Antituberculosis drugs and the genes involved in their resistance
Genes Involved in Drug Resistance:-
IsoniazidEnoyl acyl carrier protein (acp)
reductase (inhA)
Catalase-peroxidase (katG)
Alkyl hydroperoxide reductase (ahpC)
Oxidative stress regulator (oxyRj
[3-Ketocyl acyl carrier protein synthase(kasA)Rifampicin
RNA polymerase subunit B (rpoBj Pyrazinamide
Pyrazinamidase (pncA)Streptomycin Ribosomal protein subunit 12 (rpsL)
' 16s ribosomal RNA (rrs)
Aminoglycoside phosphotransferase gene (strA)
Capreomycin Haemolysin (tlyA)*
Ethambutol Arabinosyl transferase (emb A, emb B, and emb C)
! Fluoroquinolones DNA gyrase (gyr A and gyr B)
*Jhe tlyA gene in M tuberculosis encodes a 268-amino acid polypep-tide, which shows striking similarity to a haemolysin/cytotoxin, tlyA, from the spirochete Serpulina hyodysenteriae.
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The selection of
drug-resistant M.
tuberculosis depends on the frequency of the specific
drug-resistant mutants in the initially drug-susceptible bacterial population. As a consequence, the chance of selecting such mutants is the highest in the case of monotherapy. Whilst mutants resistant to a single drug may be fairly easily selected by monotherapy, the probability of selecting mutants that are resistant to multiple drugs decreases exponentially by increasing the number of
drugs
to which A/I.
tuberculosis is simultaneously exposed. The rationale for combination drug therapy was proven by a series of clinical demonstrations that provided unambiguous evidence of how the administration of multiple drugs bears a significantly lower chance of
both disease recrudescence and selection of
drug-resistant strains compared with monotherapy. Such clinical research eventually gave the current therapeutic strategy, which consists of three or four drugs in the initial phase of therapy, followed by a consolidation two-drug phase once the initial bacterial biomass has been reduced to such an extent that the chance of selecting residual
drug-resistant
mutants is exceedingly low.
Ironically, short-course chemotherapy composed of the "standard" drug combination concocted to prevent the emergence of
drug resistance may, inadvertently, create more resistance to the drugs in use. This phenomenon termed the "Amplifier Effect" occurs when resistance to some of the
drugs pre-existed at the start of the treatment. Ongoing transmission of established drug-resistant strains in a population is also a significant source of new
drug-resistant cases."
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Clinical Factors
An inadequate or poorly administered treatment regimen allows a
drug-resistant strain to become
the dominant strain in a patient infected with
TB." Errors in
TB management such as the use of single drug to treat
TB, the addition of a single drug to a failing regimen, the failure to identify preexisting resistance, the initiation of an inadequate primary regimen, the failure to identify and address non-adherence to treatment, inappropriate isoniazid preventive therapy, and variations in the bioavailability of anti-TB drugs predispose the patient to the development of MDR-TB.13 Table 2 summarizes the common causes of inadequate treatment."
Programmatic Factors
Good, reliable laboratory support is seldom available in developing nations. When facilities for growing cultures and sensitivity testing are not available, therapeutic decisions are most often made by algorithms or inferences from previous treatment. While DOTS has been shown to reduce the transmission and incidence of both drug-susceptible and drug-resistant TB even in settings with moderate rates of MDR-TB, it has been observed that the "programmatic approach" to the management of patients who do not respond to treatment may fail in certain settings. First-line therapy may not be sufficient in settings with a high degree of resistance to anti-TB drugs. Although the DOTS strategy is the basis of good TB control, the strategy should be modified in some settings to identify
drug-resistant
cases sooner and to make use of second-line drugs in appropriate treatment
regimens.