207910 is an experimental diarylquinoline anti-tuberculosis drug, which was discovered by Koen Andries and his team at Janssen Pharmaceutica...

     (Koen Andries
    Koen Andries
    Koen Andries is a Belgian scientist working at Janssen Pharmaceutica and professor at the University of Antwerp. In 2005 he and his team published a discovery about a new di-Aryl-Quinoline-based drug which promises a shorter and simpler treatment for Tuberculosis .-Career:He graduated as a...

     et al., under development by Johnson & Johnson
    Johnson & Johnson
    Johnson & Johnson is an American multinational pharmaceutical, medical devices and consumer packaged goods manufacturer founded in 1886. Its common stock is a component of the Dow Jones Industrial Average and the company is listed among the Fortune 500....

    )


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
National Jewish Medical and Research Center
National Jewish Health is a research institute located in Denver, Colorado specializing in respiratory, immune and allergic research and treatment. It was founded in 1899 to treat tuberculosis, and is today considered one of the world's best medical research and treatment centers...

 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.

Questions Facing Modern Medicine

The destitute patients suffering from multi-drug-resistant tuberculosis face the problem of not receiving proper treatment. This injustice pertains to the issue of human rights. Treatment and medication for chronic infectious diseases are accessible to those able to afford it, whereas others, like those living in impoverished countries, do not have access to this care. For example, areas such as Africa and Haiti, where there is not a strong foundation for healthcare, treatment is unavailable. As a consequence, only a small minority of affected people are treated. In addition, after the breakup of the Soviet Union, countries like Moldova saw their health care system crumble and were unable to stop the rising spread of MDR-TB.http://pulitzercenter.org/projects/europe/moldova-fighting-deadly-disease

See also

  • 2007 tuberculosis scare
    2007 tuberculosis scare
    The 2007 tuberculosis scare occurred when Atlanta personal-injury lawyer Andrew "Drew" Speaker flew from Atlanta, Georgia to Paris, France and then returned on a flight from Prague, Czech Republic to Montreal, Canada, when he crossed over the border and back into the United States while infected...

  • Antibiotic resistance
    Antibiotic resistance
    Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...

  • Drug resistance
    Drug resistance
    Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...

  • Extensively drug-resistant tuberculosis
    Extensively drug-resistant tuberculosis
    Extensively drug-resistant tuberculosis is a form of TB caused by bacteria that are resistant to the most effective anti-TB drugs. Some contend that XDR-TB strains have emerged from the mismanagement of multidrug-resistant TB and once created, can spread from one person to another...

     (XDR-TB)
  • MRSA
  • Vancomycin-resistant enterococcus
    Vancomycin-Resistant Enterococcus
    Vancomycin-resistant Enterococcus, or vancomycin-resistant enterococci , are bacterial strains of the genus Enterococcus that are resistant to the antibiotic vancomycin. To become VRE, vancomycin-sensitive enterococci typically obtain new DNA in the form of plasmids or transposons which encode...

     (VRE)


Community-based treatment programs such as DOTS-Plus, a MDR-TB-specialized treatment using the popular DOTS (directly observed treatment, short-course) initiative, have shown considerable success in the treatment of MDR-TB. 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%.

External links

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