INTRODUCTION:

Drug resistant tuberculosis is defined as a case of tuberculosis excreting bacilli resistant to one or more anti-tubercular drugs. Multi-drug resistant tuberculosis is defined as disease due to M.tuberculosis which is resistant to Isoniazid (H) and Refampin (R) with or without resistance to other drugs. Tuberculosis is undergoes distinction between¹:

1. Latent TB/Inactive TB: In this condition, there is a TB infection, but the bacteria remain in body in an inactive state and cause no symptoms. it is not contagious. It can turn into active TB, so treatment is important for the person with latent TB and to help control the spread of TB. An estimated 2 billion people have latent TB.

2. Active TB: This condition makes people sick and can spread to others. It can occur in the first few weeks after infection with the TB bacteria, or it might occur years later.

Signs and symptoms of TB¹,²:

· Coughing that lasts three or more weeks

· Coughing up blood

· Chest pain, or pain with breathing or coughing

· Unintentional weight loss

· Fatigue

· Fever

· Night sweats

· Chills

· Loss of appetite

Tuberculosis can also affect other parts of body, including kidneys, spine or brain. When TB occurs outside lungs, signs and symptoms vary according to the organs involved. For example, tuberculosis of the spine may give back pain, and tuberculosis in kidneys might cause blood in urine.

Causes:

Tuberculosis is caused by bacteria that spread from person to person through microscopic droplets released into the air. This can happen when someone with the untreated, active form of tuberculosis coughs, speaks, sneezes, spits, laughs or sings.

Risk factors^2,3:

1. Weakened immune system:

A healthy immune system often successfully fights TB bacteria, but body can't built an effective defense if resistance is low. A number of diseases and medications can weaken immune system, including HIV/AIDS, Diabetes Severe kidney disease Certain cancer treatment, such as chemotherapy Drugs to prevent rejection of transplanted organs Some drugs used to treat rheumatoid arthritis, Crohn's disease and psoriasis, Malnutrition.

2. Traveling or living in certain areas: The risk of contracting tuberculosis is higher for people who live in or travel to countries that have high rates of tuberculosis and drug-resistant tuberculosis, including Africa, Eastern Europe, Asia, Russia, Latin America, Caribbean Islands

3. Poverty and substance abuse:

· Lack of medical care. If receive a low or fixed income, live in a remote area, have recently immigrated to the United States, or are homeless, lack the access to the medical care needed to diagnose and treat TB.

· Substance abuse. IV drug use or alcohol abuse weakens immune system and makes more vulnerable to tuberculosis.

· Tobacco use. Using tobacco greatly increases the risk of getting TB

Genetic factors:

Susceptibility to TB does not follow a Mendelian pattern and is polygenic and multifactorial. Presence of two different genomes, (TB bacillus and host) and their interaction influences on the disease

Sites of TB Disease^4,5,7

TB disease can occur in pulmonary and extrapulmonary sites.

Pulmonary:

TB disease most commonly affects the lungs and it is called as pulmonary TB. In 2011, 67% of TB cases in the United States were exclusively pulmonary. Patients with pulmonary TB usually have a cough and an abnormal chest radiograph, and may be infectious. Although the majority of TB cases are pulmonary.

Extrapulmonary:

Extrapulmonary TB disease occurs in places other than the lungs, including the larynx, lymph nodes, pleura, brain, kidneys, bones and joints. In HIV-infected persons, extrapulmonary TB disease is often accompanied by pulmonary TB. Persons with extrapulmonary TB disease usually are not infectious unless they have 1) pulmonary disease in addition to extrapulmonary disease 2) extrapulmonary disease located in the oral cavity or the larynx; or 3) extrapulmonary disease that includes an open abscess or lesion in which the concentration of organisms is high, if drainage from the abscess or lesion is extensive, or if drainage fluid is aerosolized.

Miliary TB:

Miliary TB occurs when tubercle bacilli enter the bloodstream and disseminate to all parts of the body, where they grow and cause disease in multiple sites. This condition is rare but serious. “Miliary” refers to the radiograph appearance of millet seeds scattered throughout the lung. It is most common in infants and children younger than 5 years of age, and in severely immunocompromised persons. Miliary TB may be detected in an individual organ, including the brain; in several organs; or throughout the whole body.

Central Nervous System:

When TB occurs in the tissue surrounding the brain or spinal cord, it is called tuberculous meningitis. Tuberculous meningitis is often seen at the base of the brain on imaging studies. Symptoms are headache, decreased consciousness, and neck stiffness. The duration of illness before diagnosis is variable and In many cases, patients with meningitis have abnormalities on a chest radiograph consistent with old or current TB

Classifaication of Anti TB drugs ^11,12:

a) First line : these drugs have high antitubercular efficacy as well as low toxicity , are used routinely

· e.g Isoniazid (H)

· Rifampin (R)

· Ethambutol (E)

· Streptomycin (S)

· Pyrazinamide (Z)

b) Second line: these drugs have either low antitubercular efficacy or high toxicity or both; are used in special circumstances only.

· Thiacetazone (Tzn)

· Paraaminosalicylic acid

· Ethionamide (Etm)

· Cycloserine (Cys)

· Kanamycine (Kmc)

· Amikacin (Am)

· Capreomycn (Cpr)

Newer drugs:

· Ciprofloxacin

· Ofloxacin

· Clarithromycin

· Azithromycin

· Rifabutin

Complications ^6,7:

Without treatment, tuberculosis can be fatal. Untreated active disease typically affects lungs, but it can spread to other parts of body through bloodstream. Examples are as follows:

· Spinal pain. Back pain and stiffness are common complications of tuberculosis.

· Joint damage. TB arthritis usually affects the hips and knees.

· Swelling of the membranes that cover your brain (meningitis). This can cause a lasting or intermittent headache that occurs for weeks. Mental changes also are possible.

· Liver or kidney problems: liver and kidneys help filter waste and impurities from bloodstream. These functions become impaired if the liver or kidneys are affected by TB

· Heart disorders: TB can infect the tissues that surround heart, causing inflammation and fluid collections that may interfere with heart's ability to pump effectively called as cardiac tamponade, which is fatal.

TB treatment in India^8,9,10,11

Treatment for new TB patients

All new TB patients in India receive an internationally accepted first line treatment regimen (a regimen is the prescribed course of treatment, in this case the TB drugs) for new patients. The initial phase should consist of 2 months of the drugs Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) and Ethambutol (E). The continuation phase should consist of the three drugs Isoniazid, Rifampicin and Ethambutol given for at least four months. This is alternatively written as 2HREZ/4-6HRE. In special situations the continuation phase may be extended by three to six months. The drug dosages should be given according to the body weight of the patient.

All patients receive their daily TB drugs under direct observation (DOTS).

Treatment of TB^10,11

The therapy of TB has remarkably change he conventional 12-18 monts treatment Has been replaced by more effevtive And less toxic 6 months treatment which also yields higher completion rate .the general principle of anti TB chemotherapy are:

1) Use of single drug in tb results in emergence of resistant organism and relaps in almost 3/4 patients. a combination of two or more drug must be used.

2) Isoniazide and rifampinare most efficacious drugs; their combination is definitely synergistic.duration of therapy is shortened from>12 months -9months. Addition of pyrazinamide for initial 2 months further reduses duration of treatment to 6 months.

3) A single daily dose of all first line anti tb drugs is preferred which is recommended by WHO in 1995.

4) Response is fast in first few weeks as fast dividing bacilli are eliminated rapidly.the adequacy of any regimen is decided by observing sputum conversion rates and 2-5 yr. relapse rates after completion of treatment

Short Course Chemotherapy (SCC)¹¹:

These are regimens of 6-9 months duration which is highly efficacious. all regimen have initial Intensive phase which lasts for about 2-3 months in that TB bacilli killed rapidly which brings about sputum conversion and afford symptomatic relief which followed by

Continuation phase which lasts for 4-6 months during which remaining bacilli are eliminated so relapse dose not occur. So treatment of TB is categorized by:

Site of disease (pulmonary or extra pulmonary) and its severity, sputum smear positivity/ negativity, history of previous treatment

Category wise treatment regimen are as follows:

Category I: Includes a) new (untreated ) smear positive pulmonary TB b) new smear negative pulmonary TB with extensive parenchymal involvement c) new cases of severe forms of extrapulmonary TB viz, meningitis, pericarditis, peritonitis

Category II:

It includes smear positive failure relapse and interrupted treatment cases

Category III:

It includes new cases of smear negative pulmonary TB with limited parenchymal involvement or less severe forms of extra pulmonary TB viz; lymphnode TB, peripheral joint or skin TB.

Category IV:

Which is remained or have become smear positive after completing fully supervised retreatment .these are most likely MDRcases

HIV and TB: ^10,11

Since the 1980s, the number of cases of tuberculosis has increased dramatically because of the spread of HIV, the virus that causes AIDS. Infection with HIV suppresses the immune system, making it difficult for the body to control TB bacteria. As a result, people with HIV are many times more likely to get TB and to progress from latent to active disease than are people who aren't HIV positive.

Tb category	Initial phase	Continuation phase	Total duration
I	2HRZE(S)	4HR/4H3 R3or 6HE	68
II	2HRZES+ 1HRZE	5HRE OR 5H3R3E3	8 8
III	2HRZ	4HR/4H3R3 OR HE	6 8
IV	Chronic case

Drug Name	Category	Route	Chemical Description	Mechanism Of Action
Isoniazid(INH)	1st line	Oral	Nicotinic acid hydrazide	Inhibits mycolic acid synthesis
Rifampin/rifampicin (RIF)	1st line	Oral	Rifamycin derivative	Inhibits RNA synthesis by targeting RNA polymerase
Pyrazinamide (PZA)	1st line	Oral	Nicotinamide derivative	Inhibits cell membrane synthesis
Ethambutol (EMB)	1st line	Oral	Ethylene di-imine di-1-butanol	Inhibit cell wall synthesis
Streptomycin (SM)	1st line	Injectable	Aminoglycoside	Inhibits protein synthesis
Rifabutin (Rfb) /Rifapentine	2nd line	Oral	Rifamycin derivative	Inhibits RNA synthesis by targeting RNA polymerase
Amikacin (Am)	2nd line	Injectable	Aminoglycoside	Inhibits protein synthesis
Kanamycin (Km)	2nd line	Injectable	Aminoglycoside	Inhibits protein synthesis
Capreomycin (Cm)	2nd line	Injectable	Cyclic peptide	Inhibits protein synthesis
Ofloxacin (Ofx)	2nd line	Oral	Fluoroquinolone	Inhibits DNA synthesis and

Table: some anti TB drugs with category

CONCLUSION:

Tuberculosis remains a major cause of death worldwide. The rise and spread of drug resistance and synergistic interaction with the HIV epidemic are posing difficult challenges and threatening global efforts at tuberculosis control. Newer antituberculosis drugs offer the promise of shortened treatment regimens for drug-sensitive disease and more effective treatment for drug-resistant disease and latent infection.

REFERENCES:

1. American Thoracic Society and Infectious Diseases Society of America. Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175: 367–416.

2. Rathored J, Sharma SK, Singh B, Banavaliker JN, Sreenivas V, 61. Srivastava AK, et al. Risk and outcome of multidrug-resistant tuberculosis: vitamin D receptor polymorphisms and serum 25(OH) D. Int J Tuberc Lung Dis 2012; 16: 1522-8.

3. CDC. Essential components of a tuberculosis prevention and control program: Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR 1995; 44

4. CDC. Extensively drug-resistant tuberculosis—United States, 1993–2006. MMWR 2007; 56 (11): 250–3. www.cdc.gov/mmwr/preview/mmwrhtml/mm5611a3.htm (SITES OF TB DISEASE)

5. American Thoracic Society and CDC. Diagnostic standards and classification of tuberculosis in adults and children.Am J Respir Crit Care Med 2000; 161 (4): 1376–1395.

6. http://ajrccm.atsjournals.org/cgi/reprint/161/4/1376

7. ICMR, Prevalence of drug resistance in patients with pulmonary tuberculosis presenting for the first time with symptoms at chest clinics in India II. Findings in urban clinics among all patients, with or without history of previous chemotherapy. Indian J Med Res 1969; 57:823-835.

8. Trivedi SS, Desai SC. Primary antituberculosis drug resistance and acquired Rifampicin resistance in Gujarat, India. Tubercle 1988; 69: 37-42.

9. World Health Organization (WHO). Treatment of Tuberculosis Guidelines. 4^thedition. WHO Press, World Health Oranization: Geneva, Switzerland, 2010.

10. KD Tripathi, Essentials of medical Pharmacology, Jaypee brothers medical publishers, 6 th edition, 2008; 745-750.

11. R.S. Satoskar, S.D. Bhandarkar, Nirmala. N. Rege, Pharmacology and Pharmacotherapeutics, Popular prakashan, 19^th edition 2005; 735-752.

Received on 29.06.2018 Accepted on 05.08.2018

Asian J. Pharm. Res. 2018; 8(3): 191-194.

DOI: 10.5958/2231-5691.2018.00033.3

TB treatment in India8,9,10,11

Treatment for new TB patients

TB treatment in India^8,9,10,11