MDRTB/ XDRTB

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.
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). 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 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.
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 who cannot afford therapy.

Treatment courses are generally measured in months to years; MDR-TB may require surgery, and death rates remain
high despite optimal treatment. That said, good outcomes 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 centres is significantly inferior to those patients treated in
specialist centres.

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, so, detailed
knowledge of the treatment history of that patient is essential.

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

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

 an aminoglycoside (e.g., amikacin, kanamycin) or polypeptide antibiotic (e.g., capreomycin)

 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.

Resistance to one drug within a class generally 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 only possible 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 1.0 mg/l INH, but sensitive at 0.2 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, you must still choose another drug 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 certainly 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 are 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 (particularly 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 the for the purposes of counting
drugs for MDR-TB, they count as zero (if you already have four drugs in the regimen, it may be beneficial to add
arginine or vitamin D or both, but you still need another drug to make five).

 arginine (peanuts are a good source)

 Vitamin D

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

 imipenem
 co-amoxiclav

 clofazimine

 prochlorperazine

 metronidazole
The following drugs are experimental compounds that are not commercially available, but which 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[28] (manufactured by PathoGenesis Corporation, Seattle, Washington)

 R207910[29] (Koen Andries et al., under development by Johnson & Johnson)

In cases of extremely resistant disease, surgery to remove infection portions of the lung is generally the final option.
The centre 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, 82 were
pneumonectomies. There is a 3.3% operative mortality, with an additional 6.8% dying following the operation; 12%
experienced significant morbidity (particularly 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 who suffer 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 who can afford it, while others, like those who live 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. Consequently, only a small minority of affected people are treated. [12]
Extensively drug-resistant Tuberculosis

Extensively drug-resistant tuberculosis (XDR-TB) 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 (MDR-TB) and once created, can spread from one person to another. The exact nature of this
mismanagement is not yet known, but origin of XDR-TB may coincide with the institution of new policies to
promote drug compliance, such as DOTS.

One in three people in the world is infected with TB bacteria.  Only when the bacteria become active do people
become ill with TB. Bacteria become active as a result of anything that can reduce the person’s immunity, such as
HIV, advancing age, or some medical conditions. TB can usually be treated with a course of four standard, or first-
line, anti-TB drugs. If these drugs are misused or mismanaged, multidrug-resistant TB (MDR-TB) can develop.
MDR-TB takes longer to treat with second-line drugs, which are more expensive and have more side-effects. XDR-
TB can develop when these second-line drugs are also misused or mismanaged and therefore also become
ineffective.

XDR-TB raises concerns of a future TB epidemic with restricted treatment options, and jeopardizes the major gains
made in TB control and progress on reducing TB deaths among people living with HIV/AIDS. It is therefore vital
that TB control is managed properly and new tools developed to prevent, treat and diagnose the disease.

The true scale of XDR-TB is unknown as many countries lack the necessary equipment and capacity to accurately
diagnose it. It is estimated however that there are around 40,000 cases per year. As of June 2008, 49 countries have
confirmed cases of XDR-TB.

Definition
XDR-TB is defined as TB that has developed resistance to at least rifampicin and isoniazid (resistance to these first
line anti-TB drugs defines Multi-drug-resistant tuberculosis, or MDR-TB), as well as to any member of
the quinolone family and at least one of the following second-line anti-TB injectable
drugs: kanamycin, capreomycin, or amikacin. This definition of XDR-TB was agreed by the WHOGlobal Task
Force on XDR-TB in October 2006. The earlier definition of XDR-TB as MDR-TB that is also resistant to three or
more of the six classes of second-line drugs, is no longer used, but may be referred to in older publications.

Transmission
Like other forms of TB, XDR-TB is spread through the air. When a person with infectious TB coughs, sneezes, talks
or spits, they propel TB germs, known as bacilli, into the air. A person needs only to inhale a small number of these
to be infected. People infected with TB bacilli will not necessarily become sick with the disease. The immune
system "walls off" the TB bacilli which, protected by a thick waxy coat, can lie dormant for years.

The spread of TB bacteria depends on factors such as the number and concentration of infectious people in any one
place together with the presence of people with a higher risk of being infected (such as those with  HIV/AIDS). The
risk of becoming infected increases the longer the time that a previously uninfected person spends in the same room
as the infectious case. The risk of spread increases where there is a high concentration of TB bacteria, such as can
occur in closed environments like overcrowded houses, hospitals or prisons. The risk will be further increased if
ventilation is poor. The risk of spread will be reduced and eventually eliminated if infectious patients receive proper
treatment.

Diagnosis
Successful diagnosis of XDR-TB depends on the patient’s access to quality health-care services. If TB
bacteria are found in the sputum, the diagnosis of TB can be made in a day or two, but this finding will not be able
to distinguish between drug-susceptible and drug-resistant TB. To evaluate drug susceptibility, the bacteria need to
be cultivated and tested in a suitable laboratory. Final diagnosis in this way for TB, and especially for XDR-TB,
may take from 6 to 16 weeks.[7] To reduce the time needed for diagnosis, new tools for rapid TB diagnosis are
urgently needed.

Treatment
The principles of treatment for MDR-TB and for XDR-TB are the same. Treatment requires
extensive chemotherapy for up to two years. Second-line drugs are more toxic than the standard anti-TB regimen
and can cause a range of serious side-effects including hepatitis, depression and hallucinations. Patients are often
hospitalised for long periods, in isolation. In addition, second-line drugs are extremely expensive compared with the
cost of drugs for standard TB treatment.

XDR-TB is associated with a much higher mortality rate than MDR-TB, because of a reduced number of effective
treatment options. Despite early fears that this strain of TB was untreatable, recent studies have shown that XDR-TB
can be treated through the use of aggressive regimens. A study in the Tomsk oblast of Russia, reported that 14 out of
29 (48.3%) patients with XDR-TB successfully completed treatment.[9]

Successful outcomes depend on a number of factors including the extent of the drug resistance, the severity of the
disease and whether the patient’s immune system is compromised. It also depends on access to laboratories that can
provide early and accurate diagnosis so that effective treatment is provided as soon as possible. Effective treatment
requires that all six classes of second-line drugs are available to clinicians who have special expertise in treating
such cases.
Prevention
Countries aim to prevent XDR-TB by ensuring that the work of their national TB control programmes, and all
practitioners working with people with TB, is carried out according to the International Standards for TB Care.
These emphasize providing proper diagnosis and treatment to all TB patients, including those with drug-resistant
TB; assuring regular, timely supplies of all anti-TB drugs; proper management of anti-TB drugs and providing
support to patients to maximize adherence to prescribed regimens; caring for XDR-TB cases in a centre with proper
ventilation, and minimizing contact with other patients, particularly those with HIV, especially in the early stages
before treatment has had a chance to reduce the infectiousness. Also an effective disease control infrastructure is
necessary for the prevention of XDR tuberculosis. Increased funding for research, and strengthened laboratory
facilities are much required. Immediate detection through drug susceptibility testing’s are vital, when trying to stop
the spread of XDR tuberculosis.

TB vaccine
The BCG vaccine prevents severe forms of TB in children, such as TB meningitis. It would be expected that BCG
would have the same effect in preventing severe forms of TB in children, even if they were exposed to XDR-TB, but
it may be less effective in preventing pulmonary TB in adults, the most common and most infectious form of
TB. The effect of BCG against XDR-TB would therefore likely be very limited. New vaccines are urgently needed,
and WHO and members of the Stop TB Partnership are actively working on new vaccines.

XDR-TB and HIV/AIDS

TB is one of the most common infections in people living with HIV/AIDS. In places where XDR-TB is most
common, people living with HIV are at greater risk of becoming infected with XDR-TB, compared with people
without HIV, because of their weakened immunity. If there are a lot of HIV-infected people in these places, then
there will be a strong link between XDR-TB and HIV. Fortunately, in most of the places with high rates of HIV,
XDR-TB is not yet widespread. For this reason, the majority of people with HIV who develop TB will have drug-
susceptible or ordinary TB, and can be treated with standard first-line anti-TB drugs. For those with HIV infection,
treatment with antiretroviral drugs will likely reduce the risk of becoming infected with XDR-TB, just as it does
with ordinary TB.

A research study titled "TB Prevalence Survey and Evaluation of Access to TB Care in HIV-Infected and
Uninfected TB Patients in Asembo and Gem, Western Kenya," says that HIV/AIDS is fueling large increases in TB
incidence in Africa, and a large proportion of cases are not diagnosed.

Symptoms
Symptoms of XDR-TB are no different from ordinary or drug-susceptible TB: a cough with thick, cloudy mucus (or
sputum), sometimes with blood, for more than 2 weeks; fever, chills, and night sweats; fatigue and muscle
weakness; weight loss; and in some cases shortness of breath and chest pain. A person with these symptoms does
not necessarily have XDR-TB, but they should see doctor for a check-up. TB patients whose symptoms do not
improve after a few weeks of treatment with TB and are taking treatment should inform their clinician or nurse.