Multi Drug Resistant Tuberculosis is a disease that humankind has inflicted upon itself. The treatment for tuberculosis has evolved over the last 80 years from a palliative approach to a chemotherapeutic approach. It was understood early that monotherapy was an inadequate and inadvisable treatment for Tuberculosis. Sir John Crofton's work in establishing multi drug therapy as the mainstay of Tuberculosis treatment saved lives beyond compare (WHO 2010). Despite this, the length of treatment and toxicity associated with multi drug therapy has made for poor patient compliance and the emergence of drug resistant bacteria. The following section deals with the challenges that the treatment and control of MDR-TB faces.
Issues in resistance in MDR-TB
Drug Resistance in treatment of Tuberculosis is not a new trend. Soon after the discovery of streptomycin for the treatment of TB the resistance to the monotherapy was recognized (Zhang et al 2009).
1.1. Mechanisms of Bacterial Resistance
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Spontaneous genetic mutations are thought to account for drug resistance in TB. The chromosomal mutations are thought to occur in the frequency of 10-6 to 10-8 reproductions of the Mycobacteria. The mutations that cause the drug resistance are thought to be unlinked; therefore the chance that the Mycobacteria will have drug resistance to three drugs used in combination becomes 10-18 to 10-20. Based on these estimates the chance that drug resistance will emerge is miniscule. In reality however, drug resistance is rampant and on the ever increase. This can be explained by the fact that human errors have contributed to the magnification of the chromosomal mutations. The errors include irrational drug therapy, including monotherapy, irregular drug supply and most critically poor patient compliance to the prescribed therapy. The infected patient with inadequate treatment exacerbates the problem by spreading the drug resistant bacilli in the community. The bacteria in this process accumulate mutations (Zhang et al 2009).
1.2. Individual drug resistance and types of resistance
Drug resistance to Isoniazid (INH) and Rifampicin have emerged as a serious problem since both these drugs are the core of the multidrug therapy for the treatment of TB. Data on the genetic basis of drug resistance for Mycobacteria have identified at least two modes of action for INH resistance: deletion of katG, the gene which encodes for catalase or mutation in inhA, a gene which codes for the synthesis of mycoli acid. The resistance for Rifampicin seems to occur due to mutations inside the ropB gene that codes for the β subunit of RNA polymerase (Hornick 2008).
Primary resistance is drug resistance in patients who have not received any anti-tuberculosis treatment previously. It is thought that they acquire the infection from another person who has drug resistant TB. When the resistance is to INH and Rifampicin at the least, it is designated as multi drug-resistant Tuberculosis. It also includes unknown treatment status and cases with undisclosed treatment status (Zhang et al 2009, Hornick 2008).
Secondary resistance is also called acquired drug resistance. It is thought to occur due to use of monotherapy in cavitary TB specifically INH and then the sequential addition of other drugs. It also consists of patients who have been previously treated for TB, including those who received drugs for at least one month (Zhang et al 2009, Hornick 2008).
Relapse rates when patients are treated four first line drugs viz. INH, Rifampicin, Ethambutol and Pyrazinamide for the full duration of 6 months are observed to be 2%, this increases to 10% when the treatment includes only INH and Rifampicin in the continuation period (months 4 to 6 of treatment regimen) (Zhang et al 2009). The drug resistance significantly affects disease cure rates and substantially increases the costs associated with treatment adding an increasing financial burden to the healthcare system.
The challenges in diagnosis of MDR TB are the insufficient quality assured laboratory network, non availability of protocols for second line drug susceptibility testing in high burden countries (Dr. Dholakia, e-mail communication). The Mycobacterium tuberculosis is a delicate organism and needs specialized media for growth. The Mycobacteria are a slow growing aerobic bacteria dividing once every 18-24 hours in contrast to the other bacteria which divide every 1-2 hours. The culture requires between 3-4 incubation following which the organisms are identified using acid-fast stains. This entire process accounts for the 6-8 weeks delay associated with the diagnosis of Tuberculosis (Hornick 2008). The process for identifying MDR-TB is equally tedious with additional Drug Sensitivity Testing required.
2.1. Current Diagnostic Methods
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2.1.1. Culture of Clinical Specimens: With improvements in technology currently the time to identification using culture is between 3-4 weeks. Newer media, which is a selective liquid, using various markers helps the bacteria multiply faster than traditional media and aids in monitoring growth of the bacterial colonies. Between 14-20 days, adequate DNA can be extracted for hybridization to detect the M. tuberculosis complex. Additional tests for drug sensitivity can give results in as little as a week after the culture isolate drug resistant strains (Hornick 2008).
2.1.2. Sputum Examination: Traditional sputum examination used has low sensitivity and specificity. It is unable to distinguish between M.tuberculosis and Non tuberculous Mycobacteria. Nucleic acid amplification (NAA) techniques are currently being used in interpreting sputum smears. The prohibitive cost makes it an unsuitable option for high burden countries which are also low resource setting countries. Two commercial NAA have been approved by the FDA: M.tuberculosis direct test and Amplicor TB test, the former is for negative smears while the latter is for acid fast bacilli positive smears only. (Hornick 2008).
2.1.3. Chest x-ray: This is useful in active pulmonary TB. The various lesions associated with the disease are seen in the apical lobes of the lungs and in the hilar region (Hornick 2008).
2.1.4. Mantoux Test: Also called Tuberculin test. It estimates the specific cellular immunity in the person. The test is affected by past infections, vaccination by BCG and other factors which interfere with the result and its interpretation (Hornick 2008).
2.2. Newer Methods
With the increasing incidence of MDR-TB new, rapid and accurate tests are the need of the hour. The need for these tests is acute as the disease is most prevalent in high burden low resource countries. In a recent publication seven rapid test were evaluated in a low resource high burden country. The study evaluated thirty-one strains of M. tuberculosis with the following assays: the nitrate reductase assay (NRA), microscopic observation drug susceptibility (MODS), MGITTM 960 (Mycobacterium Growth Indicator Tube 960), Genotype® MTBDRplus, Alamar blue, MTT and resazurin assays. The test results were available within 2-14 days. The study found the NRA to be the most sensitive and specific test for diagnosis of MDR-TB. The drug resistance was tested for INH and Rifampicin which are first line drugs in TB treatment. The authors concluded that despite the success of the tests in a laboratory setting, prospective trials were needed to prove the value of these tests in the clinical setting (Bwanga et al 2010).
The current need is for low cost rapid detection tests that can be used in the primary care centres and rural areas were the burden of disease is high in the countries which count TB as a public health problem. The need is for simple test kits that can be used by peripheral paramedical staff.
Over the last 30 years only 1% of the new drugs on the market were anti-microbials.There hasn't been a new therapeutic agent in the treatment of Tuberculosis in about 30 years now (O'Brien et al 2001). With the emergence of MDR-TB and its association with HIV, the search for new therapeutic agents has taken on a new urgency. As for new drug development, there can be many possibilities such as targeting drug efflux pumps, various other proteins or sites or bacterial enzymes and identifying these is a challenge in itself (Dr. Dholakia, e-mail communication). The need for new drugs in tuberculosis is: to shorten the treatment duration, to improve or provide new treatment for Multidrug- resistant tuberculosis and to treat latent tuberculosis infection (O'Brien et al 2001). The bacteria tends to stay metabolically inactive or in dormant stage and poses a challenge to treatment. There are novel approaches being tried along with trying to utilize newer generation and class antibiotics in the treatment of MDR-TB.
3.1. New Drugs
There are a number of promising drugs on the horizon some of which are summarized below:
3.1.1. Diarylquinoline: It is a new drug which can contribute to the reduction in the duration of treatment. Diarylquinoline R207910 (J compound) was found to be active against MDR-TB strains. The drug is currently under clinical trials for human use (Zhang et al 2006).
3.1.2. New fluoroquinolones: These are currently the 2nd line drugs in treatment of TB and are used in treatment of MDR-TB. Moxifloxacin and gatifloxacin have been seen to more active against M. tuberculosis than the previous generations of fluoroquinolones. The mouse models showed the drug was more effective than the existing therapy and could contribute to reduction of the treatment duration (Zhang et al 2006).
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3.1.3. Rifamycin derivatives: Rifalazil is a new semi-synthetic rifamycin derivative with better activity in mouse models both in vitro and in vivo against M. tuberculosis (Zhang et al 2006).
3.1.4. Oxazolidinones: Linezolid is under trial for MDR-TB with good results but its long term toxicity is still being scrutinized (Zhang et al 2006). Linezolid has achieved 70% culture conversion by two months in clinical trials (Dr. Saukkonen, personal communication).
3.1.5. Nitroimidazopyran PA824: It is a prodrug which is activated by bacterial enzymes and is known to be active in MDR-TB. The drug in animal models has exhibited activity against latent infection. The drug is in clinical trials and is expected to reduce the treatment duration (Zhang et al 2006).
The expectation is that over the next few years more potent drugs will become available and avert the next crisis of extensively drug resistant tuberculosis from derailing the current treatment regimens for the disease. The challenge is for the pharmaceutical industry to commit the funds required for the drug development and clinical trials that will be required to bring these drugs to the market as these will be for markets with the most disease but the least paying capacity.
3.2. New treatment regimens
The current treatment regimens are anywhere between 6-18 months for treatment of drug- sensitive tuberculosis. This is extended to 24 months for some drug resistant tuberculosis regimens. The patient compliance is extremely poor due to the long duration of drug therapy (guidelines- WHO 2010). The patients tend to abandon the treatment as they start to feel better or if the adverse reactions are not acceptable to them and thereby contribute to the spread of drug resistance. There is urgent need to reduce the treatment times for tuberculosis while striving to achieve the cure for tuberculosis. Newer drugs in development show promise in reducing the treatment duration.
Oral immune adjunct V5 is currently in phase II of clinical trials as an addition to the standard treatment regimen in treatment of tuberculosis including MDR-TB. The trials showed better sputum conversion rates associated with V5. It was found to reverse hepatotoxicity associated anti-tuberculosis treatment. Its action as an immunomodulator led to a reduction in inflammatory reaction, additionally the patients who were on V5 saw a significant weight gain (Butov et al 2011). The role of herbal supplements as immunomodulators is also being explored. It is reported in literature that use of Dzherelo (Immunoxel) was associated with an improvement in sputum conversion rates and reduction of hepatotoxicity, however limited success was reported in MDR-TB cases (Zaitzeva et al 2009).
5. Emerging obstacles to treatment of MDR-TB: XDR-TB, HIV- MDR-TB co-infection
5.1. Extensively Drug Resistant Tuberculosis (XDR-TB)
Extensively drug-resistant is defined as in vitro drug resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of the injectable drugs like capreomycin, kanamycin or amikacin (WHO WER 2006).
However, research on XDR-TB is scattered and inadequate. Definitions vary, quality control is lacking in lab diagnosis, studies are observational and there is a need for prospective studies, data is not available on standard variables. Diagnosis is hampered by the lack of rapid tests for drug resistance to second line drugs available. Literature notes that cures are seen in XDR-TB but the sputum conversion rates remain poor with longer duration of treatment and increased treatment failures and deaths (Sotgiu et al 2009).
The emergence of XDR-TB is splitting an already stretched healthcare system in various parts of the world. The cost of treatment of XDR-TB will be much higher than for drug sensitive regimens. In addition the patients are likely to be more seriously sick and will need extensive hospitalization, tying up precious resources in hospitals and communities that they can ill afford.
5.2 HIV- MDR-TB co-infection
It has been observed that HIV positive persons are susceptible to TB infection and are especially vulnerable to MDR and XDR TB. Mortality is high when these two conditions co-exist and symptoms progress rapidly to death. Early diagnosis and early introduction of 2nd line drugs may help reduce the morbidity and mortality associated with HIV and TB co-infection (Gandhi et al 2010).The co-infection condition is also associated with unique immune phenomenon like the paradoxical immune reconstitution syndromes which occurs when an individual infected by both HIV and TB and is put on anti TB treatment and started on ART, the TB deteriorates when one would expect an improved response to medicines (Dr. Dholakia, e-mail communication).
The co- infective condition is giving rise to grave concerns in control of the epidemic in countries with a high burden of TB and HIV as it divides the health resources of the country. This is discussed in detail in a separate section in the paper.