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Evolution Of Drug-Resistant Tuberculosis

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Tuberculosis (TB) is a bacterial infection that usually infects the lungs, but it can also affect the kidneys, brain, and other organs. The main TB bacterium is Mycobacterium tuberculosis (M. tuberculosis). This bacterium is spread by those who are infected in an airborne manner through droplets. The two main types of TB are latent and active and at present, the successful transmission of drug-resistant M. tuberculosis, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains in human populations, threatens tuberculosis worldwide. Different from many other bacteria, M. tuberculosis drug resistance is acquired mainly through mutations in specific drug resistance-associated genes. Human societal failures have potentiated the evolution of drug-resistant strains of the tubercle bacillus in the United States and around the world. This evolutionary change has been largely posed a threat to the health and survival of the individual whom inadequate therapy promoted the drug resistance.

Tuberculosis (TB) is an infectious bacterial disease that primarily affects the lungs through the respiratory route, but it also can infect other part of organs (Bloom et al., 2017). The main bacterium that causes TB is Mycobacterium tuberculosis (M. tuberculosis) and is belong to the member of Mycobacterium tuberculosis complex (MTBC) which is a group of closely related species that are adapted to human and animals (Echeverria-Valencia, Flores-Villalva & Espittia, 2017). The bacterium also belongs to the family of Mycobacteriaceae, which is characterized by their unique cell wall that made up of mycolic acid and is considered as a slow growing bacterium.

TB has always been the leading cause from a single infectious disease agent, and it accounts for approximately 40% of death in human immunodeficiency virus (HIV) infected patients. (MacNeil, Glaziou, Sismanidis, Maloney & Floyd, 2019). On a global level, one-third of the world population is infected with M. tuberculosis and there are 30 countries that are referred as “high burden” countries, because they account for 87% of all incident cases of TB in 2018 (“Tuberculosis,” 2019). High burden countries are mostly South-East Asia and African countries. There were an estimated 10 million incident cases of TB occurred, and approximately 1.6 million TB related death in the year of 2017 (MacNeil et al., 2019).

The genus, Mycobacterium, originated more than 150 million years ago (Dutta, 2019) and had killed millions of people since then because the disease cannot be identified, and treatments cannot be made due to the lack of diagnosis. On March 24, Dr. Robert Koch discovered M. tuberculosis, which was the first and most important step taken towards the control and elimination of this deadly disease (“Tuberculosis,” 2019).

Vaccination and antibiotics were invented in the year of 1906 and 1944 respectively, and TB incidence progressively declined (Dutta, 2019). Unfortunately, TB showed an increase during the 1990s due to the increase of acquired immunodeficiency syndrome (AIDS) epidemic. AIDS weakens one’s immune system allowing M. tuberculosis to have this opportunity to progress into active TB. Besides that, cases of drug-resistant TB also contributed to the increase of TB incidence because drug-resistant TB shows a significant challenge in TB treatment.

M. tuberculosis is a highly clonal bacteria in the absence of recombination with an extremely conserved genome and a long history of co-evolution with human (Nguyen, Contamin & Bañuls, 2018). M. tuberculosis also has a remarkable capacity of adaptation and the variety of extrinsic and intrinsic processes contribute specifically to the emergence and spread of highly drug-resistant strains (Nguyen et al., 2018). Epistasis is an example of intrinsic mechanism that drive the evolution of antibiotic resistant and it can generate the combination of a set of alleles from different loci (Nguyen et al., 2018). These sets of co-adapted alleles are then favored by the clonal reproductive mode of M. tuberculosis, leads to the spreading within the population (Nguyen et al., 2018).

Drug-resistant TB can be further divided into three categories, which are the multi-drug resistance tuberculosis (MDR-TB) which resistant to first-line antibiotics, extensively-drug resistant (XDR-TB) which resistant to second-line antibiotics and totally drug-resistant (TDR-TB) which resistant to all kinds of antibiotics. Due to the acquisition of mutations, the number of drug-resistant TB, especially MDR and XDR TB cases is progressively increasingly worldwide (Nguyen et al., 2018).

According to a case study conducted from Meacci et al., a male patient from Italy was diagnosed with active TB at the age of 29 and had a history of intravenous drug abuse. He went to Umberto I Hospital in Ancona, Italy with symptoms of TB disease and his chest radiograph showed pulmonary infiltrates in both upper lobes with extensive cavities and his sputum smear shows the presence of acid-fast bacilli. Further blood tests discovered seropositivity to HIV. After the drug susceptibility testing (DST), this patient showed susceptibility to all first-line anti-TB drugs. His treatment including TB chemotherapy and zidovudine (drug for HIV/AIDS treatment) was begun. The patient became poorly compliant with the therapy even though he showed an initial improvement. A 3-year follow-up control has revealed many acid-fast bacilli in smears of gastric aspirate and sputum samples; the strain showed resistant to multiple first-line anti-TB drugs and was identified as MDR-TB. The patient behaved in an aggressive manner towards health care providers and continuing to refuse further follow-up procedures. The patient was again admitted to the hospital with cytomegalovirus retinitis after 7 years of the onset of clinical symptoms. Chemotherapy and more antibiotics were prescribed but the patient once again poorly compliant with the anti-TB treatment and sputum test was performed again in the following year but his TB progress to XDR-TB. 12 years after his initial TB diagnosis, he died from a progressive wasting syndrome.

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This case study has clearly showed that M. tuberculosis has the ability in acquisition of mutations in genes that code for drug targets or drug-activating enzymes (Dookie, Navisha, Mahomed, Naidoo, & Kogieleum, 2018). Unlike other bacteria, resistance is not acquired via horizontal gene transfer by mobile genetic elements but mainly in the forms of single nucleotide polymorphisms (SNPs), insertions or deletions and to a lesser extent, large deletions (Dookie et al., 2018). However, mutations causing drug resistance varies depending on the lineage to which the strain belongs according to recent studies (Dookie et al., 2018).

According to Iseman, the environmental factor that is responsible for the rising prevalence of drug-resistant tuberculosis around the globe is humankind (1994). Modern genetic analysis has indicated an extremely high degree of DNA homology between M. bovis and M. tuberculosis, which means that they are virtually the same species (Iseman, 1994). This has brought to a hypothesis that the parent strain of M. bovis, is not very invasive and have posed little disease-producing capacity within human has undergone subtle host adaptation within the human body to become tubercle bacillus (Iseman, 1994). Through this evolution process, the microbe has developed some unique traits: (I) it’s only significant natural reservoir is humans, (II) it has substantially diminished virulence for most animal species other than human, and (III) it has developed a survival-transmission strategy that is unparalleled among the mycobacteria.

Although tuberculosis is a form of bacterium, it is highly resistant to conventional antibiotics, such as penicillin or sulfa. Fortunately, a soil biologist Selman Waksman discovered streptomycin which is one of the substances that has substantial activity against the tubercle bacillus in 1943-1944 and was rapidly pressed into clinical use (Iseman, 1994). Although streptomycin showed an increase in ameliorating disease manifestations, but it was not able to cure the infection because a population of M. tuberculosis has mutant offspring that was resistant to the effects of streptomycin (Iseman, 1994).

Two other medications which are the p-aminosalicylic acid and isoniazid were discovered not too long after, and clinicians found out that drug resistant did not emerge and lifetime cures of tuberculosis finally were achievable when all these drugs were given simultaneously and the reasons behind this are (I) random bacteria mutations occurred in a slow rate during microbial replication, (II) these mutations were unlinked; therefore, the probability of a microbe spontaneously developing resistance to two drugs was the product of the individual risks (Iseman, 1994).

The prevalence of drug-resistant strains of M.tuberculosishas risen dramatically in certain regions or populations as a consequence when irregular or incomplete adherence rose steadily over the past two decades (Iseman, 1994). Unfortunately, inadequate treatment programs have resulted in drug-resistant rates in excess of 30% in some developing nations where resources are limited. The most common way the M. tuberculosis resistance has evolved from patients either cryptically discontinue one or more of their multiple drugs or take less than the prescribed dosage (Iseman, 1994). An environment that selects for survival of the drug-resistant mutants was created when insufficient numbers or dosages of drugs. The drugs only tip the balance in favor of the naturally derived variants but not inducing the mutations (Iseman, 1994).

World’s tuberculosis cases involved drug-resistant organisms has been gradually increasing in this manner. Most of the drug-resistant cases have historically involved failed treatment in an individual. However, in some cases, these drug-resistant strains can be transmitted to a new patients, who then develops tuberculosis with pre-formed drug resistance but this has occurred with small amount of cases because the metabolic comprises made by the microbes to enable drug resistance have made them modestly less virulent (Iseman, 1994).

The outcome of TB infection is determined by the immune response of an individual, environmental and bacterial factors (Echeverria-Valencia et al., 2017). There are two types of TB, which are the latent TB and active TB. Individual with latent Tb is infected with M. tuberculosis but does not show any clinical symptoms, radiological abnormality or microbiological evidence while individual with active TB will show all symptoms (Lee, 2016). Most individual who are infected with TB and remained in latent stage because our body is able to fight off the infection. However, approximately 10% of the infected population will progress to active TB disease (Bloom et al., 2017).

Diagnosis of TB may include performing a Mantoux tuberculin skin test, which is given by injecting a standard does of tuberculin fluid into the skin of lower portion of the arm (Agyeman & Ofori-Asenso, 2017). Blood test will be definite test of determining if an individual has TB, but this test will not be able to distinguish between latent and active TB (Agyeman & Ofori-Asenso, 2017). Therefore, chest x-rays and sputum test will be carried out to reconfirm the diagnosis of latent or active TB. Chest x-rays are performed to detect chest abnormalities and sputum culture test is considered as diagnostic gold standard for active TB (Agyeman & Ofori-Asenso, 2017). Furthermore, drug susceptibility testing (DST) is performed on the isolated tubercle bacilli specimen that was isolated from the sputum culture to test for any drug-resistant TB (Agyeman & Ofori-Asenso, 2017).

The treatment for latent TB needs to be treated and not ignored because it has a possibility of progressing into active TB. Treatment varies between patients and typically antibiotics will be given accordingly. For active TB treatment, a cocktail of antibiotics for an average of 6 to 9 months. The four drugs in the cocktail termed RIPE, which are Rifampin, Isoniazid, Pyrazinamide and Ethambutol (Mitnick, McGee & Peloquin, 2010). This effective treatment was developed in the early 1970s and it has showed a cure rate as high as 98% (Nguyen et al., 2018).

In conclusion, tuberculosis remains to be an ancient disease that is a global health issue and has costed many deaths in human population. Human societal failures have potentiated the evolution of drug-resistant strains of the tubercle bacillus in the United States and around the world. This has largely posed a threat to the health and survival of the individual in whom inadequate therapy has promoted the drug resistance until recently.


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