Drug Resistant Tuberculosis

Drug resistant Tuberculosis is a severe form of tuberculosis disease which is untreatable through regular measures due to its nature. Tuberculosis itself is a bacterial infection caused by Mycobacterium tuberculosis. Though lungs are usually the prey of the disease but the bacterium can often attack spine, brain, and kidneys.

The drug resistant disease occurs when some bacteria become resistant to the effects of antibiotics or anti TB drugs. The resistance formed can be due to multiple of reasons such as 1) people who have already been diagnosed and are on treatment therapy leaving it halfway 2) using drugs of poor quality for treatment, taking drugs irregularly 3) and coming from areas where drug resistant TB is very common.

MDR TB Treatment: Multi-Drug Resistant Tuberculosis Treatment 

There are two types of such resistant TB infections; multidrug-resistant TB (MDR TB) and extensively drug-resistant TB (XDR TB); where former is resistant to only a few antibiotics but the latter is resistant to multiple potent TB drugs. Extensively Drug-resistant TB (XDR TB) is extremely hazardous for patients with weakened immune systems such as the ones with HIV. Both forms can exist as a latent infection and an active TB disease.

They also show similar symptoms to those of a simple TB disease which can include persistent cough for three or more weeks, pain in the chest, and coughing with blood and sputum which is phlegm from deep in the lungs. Other signs include weight loss, no appetite, fever, sweating at night, chills, and weakness often accompanied by fatigue.

According to WHO estimates, five percent of all disease cases are in fact multidrug resistant which makes up nearly 480 000 cases and 190 000 deaths each year globally. Nearly nine percent of the patients with the bacterium develop extensively drug resistant tuberculosis.

Discovery Of TB Drug Resistance

Drug resistant TB was first recognized in 1948, when British Medical Research Council (MRC) published its report on streptomycin therapy. The researchers noted that the death rates of patients treated with streptomycin for pulmonary Tb were similar to those which were not treated and had the disease. This meant that therapy was not providing any visible health function.

When the phenomenon surfaced multiagent chemotherapy for TB was adopted. This proved quite efficient. Throughout 1960s, 1970s, and 1980s little attention was paid to what was a clear resistance to anti-Tb drugs.

The issues sporadic in nature remained ignored till multiple drug resistant TB was seen in United States in early 1990s. Identified as epidemics the cases were seen to be resistant to at least isoniazid and rifampin in the states of New York, New Jersey, and Florida.

Majority of these cases were transmitted among people in hospitals, jails, and homeless shelters. Death trends in those patients were consistent in both HIV infected and uninfected people.Aggressive economical and financial interventions did help to stop and contain the outbreak but not before the disease claimed many lives.

Emergence Of Extensively Drug Resistant Tuberculosis

Extensively Drug resistant tuberculosis; The term introduced first in 2005 but became popularly known as such when a survey study found that in rural South Africa a large portion of patients with MDR-TB had extensive drug resistance. The infections were also associated with Human Immunodeficiency Virus (HIV) and had quite a high death toll, despite receiving antiretroviral therapy.

Nearly forty five countries report this kind of antibiotic and drug resistance excluding countries which do not have laboratory facilities to detect second line drug resistance.

Prevalence Of TB drug Resistance

Efforts to estimate global distribution of drug resistant TB were first stated in 1994 when international union against Tuberculosis and Lung disease (IUATLD) along with world Health Organization (WHO) proposed and launched the Global Project on Anti-tuberculosis Drug Resistance Surveillance.

The first results to be ever published in 1998 showed that in 35 countries from five different continents, nearly 9.9 percent of the patients diagnosed with TB had drug resistance. Special countries warranting attention at the time were Dominican Republic, Soviet Unit, and Argentina.

The second 2000 (WHO antituberculosis survey) report covering 72 countries and regions showed that a high level multiple drug resistant tuberculosis (nearly 3% overall prevalence) was found in fourteen countries. MDR-TB was especially prevalent in Sierra Leone, Peru, Brazil, Nepal, Korea, Bolivia, Swaziland, Zimbabwe, and Romania.

Here a major problem identified were also the Russian prisoners in jail where nearly 10 percent of the one million prisoners have active TB. High rates of incidence in China and India is also worrisome as these countries have nearly forty percent of all the TB cases worldwide.

WHO’s 2008 report concludes that the estimated proportion of people (globally) with MDR-TB was 2.9 and 15.3 percent for new and old cases respectively in 2006. In Soviet Union half of all the cases were resistant to at least one drug and nearly twenty percent had multidrug resistance of which nearly twenty percent also had extensive drug resistance TB.

In United Kingdom nearly 7.7 percent cases had some sort of antibiotic resistance in Wales, England and Northern Ireland also showed some resistance with nearly 7 percent to isoniazid and 0.9 percent to multiple drugs. Since 2006 two more cases have been reported and highest isoniazid resistance has been shown in London and then Northern Ireland.

In United States the resistant TB is not as big of a problem. The risk of acquiring it is also low but not zero. According to the National Tuberculosis Surveillance System (NTSS) there have been only 63 cases of extensively resistant Tb from 1993 to 2011. The percentage of multi drug resistant cases decreased from 1.4 in 2013 percent to 1.3 percent in 2014. The number of cases respectively was 96 and 91.

Diagnosis Of Resistant TB

For more than hundred years the standard way to detect TB in patients has been the finding of acid fast bacilli in clinical samples (Ziehl- Neelsen staining). However, detecting drug resistant tuberculosis has been much harder as it requires pure cultures of Mycobacterium tuberculosis. Compared to normal drug susceptibility tests for rapidly growing bacteria M.

Tuberculosis takes nearly twenty four hours to replicate and a month to show clear growth on solid media.  Testing for drug resistance can take up to six to eight weeks and requires special laboratory facilities. These kinds of facilities are unavailable in settings where this form of TB usually persists.

New molecular methods which detect bacterial gene mutations for resistance are becoming increasingly available. In United Kingdom Mycobacterial Reference Units uses a commercial assay to identify the bacterium and mutations responsible for rifampicin resistance. The assay is available under the name INNO-LiPA Rif TB assay, Innogenetics, Belgium.

The assay when compared to other tests had sensitivity at 85.2 percent and specificity at 88.2 percent when used on collected sample. On pure bacterial culture the same rates proportions were at 98.7 and one hundred percent respectively.

However new efforts are being made to develop tests and assay which can be made accessible in low or limited recourse setting. One of such tests is the microscopic observation drug susceptibility (MODS) assay based on the unique appearance of the bacterium in liquid media, when observed under a microscope. Resistance is quantified by observing growth in the presence of the drugs.

The test can detect ninety nine percent of the multi drug resistant bacteria when compared to other techniques. The assay can give the results within seven days.

WHO has recently endorsed a novel diagnostic test for future use known as MTBDRsI which is DNA based. The test identifies genetic mutations in multi drug resistant strains, which makes then resistant to injectable second line TB drugs and fluoroquinolones. The test can produce results within forty eight hours which was previously at three months.

The fast testing services makes sure that the management and treatment of the disease can begin quickly and the patients can be placed on second line appropriate drugs.

WHO reports that only twenty percent of the total MDR-TB patients worldwide are currently being treated in a proper manner. The test helps determine which patients are to be put on newer and shorter drug regimen and which patients should be not so that development of extensively drug resistant TB or XDR-TB can be avoided.

How To Manage MDR TB Treatment

Understanding how such infections are treated requires the basic knowledge of first line TB drugs and second line Tb drugs. The five basic drugs used to treat the disease are

  • Isoniazid
  • Rifampicin
  • Pyrazinamide
  • Ethambutol
  • Streptomycin

These drugs are the core interventions made when treating the disease. These drugs are given to patients who have not been treated for TB before. Other drugs are second line drugs or reserve TB drugs.

Drugs used to treat resistant infections are classified into five groups. The first line drugs are in the first group, besides streptomycin, which is in the second group. All the other drugs are from second line of drugs.

Group 1 TB drugs: First Line Oral Agents

Group 2 TB drugs: Injectable Agents (amikacin, kanamycin, capreomycin)

Group 3 TB drugs: Fluoroquinolones (levofloxacin, ofloxacin, moxifloxacin)

Group 4 TB drugs: Oral Bacteriostatic Second Line Agents (cycloserine, terizidone, thionamide, protionamide)

Group 5 TB drugs: Agents with an unclear role in the treatment of drug resistant TB (alofazimine, linezolid, thioacetazone, amoxicillin, high dose isoniazid, clarithromycin)

The fifth group of drugs are rarely used and their effectively and mode of action are not well understood.

Treating drug resistant TB is difficult and often complicated, though no established parameters exist but experts are employed to set specific treatment options for individual cases.

Multi drug resistant Tb is often resistant to one first line TB drug and at least isoniazid and rifampin. With extensive drug resistant TB the bacteria are often resistant to rifampin, isoniazid, any fluoroquinolone and at least one of three injectable second-line drugs such as kanamycin, amikacin, and capreomycin.

New WHO recommendations for resistant TB infections specifically MDR-TB have been approved recently. The new treatment which would last for nine to twelve months would cost 1000 US dollars per patient. Previously such infections were treated for nearly two years duration. Due to the longer durations patients often did not comply with the strict schedule of dosages and this resulted into low cure rates of only fifty percent.

The new and shorter treatment is for patients with uncomplicated TB conditions like whose infections are not resistant to the most of important drugs such as fluoroquinolones and injectables also known as “second-line drugs”.

These recommendations are not based on clinical findings but are rather designed by some health organizations working on the disease. Before the implementation the process has been tested in nearly a thousand people and is also being investigated currently in a trial in Mongolia.

Food and drug administration (FDA) in United States has recently advised the restriction of fluoroquinolone antibiotic use for certain uncomplicated infections. The suggestion comes as a result of suspecting possible side effects of these drugs. The agency argues that the harms of the drugs are more than the benefits when these drugs are used to treat bronchitis, sinusitis, and uncomplicated urinary tract infection when other options may be available.

Though these particular drugs can also give rise to complications in Tuberculosis patients when used in the same fashion, they are, however, still essential for some people who cannot tolerate the first line of TB drugs. People with drug resistance Tb may have no other choice and for them these drugs are a better alternative.

Though the incidence of the resistant TB is low in United States, their treatment and management can be highly expensive and harmful. A high proportion of patients receiving this kind of treatment can experience side effects like depression, hearing loss, psychosis, hepatitis, and kidney impairment.

Average costs of resistant TB treatment increase as the Tuberculosis bacterium resistance grows. In 2014, the costs could range from $17 000 for drug susceptible infection to $ 482 000 to treat highly resistant infections. These costs are excluding the opportunity costs which are the productivity losses (lost income) a person experiences when receiving the treatment and the disease.

National Action Plan For Multidrug Resistant Tuberculosis

The need to reverse and hinder the transmission of multidrug resistant tuberculosis throughout the world, prevent any national outbreaks, and maintain decades of investment into public health has lead to building up a Nation Action Plan to fight this disease.

The plan identifies some key interventions and targets needed to address domestic and global challenges posed by the MDR-TB and XDR-TB. The plan is a comprehensive strategy aimed to develop political momentum, gather financial support and commitments from donors and private sector.

The goals of the National Action Plan are:

  • Fortify the national and domestic capacity to fight multidrug resistant TB
  • Improve international relations to work on capacity building and collaboration efforts to combat MDR-TB
  • Accelerate research (basic and applied) and development efforts to fight spread of MDR-TB

Implementation is based on mutual US and partner efforts, according to laws already in place, to coordinate different outlets working on applying new and existing scientific and technological tools and expertise to the fight against the infection.

The plan includes the previous plan of the US government to support the appropriate treatment of TB for more than 16 million people and achieve and maintain a ninety percent treatment success rate.

WHO Prevention Efforts: DOTS-Plus

WHO’s efforts to prevent MDR-TB and XDR-TB spread revolves around DOTs or direct observed treatment short course strategy for TB. The Stop TB programme incorporates this policy into all its guidelines.

WHO works not only by providing guidelines but also on collecting political commitment, assurances of quality case detection services, provision of standardized and appropriate treatment and by helping countries acquire effective drug supply. The international health agency also works on monitoring and evaluation of enacted programmes for TB prevention and control.

To deal with the multi resistant infection of TB in limited recourse settings WHO uses DOTS-plus (an enhanced DOTs programme). The programme recommends the use of additional investment efforts into facilities providing testing services for TB and supply of appropriate second line anti TB drugs.

The practical guidelines suggest the use of infection control practices to limit the exposure of TB to other people in hospital settings and outside. Key areas of focus for preventionofTBbyWHO include:

  • Finance Control and Treatment for MDR-TB and XDR-TB
  • Abolishing financial barriers
  • Engaging all care providers in appropriate MDR-TB prevention and Control
  • Optimization of MDR-TB and XDR-TB management and care
  • Addressing laboratory crisis
  • Ensuring access to quality assured anti-TB drugs
  • Prioritization of TB infection control
  • Addressing global health workforce crisis
  • Improvement of surveillance systems
  • Investments into research and development of new diagnostic tests, drugs and vaccines

In countries with greater resources it is recommended to focus on latent infections and monitoring of recent cases if any. In resource limited settings, the focus should be kept on active cases and detection of latent infections. People working in high risk settings should be regularly tested and counseled in all kind of settings.

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