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1 Mycobacterium tuberculosis has been present in the human population since antiquity - tian mummies from 2400 B.C. show definite fragments of the spinal column from Egyp pathological signs of tubercular decay. The term phthisis, consumption, appears first in Greek literature. Around 460 B.C., Hippocrates identified phthisis as the most widespread disease of the times, and noted that it was almost always fatal. Due to common phthisis related fatalities, he wrote something no doctor would dare write today: he warned his colleagues against visiting se their inevitable deaths might damage the cases in late stages of the disease, becau reputations of the a ttending physicians. Exact pathological and anatomical descriptions of the disease began to appear in the Opera Medica seventeenth century. In his of 1679, Sylvius was the first to identify actual tubercles as a consistent a e lungs and other areas of nd characteristic change in th eir progression to abscesses and cavities. consumptive patients. He also described th miliary tuberculosis in 1702. The earliest Manget described the pathological features of references to the infectious nature of the disease appear in seventeenth century Italian e Republic of Lucca in 1699 states that, medical literature. An edict issued by th endangered by objects remaining after the "henceforth, human health should no longer be death of a consumptive. The names of the d eceased should be reported to the authorities, and measures undertaken for disinfection." In 1720, the English physician Benjamin Mart en was the first to conjecture, in his publication, A New Theory of Consumption , that TB could be caused by "wonderfully minute living creatures", which, once they had gained a foothold in the body, could disease. He stated, moreover, "It may be generate the lesions and symptoms of the ng in the same bed with a consumptive patient, therefore very likely that by an habitual lyi constantly eating and drinking with him, or by very frequently conversing so nearly as to draw in part of the breath he emits from th e Lungs, a consumption may be caught by a ng with consumptive pati sound person...I imagine that slightly conversi ents is seldom or never sufficient to catch the disease." For the early eighteenth century, Dr. Marten's writings display a great degree of epidemiological insight. In contrast to this signifi cant level of understanding about the etiology of consumption, which was already enabling prevention and a break in the chain of infection, those attempting to cure the disease we re still groping in the dark The introduction of th e sanatorium cure provided the first really step against TB. Hermann Brehmer, a Silesian botany student suffering from TB, was instructed by his doctor to seek out a healthier climate. He tr aveled to the Himalayan mountains where he could pursue his botanical studies while trying to rid himself of the disease. He returned home cured and began to study medicine. In 1854, he presented his doctoral dissertation bearing the auspicious title, Tuberculosis is a Curable Disease >. In the same year, he built an institution in Gorbersdorf where, in the midst of fir trees, and with good nutrition, patients were exposed on their balconies to continuous fresh air. This setup became the

2 blueprint for the subsequent de velopment of sanatoria, a po werful weapon in the battle against an insidious opponent. New advances then followed in rapid succes sion. In 1865, the French military doctor Jean-Antoine Villemin single-handily demons trated that consumption could be passed from humans to cattle and from cattle to ra bbits. On the basis of this revolutionary evidence, he postulated a specific microorganism as the cause of the disease, finally laying to rest the centu ries-old belief that consumption arose spontaneously in each affected organism. In 1882, Robert Koch discovered a staining technique that enabled him to see . What excited the world was not so much the scientific Mycobacterium tuberculosis brilliance of Koch's discovery, but the accompanying certainty that now the fight against humanity's deadliest enemy could really begin. ill modest. Improving so The measures available to doctors were st cial and sanitary conditions, and ensuring adequate nutrition were all that could be done to strengthen the body's defenses against the TB bacillus. Sanatoria, now to be found throughout Europe and the United States, ated the sick, the source of provided a dual function: they isol infection, from the general populatio n, while the enforced rest, t ogether with a proper diet and the well-regulated hospital life assisted the healing processes. These efforts were reinforced by the observa tion of the Italian Forlanini, that lung collapse tended to have a favorable impact on the outcome of the disease. With the introduction of artificial pneumothorax and su rgical methods to reduce the lung volume, face of advanced TB was over, and active the depressing era of helplessness in the therapy had begun. A further significant advance came in 1895 when Wilhelm Konrad von Rontgen ears his name. Now the progress and severity of a patient's discovered the radiation that b disease could be accurately followed and reviewed. Another important development was provided by the French bacteriologist Calmette, who, together with Guerin, used specific cu lture media to lower the virulence of the bovine TB bacterium, creating the basis for the BCG vaccine still in widespread use today. Then, in the middle of World War II, came the final breakthrough, the greatest challenge to the bacterium that had threatened humanity for thousands of years - chemotherapy. In fact, the chemotherapy of infectious dis eases, using sulfonamide and penicillin, had been underway for several years, but th ese molecules were ineffective against Mycobacterium tuberculosis . Since 1914, Selman A. Waksman had been systematically screening soil bacteria and fungi, and at the University of Ca lifornia in 1939 had discovered the marked inhibitory effect of certain fungi, especia lly actinomycete, on bacterial growth. In 1940, he and his team were able to isolate an effective anti-TB

3 antibiotic, actinomycin; however, this prove d to be too toxic for use in humans or animals. Success came in 1943. In test anim , als, streptomycin, purified from Streptomyces griseus with relatively M. tuberculosis low toxicity. On combined maximal inhibition of a critically ill TB November 20, 1944, the antibiotic was administered for the first time to pressive. His advanced disease was visibly patient. The effect was almost immediately im arrested, the bacteria disappeared from his sputum, and he made a rapid recovery. The especially on the inner ear new drug had side effects - M. - but the fact remained, tuberculosis on, it could be as sailed and beaten was no longer a bacteriological excepti into retreat within the human body. A rapid succession of anti-TB drugs appear ed in the following years. These were important because with streptomycin monotherapy, resistant mutants began to appear antibiotic therapy. However, it was soon with a few months, endangering the success of rcome with the combination of two or three demonstrated that this problem could be ove drugs. Chemotherapy Today Following streptomycin, p -aminosalicylic acid (1949), is oniazid (1952), pyrazinamide (1954), cycloserine (1955), ethambutol ( 1962) and rifampin (rifampicin; 1963) were ides such as capreomycin, viomycin, introduced as anti-TB agents. Aminoglycos es (e.g. ofloxacin and ciprofloxacin) are kanamycin and amikacin, and the newer quinolon ituations. Combinations of a B -lactam antibiotic with a B only used in drug resistance s - lactamase inhibitor enhance treatment effectiveness, but the newer drugs, including the macrolides, have not received much clinical testing. Two properties of anti-TB drugs are importa nt: antibacterial activity, highest in I. isoniazid rifampin streptomycin and their capacity to inhibit the development of resistance, the most effective drugs being isoniazid rifampin ethambutol With the proper four drug regimen, there shou ld be a rapid clinic al improvement and a significant fall in the ba cterial count. After a month, the pa tient should be afebrile, feel well and have regained we ight. Coughing and sputum s hould have diminished and improvements will be visible on the X-rays.

4 Although bacteria will still be present in th e smears, they will become more and more difficult to culture. Improvements will be visible on the X-rays for three to four months. If the disease was initially severe, though, the end of treatment may not be reached for a year. the first three months should be grounds for The absence of radiological improvement in apy is needed. Patient compliance and the concern and indicate that a change in ther bacteria's drug sensitivity should be reeval uated. Relapses usually occur within six cases are due to poor patient compliance. months of the end of treatment, and in most Patient compliance must be monitored througho ut treatment; this is done at the National Tuberculosis Center through Directly observed therapy treated patient, there is a high chance that When TB becomes active again in a previously ny current therapy must be suspended until the bacteria will now be drug resistant. A multiple drugs are found to which the pathogen is fully sensitive, and treatment can be resumed with the addition of these drugs to ver add a single drug the original regimen. Ne to a failing regimen. If the microorganism is resi stant to the standard dr ugs, then it will be necessary to administer more toxic medications such as ethionamide pyrazinamide cycloserine capreomycin viomycin kanamycin The Recent TB Epidemic worldwide roughly correlates with economic The registered number of new cases of TB conditions: the highest incidences are seen in those countries of Africa, Asia, and Latin America with the lowest gross national pr oducts. WHO estimates that eight million people get TB every year, of whom 95% liv e in developing countries. An estimated 3 million people die from TB every year. In industrialized countries, the steady drop in TB incidence began to level off in the mid 1980s and then stagnated or even began to incr ease. Much of this ri se can be at least partially attributed to a high rate of immigr ation from countries with a high incidence of TB. It is also difficult to perform epidem iological surveillance and treatment in immigrant communities due to various cultural differences.

5 A great influence in the rising TB trend is HI V infection. Chances are that only one out of M. tuberculosis ten immunocompetent people infected with will fall sick in their lifetimes, but among those with HIV, one in ten per year will develop active TB, while one in two or three tubercul in test positive AIDS patients will develop active TB. In many industrialized countries this is a trage dy for the patients involved, but it these cases developing countries , the impact of HIV make up only a small minority of TB cases. In especially in the 20-35 age infection on the TB situation, group, is worthy of concern. A final factor contributing to the resurgence of TB is the emergence of multi-drug resistance. Drug resistance in TB occurs as a result of tubercle bacillus mutations. These upon the presence of the drug. E xposed to a single effective mutations are not dependent anti-TB medication, the predominant bacilli, se nsitive to that drug, are killed; the few drug resistant mutants, likely to be present if the bacterial population is large, will, multiply freely. Since it is very unlikely that a single bacillus will spontaneously mutate to resistance to more than one drug, giving mu ltiple effective drugs simultaneously will nts. This is why it is absolutely essential inhibit the multiplication of these resistant muta to treat TB patients with the recommended four drug regimen of isoniazid, rifampin, pyrazinamide and ethambutol or streptomycin. While wealthy industrialized countries with good public h ealth care systems can be expected to keep TB under control, in much of the developing world a catastrophe awaits. It is crucially important that support be given to research efforts devot ed to developing an effective TB vaccine, shortening the amount of time required to ascertain drug sensitivities, improving the di agnosis of TB, and creating ne w, highly effective anti-TB medications. Without support for such efforts, we run the risk of losing the battle against TB. Written by John Tranotti

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