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.
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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.