D.T.C.D. (WALES), F.C.C.P. (AMERICA),

DIRECTOR

OJHA INSTITUTE OF CHEST DISEASES

KARACHI.

Dr. Karel Styblo, director of scientific activities at the international union against tuberculosis has estimated that three million people die form tuberculosis every year. Four to five million new cases of acute, highly contagious pulmonary tuberculosis emerge each year, plus and equal no: of new cases of less serious or less contagious forms, which are nevertheless dangerous (including those found in children or adolescents & extra pulmonary forms).

Without treatment new bacillary case remain contagious for about two years before either death intervenes or more or less precarious cure occurs spontaneously. This makes a total at any given time throughout the world of at least ten million distributors of the bacillus who spread infections all around them.The outlook for the patient with tuberculosis, once “captain of the men of death” has improved enormously since effective drugs to counteract the disease became available during the last 40 years. However in the decade of 80’ we are arises from the following factors.

i) With today’s chemotherapeutic armamentarium its possible to offer a life time cure to virtually any patient anywhere in the world.

ii) This promise of universal cure is thwarted by two major barriers: patient non-compliance and the financial burden of available resources.

Patients in whose sputum acid fast bacilli can be detected by direct sputum examination are the main sources of transmission of the disease. Therefore the most important contribution in the control of tuberculosis is to find these patients & render them non- infectious as quickly as possible. It takes usually about 20 hours for the tubercle bacillus to multiply & in less that a month assuming that 30 divisions take place, more than a month million bacilli are produced form a single cell. This would approximate the number found in a cavity. Hence cur top most priority should be to treat this human reservoir with most effective chemotherapeutic regiment and to ensure that the patient actually adhere to it for the prescribed period of time.

The introduction of isoniazid (1951/52) made it possible to devise the first form of curative standard therapy for previously untreated tuberculosis. This consisted in the combined use of what at that time were the best antituberculous agents available I.E. isoniazid, streptomycin and para-aminosalicylic acid (P.A.S.).

The programme of treatment was divided into three phases. In the intial intensive phase all three drugs were administered simultaneously to achieve as rapid as possible a reduction in the bacterial count and thus also in infectivity- as well as quickest possible elimination of primary resistant organisms, this phase lasted from 3-6 months depending on the extent of the tuberculous lesions. There then followed the so called stabilization phase, during which only tow drugs (INH & PAS) were given for 6-9 months this was aimed at a further reduction in the bacterial count and at the total elimination of resistant mutants.

In the ensuing consolidation phase which lasted until the end of the total two years course of treatment isoniazid was use as monotherapy in order to destroy persisting organisms and so to provide greater protection against relapse. In our country even in consolidation phase tow drugs were used.

This regimen (SHP) continued in 50’s & 60’s & came to be called 100% successful therapy with low relapse rate at about 1%. In 1962 ethambutol was introduced and it replaced P.A.S. which was poorly tolerated. In some countries P.A.S. was superceded by thiacetazone. The turning point in treatment for tuberculosis came only with the discovery and introduction of rifampicin, since late 1960’s at about the same time, the concept of replacing three phase with the so called two phase therapy arose from three recurring observations.

i) That multiplication of sensitive organisms is already inhibited during the first few days of effective treatment.

ii) That a patient with pulmonary tuberculosis ceases to be infectious after as little as tow weeks of appropriate chemotherapy and.

iii) That sputum conversion often occurs during the first few months of treatment.

A typical two phase program consists of relatively short initial intensive phase of treatment with 3 or more drugs daily followed by a longer continuation phase in which tow drugs are given either daily or intermittently.

In relation to tubercle bacillus antituberculous drugs can be divided into bactericidal and bacterioustatic.

The chief bactericidal drugs are isoniazid, rifampicin, pyrazinamide and streptomycin and the more common bacterio-static drugs are ethambutl, P.A.S. ethionamide and thioacetazone. It is believed that bactericidal drugs kill those bacilli that are actively dividing ant that by doing this quickly large populations of tubercle bacilli are destroyed early on in treatment. In short course chemotherapy this is very important, as a rapid reduction in they bacillary population prevents the development of resistant strains.

Another significant bactericidal action and one which is vital in short course chemotherapy is to eliminate those bacilli that are not dividing so actively all the time. These are population of bacilli that divide only at irregular intervals or very slowly, they may be dormant or semidormant and only multiply for short periods of time: Rm & PZ are though to be particularly effective against those bacilli whose multiplication may be inhibited by an acid environment. The bactericidal action mya then be divided into.

a) Initial killing of large numbers of actively dividing bacilli and

b) Sterilizing activity to eliminate persisting bacilli.

Indeed, these are two important issues in the chemotherapy of tuberculosis. The first is to kill dividing bacilli in the shortest possible time to get bacteriological oure and prevent development of secondary resistance, and the second is to kill those persisting bacilli in order to avoid relapses and so achieve a permanent cure.

The efficacy of the older chemotherapeutic regimens depended mainly on the extent to which it was possible by combining the bastericidal and bacteriostatic agents then available, to prevent secondary resistance and allow sufficient opportunity for body’s own defences to destroy those bacilli that were inaccessible, the efficacy of short course chemotherapy on the other hand depend exclusively on its bactericidal potency and bacteriostatic agents have no role to play. Short course chemotherapy is based on the concept that the drugs employed should have a dual bactericidal actin i.e. both against metabolically active bacilli and also against persisters.

Advantages of short course therapy.

1) More rapid & reliable cure substantially reduces medical & social costs.

2) Relapses very few, pretreatment costs are lower.

3) Individual cases impose less burden on health services so that mo patients can be treated for the same outlay.

4) The reliable sterilizing effect makes much routine follow up work unnecessary.

5) The decrease in the total amount of drugs required to be taken also reduces their side effects.

6) The shorter treatment period helps to improve patient compliance.

7) More rapid sputum conversion reduces the risk of relapses in cases where treatment is stopped prematurely.

8) Earlier discharge from treatment has a positive psychological effect the patient is less likely to be regarded as chronically ill and unfit for work.

The first short course study which included.

Rifampicin was carried out in east Africa by British medical research council in early 1970’s (E. Africa/BMRC, 1972).

Since they many other well controlled clinical studies involving a large no: of different therapeutic regimens have been carried out in almost every part of the world.

Two criteria’s were adopted as yardstick of successful therapy:

a) The rate of negativization in culture (sputum conversion) after two months of treatment as an indicator of the bactericidal activity of a given regimen and

b) the relapse rate, as an indication of its sterilizing effect.