Evidenced-based Pharmacology Paper

Tuberculosis is one of the major health concerns in the world. Tuberculosis is an acute or chronic disease usually caused by a bacterial bacillus called Mycobacterium tuberculosis. In other occasions, it is cause by Mycobacterium africanum and Mycobacterium bovis. The name ‘tuberculosis’ is derived from cellular structures referred to as tubercles that form in the body as the result of an infection; the bacilli are trapped in the structures that tend to be walled off. The management of tuberculosis is complex due to the issues associated with drug adherence and the emergence of drug-resistant TB. The treatment is comprehensive and it utilizes multi-approach strategies that can involve both pharmacological and non-pharmacological methods. Patient education, patient follow-ups, fixed- dose therapy, HIV testing, drug adherence plans, and directly observed therapy are some of essential strategies applied in TB management. This paper aims to discuss tuberculosis (TB), and it covers several concepts, including risk factors, assumptions and unresolved issues, pathophysiology, host genetic issues, and management of the disease.

Sources of Literature Information

The paper derives its content from peer-reviewed journals found in online digital libraries. Google Scholar is both a critical search engine and a huge research database that has helped in locating the essential literature about the topic. The keywords associated with this topic include tuberculosis treatment, pathophysiology, drug resistance, drug adherence, and follow-up.

Literature Review

Mycobacterium tuberculosis is the causative agent of tuberculosis. The immune system in most of the cases contains TB infection; however, compromised immunity due to diabetes, HIV and other factors can elicit TB to transform from inactive to active infection (Smith et al., 2016). The findings of Smith et al., (2016) indicate that inactive Tb infection could be reactivated by air pollutants that tend to alter the function of the macrophages; this influence on the macrophages has been found to increase the susceptibility to active TB infection. TB prevalence in the United States of America has been on decline since 1992 when the incidences were at peak (Dawson, Perri, & Ahuja, 2016). However, it continues to affect the poor, ethnic, and racial minorities, the population with substance abuse, and other marginalized groups. Furthermore, TB tends to affect the hard to access population, which presents a challenge to TB programs that aim to prevent and cure the disease (Dawson, Perri, & Ahuja, 2016).

Mycobacterium tuberculosis’ biological characteristics have presented a major challenge in treatment; the features confer the resistance to drugs. Mycobacterium tuberculosis is a rod-shaped in structure, non-spore forming, and aerobic microbe. Mycobacteria tuberculosis microbes usually measure 0.5 ?m by 3?m (Rossoni et al., 2016), they are acid-fast bacilli and they have a unique cell wall, which is a key to their survival. The cell wall is developed well; it contains fatty acids and mycolic acids that are covalently attached to the underlying peptidoglycan. This provides a lipid barrier that plays a role in drug resistance and tends to challenge the host defense mechanisms. The quantity and the composition of the cell wall significantly contribute to mycobacterial bacilli virulence and growth. The peptidoglycan layer is external to the bacterial cell membrane, and it confers the cell wall rigidity as well as influences the permeability. It is not just the peptidoglycan layer and lipid barrier that are unique to mycobacterium tuberculosis but also the lipoarabinomannan (Rossoni et al., 2016). The lipoarabinomannan is a structural carbohydrate antigen that is also a part of the cell wall components. It is immunogenic and found in the external region of the bacilli, and it helps the mycobacteria to survive in the microphages. It is essential to study the structural features, biosynthesis pathways, and genetic roles; the understanding of these particular concepts of mycobacteria helps and guides in the synthesis of effective drugs.

TB is one of the chronic illnesses and it can affect more than one body organ. The features of the TB bacilli enable them to evade the body immune response. Sometimes, the mycobacterial bacilli undergo genetic alteration, resulting in the emergence of new strains and creating a drug-resistant TB. The host genetics have been shown to play a role in susceptibility to TB; however, proper information about host genetic has remained elusive (Cegielski et al., 2012)

Transmission

Tuberculosis is spread via small airborne droplets (droplet nuclei) as the result of coughing, sneezing, talking, or singing near the person affected by laryngeal or pulmonary tuberculosis. The small airborne droplets can remain in the air for few minutes to even hours after expectoration. The transmission of the bacilli can be influenced by several factors, including the degree of ventilation, the virulence of the mycobacteria, the amount of the bacilli in the droplets, and the scenario for aerosolization (Rossini, 2016). The access to the lungs by the bacilli leads to a respiratory infection; it is vital to note that the bacilli can spread to other parts of the body, including bones and joints, pleura, lymphatic system, and meninges. The bacilli invasion of other body organs is described as extra-pulmonary tuberculosis.

Unresolved Issues and Missing Information in Tuberculosis Prevention and Control

The prevalence of tuberculosis has been on a decline in most high-income countries. However, there are no signs of this disease disappearing in a near future (Abubakar et al., 2012). The Western European states have exhibited a steady decline in the rates of tuberculosis; however, some countries have reported increasing cases of TB while others have experienced a decreasing rate of TB in the recent years. The burden of TB adversely affects the high-risk groups that include homeless persons, migrants, the poor, and prisoners. It would be recommendable to focus on the high-risk population when managing tuberculosis since it can minimize health care costs (Abubakar et al., 2012).

The issue of TB resistance has presented controversies because it is poorly understood. The World Health Organization (WHO) convened a meeting in 2012 to classify highly resistant tuberculosis. The proposed definition of resistant TB was ambiguous. The new definitions were not significantly different from an earlier version. There is no sufficient evidence to suggest that the newly proposed ‘totally resistant tuberculosis’ is distinct from the strains covered in extensively drug-resistant (XDR) TB (Cegielski et al., 2012). The susceptibility tests for various drugs are poorly reproducible. Furthermore, there is no agreed upon or consensus list of all the anti-TB drugs. The definition of tuberculosis in some instances as fully resistant might make the health care providers think that the disease is completely untreatable (Cegielski et al., 2012). Therefore, proper studies and investigations need to be undertaken to unravel the mystery of drug-resistant TB and to establish the drug efficacy accurately similar to developing a consensus on the TB drugs list. Information associated with TB resistance remains missing or assumed.

Risk Factors for Tuberculosis

Various factors contribute to the development of tuberculosis. These factors include congestions, lower economic, social classes, HIV/AIDs (which reduces the immune system), being in prison, and any other conditions that might impair one’s immunity. The children under five years are more predisposed to tuberculosis due to poorly developed immune system; thus, the extra focus should be given to minimizing any chances of transmission among children.

The Pathophysiology of Tuberculosis

After inhalation, most bacilli are trapped in the upper respiratory system that has abundant goblet cells that produce mucus. The movement of the cilia will attempt to expel the bacilli that are trapped by mucus as foreign elements. The mucus and the cilia provide the initial body immunity defense. The bacilli that bypass the mucociliary defense system proceed to the lungs, where the alveolar macrophages engulf them; this is the second line of defense, whereby the alveolar macrophages will attempt to destroy the bacilli and prevent the infection. The lipoarabinomannan found on the bacilli is a critical ligand that acts as a receptor for the macrophage. The complementary immune system plays a unique role in the phagocytosis of the bacilli. The complementary protein C3 attaches to the bacilli cell walls to enable the recognition of the mycobacteria by the macrophages. The process of allowing the recognition is referred to as opsonization. Opsonization by the complementary protein C3 is rapid even in cases where there is no history of previous exposure to the Mycobacterium tuberculosis infection.

The phagocytosis of the bacilli results in a series of events that can lead to either successful control of infection, accompanied by latent tuberculosis, or progress to progressive primary tuberculosis that can be described as an active disease. The outcome is determined by the standard of the host defense mechanisms and the balance between the interaction of the invading bacilli and the host defense immune response. Even after being surrounded, ingested, and phagocytosed by the macrophages, the bacilli continue to multiply. The proteolytic enzymes and cytokines are released by the macrophages in a bid to destroy the bacilli. The produced cytokines tend to attract the T lymphocytes to the site of infection; this is part of the cell-mediated immunity. The macrophages will provide the bacilli antigens on their surfaces to the T lymphocytes; this immune response continues for 2-12 weeks (Duque-Correa et al., 2014). The mycobacterial bacilli will keep multiplying until they have attained sufficient numbers that can elicit full cell-mediated immunity; the skin test can be used to confirm the full cell-mediated immunity, which signifies a huge number of bacilli.

The cell-mediated immunity results in the generation of granulomas that surround the mycobacteria; this usually occurs in the persons with the intact cell-mediated immunity. The granulomas are nodular lesions that emerge from an accumulation of T lymphocytes and macrophages around the mycobacteria. The activated T lymphocytes and the macrophages accumulation create a hostile environment that limits the multiplication of the mycobacterial bacilli. The unfavorable environment results in the destruction of the macrophages and formation of solid necrosis located at the center of the lesion. In spite of such a hostile immune response environment, the mycobacteria can still challenge the immune system and survive through changing of their phenotypic expressions, for example, protein regulation.

After about 2-3 weeks, the necrotic tissue tends to resemble soft cheese. It is described as caseous necrosis characterized by the low PH, limited nutrients, and low oxygen levels. The low oxygen availability, the limited amount of nutrients, and reduced PH levels are harsh conditions that lead to restricted bacilli multiplication and tend to establish latency (Duque-Correa et al., 2014).

The lesions will undergo calcification and fibrosis in the persons with intact immunity system. The infection is adequately controlled, and the bacilli are trapped in the healed lesions. However, in the cases whereby the immunity of persons is compromised or is relatively weak, the lesions tend to progress to progressive primary tuberculosis. The granulomas may be formed in the less immunocompetent individuals, but such granulomas cannot contain the mycobacterial bacilli. The necrotic tissue in the persons with compromised immunity system tends to undergo liquefaction, and its fibrous wall lacks structural integrity (Duque-Correa et al., 2014).

The semiliquid necrotic tissue can flow into the bronchus or it can be drained into blood vessels, leaving a cavity filled with air. The semiliquid tissue in the bronchus can be expectorated and it can lead to the transmission to other people. Similarly, the semi-liquid necrotic tissue, which flows into the blood vessels, leads to extra-pulmonary tuberculosis that can be characterized by the wide spread of the bacilli to the various body organs and tissues. Furthermore, the necrotic tissue semiliquid can get discharged into the lymphatic system and probably accumulate in the lung tracheobronchial lymph nodes; the mycobacterial bacilli can form new caseous granulomas in these lymph nodes again.

Age is been pinpointed as a factor in tuberculosis disease. Research findings have indicated that patients from Asia and Somalia between ages 45-64 and 25-44 are more likely to have extrapulmonary tuberculosis than the persons between 15-25 years of age (Zhang et al., 2011). However, the results from the same study in Greenland were different; the persons in the two older age groups were less likely to have extrapulmonary TB than the younger group (15-24years) (Zhang et al., 2011). Furthermore, the prevalence of extrapulmonary TB varied among diverse age groups and places of origin.

Genetic issues in Tuberculosis Pathogenesis

The host genetics to TB remains a major research challenge. Recently, TB susceptibility locus has been found in the long arm of human chromosome (Schurr, 2011). Schurr (2011) has further noted that heritability plays a role in host genetics that influences antimyobacterial immunity. Some host genetic factors have been implicated in TB susceptibility; however, strong genetics on TB have been difficult to identify by genome-wide and candidate gene association studies. Most studies focus on the gene variants that impact disease progression. Fewer studies explain the genes that influence resistance to mycobacterial infections or identify genes that control the degree of antimyobacterial immunity (Schurr, 2011). Thus, clear explanations on susceptibility and resistance have remained relatively unknown. The host genetics associated antimyobacterial immunity have been a barrier in the development of an efficient TB vaccine; the strategy of overcoming this problem has largely remained unknown (Schurr, 2011).

Tuberculosis Symptoms and Diagnosis

The symptoms of tuberculosis infection may not be exhibited unless the person is afflicted with the active disease. Some of the classical tuberculosis symptoms include weight loss, night sweats, the loss of appetite, daily fatigue, chest pain, chills, persistent cough, fever, and coughing out blood. It is important to recognize these particular symptoms as they can guide the process of diagnosis.

Two tests can be done to detect the presence of the TB bacilli in the body. These tests include blood and TB skin tests; these diagnostic steps do not confirm whether an individual has a latent TB infection or an active TB disease. Extra tests, such as sputum test and X-ray, can confirm the presence of the active disease.

Management of Tuberculosis/Treatment

Vaccination is a critical exercise that has helped prevent millions of tuberculosis cases (Mangtani et al., 2014). Bacillus Calmette–Gu?rin (BCG) vaccine is administered to the healthy babies at the time of birth. The vaccines elicit the development of immunity, which can act as an immune defense against TB infection later.

Tuberculosis is one of the burdensome diseases in the world. It adversely influences the quality of health, particularly in developing countries. An elaborate management plan ought to be developed that is aimed at curing the specific patients, reducing the risk of death and disability, and minimizing the transmission of the mycobacteria from the infected person to other people. The three said goals could only be achieved if the tuberculosis is treated for six months or more. Most of the bacilli will be destroyed after approximately eight weeks of treatment. Some bacteria are resilient to drug treatment due to their biological features, which necessitates the need to prolong the duration of the treatment. Drug-resistant tuberculosis requires sufficient treatment time that enables the eradication of the bacilli and allows avoiding the recurrence of the infection. Adequate treatment guarantees recovery for the patients. The regimen for treatment of tuberculosis must have multiple drugs, to which tuberculosis bacilli are susceptible. The drug regimen is constituted by four types of drugs that facilitate a complete eradication of mycobacterial bacilli and prevent the emergence of the drug-resistant forms.

The World Health Organization guidelines recommend a systematic testing and the treatment of persons diagnosed with the latent tuberculosis infection (Getahun et al., 2015). Some of the persons who ought to undergo this process include the people diagnosed with HIV, children exposed to TB cases, patients on dialysis, and the patients who have silicosis. For the high-risk population, such as the immigrants from regions with high burden of TB, the WHO guidelines recommend TB testing and subsequent treatment if confirmed positive for TB (Getahun et al., 2015).

A newly diagnosed tuberculosis patient has to be subjected to a comprehensive course of management. A specific treatment plan and follow-up ought to be initiated. The management plan should contain particular elements. Firstly, the plan should describe the treatment regimen that involves specific drugs, dosages, and schedules. Secondly, strategies should be put in place that ensure adherence to a given drug regimen. Methods of assessing adherence should be available too. Thirdly, there ought to be the tools to monitor the adverse reaction to drugs. Finally, there is a need to evaluate the outcome of the treatment.

Drug non-adherence has been a critical issue in the treatment of tuberculosis. The non-adherence to a treatment regimen can lead to treatment failure, relapse, the transmission to other people, and the emergence of drug resistance. It is the responsibility of the clinician to ensure that tuberculosis (TB) patients adhere to the prescribed course of treatment. Health care providers ought to work with TB control programs in ensuring the adherence to treatment by the TB patients. TB control programs will help the clinicians to evaluate the barriers to drug adherence and suggest directly observed therapy (DOT) (Pasipanodya & Gumbo, 2013). Incentives can be used to encourage drug regimen adherence. Incentives are small rewards that are given to clients to encourage them to attend clinics or to adhere to drug regimen. If such efforts are unsuccessful, TB programs should initiate the more restrictive actions, including court-ordered DOT and involuntary isolation of a TB client who is unwilling to respect drug compliance concept. Such actions are taken in a bid to protect the public from the continuous transmission and to protect the patient from the emergence of drug resistant TB, which can be a serious health issue. Involuntary isolation is the last resort action if all other methods of ensuring adherence have failed.

Some patient can be on self-administered TB medication. These particular patients should be asked about drug adherence during follow-up visits. The pills should be consistently counted, and blood or urine tests can be done to determine blood serum levels of the drugs or the availability of urine drug metabolites. The response to treatment should be evaluated too; it is recommendable to do drug response evaluation two months after initiation of the treatment through carrying out bacterial culture. If the bacterial culture results are not negative after treatment, the patient ought to be reassessed and directly observed therapy (DOT) should be implemented for the remainder of the treatment (Pasipanodya & Gumbo, 2013).

Patient education is a key in TB management. It can help in the successful completion of the therapy. The role of the clinician in patient education is to explain clearly which medication should be taken, how often to take drugs, and when to take them. The patient should be informed about the role of the regimen, possible adverse effects of medication, and the situations, in which they need to seek medical help. Furthermore, it is essential that the patients be informed about the consequences of failing to take medication. Patient education should also involve education of the clients on infection control measures and the possible need for isolation. The clients can be encouraged to undertake HIV tests and counseling; however, it should remain voluntary.

Case management is an efficient approach to ensuring that TB patient comply with a prescribed course of treatment. The case management in TB patients involves assigning responsibilities, implementation of regular systemic reviews, and initiating a plan to address barriers to drug compliance (Pasipanodya & Gumbo, 2013). The case managers can be nurses or any other health care staff. They are usually assigned roles of managing particular patients. They are responsible for facilitating patient education and ensuring the implementation of better treatment. A case management approach is a patient-centered approach that takes into account several concepts, including the patient’s interests, cultural dynamics, and professional values. The DOT is the recommended management strategy recommended by the Center for Disease Control in relation to TB management (Pasipanodya & Gumbo, 2013). The DOT concept has been entrenched in clinical case management. TB drugs can be administered intermittently if they are under directly observed therapy (DOT); this reduces the number of dosages and patients’ encounters with the health care providers and it can result in the reduction of costs. The approach can be efficient in the management of drug-susceptible TB.

A different strategy ought to be employed in the treatment of drug-resistant TB. The drug-resistant TB should be treated with a daily regimen under a direct observation. The intermittent drug regiments for multi-drug resistant TB are unavailable; thus, if the regimen is twice a day, then, the DOT will be observed twice. The directly observed therapy can be carried out in clinical settings, patient’s home, place of employment, school, or any other agreed upon place. The directly observed therapy can be provided by TB program workers, health care providers, or designated community members. However, family members acting as providers of DOT are discouraged.

Pharmacological intervention has been the mainstay TB management strategy. Fixed-dose combination therapy can be given when DOT is available or not possible. The utilization of fixed-dose drug combination capsules or tablets is recommended because it reduces the chances of error via intake of fewer tablets, and there is no drug selectivity among patients, which leads to the prevention of acquired drug resistance. In the United States of America, the Food and Drug Administration has approved the use of isoniazid and rifampin fixed dose combination and isoniazid, rifampin, and pyrazinamide as a fixed-dose drug combination as well.

Various medications are used for TB management. Levofloxacin, Gatifloxacin, and moxifloxacin are fluoroquinolones drugs that can be used to treat TB caused by drug-resistant mycobacteria, and they are used for the patients who have a low tolerance for first-line TB drugs (Dartois, 2014). However, they have not been approved by the U.S Food and Drug Administration. Amikacin and kanamycin, which are aminoglycosides drugs, can be used to treat drug-resistant TB. However, they have not yet been approved by the U.S Food and Drug Administration. Rifabutin is used to prevent Mycobacterium avium complex disease among the HIV patients, but it is not indicated for tuberculosis. Particular antiretroviral viral drugs can interact with rifampin; thus, this necessitates the use of rifabutin as an alternative option.

The mainstay treatment, which has been approved and which acts as the first-line course of treatment, involves specific fixed-dose drug combinations. The approved drugs include rifampin (RIF), ethambutol (EMB), isoniazid (INH), and pyrazinamide (PZA); these drugs act as the first-line course of treatment and they are given in a combined form. Rifabutin may also be considered the first-line drug in given circumstances. Rifabutin can act as a substitute for rifampin for all cases of TB, to which the causative organism is presumed to be susceptible. Streptomycin was initially considered to be the first-line drug; however, the increase in the prevalence of resistance by mycobacteria to it has reduced its usefulness (Dartois, 2014).

Follow-up of a Tuberculosis Patient

Follow-up is not necessary to a client who has had a positive response to treatment for the prescribed period of therapy. The treated clients should be encouraged to report back if they experience any symptoms that may be associated with TB. The patients who had resistance to isoniazid and rifampin should be evaluated two years post-treatment. The follow-ups should always be individualized.

Conclusion

Tuberculosis is an infection disease caused by the mycobacterial bacilli. It is transmitted via respiratory droplets. It affects the lungs and other body organs and tissues. The risk factors for tuberculosis include the compromised immunity and congestion, as examples. Many questions are still unanswered about the drug resistance and the available medications. Drug adherence is a critical issue in the management of tuberculosis because non-adherence has been associated with treatment failures and the emergence of drug-resistant TB. Thus, elaborate measures, which involve plans that will reinforce adherence, have been initiated. Case management, directly observed therapy (DOT), and follow-ups are some of the strategies utilized to boost TB treatment. The scientific advancement is a significant step in TB prevention; due to the development of BCG as a vaccine and its usage, the cases of TB have reduced drastically. Finally, there are still challenges facing TB control and prevention. Host genetics’ influence on antimyobacterial immunity remains poorly understood. Further studies need to be done to ascertain the role of host genetics in TB susceptibility and antimyobacterial susceptibility.