Multi-drug-resistant tuberculosis

Multi-drug-resistant tuberculosis (MDR-TB) is defined as TB that is resistant at least to isoniazid (INH) and rifampicin (RMP), the two most powerful first-line anti-TB drugs.^[1] 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.^[2]

Epidemiology

MDR-TB most commonly develops in the course of TB treatment,^[3] 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).^{[4][5][6][7][8]} Outbreaks among non immunocompromised healthy people do occur,^[9] but are less common.^[3] 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 in that area.^[10][11]

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.^[1] 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.^[12]

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.^[13]

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+isonicotinyl Hydrazine+Rifampicin+Ethambutol+pyraZinamide)+MXF+cycloserine 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,^[14] so, detailed knowledge of the treatment history of that patient is essential.

A gene probe for rpoB 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+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)
• PZA
• EMB
• a fluoroquinolone: e.g., moxifloxacin (ciprofloxacin should no longer be used^[15]);
• 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

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.^[16]

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.^[17]

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^[18] (peanuts are a good source)
• Vitamin D^[19]
• Immunoxel/Dzherelo^[20]
• V5 Immunitor^[21]

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^[22]
• co-amoxiclav^[23][24]
• clofazimine^[25][26][27]
• prochlorperazine^[28]
• metronidazole^[29]

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^[30] (manufactured by PathoGenesis Corporation, Seattle, Washington)
• R207910^[31] (Koen Andries et al., under development by Johnson & Johnson)

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.

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.^[12] 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.[1]

See also

• 2007 tuberculosis scare
• Antibiotic resistance
• Drug resistance
• Extensively drug-resistant tuberculosis (XDR-TB)
• MRSA
• Vancomycin-resistant enterococcus (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%.^[32]

References

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
• Pulitzer Center Project on MDR-TB in Moldova
• MDR-TB (DOTS Plus) protocol followed under RNTCP in India (PDF)