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Tuberculosis is the most common cause of infectious disease related to mortality worldwide1. The World Health Organization estimates that 2 billion people have latent TB, while another 3 million people worldwide die of TB each year. In addition, the prevalence of drug-resistant TB is also increasing worldwide. Co-infection with HIV has been an important factor in the emergence and spread of resistance.Â Infection with human immunodeficiency virus (HIV) brings about a host of changes that is conducive to tuberculosis infection as well as further development of the disease2,3 .New TB treatments are being developed, and new TB vaccines are currently under investigation.
Tuberculosis (TB) is an infectious disease that has plagued humans since the Neolithic times. The chief two organisms responsible for causing tuberculosis are Mycobacterium tuberculosisÂ and Mycobacterium. M. tuberculosisÂ is a rod-shaped, slow-growing bacterium, requiring 4-8 weeks for visible growth on solid medium. The organism grows in parallel groups called cords, with an outer cell wall rich in peptidoglycans and mycolic acids4. This waxy envelope makes organism difficult to treat with chemotherapy since passage through this membrane is difficult. M. tuberculosis cell wall has high acid content, which makes it hydrophobic; resistant to oral fluids it retains many stains after decoloration with acid-alcohol, which is the basis of acid-fast stains.
Tuberculosis. Acid-fast bacillus smear showing ch...
Acid-fast bacillus smear showing Â Mycobacterium tuberculosis.
Causes and symptoms
All cases of TB are transmitted from person to person via droplets. When someone with TB infectionÂ coughs, sneezes, or talks, tiny droplets of saliva or mucus are expelled into the air, which can be inhaled by another person. People who have inhaled the TB bacteria, but in whom the disease is controlled, are referred to as infected. Their immune system has walled off the organism in an inflammatory form known as a granuloma. They have no symptoms, frequently show a positive skin test for TB, yet cannot transmit the disease to others. This is referred to as latent tuberculosis infection or LTBI5. Risk factors for TB include the following: low socioeconomic status, Immunodeficiency diseases including HIV infection, alcoholism, and migration from a country with a high number of TB cases. The general symptoms of infection include lossÂ of weight, loss of energy, poor appetite,Â fever, a productiveÂ cough, and nightÂ sweats. The various site of infection includes lungs, lymph nodes, genitourinary tract, bone joints, meanings and the lining covering the outside of the gastrointestinal tract6.
Based on the site of infection, the tubercular infections may be classified as
Pulmonary tuberculosis (Lung)
Â Tuberculosis meningitis (Brain)
Â Skeletal TB (Spine)
Â Genitourinary TB (Genitourinary tract)
Gastrointestinal TB (Gastrointestinal tract)
Â Tuberculosis lymphadenitis (scrofula- neck)
Â Cutaneous TB (face or extremities or tender nodules or abscesses)
Humans are the only known reservoir forÂ Mycobacterium tuberculosis. TB is transmitted by airborne droplet nuclei, which may contain fewer than 10 bacilli. TB exposure occurs by sharing common airspace with an individual who is in the infectious stage of TB. When inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. Once inhaled, the bacteria are attacked by the host's immune system and are phagocytosed by macrophages. The macrophages aggregate and form granulomas, also known as tubercles upon encountering the bacilli, macrophages ingest and transport the bacteria to regional lymph nodes.
However, when the immune system is weakened, for example, by age, malnutrition or HIV infection, there is possibility of reactivation of the infection and relapse. For individuals with a normal immune system the risk of developing the disease after infection is only about 10%, but when the immune system is compromised the risk can increase to 50%.
History of antitubercular agents
Tuberculosis is an ancient disease, manifested already in Pharaonic Egypt as shown by the examination of the bones of mummies. Its origin was unknown until 1882, when Robert Koch isolated and grew the contagious bacterium, later named Mycobacterium tuberculosis. Koch's discovery, together with advances in the development of antibiotics and antibacterial medicines, made it possible to develop drugs to combat this previously untreatable disease.
In 1943, streptomycin became the first chemical with a proven clinical effect, and in 1952 Salman Waksman was awarded the Nobel Prize for its discovery. The discovery of streptomycin was closely followed by that of another anti-TB drug, paraamino salicylic acid7. However, resistance to both drugs emerged quite early on, and in an effort to overcome this, the first combination therapy was introduced in 1949.The most potent anti-TB drug till date, Isoniazid, was discovered simultaneously in 1952 by three companies, Bayer, Squibb and Hoffman Lab.
Tuberculosis continues to be a major health problem worldwide. In 2008, the World Health Organization (WHO) estimated that one-third of the global population was infected with TB bacteria. 8.8 million New cases of TB developed. Each person with untreated active TB will infect on average 10-15 people each year3. The emergence of drug-resistant organisms threatens to make this disease once again incurable.
TB disease in India: age group distribution, 2003.
Traditionally, there have been three approaches to the epidemiology of tuberculosis, namely:
A. the Etiologic Approach (analytic epidemiology): mainly dealing with the risk
Factors associated with the agent - M. tuberculosis;
B. The Descriptive Approach: dealing with the traditional incidence and
Prevalence of tubercular infection.
c. The Predictive Approach: dealing with what happens next - forecasting the tubercular
Epidemiology is essential for the successful implementation of a national tuberculosis control programme. For a basic understanding of the epidemiological basis of tuberculosis control, a model that follows the pathogenesis of tuberculosis from exposure to death is useful. The model should be simple enough to explain the dynamics of the disease but complex enough to allow the distinction between the major determinants of epidemiology.
The tuberculosis vaccine, known as Bacille Calmette-Guérin (BCG) may prevent the spread of tuberculosis andÂ tuberculous meningitisÂ in children, but the vaccine does not necessarily protect against pulmonary tuberculosis. It can, however, result in a false-positive tuberculin skin test that in many cases can be differentiated by the use of the QuantiFERON-TB Gold test.
The standard "short" course treatment for TB isÂ isoniazid,Â rifampicinÂ ,pyrazinamide, andÂ ethambutolÂ for two months, then isoniazid and rifampicin alone for a further four months7. The patient is considered cured after six months of therapy (although there is still a relapse rate of 2 to 3%). ForÂ latent tuberculosis, the standard treatment is six to nine months of Isoniazid alone. If the organism is known to be fully sensitive, then treatment is given with Isoniazid, rifampicin, and pyrazinamide for two months, followed by isoniazid and rifampicin for four months8. Directly observed therapy (DOT) is recommended for all patients. The diagnosis of Multidrug resistance (MDR-TB) is established with an isolate that is resistant to both isoniazid and rifampin. Multi-drug resistant strains of Mycobacterium tuberculosis have markedly reduced the effectiveness of standard treatment regimens. Directly observed therapy (DOT) is recommended for all patients. Patients on the above regimens as DOT can be switched to 2- to 3-times per week dosing after an initial 2 weeks of daily dosing9.
Commonly used antitubercular Drugs
The following first and second line drugs10 are commonly used for the treatment of tuberculosis
Isoniazid (INH), 1952
Target: Long Chain ACP-Enoyl Fatty Acid Reductase
Isoniazid (INH) illustrationIsoniazid three-dimensional image
Rifampin (RMP), 1957
MIC = 0.06-0.5 ÂÂµg/mL
Target: RNA Polymerase
Rifampin (RMP) illustrationRifampin three-dimensional image
Ethambutol (EMB), 1962
MIC = 0.95-7.5 ÂÂµg/mL
Target: Synthesis of Arabinose, Arabinomannan and Lipoarabinomannan
Ethambutol (EMB) illustrationEthambutol three-dimensional image
Pyrazinamide (PZA),Â 1952
MIC = 6-60 ÂÂµg/mL
Pyrazinamide (PZA) illustrationPyrazinamide three-dimensional image
MIC = 0.25-2 ÂÂµg/mL
Target: 30S Ribosomal Subunit
Toxicity: 8th Cranial Nerve
Streptomycin illustrationStreptomycin three-dimensional image
Target: RNA Polymerase
Rifapentine illustrationRifapentine three-dimensional image
P-Amino salicylic acid (PAS), 1946
MIC = 1-10 ÂÂµg/mL
Target: Folate Synthesis, Iron Transport
Toxicity: GI, Hypersensitivity
p-aminosalicylic acid (PAS) illustrationp-Aminosalicylic acid three-dimensional image
MIC = 6-25 ÂÂµg/mL
Target: Dipeptide Synthetase and Alanine Racemase
Cycloserine illustrationCycloserine three-dimensional image
Ethionamide (ETA), 1956
MIC = 0.3-10 ÂÂµg/mL
Target: Long Chain ACP-Enoyl Fatty Acid Reductase
Ethionamide (ETA) illustrationEthionamide three-dimensional image
First-Line Treatment of Tuberculosis (TB)
Schematic representation of target sites of antitubercular drugs
Need for new antitubercular drugs:
Some of the reasons necessitating the emergence of newer antitubercular drugs11 are
To improve current course of treatment by shortening its total duration.
Viable effective treatment for latent tuberculosis infection (LTBI).
To facilitate drug compliance by providing with less intensive supervision
To combat drug-resistant tuberculosis.
To provide MDR treatment at an economical rate as the global rates of MDR-TB are on the higher side.
Drugs with lesser frequency of administration which permits widely spaced intermittent treatment.
New antitubercular drugs in the pipeline
The newer chemical entities of antitubercular drugs which are in development process is depicted in the following figure
New TB Drugs Under Development illustration
Drug development for TB and other diseases has been at a standstill for decades. But TB Alliance-global alliance TB drug development, created in 2000 increased the TB drug pipeline than it has been in last 40 years12. This TB alliance focuses on both pre-clinical and clinical development of candidate compounds for TB chemotherapy and is associated with projects aimed to identify the compounds currently developed. In addition to this, increased public awareness on the lack of research and development for neglected diseases have led to some multinational pharmaceutical companies setting up R&D institutes on a no profit-no loss basis for development of drugs against tuberculosis, malaria, leishmaniasis.