Multidrug-resistant Mycobacterium tuberculosis: A Brief Review
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.
Received: April 28, 2010;
Accepted: June 12, 2010;
Published: September 09, 2010
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
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 physicians
errors (drugs, dosing, intervals and duration).
|| Factors associated with development of MDR-TB
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,
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,
|| Anti-TB agents and the gene(s) involved in their resistance
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.,
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
||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
||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).
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 OBrienz, 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).
When MDR-TB is suspected on the basis of history or epidemiological information, the patients 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,
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).
|| Dose and toxicity of second-line antitubercular drugs
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
||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 hosts 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,
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
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.,
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).
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.
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.
1: Duraiswami, P.K. and S.M. Tuli, 1971. Five thousand years of orthopedics in India. Clinorthop, 75: 269-280.
2: Dhillon, M.S. and S.M. Tuli, 2001. Osteoarticular tuberculosis of the foot and ankle. Foot Ankle Int., 22: 669-686.
3: WHO, 2009. Global tuberculosis control: Epidemiology, strategy, financing. WHO Report 2009. http://www.who.int/tb/publications/global_report/2009/en/index.html
4: Prasad, R., 2005. MDR TB: Current status. Indian J. Tub., 52: 121-131.
Direct Link |
5: Carpenter, J.L., A.J. Obnibene, E.W. Gorby, R.E. Neimes, J. Koch and W.L. Perkins, 1983. Antituberculosis drug resistance in south texas. Am. Rev. Respir. Dis., 128: 1055-1058.
6: Kato, M.M., P.J. Bifani and B.N. Krieswirth, 2001. The nature and consequence of genetic variability in mycobacterium tuberculosis. J. Clin. Invest., 107: 533-537.
7: Sharma, S.K. and A. Mohan, 2004. Multidrug-resistant tuberculosis. Indian. J. Med. Res., 120: 354-376.
Direct Link |
8: Ramaswamy, S. and J.M. Musser, 1998. Molecular genetic basis of anti- microbial agent resistance in mycobacterium tuberculosis. Tuber. Lung. Dis., 79: 3-29.
9: Sharma, S.K. and A. Mohan, 2006. Multidrug-resistant tuberculosis: A menace that threatens to destabilize tuberculosis control. Chest, 130: 261-272.
10: Iseman, M.D., 1993. Treatment of multidrug-resistant tuberculosis. N. Engl. J. Med., 329: 784-791.
Direct Link |
11: Sharma, S.K. and A. Mohan, 2003. Scientific basis of directly observed treatment, short course(DOTS). J. Indian Med. Assoc., 101: 157-158.
12: Mwinga, A., 2001. Drug resistant tuberculosis in africa. Ann. N. Y. Acad. Sci., 953: 106-112.
13: Chan, E.D. and M.D. Iseman, 2002. Current medical treatment for tuberculosis. Br. Med. J., 325: 1282-1286.
Direct Link |
14: Goble, M., M.D. Iseman and L.A. Madsen, 1993. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampicin. N. Engl. J. Med., 328: 527-532.
Direct Link |
15: Jacaban, R.F., 1994. Multiple drug resistant tuberculosis. Clin. Infect. Dis., 19: 1-10.
Direct Link |
16: Datta, M., M.P. Radhamani, R. Selvaraj, C.N. Paramasivan, B.N. Gopalan, C.R. Sudeendra and R. Prabhakar, 1993. Critical assessment of smear-positive pulmonary tuberculosis patients after chemotherapy under the district tuberculosis programme. Tuber. Lung. Dis., 74: 180-186.
17: Johnson, J., A. Kagal and R. Bharadwaj, 2003. Factors associated with drug resistance in pulmonary tuberculosis. Indian J. Chest Dis. Allied Sci., 45: 105-109.
18: Drobniewski, F.A. and Y.M. Balabanova, 2002. The diagnosis and management of multiple drug-resistant tuberculosis at the beginning of the new millennium. Int. J. Infect. Dis., 6: 21-31.
19: Amita, J. and D. Pratima, 2008. Multidrug resistant to extensively drug resistant tuberculosis: What is next. J. Biosci., 33: 105-116.
20: David, H.L., 1980. Drug-resistance in M. tuberculosis and other mycobacteria. Clin. Chest Med., 1: 227-230.
21: Cole, S.T., 1994. The Molecular Basis of Drug Resistance. In: Tuberculosis Backto the Future, Porter, J.D.H. and K.P.W. McAdam (Eds.). John Wiley and Sons, Chicester, pp: 225-230
22: Mani, C., N. Selvakumar, S. Narayanan and P.R. Narayanan, 2001. Mutations in the rpobgene of multidrug-resistant mycobacterium tuberculosis clinical isolates from India. J. Clin. Microbiol., 39: 2987-2990.
23: Siddiqi, N., M. Shamim, N.K. Jain, A. Rattan, A. Amin and V.M. Katoch, 1998. Molecular genetic analysisof multi-drug resistance in Indian isolates of mycobacterium tuberculosis. Mem. Inst. Oswaldo. Cruz., 93: 589-594.
Direct Link |
24: Prasad, R., R.G. Nautiyal and R.C. Ahuja, 2002. Treatment of new pulmonary tuberculosis patients: What do allopathic doctors do in India. Int. J. Tuberc. Lung. Dis., 6: 895-902.
25: Edlin, B.R., J.I. Tokars, M.H. Grieco, J.T. Crawford and J. Williams et al., 1992. An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome. N. Engl. J. Med., 326: 1514-1521.
26: Shafer, R.W., P.M. Small, S.P. Singh, P. Kelly and C. Larkin et al., 1995. Temporal trends and transmission patterns during the emergence of multidrug-resistant tuberculosis in New York City: A molecular epidemiologic assessment. J. Infect. Dis., 152: 171-176.
27: Friedman, C.R., M.Y. Stoeckle, W.D. Johnson, J. Berger and B.N. Kreiswirth et al., 1995. Transmission of multidrug resistanttuberculosis in a large urban setting. Am. Jrespir. Crit. Care Med., 152: 155-159.
Direct Link |
28: Berning, S.E., G. Huitt, M.D. Eseman and C.A. Peloquin, 1992. Mal-absorption of antituberculosis medications by a patient with AIDS. N. Engl. J. Med., 327: 1817-1818.
29: Vareldzis, B.P., J. Grosset, I. Kantor, J. Crofton, A. Laszlo and M. Felten, 1994. Drug-resistant tuberculosis: Laboratory issues. World Health Organization recommendations. Tuber. Lung. Dis., 75: 1-7.
30: Citron, K.M. and D.J. Girling, 1987. Tuberculosis. Crofton and Douglass Respiratory Diseases. Vol. 5., Oxford University Press/English Language Book Society, Oxford, pp:278-299
31: Roberts, G.D., N.L. Goodman, L. Heifets, H.W. Larsh, T.H. Lindner and J.K. McClatchy, 1983. Evaluation of the bactec radiometric method for recovery of mycobacteria and drug susceptibility testing of mycobacterium tuberculosis from acid-fast smear-positive specimens. J. Clin. Microbiol., 18: 689-696.
32: Lee, C.N. and L.B. Heifets, 1987. Determination of minimal inhibitory concentrations of antituberculosis drugs by radiometric and conventional methods. Am. Rev. Respir. Dis., 136: 349-352.
33: Bemer, P., F. Palicova, S. Rusch-Gerdes, H.B. Drugeon and G.E. Pfyffer, 2002. Multicenter evaluation of fully automated BACTEC mycobacteria growth indicator tube 960 system for susceptibility testing of mycobacterium tuberculosis. J. Clin. Microbiol., 40: 150-154.
34: Cohn, D.L. and R.J. O`Brienz, 1998. The use of restriction fragment length polymorphism (RFLP) analysis for epidemiological studies of tuberculosis in developing countries. Int. J. Tuberc. Lung Dis., 2: 16-26.
35: Goulding, J.N., J. Stanley, N. Saunders and C. Arnold, 2000. Genome sequence- based fluorescent amplified-fragment length polymorphism analysis of mycobacterium tuberculosis. J. Clin. Microbiol., 38: 1121-1126.
Direct Link |
36: Bardarov, S.J., H. Dou, K. Eisenach, N. Banaiee, S. Ya and J. Chan, 2003. Detection and drug-susceptibility testing of m.tuberculosis from sputum samples using luciferase reporter phage: Comparison with the Mycobacteria Growth Indicator Tube (MGIT) system. Diagn. Microbiol. Infect. Dis., 45: 53-61.
Direct Link |
37: Banaiee, N., M. Bobadilla-Del-Valle, S.J. Bardarov and P.F. Riska, 2001. Luciferase reporter mycobacteriophage for detection, identification and antibiotic susceptibility testing of mycobacterium tuberculosis in Mexico. J. Clin. Microbiol., 39: 3883-3888.
Direct Link |
38: Takiff, H. and L. Heifets, 2002. In search of rapid diagnosis and drug resistance detection tools: Is the fast plaque TB test the answer. Int. J. Tuberc. Lung. Dis., 6: 560-561.
39: Albert, H., A.P. Trollip, R.J. Mole, S.J. Hatch and L. Blumberg, 2002. Rapid indication of multidrug-resistant tuberculosis from liquid cultures using fast plaque tb-RIF: A manual phage-based test. Int. J. Tuberc. Lung. Dis., 6: 523-528.
Direct Link |
40: Soini, H. and J.M. Musser, 2001. Molecular diagnosis of mycobacteria. Clin. Chem., 47: 809-814.
Direct Link |
41: Troesch, A., H. Nguyen, C.G. Miyada, S. Desvarenne and P.M. Kaplan et al., 1999. Mycobacterium species identification and rifampin resistance testing with high-density DNA probe arrays. J. Clin. Microbiol., 37: 49-55.
42: Blumberg, H.M., W.J. Burman, R.E. Chaisson, C.L. Daley and S.C. Etkind et al., 2003. American thoracic society/centers for disease control and prevention/infectious diseases society of America: Treatment of tuberculosis. Am. J. Respir. Crit. Care Med., 167: 603-662.
CrossRef | PubMed | Direct Link |
43: Crofton, J., P. Chaulet, D. Maher, J. Grosset, W. Harris and N. Horne, 1997. Guidelines for the Management of Drug Resistant Tuberculosis. WHO, Geneva
44: Schluger, N.W., 2000. The impact of drug resistance on global tuberculosis epidemic. Int. J. Tuberc. Lung Dis., 4: 71-75.
45: Iseman, M.D., 1998. MDR-TB and the developing world: A problem no longer to be ignored: The WHO announces DOTS plus strategy. Int. J. Tuberc. Lung Dis., 2: 867-867.
46: Gupta, R., J.P. Cegielski, M.A. Espinal, M. Henkens and J.Y. Kim et al., 2002. Increasing transparency in partnerships for health - introducing the green light committee. Trop Med. Int. Health, 7: 970-976.
47: Kim, J.Y., J.S. Mukherjee, M.L. Rich, K. Mate, J. Bayona and M.C. Becerra, 2003. From multidrug-resistant tuberculosis to DOTS expansion and beyond: Making the most of a paradigm shift. Tuberculosis, 83: 59-65.
48: Stover, C.K., P. Warrener, D.R. VanDevanter, T.M. Arain and M.H. Langhorne, 2000. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature, 405: 962-966.
49: Pomerantz, M., L. Madsen, M. Goble and M. Iseman, 1991. Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann. Thorac. Surg., 52: 1108-1111.
50: Park, S.K., C.M. Lee, J.P. Heu and S.D. Song, 2002. A retrospective study for the outcome of pulmonary resection in 49 patients with multidrug-resistant tuberculosis. Int. J. Tuberc. Lung. Dis., 6: 143-149.
51: Sharma, S.K. and A. Mohan, 1997. Clinical manifestations of tuberculosis: Molecular mechanisms. Indian J. Chest Dis. Allied Sci., 39: 1-4.
Direct Link |
52: Iseman, M.D., 2000. A Clinicians Guide to Tuberculosis. 1st Edn., Lippincott Williams and Wilkins, Philadelphia. ISBN-10: 0781717493, pp:460
53: Stanford, J.L., 1997. Frontiers in Mycobacteriology. Symposium sponsored by National Jewish Center for Immunology and Respiratory Medicine. National Jewish Center for Immunology and Respiratory Medicine, Vail, Colarado
54: Raad, I., R. Hachem, N. Leeds, R. Sawaya, Z. Salem and S. Atweh, 1996. Use of adjunctive treatment with interferon-gamma in an immunocompromised patient who had refractory multidrug-resistant tuberculosis of the brain. Clin. Infect. Dis., 22: 572-574.
55: Giosue, S., M. Casarini, F. Ameglio, P. Zangrilli, M. Palla, A.M. Altieri and A. Bisetti, 2000. Aerosolized interferon- alpha treatment in patients with multi-drug-resistant pulmonary tuberculosis. Eur. Cytokine Netw., 11: 99-104.
56: Reyes-Teran, G., J.G. Sierra-Madero, V. Martinez del Cerro, H. Arroyo-Figueroa, A. Pasquetti and J.J. Calva, 1996. Effects of thalidomide on hiv-associated wasting syndrome: A randomized, double-blind, placebo-controlled clinical trial. AIDS, 10: 1501-1507.
57: Strieter, R.M., D.G. Remick, P.A. Ward, R.N. Spengler, J.P.3rd. Lynch, S.L. Kunkel and J. Larrick, 1988. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem. Biophys. Res. Commun., 155: 1230-1236.
PubMed | Direct Link |
58: Dezube, B.J., 1994. Pentoxifylline for the treatment of infection with human immuno deficiency virus. Clin. Infect. Dis., 18: 285-287.
Direct Link |
59: Yaseen, N.Y., A.J. Thewaini, N.G. Al-Tawil and F.Y. Jazrawi, 1980. Trial of immuno potentiation by levamisole in patients with pulmonary tuberculosis. J. Infect., 2: 125-136.
60: Singh, M.M., P. Kumar, A.N. Malaviya and R. Kumar, 1981. Levamisole as an adjunct in the treatment of pulmonary tuberculosis. Am. Rev. Respir. Dis., 123: 277-279.
61: Whitcomb, M.E. and R.E. Rocklin, 1973. Transfer factor therapy in a patient with progressive primary tuberculosis. Ann. Intern. Med., 79: 161-166.
Direct Link |
62: Hirsch, C.S., J.J. Ellner, R. Blinkhorn and Z. Toossi, 1997. In vitro restoration of T cell responses in tuberculosis andaugmentation of monocyte effector function against mycobacterium tuberculosis by natural inhibitors of transforming growth factor beta. Proc. Natl. Acad. Sci. USA., 94: 3926-3931.
63: Pattan, S.R., R.L. Hullolikar, J.S. Pattan, B.P. Kapadnis and N.S. Dighe et al., 2009. Synthesis and evaluation of some new pyrazolo phenoxy acetic acid derivatves for their antitubercular activity. J. Pharm. Sci. Res., 1: 63-68.
Direct Link |
64: Nikalje, A.P., S. Pattan and A. Mane, 2010. Microwave-assisted solvent free synthesis and biological evaluation of 2-(4-arylthiazol-2-yl-amino)-n-aryl acetamides. Asian J. Exp. Biol. Sci., 1: 344-351.
Direct Link |