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Review Article
 

Multidrug-resistant Mycobacterium tuberculosis: A Brief Review



A.G. Nikalje and P. Mudassar
 
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ABSTRACT

Multidrug resistant tuberculosis (MDR-TB) is a man-made problem. While, tuberculosis is hundred percent curable, MDR-TB is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to this type of drug resistance. Emergence of MDR-TB is reported worldwide. Better management and control of tuberculosis specially drug resistant TB by experienced and qualified doctors, access to standard microbiology laboratory, co-morbidity of HIV and tuberculosis, new anti-TB drug regimens, better diagnostic tests, international standards for second line drugs (SLD) susceptibility testing, invention of newer antitubercular molecules and vaccines and knowing the real magnitude of MDR-TB are some of the important issues to be addressed for effective prevention and management of MDR-TB.

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  How to cite this article:

A.G. Nikalje and P. Mudassar, 2011. Multidrug-resistant Mycobacterium tuberculosis: A Brief Review. Asian Journal of Biological Sciences, 4: 101-115.

DOI: 10.3923/ajbs.2011.101.115

URL: https://scialert.net/abstract/?doi=ajbs.2011.101.115
 
Received: April 28, 2010; Accepted: June 12, 2010; Published: September 09, 2010



INTRODUCTION

Tuberculosis, a disease caused by Mycobacterium tuberculosis, has been recorded in history since the Greco-Roman and Egyptian civilizations, with evidence of spinal tuberculosis being recorded as long ago as 3400 BC. Ancient Indian scriptures also mention this disease (Duraiswami and Tuli, 1971) with the first known description of tuberculous spondylitis being written in Sanskrit sometime between 1500 and 700 BC. However, the modern name of the disease has been attributed to Laennec in the 1800s (Dhillon and Tuli, 2001). According to the 13th annual tuberculosis report of the World Health Organization (WHO) published on World TB Day, March 24, 2009 there were an estimated 9.27 million new cases of tuberculosis worldwide in 2007. Although, this figure represents an increase from 9.24 million in 2006, the world population has also grown, making the number of cases per capita a more useful measure of the problem (WHO, 2009). Multi-drug resistant tuberculosis (MDR-TB) has been a topic of growing interest in the last decade. The exact magnitude of the problem of resistance to anti tubercular drug worldwide was not known till the 1994-97 global projects on anti tubercular drug resistance surveillance initiated by WHO and IUAT-LD. Prevalence of MDR-TB mirrors the functional state and efficacy of tuberculosis control programmes and realistic attitude of the community towards implementation of such programmes (ICMR, 1999). With potent anti tubercular drugs and effective treatment strategies like DOTS presently available worldwide, we hope to prevent the further development of MDR-TB.

DEFINITIONS

The MDR-TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other anti-TB drugs. The XDR-TB is defined as resistance to at least Isoniazid and Rifampicin (i.e., MDR-TB) plus resistance to any of the fluoroquinolones and any one of the second-line injectable drugs like amikacin, kanamycin, or capreomycin (Prasad, 2005).

DEVELOPMENT OF MDR-TB

Factors responsible for development of MDR-TB include genetic factor, factors related to previous antituberculosis treatment and other factors are as follows and are enlisted in Table 1.

Genetic factors: The basis for the development of MDR-TB is the accumulation of changes in the genomic content, occurring through gene acquisition and loss is the major underlying event in the emergence of fit and successful strain variants in the M. tuberculosis complex (Carpenter et al., 1983) and (Kato et al., 2001). Spontaneous chromosomally borne mutations occurring in M. tuberculosis at a predictable rate are thought to confer resistance to anti-TB drugs (Sharma and Mohan, 2004; Ramaswamy and Musser, 1998).

Factors related to previous anti tuberculosis treatment
Incomplete and Inadequate treatment:
A review of the published literature (Sharma and Mohan, 2006) strongly suggests that the most powerful predictor of the presence of MDR-TB is a history of treatment of TB, though some individuals who did not have previous TB treatment can be infected by MDR-TB. Many new cases of MDR-TB are created each year by physician’s errors (drugs, dosing, intervals and duration).

Table 1: Factors associated with development of MDR-TB
Image for - Multidrug-resistant Mycobacterium tuberculosis: A Brief Review

Professor Michael Iseman, the US guru of MDR-TB, has shown that two to four errors are needed to turn a fully susceptible organism in to a case of MDR-TB (Iseman, 1993). The MDR-TB develops due to error 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 pre-existing resistance, the initiation of an inadequate regimen using first line anti-TB and variations in bioavailability of anti-TB drugs predispose the patient to the development of MDR-TB (Sharma and Mohan, 2003). Shortage of drugs is one of the most common reasons for the inadequacy of the initial anti-TB regimen, especially in resource poor settings (Mwinga, 2001). Other major issues significantly contributing to the higher complexity of the treatment of MDR-TB is the increased cost of treatment (Chan and Iseman, 2002).

Inadequate treatment adherence: Non-adherence to prescribed treatment is one of the important factors for development of MDR-TB. Certain factors such as psychiatric illness, alcoholism, drug addiction and homelessness do predict non-adherence to treatment (Sharma and Mohan, 2004). Poor compliance with treatment is also an important factor in the development of drug resistance (Goble et al., 1993; Jacaban, 1994). A study conducted in South India (Datta et al., 1993), observed that only 43% of the patients receiving short course treatment (n = 2306) and 35% of those receiving standard chemotherapy (n = 1051) completed 80% or more of their treatment. The various reasons for default included travel to different places, symptom relief, adverse drug reactions and inability to afford treatment (Johnson et al., 2003). The MDR-TB requires a longer period of treatment compared with the drug susceptible TB. Shortest treatment course so far validated for drug susceptible TB is six months long (Chan and Iseman, 2002). The longer time that is required to treat MDR-TB clearly implies an additional risk of poor treatment adherence and consequently of treatment failure (Drobniewski and Balabanova, 2002).

Other factors: Some other factors responsible for the development of MDR-TB include as poor administrative control on purchase and distribution of the drugs with no proper mechanism on quality control and bioavailability tests. Tuberculosis control program implemented in past has also partially contributed to the development of drug resistance due to poor follow up and infrastructure (Prasad, 2005; Amita and Pratima, 2008).

BIOLOGIC AND MOLECULAR BASIS O MDR-TB

Spontaneous chromosomally borne mutations occurring in M. tuberculosis at a predictable rate is thought to confer resistance to anti-TB. Resistance to a drug is usually not associated with resistance to an unrelated drug. A tuberculosis cavity usually contains 107 to 109 bacilli. If mutations causing resistance to isoniazid occur in about 1 in 106 replications of bacteria and the mutations causing resistance to rifampicin occur in about 1 in108 replications, the probability of spontaneous mutations causing resistance to both isoniazid and rifampicin would be 106x108 = 1 in 1014. Given that this number of bacilli cannot be found even in patients with extensive cavitatory pulmonary tuberculosis, the chance of spontaneous dual resistance to rifampicin and isoniazid developing is practically remote (David, 1980; Jacaban, 1994). Thus, the fact that mutations are unlinked forms the scientific basis of antituberculosis chemotherapy. The primary mechanism of multiple drug resistance in tuberculosis is due to perturbations in the individual drug target genes (Cole, 1994).

Table 2: Anti-TB agents and the gene(s) involved in their resistance
Image for - Multidrug-resistant Mycobacterium tuberculosis: A Brief Review

Table 2 lists the molecular mechanisms of drug resistance as they are understood today. In studies published from India in addition to the previously reported mutations, several novel mutations were also observed in the rpoB (rifampicin), katG and the ribosomal binding site of inhA (isoniazid), gyr A and gyr B (ofloxacin) and rpsL and rrs (streptomycin). Fifty three mutations of 18 different kinds, 17 point mutations and one deletion were observed in 43 of 44 resistant isolates. Three novel mutations and three new alleles within the Rifampicin Resistance-Determining Region (RRDR), along with two novel mutations outside the RRDR, were reported (Mani et al., 2001). These observations suggest that while certain mutations are widely present, pointing to the magnitude of the polymorphisms at these loci, others are not common, suggesting diversity in the multidrug-resistant. Further, it was observed that rifampicin resistance was found to be an important marker for checking multi-drug resistance in clinical isolates of M. tuberculosis (Siddiqi et al., 1998).

TYPES OF MDR-TB

There are two types of drug resistances-Primary and Acquired. Primary drug resistance may be defined as drug resistance in a patient who has not received any anti-tubercular treatment in the past. Acquired drug resistance may be defined as drug resistance in a patient who has received prior chemotherapy. When one is not sure whether the resistance is primary or acquired due to concealed history of previous treatment or unawareness of treatment taken before, it is known as initial drug resistance. Combined resistance is defined as sums of primary and acquired resistance (Prasad, 2005).

HIV infection and MDR-TB: The accelerating and amplifying influence of HIV infection and the delay in recognition and diagnosis of tuberculosis were found to contribute to breaks of MDR-TB among HIV infected patients in USA (Prasad et al., 2002; Edlin et al., 1992). Shafer et al. (1995) studied temporal trends and transmission patterns in New York City using Restriction Fragment Length Polymorphism (RFLP) and found clustering of MDR-TB cases, particularly among HIV infected persons, who suffered disproportionately from drug-resistant disease. A subsequent survey of 167 consecutive cases of tuberculosis seen at five New York hospitals during 1992 and 1993 demonstrated that HIV-infected persons were significantly more likely to have been recently infected with MDR-TB; indeed, 79% of the drug-resistant cases were shown by RFLP to be clustered with the clear implication of recent transmission (Friedman et al., 1995). An association between HIV/AIDS and MDR-TB may be due to following reasons:

Increase in the number of cases of tuberculosis due to HIV/AIDS will give rise to an increase in the number of cases with primary drug resistance
Overloading of the tuberculosis treatment services because of the expected increase in the number of cases will give rise to more cases with acquired drug resistance
Immune compromised status of HIV patients may lead to decreased efficacy of antituberculosis treatment regimens and thereby increasing the chance of acquired drug resistance
The malabsorption of antituberculosis drugs has been shown to occur with high frequency among persons with AIDS, presumably because of various HIV-caused, parasitic or other enteropathies

Potentially, this could lead to grossly disparate drug levels, resulting in acquired resistance despite adherence to the prescribed regimen. Lately, however, several studies in India and other South East Asian countries, having high prevalence of HIV seropositivity, have reported very low prevalence of MDR-TB in HIV seropositive patients, contrary to western literature. Though the association between MDR-TB and HIV infection is not very significant in these countries, it would not be too long before witnessing a rapid surge of MDR-TB among HIV patients, if adequate measures are not taken (Berning et al., 1992).

DIAGNOSIS OF MDR-TB

Conventional methods: Conventional methods require 6-8 weak time before sensitivity results are known. Traditionally, Lowenstein-Jensen (LJ) culture has been used for drug sensitivity testing using (1) Absolute concentration method; (2) The resistance ratio method; and (3) The proportions method. In absolute concentration method, the Minimal Inhibitory Concentration (MIC) of the drug is determined by inoculating the control media and drug containing media with inoculums of M. tuberculosis. Media containing several sequential two-fold dilutions of each drug are used. Resistance is indicated by the lowest concentration of the drug which will inhibit growth (defined as 20 colonies or more at the end of four weeks). In resistance ratio method, MIC of the isolate is expressed as a multiple of the MIC of a standard susceptible strain, determined concurrently, in order to avoid intra and inter-laboratory variations. These two methods require stringent control of the inoculum size and hence are not optimal for direct sensitivity testing from concentrated clinical specimens. In the proportions method, the ratio of the number of colonies growing on drug containing medium to the number of colonies growing on drug free medium indicates the proportion of drug resistant bacilli present in the bacterial population. Below a certain proportion called critical proportion, a strain is classified as susceptible and above that as resistant (Vareldzis et al., 1994) and (Citron and Girling, 1987).

Modern methods
BACTEC system: In the BACTEC-460 (Becton-Dickinson) radiometric method, 7H12 medium containing palmitic acid labeled with radioactive carbon (14C-palmitic acid) is inoculated. As the mycobacteria metabolize these fatty acids, radioactive carbon dioxide (14CO2) is released which is measured as a marker of bacterial growth. The proportions method has been modified by incorporating the BACTEC technique in place of the conventional Lowenstein-Jensen culture. With this modification, sensitivity results will be available within 10 days (Roberts et al., 1983) and (Lee and Heifets, 1987).

Mycobacteria growth indicator tube: The mycobacteria growth indicator tube (MGIT) system is a rapid, nonradioactive method for detection and susceptibility testing of M. tuberculosis. The MGIT system relies on an oxygen-sensitive fluorescent compound contained in a silicone plug at the bottom of the tube which contains the medium to detect mycobacterial growth. The medium is inoculated with a sample containing mycobacteria and with subsequent growth mycobacterium utilize the oxygen and the compound fluoresces. The fluorescence thus produced is detected by using an ultraviolet trans illuminator (Bemer et al., 2002).

Restriction fragment length polymorphism: Restriction fragment length polymorphism (RFLP) patterns have facilitated the elucidation of molecular epidemiology of TB. In this technique, DNA is extracted from the cultured bacilli. A restriction endonuclease such as PvuII cleaves the element at base pair 461. Subsequent steps involve separation of DNA fragments by electrophoresis on an agarose gel, transfer of the DNA to a membrane (Southern blotting) and followed by hybridization and detection with a labeled DNA probe. The DNA from each mycobacterial isolate is depicted as a series of bands on an X-ray film to create the fingerprint. A banding pattern reflecting the number and position of copies of IS6110 (a 1361 base pair insertion sequence) within the chromosomes is obtained and this depends on the number of insertion sequences and the distance between them. As the DNA fingerprints of M. tuberculosis have been observed not to change during the development of drug resistance, RFLP analysis has also been used to track the spread of drug resistant strains (Cohn and O’Brienz, 1998; Goulding et al., 2000).

Ligase chain reaction: Ligase Chain Reaction (LCR) involves the use of an enzyme DNA ligase which functions to link two strands of DNA together to continue as a double strand. This can occur only when the ends are complementary and match exactly and this method facilitates the detection of a mismatch of even one nucleotide. It is based on the gene coding for luciferase, an enzyme identified as the light producing system of fireflies. In the presence of adenosine triphosphate (ATP), it interacts with luciferin and emits light. The luciferase gene is placed into a mycobacteriophage. Once this mycobacteriophage attaches to M. tuberculosis, the phage DNA is injected into it and the viral genes are expressed. If M. tuberculosis is infected with luciferase reporter phage and these organisms are placed in contact with antituberculosis drugs, susceptibility can be tested by correlating the generation of light with conventional methods of testing. This technique has the potential to identify most strains within 48 h (Bardarov et al., 2003; Banaiee et al., 2001).

Rapid bacteriophage-based test: A rapid bacteriophage-based test is used to identify rifampicin susceptibility in clinical strains of M. tuberculosis after growth in the BACTEC-460 semi-automated liquid culture system has also shown potential to rapidly aid in the diagnosis of MDR-TB (Takiff and Heifets, 2002; Albert et al., 2002).

Single stranded confrontation polymorphism in conjunction with PCR: Polymerase chain reaction (PCR) based sequencing has often been employed to understand the genetic mechanisms of drug resistance in mycobacteria. This technique allows for detection of both previously recognized and unrecognized mutations. The PCR-based methods are not readily applicable for routine identification of drug resistance mutations because several sequencing reactions need to be performed for each isolate. However, for targets such as rpoB, where mutations associated with rifampicin resistance is concentrated in a very short segment of the gene; PCR-based sequencing is a useful technique (Soini and Musser, 2001).

Line probe assay: The Line Probe assay (LiPA) has been used for rapid detection of rifampicin resistance. LiPA technique is based on the reverse hybridization method and consists of PCR amplification of a segment of the rpoB gene followed by denaturation and hybridization of the biotinylated PCR amplicons to capture probes bound to a nitrocellulose strip and detection of the bound amplicons producing a colour reaction. The interpretation of the banding pattern on the strip allows the identification of M. tuberculosis complex and detection of rpoB mutations. DNA microarray technology used for mycobacterial species identification has also been used for rapid detection of mutations that are associated with resistance to antituberculosis drugs. However, most of the modern diagnostic methods are confined to research laboratories and are several years away from being available for use in the field setting (Troesch et al., 1999).

MANAGEMENT

When MDR-TB is suspected on the basis of history or epidemiological information, the patient’s sputum must be subjected to culture and antituberculosis drug sensitivity testing and the empirical regimens employing second-line reserve drugs suggested by the American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society of America (ATS/CDC/ IDSA) must be initiated. These guidelines clearly mention that a single drug should never be added to a failing regimen. Furthermore, when initiating treatment, at least three previously unused drugs must be employed to which there is in vitro susceptibility. When susceptibility testing reports are available and there is resistance to isoniazid and rifampicin (with or without resistance to streptomycin) during the initial phase, a combination of ethionamide, fluoroquinolones, another bacteriostatic drug such as ethambutol, pyrazinamide and aminoglycoside like kanamycin, amikacin, or capreomycin are used for three months or until sputum conversion. During the continuation phase, ethionamide, fluoroquinolones and another bacteriostatic drug (ethambutol) should be used for at least 18 months after smear conversion. If there is resistance to isoniazid, rifampicin and ethambutol (with or without resistance to streptomycin) during the initial phase, a combination of ethionamide, fluoroquinolones and another bacteriostatic drug such as cycloserine or PAS, pyrazinamide and aminoglycoside such as kanamycin, amikacin, or capreomycin are used for three months or until sputum conversion. During the continuation phase, ethionamide, ofloxacin, another bacteriostatic drug (cycloserine or PAS) should be used for at least 18 months after smear conversion.

The recently published ATS/CDC/IDSA guidelines suggest that among the fluoroquinolones, levofloxacin is most suited for the treatment of MDR-TB given its good safety profile with long-term use. When administering antituberculosis drugs by the parentral route, proper precautions must be taken. This is particularly relevant in countries like India where, disposable syringes are not always available for giving the injections and the use of improperly sterilized needles would be a health hazard especially in patients with HIV infection and AIDS (Blumberg et al., 2003; Crofton et al., 1997).

Second-line drugs are very difficult to obtain in small towns and rural areas in India. Moreover, there is a wide variation in the price range between different pharmaceutical brands. Reliable pharmacokinetic data regarding bioavailability of most of these formulations are not available and there is no assurance that the most expensive brand names have the best bioavailability profile. Even considering the cheapest brand names available, the cost of drug treatment alone is much beyond the means of the average Indian patient. Therefore, long term compliance is not very good. All these factors constitute significant therapeutic challenges for the clinicians treating MDR-TB. Population migration due to poverty to seek better job opportunities, natural disasters, wars, political instability and regional conflicts also create mobile populations. These factors make treatment of MDR-TB difficult (Schluger, 2000; Iseman, 1998).

DOTS-plus strategy: DOTS is a key ingredient in the tuberculosis control strategy. In populations where MDR-TB is endemic, the outcome of the standard short-course regimen remains uncertain. Unacceptable failure rates have been reported and resistance to additional agents may be induced. As a consequence, there have been calls for well-functioning DOTS programmes to provide additional services in areas with high rates of MDR-TB. These DOTS-plus for MDR-TB programmes may need to modify all five elements of the DOTS strategy:

The treatment may need to be individualized rather than standardized
Laboratory services may need to provide facilities for on-site culture and antibiotic susceptibility testing
Reliable supplies of a wide range of expensive second-line agents
Operational studies would be required to determine the indications
Financial and technical support from international organizations and Western governments would be needed in addition to that obtained from local governments (Gupta et al., 2002; Kim et al., 2003)

Monitoring response to treatment: Patients receiving treatment for MDR-TB should be closely followed up. Clinical (e.g., fever, cough, sputum production, weight gain), radiological (e.g., chest radiograph), laboratory (erythrocyte sedimentation rate) and microbiological (e.g., sputum smear and culture) parameters should be periodically reviewed to assess the response to treatment. In addition, considerable attention must be focused on monitoring the adverse drug reactions which often develop with the second-line antituberculosis drugs. Majority of the patients who respond to treatment begin to show favorable signs of improvement by about four to six weeks following initiation of treatment.

Newer antitubercular drugs: Currently available second-line drugs used to treat MDR-TB (Table 3) are four to ten times more likely to fail than standard therapy for drug-susceptible tuberculosis. After the introduction of rifampicin, no worthwhile anti tuberculosis drug with new mechanism(s) of action has been developed over thirty years. Moreover, no new drugs that might be effective in treatment of MDR-TB are currently undergoing clinical trials. It appears that effective new drugs for tuberculosis are at least a decade away. Recently, a series of compounds containing a nitro- imidazopyran nucleus that possess antitubercular activity have been described. Mechanism of action includes activation of M. tuberculosis F420 cofactor, thus synthesis of protein and cell wall lipid are inhibited. In contrast to current antitubercular drugs, nitro-imidazopyran exhibited bactericidal activity against both replicating and static bacilli. It is being hoped that these nitro-imidazopyrans will offer the practical qualities with the potential for the treatment of tuberculosis (Stover et al., 2000).

Table 3: Dose and toxicity of second-line antitubercular drugs
Image for - Multidrug-resistant Mycobacterium tuberculosis: A Brief Review

Surgery: Various surgical procedures performed for patients with MDR-TB have ranged from segmental resection to pleuro-pneumonectomy. Based on the experience reported in the literature about surgery for MDR-TB, it can be concluded that the operation can be performed with a low mortality (<3%). However, the complication rates are high with Broncho Pleural Fistula (BPF) and empyema being the major complications. Sputum positivity at the time of surgery, previous chest irradiation, prior pulmonary resection and extensive lung destruction with polymicrobial parenchymal contamination are the major factors affecting morbidity and mortality. Over 90% of the patients achieve sputum negative status post-operatively. Although, operation related mortality is less than 3%, deaths due to all causes occur in about 14% patients. Even this compares favorably with over 22% mortality due to TB in a similar group of patients treated medically. More liberal use of muscle flaps to reinforce the bronchial stump and fill the residual space has helped significantly in reducing the rates of BPF, air leaks and residual space problems. These must be used in patients with positive sputum, when residual post-lobectomy space is anticipated; when BPF already exists pre-operatively or when extensive polymicrobial contamination is present. Indications for surgery in patients with MDR-TB include:

Persistence of culture-positive MDR-TB despite extended drug retreatment; and/or
Extensive patterns of drug resistance that are associated with treatment failure or additional resistance; and/or
Local cavity, necrotic/destructive disease in a lobe or region of the lung that was amenable to resection without producing respiratory insufficiency and/or severe pulmonary hypertension.

It should be performed after minimum of three months of intensive chemotherapeutic regimen, achieving sputum-negative status, if possible. The operative risks are acceptable and the long-term survival is much improved than that with continued medical treatment alone. However, for this to be achieved, the chemotherapeutic regimen needs to continue for prolonged periods after surgery also, probably for well over a year, otherwise recrudescence of the disease with poor survival is a real possibility (Pomerantz et al., 1991; Park et al., 2002).

Nutritional enhancement: The degree of cachexia is most profound when MDR-TB occurs in patients with HIV-infection/AIDS. While, the mechanisms involved in weight loss are not well known, current evidence points to tumor necrosis factor-α (TNF-α) to be the cytokine responsible for this phenomenon. TNF-α is responsible for inducing immunopathological effects such as tissue necrosis and fever, is also thought to induce the catabolic response. Further, several second-line drugs used to treat MDR-TB such as PAS; fluoroquinolones cause significant anorexia, nausea, vomiting and diarrhea interfering with food intake, further compromising the cachectic state. Therefore, nutritional support is a key factor in the care of patients with MDR-TB, especially those undergoing major lung surgeries (Sharma and Mohan, 1997).

Immunotherapy: Various agents are used to enhance the immunity for MDR-TB patients. Agents with potential for immunotherapy are discussed below.

Mycobacterium Vaccae vaccination: Transiently favorable results were observed when immune enhancement using Mycobacterium vaccae vaccination was used to treat drug-resistant tuberculosis patients who failed chemotherapy. It was postulated that Mycobacterium vaccae redirected the host’s cellular response from a Th-2 dominant to a Th-1 dominant pathway leading to less tissue destruction and more effective inhibition of mycobacterial replication. However, subsequent reports from randomized controlled trials have not confirmed these observations.

Cytokine therapy: With further understanding of the molecular pathogenic mechanisms of tuberculosis, several attempts have been made to try cytokines in the treatment of MDR-TB. Recent data, however, suggest that interferon-α (IFN-α) and interferon-α (IFN-α) may improve disease evolution in subjects affected with pulmonary tuberculosis caused by multidrug-resistant (IFN-α) and sensitive (IFN-α) strains. It has been reported that IFN-α secreting CD4+Th cells may possess antituberculosis effects. In addition, IFN-α can induce IFN-α secretion by CD4+Th cells and both types of IFN may stimulate macrophage activities (Iseman, 2000; Stanford, 1997).

Aerosolized IFN-α: Aerosolized IFN-α has been found to produce transient, but clinically encouraging responses in patients with MDR-TB in an open-label trial. The observed benefits included un sustained sputum smear conversion to negative, delayed growth of cultures and shrinkage of cavities. Granulocyte macrophage colony-stimulating factor (GM-CSF) has been used simultaneously with IFN-? in the successful treatment of a patient with refractory central nervous system MDR-TB (Raad et al., 1996).

Interleukin-2: Interleukin-2 (IL-2) has been used in the treatment of lepromatous leprosy and is believed to act by enhancing IFN-α production. By the same analogy, IL- 2 may be useful in the treatment of MDR-TB. Johnson et al reported the usefulness of low-dose recombinant human interleukin 2 (rhuIL-2) adjunctive immunotherapy in MDR-TB patients. In this study MDR-TB patients on best available antituberculosis chemotherapy also received rhuIL-2 for 30 consecutive days (daily therapy), or for five days followed by a nine day rest, for three cycles (pulse therapy). Placebo control patients received diluent. The cumulative total dose of rhuIL-2 given to each patient in either rhuIL-2 treatment group was the same. Patient immunologic, microbiologic and radiologic responses were compared. The three treatment schedules induced different results. Immune activation was documented in patients receiving daily rhuIL-2 therapy. These patients showed increase in numbers of CD25+and CD56+cells in the peripheral blood, but not in patients receiving pulse rhuIL-2 or placebo. In addition, 62 per cent patients receiving daily rhuIL-2 demonstrated reduced or cleared sputum bacterial load while only 28 per cent pulse rhuIL-2 treated and 25 per cent controls showed bacillary clearance.

Chest radiographs of 58% patients receiving daily rhuIL-2 showed significant improvement over six weeks. Only 22% pulse rhuIL-2-treated patients and 42% placebo controls showed radiologic improvement. The authors concluded that daily low dose rhuIL-2 adjunctive treatment stimulates immune activation and may enhance the antimicrobial response in MDR-TB (Giosue et al., 2000).

Other agents: There are other several agents that evoked interest as potential adjunctive treatment for patients with MDR-TB. Though very little information is available regarding their clinical usefulness. Thalidomide (Reyes-Teran et al., 1996) and pentoxifylline (Strieter et al., 1988; Dezube, 1994) have been shown to combat the excessive effects from TNF-α. The wasting associated with MDR-TB may be limited by using these agents. Other agents which can be used include, levamisole (Yaseen et al., 1980; Singh et al., 1981) transfer factor (Whitcomb and Rocklin, 1973), inhibitors of transforming growth factor-β (TGF-β) (Hirsch et al., 1997), interleukin-12 (IL-12) (Iseman, 2000), interferon-a (IFN-α) and imiquimod, an oral agent which stimulates the production of IFN-α. Though there have been anecdotal reports of their usefulness, further studies are required to clarify their role. Literature survey has revealed that some new pyrazolo phenoxy acetic acid derivatves have shown moderate anti tubercular activity (Pattan et al., 2009) and biological evaluation of 2-(4-arylthiazol-2-yl-amino)-n-aryl acetamides has shown promising antitubercular activity (Nikalje et al., 2010).

CONCLUSION

The topic of MDR-TB has been an area of growing concern among clinicians, epidemiologists and public health workers worldwide. New researches must be done in the areas involving molecular biology and application of these in the field of epidemiology to help in better understanding of the mechanisms of MDR-TB, development of newer diagnostic tools and effective drugs to control multidrug resistant tuberculosis. MDR-TB can be managed with careful use of second line agents at specialized centers to reduce morbidity and mortality and transmission. Limited evidence suggests that when strong TB control programme is in place, use of second line drugs is feasible and cost effective. Several pilot projects are underway in developing countries that will provide necessary evidence to design policy guidelines for management of MDR-TB. With second line drugs and effective treatment strategies like DOTS presently available worldwide, we hope to prevent the further development of MDR-TB. The challenge is to make this approach a sustainable reality worldwide.

ACKNOWLEDGMENT

Authors are grateful to Chairman, Mrs. Fatma Rafiq Zakaria, Maulana Azad Education Trust and Dr. M.H. Dehghan, Principle, Y.B. Chavan College of Pharmacy, Aurangabad for their encouragement and support.

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