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MDR-TB
Antibiotic resistance in Mycobacterium tuberculosis
are of two types, primary and secondary. Primary resistance is the
resistance pattern seen in new patients, who have not been exposed to
anti-TB drugs previously. Secondary resistance is the resistance pattern
in patients with previous history of anti-TB treatment and is due to
ineffective chemotherapy. Multi-drug resistance in
M.tuberculosis refers to simultaneous resistance to at least
Rifampicin and Isoniazid (INH), with or without resistance to other
drugs.
XDR-TB (CDC definition): Extensively drug resistant
TB (XDR-TB) is a rare type of multidrug-resistant
tuberculosis (MDR-TB) that is resistant to isoniazid and
rifampin, plus any fluoroquinolone and at least one of
three injectable second-line drugs (i.e., amikacin,
kanamycin, or capreomycin).
Development of MDR-TB:
1960s, 1-2% of isolates were resistant to 2+
drugs.
1970s, 3-5% of isolates were resistant to 2+
drugs.
1991, 33% of isolates resistant to 1+ drugs, 13%
resistant to the 4 front-line drugs.
Mechanism of drug resistance:
Resistance is usually acquired by the bacilli either by
alteration of the drug target through mutation or by titration of the
drug through overproduction of the target. MDRTB results primarily from
accumulation of mutations in individual drug target genes. Multiple-drug
resistance in mycobacteria is the result of the step-wise accumulation
of resistance to individual drugs. Mutations in the catG and inhA genes
are associated with isoniazid resistance, while the rpoB gene
responsible for RNA polymerase is altered in many clinical isolates
resistant to rifampin. In addition to accumulation of mutations in the
individual drug target genes, the permeability barrier imposed by the
M.tuberculosis cell wall can also contribute to the development
of low-level drug resistance.
Resistance to a drug does not
confer any selective advantage to the bacterium unless it is exposed to
that drug. Under such circumstances, the sensitive strains are killed
and the drug-resistant mutants flourish. When the patient is exposed to
a second course of drug therapy with yet another drug, mutants resistant
to the new drug are selected, and the patient may eventually have
bacilli resistant to two or more drugs. Serial selection of drug
resistance, thus, is the predominant mechanism for the development of
MDR strains.
Chance of a random mutation conferring
drug-resistance:
The probability of resistance is very high for less
effective antitubercular drugs such as thiacetazone, ethionamide,
capreomycin, cycloserine, and viomycin; intermediate for drugs such as
INH, Streptomycin, Ethambutol, Kanamycin, and p-amino salicylic acid;
and lowest for Rifampicin. The probability of a mutation is directly
proportional to the bacterial load. A bacillary load of 109 will contain
several mutants resistant to any one antitubercular drug.
MDRTB and AIDS:
Outbreaks among AIDS patients of an MDR strain of TB that is at
least resistant to INH, rifampicin, streptomycin, ethambutol,
ethionamide, and Kanamycin have been reported. The strain spreads
rapidly among hospitalized AIDS patients and also health care workers
and visitors. There is a 72-89% fatality rate with a very short interval
from diagnosis to death (4-16 weeks).
Detection of MDRTB:
1. Conventional detection of resistance by one of the following
techniques:
a. Absolute
concentration technique
b. Resistance
ratio method
c. Proportion
method
2. Radiometric detection by BACTEC system
3. Indirect detection of
INH resistance by negative catalase and peroxidase tests.
4. One of
the most exciting techniques involves the use of a luciferase reporter
gene, which is introduced into the clinical isolate on a
mycobacteriophage. Light production in the presence of the drug reveals
resistance, and can be detected very quickly.
5. Rapid detection of
resistance by detection of mutated gene by molecular techniques such as
PCR.
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