Multidrug-Resistant Tuberculosis Research Paper

Multidrug-Resistant Tuberculosis

Tuberculosis is an airborne infectious disease caused by tubercule bacilli, spread from person to person (CDC 2011). It affects the lungs and other parts of the body, such as the brain, the kidneys and the spine. It is curable but an infected person can also die of it if he does not get proper treatment (CDC)


Multidrug-resistant tuberculosis or MDRTB is TB that does not respond to the action of at least two of the best drugs, isoniazid and rifampicin, the first-line treatment of TB (CDC 2011). Extensively drug-resistant TB or XDRTB is the rare type, which is resistant to these two major drugs, to any fluoroquinolone and at least one of three injectable second-line drugs. These injectable drugs are amikacin, kanamycin and capreomycin. These additional drugs are considered second-line treatment for TB. Those with XDR TB resort to less effective options. Among those affected are persons with HIV or other infections, which weaken the immune system. They are more disposed to TB and have a higher risk of death from TB. MDR TB spreads in the same way as TB, which is by coughing, sneezing, speaking or even singing. MDR TB germs remain in the air for several hours, depending on the environment. Those who breathe the air where these germs are suspended can inhale them and get infected (CDC).

Anti-TB Drug Resistance, MDR TB Prevention

Resistance to anti-TB drugs results from their wrong use or management (CDC 2011). This can occur with incomplete course of treatment, wrong treatment, wrong dose, long duration, unavailability of the drugs, or poor quality of the drugs. This is more likely in persons who do not take their TB medicines regularly or omit them as instructed by their doctor or nurse. TB can reactivate in them even after TB medicines if they come from places where MDR TB is common or prevalent (CDC).

MDR TB can be preventing by taking medications exactly as directed and without missing a single dose (CDC 2011). Travelers with this sickness should make sure they have enough medications to last their trip. Prompt diagnosis will help prevent the spread or worsening of the condition. The patient should follow recommended guidelines. Health care providers should monitor patient response and completion of therapy. Another prevention is avoiding exposure to those already infected or suspected of being infected. Crowded and likely places should be avoided as much as possible, such as hospitals, prisons and shelters for the homeless. A vaccine called Bacille Calmette-Gurin is used for children in some countries but not generally recommended in the United States for its limited effectiveness. Those who are exposed to persons with the disease should get a TB skin or blood test (CDC).

TB Control in the 21st Century

The TB outbreaks in the U.S. In the late 80s and 90s spurred the use of massive resources that would insure safe workplaces (Sepkowitz 2001). This greatly decreased the transmission and actual cases nationally. Federal standards were established to insure a working environment free of the bacilli for U.S. workers exposed. This measure may, however, be costly and detrimental to the delivery of care (Sepkowitz).

It was only in the 50s and 60s that the risk of exposure to TB among health workers caring for patients became a concern (Sepkowitz 2001). The discovery that the infection is air-borne was new at the time and caught little attention. Outbreaks of TB and MDR TB in the 80s and the 90s in U.S. And European hospitals called the attention it lacked. More than 20 health care workers got infected with MDR TB and at least 10 of them died. Hundreds of them may have remained carriers and pose serious risk of future activation of the illness. These outbreaks have been substantially controlled but their consequences persist and can still be felt. One consequence is the confusion on which of the many interventions are still effective. In addition, current control measures continue to bank on the outdated PPD test and the insensitive sputum AFB smear. Reliance on these inadequate diagnostic tests is unlikely to improve gains in TB control. As far as can be gleaned, TB control will lean on the low-tech measures of isolation of potential or suspected persons, masks, and shutting doors of potential patients in hospitals (Sepkowitz).

Extensively Drug-Resistant Tuberculosis

The first 74 cases of this new type were first reported in November 2005 by the U.S. National TB Surveillance System (Morbidity & Mortality Weekly 2007). The World Health Organization Emergency Global Task Force in October 2006 came up with a new definition of XDR TB. It is resistance to at least isoniazid and rifampin among the first-line anti-TB drugs, any fluoquinolone and at least one injectable drug, particularly amikacin, capreomycin or kanamycin. After approximately 30 years of decline, TB epidemic increased between 1985 and 1992 with more than 22,000 cases in 1985 rising to more than 26,000 in 1992. While still largely unknown before 1993, numerous outbreaks of MDRTB already occurred in the late 80s and early 90s. The 1992 National Action Plan to Combat MultiDrug-Resistant Tuberculosis quickly reduced the incidence by improving laboratory services and infection control and strengthening National TB Surveillance System tests starting in 1993. These improvements appeared to account for the rapid 34% decrease in overall TB cases from 1993 to 1999 in the United States. Comparison with 2000-200 cases showed that XDR-TB had an overall decrease in incidence among HIV-infected persons, an in increase among foreign-born persons, and an increase among Asians with XDR-TB (Morbidity & Mortality Report).

Effective treatment of MDRTB requires 18-24 months of 4-6 drugs to which the person is susceptible, including multiple second-line drugs (Morbidity & Mortality Report 2007). The use of second-line drugs went up substantially with the treatment of increasing number of cases starting in the 80s by physicians and TB-control programs. This increased use produced MDRTB strains extensively resistant to both first-and-second-line drugs (Morbidity & Mortality Report).


Close to 500,000 or 5% of all new cases of TB diagnosed in 2006 were MDRTB, as they were resistant to isoniazid and rifampicin (Mitnick et al. 2008, Mortality & Morbidity Weekly 2006). This reflected a 12% increase over the 2004 incidence and 56% over 2000. About 1-1.5 million more cases surfaced in 2006, bringing to 2 million the number of those actively afflicted. The treatment of MDRTB consists of second-line drugs, which are too costly for those in resource-poor settings. The World Health Organization addressed the shortage by creating the Green Light Committee in 2000, which would make second-line agents accessible to these settings and strictly supervise their use. A significant decrease in incidence was achieved by the Committee. However, drug-resistant TB continues to grow and create trouble in most settings. The seriousness of the problem and the increase in related illnesses and deaths prompted a proportionate increase in research and scaled-up treatment. Some studies explored the molecular mechanisms of resistance, risk factors for drug-resistant TB and HIV, and global epidemiology of TB (Mitnick et al., Morbidity & Mortality Weekly).

The estimated burden of MDRTB is significant enough to call for concerted action (Mitnick et al. 2008, Morbidity & Mortality Weekly 2006). All appropriate interventions require scale-up of laboratories and early treatment containing enough second-line drugs. Ambulatory treatment and improved infection control will facilitate scale up by reducing the risk of nosocomial transmission. Obstacles to worldwide scale-up of treatment mostly point to inadequate human, drug, and financial resources. Increased delays can enhance risk of continued transmission of resistant TB and associated illnesses and deaths (Mitnick et al., Morbidity & Mortality Weekly).

Molecular Epidemiology

Outbreaks in the 80s and early 90s in New York City caused widespread transmission of MDRTB strains in hospitals and state prisons (Munsiff et al. 2002). The W. strain was identified in the outbreaks. This strain is resistant to isoniazid, rifampin, ethambutol, and streptomycin and, often, also kanamycin. Surveys later showed the presence of the same strain in New York City, suggesting recent transmission. An enhanced Tuberculosis Control Program in 1992 reduced the number of TB cases by 21% in 1994 and MDRTB by 60%. No documentation of outbreaks have been undertaken in the City since then (Munsiff et al.).

The New York City Tuberculosis Control Program conducted DNA genotyping of MDRTB strains for new cases from 1995-1997 to better understand the occurrence, transmission and control of MDRTB (Munsiff et al. 2002). MDRTB was diagnosed in 241 patients, 217 or 90% of whom had not had treatment and 166 or 68.9% born in the United States or Puerto Rico. MDRTB patients are more likely to be born in the United States, have HIV infection and work in the health care sector. Of this number, 30 or 12.8% were likely exposed to and contaminated by those afflicted during the outbreaks in the early 90s in the City. These patients appeared to have more bacilli and thus more infectious.

It was possible that many of those infected were already with HIV during the outbreaks. MDRTB progresses much faster in HIV-infected patients than in non-HIV patients. These highly resistant strains transmitted in the late 80s and early 90s were the W, W1, P, P and H. These were among the 8 clustered strains linked with hospital outbreaks in those years. DNA results showed that 10 out of 14 health care workers had one of these strains (Munsiff et al.).

A particular MDRTB strain was also found in a community of HIV-infected, homeless persons and drug users (Munsiff et al. 2002). At least 14 of them were identified and confirmed by genotyping. The strain was likely transmitted for many years among drug users frequenting drug dens in the area. These places were closed in the late 90s and the groups disbanded. Transmission was therefore interrupted but found in two patients between 1998 and 2001. Most of the major strains identified by the study were traced to patients in New York City from 1998 to 2001. The improved Tuberculosis Control Program of 1992 was effective against newly acquired drug resistance. Because MDRTB as well as other primary strains were prevalent in the area before 1995, they were spread through the community, as most of them had no histories of prior treatment for unique strains (Munsiff et al.).

Resistance to Pyrazinamide and Ethambutol

MDRTB is resistance to at least isoniazid and rifampicin and a global concern (Hoek et al. 2009). The WHO recommended that treatment should include at least 4 effective drugs as standard treatment according to the resistance pattern of each region. Treatment regimens should not depend on results of drug susceptibility testing for ethambutol or pyrazinamide. Ethambutol may be part of the regimen as long as it is not one of the 4 effective drugs to be administered. Pyrazinamide may also be used as part if it is effective but not as one of the 4 effective drugs. Ciprofloxacin is no longer recommended for TB (Hoek et al.).

The South African National TB Control Program devised its own policy guidelines, based on WHO recommendations (Hoek et al. 2009). These guidelines address diagnostic delay and the treatment of MDRTB and XDRTB. DST should be performed on patients who do not improve after 2 months of treatment or 3 months for those with extended treatment. These Program guidelines deviate from those of the WHO by recommending that DST for EMB should determine the treatment regimen for MDRTB or XDRTB. If the patient is susceptible, EMB should be part of the regimen as the fifth effective drug. If he is resistant, it should be replaced by terizidone or cycloserine as the 5th effective drug.

The inclusion of PZA as one of the 4 effective drugs is also recommended. There are high levels of resistance of PZA associated with MDTB, such as in South Africa. In the absence of DST for PZA, it should not be used as one of the effective drugs but may be included in the regimen (Hoek et al.).

In the face of high levels of still-undetected resistance to EMB and PZA in South Africa, revised guidelines for MDRTB treatment should be undertaken in places like South Africa with improved and routine DST (Hoek et al. 2009). Until this can be done, it should be assumed that all MDRTB cases are resistant to EMB and PZA. They should continue to be used as treatment but not as among the 4 effective drugs. This is to prevent additional resistance and the possible progression of XDRTB (Hoek et al.).

Double Infection

One can get infected with a resistant and a multidrug-resistant strain of mycobacterium tuberculosis (Niemann et al. 2000). Inappropriate treatment can lead to further drug resistance and similarly unsuccessful therapy. Additional infections or re-infections can occur when therapy fails. Inconsistent susceptibility patterns or late response to treatment can mean exogenous re-infection with a resistant strain to multiple. It may also indicate mixed infection with a sensitive and an MDRTB strain. These infections afflict only immuno-compromised and immuno-competent persons. They are more common in places with high prevalence of resistant TB strains (Niemann et al.).

The case of an immuno-competent patient with pulmonary TB and double infection with a resistant and MDRTB strain, which led to failure of therapy, illustrates the above information (Niemann et al. 2000). The patient received treatment for two years. He developed resistance to 8 anti-tuberculosis drugs, including the strongest first-and-second-line treatments after two years of treatment despite clinically supervised hospital therapy. Resistance to a ninth drug developed four months later. The initial cause was a progressive disease from a second multidrug-resistant TB strain, in turn identified by molecular strain typing methods. Therapy was based on data not derived from present drug-resistant patterns. This led to improper treatment and long durations of only one effective drug. The TB strain was likely to have become more resistant in that length of time of a single drug for therapy. A more successful outcome could have been obtained if the second infection was identified earlier. A mixed strain or exogenous re-infection could be the cause of the second multidrug-resistant TB strain. The patient was an immigrant from Kazakstan where high rates of resistant TB have been reported. It was possible he was infected with second multidrug-resistant strain in his country (Niemann et al.).

He was seronegative for HIV (Niemann et al. 2000). There were no indications of immuno-suppression and, thus, addition infection was unconnected to his immune status. These mixed-strain infection with at least one resistant strain can make therapy fail. Cases of this kind can proliferate in areas with high levels of drug-resistant TB. Standard TB therapy does not seem to be an effective prevention measure from infection with a second multidrug-resistant TB strain (Niemann et al.).

Additional infection with multidrug-resistant TB is possible when TB therapy fails and clinicians should consider this (Niemann et al. 2000). Inappropriate treatment regimens and delayed follow-ups of susceptibility tests enhance additional resistance. This can make therapy quite difficult. Adding single drugs to failing treatment regimens should be avoided, whatever the cause. Re-treatment should be started only when culture sensitivity results become available (Niemann et al.).

MDRTB Strain Imported

The identification of a specific MDRTB in Spain transmitted from Equatorial Guinea reveals that strains can be spread across continents, making it a global threat (Gavin et al. 2009). Equatorial Guinea is a country where the extent and characteristics of TB and MDRTB are very little known. The Spanish Multidrug-resistant Tuberculosis Surveillance Network to trace isolates from 10 patients in Equatorial Guinea from data gathered from 2000 to 2008. All the patients were from the country, which is located in the Gulf of Guinea. It has a population of approximately 500,000 and with an MDRTB rate of less than 2%. It also has an estimated 3.2% HIV prevalence among its adult population. The patients were distributed in 6 different Spanish cities. They arrived in Spain at three months’ interval before the start of TB treatment. Three of them were clinically ill at the time of arrival. Of the 10, 7 were men, 2 were women and 1 was an eight-year-old girl. Their mean age was 30 years. Three of them were sero-positive and 4 were seronegative for HIV. Seven had anti-TB treatment and only 1 had TB chemotherapy. Three of them died before treatment could be completed. Two of them had military TB. The third, a student, had HIV without a history of immunosuppression and lived in Spain for two years. The study did not find any link of contamination among the patients. Because the strain developed in most patients within three months suggested that it was taken into Spain. It also implied that active transmission of the cloned strain may be existing and spreading in Equatorial Guinea. Increased international measures should be undertaken to provide more appropriate tools to this resource-limited area in its fight against MDRTB and in preventing the development of XDRTB (Gavin et al.).

Multidrug Resource-Limited Settings

Evidence of successful treatments of MDRTB comes mainly from referral hospitals in advanced or high-income countries (Nathanson et al. 2006). The treatment management of the disease in select resource-limited countries was conducted in Estonia, Latvia, Peru, the Philippines, and the Russian Federation. All activities were approved by the Green Light Committee for access to second-line drugs at reduced price. Of the 1,047 patients studied, 119 or 11% were newly treated and more than 89% received previous treatment. More than half of these previously treated patients received both first-hand and second-hand drugs. About 65% of all the respondents showed infections resistant to both of these categories of drugs. Treatment proved effective in 70% of all the patients, 77% higher among the new than among those previously treated at 69% (Nathanson et al.).


The new World Health Organization said that almost 500,000 MDRTB cases occurred in 2004 and more than half were found in China and India (Nathanson et al. 2006). The highest estimated prevalence was found in the Soviet Union and some provinces in China. Direct Observation Treatment for TB or DOTS is the internationally recommended strategy for a six-month regimen with first-line drugs for new patients and an eight-month treatment for previously treated patients. Drugs for new patients are isoniazid, rifampin, pyrazinamide, and ethambutol. Drugs for re-treatment are isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin. DOTS prevents drug resistance but produces inadequate cure rates. A study conducted on the effectiveness of the treatment in 6 countries showed that it had a 52% cure rate among new cases and 29% among previously treated cases. Results suggested that these second-line drugs may achieve a 65% level of cure or higher as well as suppress ongoing transmission. These results, however, were taken from referral hospitals in high-income countries (Nathanson et al.).

The WHO and partner agencies launched DOTS+ to address MDRTB in limited-resource settings in 1999 (Nathanson et al. 2006). The group believes that effective control consists of the 5 tenets of DOTS strategy and adjusting each of these tenets to the peculiarities of the treatment. Part of the strategy was the creation of the Green Light Committee for the access and use of second-line drugs needed in the treatment. These second-line drugs, as they appear in the WHO models list of essential medicines, are amikacin, capreomycin, ciprofloxacin, cycloserine, ethionamide, kanaycin, levofloxacin, ofloxacin, p-aminosalicylic acid, and prothionamide. The Committee processes applications of those desiring to integrate MDRTB therapy into a DOTS-based TB control program. If an applicant agrees to the strategy and the Committee’s procedures, he is given access to reduced-price but quality second-line drugs. Requirements include a properly functioning DOTS program, long-term political commitment, acceptable case-finding strategies, a diagnosis of MDRTB by drug susceptibility testing, treatment strategies, continuous supply of quality second-line drugs, and a suitable reporting system for MDRTB control programs. Projects must be adapted to the location’s specific conditions. This means that MDRTB control programs will differ according to settings. These differences include categories of patients with culture and DST or only those with increased risk for MDRTB, an individualized second-line treatment regimen, and hospitalization of the applicant-patient or provision for ambulatory treatment (Nathanson et al.).

Because countries buy these second-line drugs themselves, misuse and the creation of new TB strains are always a possibility (Nathanson et al. 2006). The system set up by the Committee provides access to care and assures the correct and effective use of these drugs. Applications for these drugs have been coursed through the Global Fund to Fight AIDS, Tuberculosis and Malaria since 2002 in order to prevent misuse. As of May 2006, the Committee had endorsed 41 MDRTB control projects in 37 countries. Less than 21,000 MDRTB patient applications in these projects were approved for treatment. Committee programs have rapidly multiplied because of increased funding and the incorporation of MDRTB into general TB management. But among recent cases, most have remained undiagnosed and untreated. It may be necessary to expand existing projects and hasten the gathering of evidence in order to develop international policies cocerning MDRTB. Success in resource-limited settings depends on the ability of the donor community and the involved agencies and the countries themselves to expand and strengthen their respective MDRTB control programs (Nathanson et al.).

Methods for Drug Susceptibility Testing

WHO reported that there were 511,000 MDRTB cases in 2007 or 5% of all TB cases worldwide (Richter et al. 2009). On the other hand, XDRTB strains were found in at least 55 countries. These findings urge the need for fast and effective methods of testing for drug susceptibility to mycobacterium tuberculosis. Many countries still use the egg-and-agar-based media as reference methods, which require 3-4 weeks to produce results. Fortunately, many new, faster and more reliable methods have been developed and become available. These are drawn from either the phenotypic or the genetic detection of resistance. The phenotypic type has been the more commonly practiced. The techniques are mainly liquid culture-based, used manually or as automated systems. Many of them have been studied and have proved reliable and accurate, while others need to be re-evaluation for bio-safety risks. Among the molecular type of tests, line-probe assays offer the strongest promise of fast, specific and sensitive detection of MDRTB. They detect mutations rapidly. Line-probe assays can detect rifampicin resistance quite accurately even on clinical specimens. Genetic-based techniques detect genetic mutations. These techniques offer faster turnaround times and may omit cultures. Knowledge of specific molecular changes associated with resistance is required. Random genetic mutations in particular genes alone account for drug resistance in the M. tubeculosis complex isolates.

On account of the promising performance of molecular line-probe assays, WHO adopted their use for the rapid screening of those at risk of MDRTB as a matter of policy in 2008. The policy was extended by UNITAID to 27 countries in May 2009 (Richter et al.).

The use of molecular assays for the rapid detection of MDRTB is seen to continue increasing in the next few years, mainly in regions with high incidence of MDRTB (Richter et al. 2009). They are likely to reduce diagnostic work at laboratories, which are often inadequate in resource-deprived countries. Cheaper culture-based techniques, such as NRA, colorimetric assays or MODS will continue to serve as screening tools in meeting bio-safety requirements. Over and above, liquid culture-based techniques, manual or automated, will probably increase in use. They are necessary inputs to drug susceptibility tests of all second-line drugs. They are also necessary for the identification of resistant strains. Molecular assays cannot detect these resistant strains because of mutations not targeted by the tests (Richter et al.).

Newer Diagnostics

Recent advances in the field led to the development of new tools for faster TB diagnosis (Palomino 2006). Non-conventional diagnostic tools are among them. Nucleic acid amplification techniques, commercial and in-house, and non-molecular methods are under evaluation. The accuracy of most of these is encouraging. Some of them can also be easily used in clinical mycobacteriology laboratories (Palomino).

Both the genotypic and phenotypic methods have been designed and commercially available as a kit (Palomino 2006). The rest are as in-house methods. These have been evaluated for their use on M. TB strains and few have been applied directly on clinical cases. They should be adapted for both cultures and clinical samples if they must become effective alternatives to TB diagnosis for detection of drug resistance. They must also be evaluated in well-designed and controlled clinical trials in resource-limited with high incidence. Tests are more needed and relevant in these settings for a realistic control of TB (Palomino).


The proper implementation of the DOTS strategy can cure TB and prevent the development of drug resistance (Tam et al. 2009). Innovations in the strategy, such as the development of new drugs, can further improve its effectiveness. The control of MDRTB strains needs longer treatment duration of between 18 and 24 months. It also requires alternative chemotherapeutic forms of treatment but which are costlier and more toxic than non-chemotherapeutic forms. Yet the programmatic MDRTB treatment must be made in order to manage the development and spread of drug resistance (Tam et al.).

Among the most valuable drugs for treating MDRTB are the fluoroquinolones (Tam et al. 2009). They must be used correctly for both TB and bacterial infections. The recent emergence of extensively drug-resistant TB is a global threat that calls for worldwide resources to address it. Current approaches must provide better and faster drug susceptibility testing, regular and accurate monitoring and the development of new drugs and other therapies and intensive infection control, especially in places of high HIV incidence. It also prompts more effective use of DOTS and drug-resistance programs. New anti-TB drugs being developed include moxifloxacin, TMC-207, 0PC-67683, PA-824, LL-3858, SQ-109 and oxazolidinones (Tam et al.). #


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