TUBERCULOSIS: A Communicable infectious disease caused by Mycobacterium species, mostly by M.tuberculosis, which affects the lungs, pleura but may also involve the other parts of the body.
MULTI-DRUG RESISTANT TUBERCULOSIS: TB that is resistant to atleast isoniazid(INH) and rifampin(RIF) which are first line anti-TB drugs is considered to be multi drug resistant TB(MDR-TB). TB has become a major dreadful disease by killing millions of people annually. This is seen mostly in the developing nations. Though there are many effective drugs currently used in the market for the treatment , the incidence and development of resistance by the organism to these drugs has become a major challenge for the scientists. Not only this factor, but the association of active TB with the Human Immuno Virus (HIV) is also trimming hopes of the elimination of this disease. The World Health Organisation has aimed to eradicate this horrendous disease by 2015. But the development of these drug resistant strains is hampering the growth of elimination. The reason for this development of resistance is identified to be the improper usage of medications by the patient, incomplete treatment either by the doctors or by the patients. Hence an awareness is to be brought by the anti-TB organisations regarding the care and need for proper usage of medications during the treatment period, so that the incidence of this multi-drug resistant tuberculosis can be reduced. By the development of new drugs, which are as affective as the first-line medications that are used now, this problem can be some how managed to some extent.
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MECHNISM OF ACTION OF ANTI-TB DRUGS: Isoniazid(INH) is a prodrug, which is used as a first line anti ââ‚¬"TB drug. INH mainly targets the enzymes that are actively involved in the synthesis of mycolic acid and hampers its production. This depletion aids the killing of bacteria. Rifampin(RIF) is another promising first line drug that acts by inihibiting the protein synthesis in M.tuberculosis. It binds to ab-subunit of RNA polymerase and inihibits RNA transcription, there by suppressing the protein synthesis. Resistance to atleast these two first-line anti-TB drugs may result in the development of MDR-TB. The chemical structures of INH and RIF are given below.
DEVELOPMENT OF RESISTANCE: M.tuberculosis has developed many mechanisms to generate resistance to these drugs. One of the mechanism may be by the alteration of the cell wall permeability or drug efflux, titration of the drug due to the overproduction of the targets, and alteration of the targets by mutations. INH is mainly activated by catalase-peroxidase enzyme encoded by katG. This is the main target where the organism undergoes several point mutations, in several genes. Similarly mutations at different sites like rpoB codon 511,518 or 522 causes low-level RIF rasistance and that of codon 516,526 or 531 will raise high-level RIF resistance. Resistance to atleast these two first-line anti-TB drugs may result in the development of MDR-TB. The resistance to RIF always acts as a good marker for the development of MDR-TB since 85-90% of RIF resistant strains are also resistant to INH.
DIAGNOSIS OF MDR-TB: The earlier the detection of drug resistance by the organism, the effective the treatment of TB will be. Hence in this context many statistical and effective methods are being developed by the scientists for the diagnosis of drug resistant TB as well as MDR-TB. They are,
Conventional (phenotypic) methods.
Molecular (genotypic) methods.
Conventional methods: These methods are mainly done by using culture medium where the growth of M.tuberculosis is measured in the presence of anti-TB drugs. One of the three factors, proportion (or) resistance ratio (or) absolute concentration, are measured on solid media. The becton Dickinson method is regarded as the golden standard for culture and Drug Resistance Test(DST) of M.tuberculosis to all the first and second-line drugs, which is a broth based semi automated BACTEC 460 TB system. The reports are usually reported with in 4-12 days from primary cultures, where as it takes 3 weeks if we use solid media based methods.
The results can also be obtained with in 2 weeks by employing liquid media based microscopic observation drug susceptibility testing. These are rather low-cost and are rapid direct assay methods for detecting and DST of M.tuberculosis in sputum. Indirect identification and frequent microscopic observations are the limitations of these tests.
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Another alternative for the detection of drug resistance are the calorimetric methods, which measure the amount of redox indicator that is reduced by the organism during the growth in the culture medium. 3-(4,5-dimethylthiazol-2-yl)-2.5-diphenyl tetrazolium bromide (MTT) is an example of an indicator, yellow in color, used in the tetrazolium salt-based assay. Other types of conventional methods include phage-based assays where mycobacteriophages are employed to infect live M.tuberculosis in the presence and absence of drugs. By using phage amplification (or) by the production of light these bacilli are detected. This method provides the results with in 2 days and are accurate when compared to the other conventional methods.
Molecular methods: The detection of resistance associated with the mutations in the target genes of M.tuberculosis is the major area of concentration of the Molecular methods. These methods directly involve the smear positive sputum and other clinical aymptoms. The major priority of these methods is the detecton of resistance to RIF. This is due to the fact that 90-95% RIF resistant strains are almost liable to develop MDR-TB. Though genotypic methods are employed for all the first line and many second line drugs. Several genotypic methods are developed in cocern with the mutations in MDR-TB strains.
Among all the methods the most simplest, in-expenssive and rapid method is PCR- restriction fragment length polymorphism (PCR-RFLP). This method involves in the detection of polymorphism at a single (or) few codons that are mutated in drug resistant strains. For the rapid detection of INH and Ethambutol(EMB) resistance PCR-RFLP is used.
The targeted DNA sequencing is also another Molecular method which is used for the detection of mutations that are responsible for the development of resistance to RIF,INH and pyrazinamide(PZA). But the developing nations consider this method as an in-appropriate method for itz utilizing of large number of samples. Other methods like Real time PCR assays, Reverse hybridization based line probe assays and Micro array based assays have also been developed for the detection of MDR-TB strains in clinical specimens. Due to the expensive processes all the above new methods are of limited usage. However, cost-effective, rapid and accurate methods are also being developed.
TREATMENT OF MDR-TB: Many of the first line and second line drugs are being developed all these years for the treatment of tuberculosis. But due to the evolution of this drug resistance and MDR-TB the treatment has become a bit complicated especially in the case of HIV co-infected patients.
First-line anti-TB drugs: Isoniazid and Rifampin are the major anti-TB first line drugs. These are considered as the back bone of the treatment of TB. With the available other first line drugs the patients with MDR-TB can still be successfully managed if the resistance to these INH and RIF develops. Mono resistance to INH is seen most frequently, but RIF resistance is uncommon and is mostly associated with the patients co-infected with HIV. With the increase in the duration of treatment up to12 months the patients can be successfully treated, but the RIF resistant strains will show poor prognosis.
List of first line anti-TB drugs:
Biological process inhibited
Nicotinic acid hydrazide
Mycolic acid synthesis
Ethylene diimino di-1-butanol
Lipid/cell wall synthesis
INH, isoniazid; RIF, rifampin; PZA, pyrazinamide; EMB, ethambutol;
Second line anti-TB drugs: when the resistance by the organism for both these INH and RIF is developed, the second line drugs must be considered. The extensive usage of these is required in the caser where the patients are co-infected with HIV along with TB. Second-line drugs include aminoglycosides (kanamycin, KAN; amikacin, AMI and streptomycin, SM), the polypeptides (capreomycin, CAP and viomycin, VIO), the thioamides (ethionamide, ETH and prothiona- mide, PTH), several fluoroquinolones (FQs) (such as ofloxacin, OFX; levofloxacin, LFX; moxifloxacin, MFX; and gatifloxacin, GFX), para- amino salicylic acid (PAS) and D-cycloserine (CS). The second line drugs are considered to be costly and are bacteriostatic. These are less effective and are also considered to cause many drug-related side effects.There are also many drugs which are not classified in any of the first-line or second line drugs, that are known to show positive effect on the patients with MDR-TB. These drugs include clarithromycin(CLR), clofazimine(CFZ), amoxicillin-clavulanic acid (AMX-CLV) and linezolid (LZD).
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The therapy of MDR-TB includes 5 to 7 drugs during initial stages. Other treatment procedures like increased therapy for more than 3 months with 6 or more active drugs and use of an effective injectable agent for atleast 6 months, oral treatment for more than18 months may also influence rapid sputum conversion and improve treatment outcome. Until sputum culture conversion is achieved regular monitoring of sputum, atleast once in a month, for smear microscopy is needed. Thus DST indicates a response to the treatment.
Potential regimens for the treatment of patients with MDR-TB and XDR-TB.
Different patterns of resistance to anti-TB drugs
Appropriate therapy regimens
Duration of treatment(months)
no. of active drugs for favorable outcome
INH, isoniazid; RIF, rifampin; PZA, pyrazinamide; EMB, ethambutol; SM, strepto- mycin; FQ, ciprofloxacin or ofloxacin or levofloxacin or moxifloxacin or gatifloxacin; INJ, injectable agents like SM or kanamycin or amikacin or capreomycin or viomycin; SLD, second-line drugs like rifabutin, ethionamide, prothionamide, para- amino salicylic acid, D-cycloserine and thiacetazone; TLD third-line drugs.
Conclusion: The lack of knowledge, resources, awareness, poor case detection, inadequate therapy during the past decades are the major factors contributing for the current MDR-TB epidemic. However, due to the development of latest diagnostic procedures and DST for the first and second line drugshas almost enhanced the detection of MDR-TB. Treatment with several drugs in the initial phases itself has also emphasized the prognosis of the disease. But in the case of developing countries, the situation is still hazardious. Inadequate laboratory facility is obstructing the successful treatment of patients. The development of cost-effective, rapid treatment methods is creating hope in those resource poor countries. Overall the new drugs under development and the latest technologies assure us that this TB and MDR-TB epidemic can still be eliminated.