23/12/2019
Why increasing anti-biotic resistance?
(With special reference to EMERGING TRENDS OF MULTI-DRUG- RESISTANT TUBERCULOSIS AND ATYPICAL MYCOBACTERIUM STRAINS IN INDAIA.)
Dr. Rakesh Kumar Shrivastava
MD (Medicine AIIMS), MD (Internal Medicine, Harvard ), FACP(USA), FICA(Boston), FCCP(USA)
“Even old pathogens invent new tricks. Recently evolved drug resistant strains of tuberculosis bacillus have been plaguing Industrial Urban Centers. Will such developments change the comfortable dead lock? Will Homo- sapiens and Microbes continue to co- exist, or will one side win?”, Avrien Mitchison, the German Microbiologist, Director of Deutsches Rheuma Forschungszentrum, Berlin, in American Science Journal, Article “Will We Survive?” wrote asking the whole community of medical scientists and medical experts in a very sullen tone.
Humanity’s ancient enemies are after all, microbes. They didn’t go away just because science invented drugs, antibiotics, antivirals and vaccines. They didn’t disappear from the planet and they certainly won’t become extinct simply because human beings chose to ignore their existence.
The robust mycobacterium tuberculosis is impossible to eradicate, as half of the world’s population at any given time is infected with the bacteria. In case of pulmonary tuberculosis, to take hold in the human body, the bacteria has to be carried inside droplets small enough to pass through the barriers of the upper respiratory tract. Such tiny droplets remain suspended in the air, drifting on currents, for days, containing live, infectious tuberculosis germs.
For most people, Mycobacterium tuberculosis infection is a benign event; the microbe is kept in check by immune system and the individual never, throughout his or her life, fell ill. On average, infected people have a ten percent chance of developing active disease sometime during their lives, and a one percent chance of coming down with a lethal TB illness.
Any ailment that taxes the immune system can create opportunities for Mycobacterium tuberculosis, since it exploits vulnerabilities. It is an opportunist. For decades, it might silently lurk inside a Homo-sapiens awaiting a moment when defenses are down, and then, when the victim’s immune system is pre-occupied with malaria or cancer, pneumonia or diabetes, it would strike. It is also possible for people living in densely crowded situations to be continuously re-exposed to the mycobacterium tuberculosis exhaled by others which greatly increases their risk for developing an active case of the disease. That’s why TB had historically been so strongly linked with urbanization and institutionalization.
There occur over 8 million new cases of active mycobacterium tuberculosis infection of lungs in the world each year. Cases of extra- pulmonary tuberculosis, occurs in roughly one sixth of all adults with active disease. It is estimated that pulmonary tuberculosis is responsible for 2 million of all world- wide deaths in the people over 5 years old, excluding sero- positive HIV cases. And this percentage is proportionally quite high in developing nations, especially in India.
Apart from poverty, illiteracy, poor hygiene and deplorable sanitary conditions, emergence of HIV infections, all attributable to rising TB menace, geometric progression in sputum positive and Multi-Drug-Resistant Tuberculosis (MDR- TB) has not properly been evaluated in right perspective.
For example, there are about 1.2 million registered cases of pulmonary tuberculosis with government in Madhya Pradesh as per available data. Out of these, about 30% or 0.36 million cases are sputum positive, each one infecting about 15 to 20 persons every year, converting about 5.4 million normal healthy persons into new tuberculosis patients every year in the state of Madhya Pradesh only.
Out of these, 0.36 million sputum positive for AFB cases, approximately 13 to 15% cases are Multi – Drug Resistance Tuberculosis (MDR-TB) cases, each one, spreading infection to about 10 to 15 persons every years that makes 1.8 million new cases of MDR- TB , thereby cumulating to 2 million cases by the next year.
Now days, Multi – Drug Resistant Tuberculosis (MDR-TB) is termed as XDR-TB by physicians, pulmonologists and pathologists exhibit a kind of helplessness because of resistance to one and all of anti-tuberculosis drugs, but I will continue to use MDR-TB instead of XDR-TB for I haven’t given up.
Rapidity of this geometric progression of infected people is to engulf the entire population, sooner than later, unless right steps are taken to prevent the menacing microbe.
The prevalent endemic malaria and diabetes are the strong contributory factors that impair the human host defense mechanism thus rendering humans more vulnerable to infectious diseases. It will not been out of context to remind that diabetes is on rise. The present diabetic population of India will double by in next decade as the trend indicates.
And malaria is omnipresent, sparing no one. In this scenario, when there are 33% MDR- TB registered cases in Gujrat, 40% in Uttar Pradesh & Nepal & 40% overall in entire Indian peninsula, and as far as isolated drug resistance is concerned, it is 99% varying from region to region, the cumulative figure of TB cases including sputum negative and extra- pulmonary tuberculosis is staggering and frightening.
MDR- TB has emerged in the potent proportions that the mutant microbes are so broadly resistant to antibiotics that in practical terms, they are invulnerable. But it did not emerge overnight, on the contrary, the new mutant strains made numerous tentative incursions into the human population over a period of years. It almost seemed as if human beings were deliberately ignoring the plentiful warning signs. It was in the wealthy and medium income countries where billions of dollars were spent on antibiotics and antivirals to be used and misused. And it was in the wealthy nations that resistant strains most commonly emerged. But it was the poor nations, unable to afford alternative drugs that paid the highest price.
From the perspective of developing countries, the pharmaceutical industry and western governments that acted in its support were solely concerned with the pursuit of profits, and would conduct any practice they saw fit to maintain their monopoly on the global medicinal market.
In 1991, with the world facing a tuberculosis crisis, when MDR-TB cases exploded in American prisons, it was suddenly noted that the global supply of streptomycin was tapped out. The second oldest antibiotic was no longer manufactured by any pharmaceutical company anywhere in world. Unpatented, cheap, and needed solely in developing countries, it offered no significant profit margin to potential manufacturers. When MDR- TB surfaced in major US cities that year, the FDA would find itself in a mad scramble to entice drug companies back into the streptomycin manufacturing business. Exactly same happened with PAS (Para-amino Salicylic Acid) and Ethionamide, which resurfaced with stupendous price-tags, beyond affordance of poor victims of tuberculosis.
WHO guidelines to combat tuberculosis, and implemented through national TB program, by the union government of India, in 1962, failed miserably. Although USA had already rejected the prescription prepared by WHO on the dosage of four first- line with streptomycin in relapse and treatment failure cases, where streptomycin was to be the drug of first choice in cases of infective tuberculosis. But the Indian authorities responsible for Tuberculosis eradications program, right from 1962, continued the same treatment regimen for over 45 years despite dismal results. Moreover adherence to WHO recommendation of Thiacetazone, which causes severe anorexia, nausea, vomiting, and Steven Johnson Syndrome or Exfoliative dermatitis, which is otherwise uncommon but lethal, under the pretext of being cheap, was ridiculous.
To a large extent, fight against TB in India had been affected by most physician’s and practitioner’s non- compliance with observation therapy, poor Government policy and drug manufactures in India producing the anti- tuberculosis kit comprising the four first line drugs blindly or deliberately following the WHO guidelines when the world- body’s very efficacy is being questioned. Dr. S.K. Agrawal, Head of the Department of Pulmonary Medicine, in the Institute of Medical Sciences, Banaras Hindu University, categorically criticized this approach by saying that “the sub- therapeutic or lower dose causes drug resistance while higher dose causes toxicity. Therefore, it is necessary that the right dose in right quantity be given to patients according to observation and not at random dosage as has been given under the National TB program. The reality is in such cases, the patient have TB bacilli resistant to almost all anti- tuberculosis drugs taken earlier.”
Physicians of substance, explicitly exposed to the intricacies of modern medicine, adopted the universal modifications, but the majority of practitioners treating tuberculosis in our country, unfortunately devoid of the knowledge of Immunology and Respiratory Disorder Mechanism failed to understand or notice warnings of the inevitable disaster.
The efficiency of standard chemotherapy is adversely affected by the level of the drug resistance of the community. It is largely due to the inappropriate use of drugs in the past; a combination of just two drugs; large- scale treatment by general practitioners using inadequate regimes. And if private treatment of tuberculosis is readily available for poor masses at negotiable cost, patient may discontinue drugs once they get initial response and run short of money, thus converting into resistant carriers.
MDR-TB continues to occur as a result of poor compliance or inadequate treatment. It has a very high morbidity and mortality even when aggressive surgical and medical strategies are combined.
Dr. A.L. Anand and his colleagues conducted a study on 100cases. MDR-TB was defined as a case of TB presenting in vitro resistant to Isoniazid and Rifampicin plus at least 3rd anti- TB drugs. Different management options were; reserve drugs and reserve drugs plus surgery. Surgical therapy was used in 30 cases with predominately localized disease. There were 12 pneumonectomies, 8 lobectomies and 10-thoroco-plasties. The outcome was not different than the studies carried at the National Jewish Centre for Immunology and Respiratory Medicine in Denver, Colorado, the best TB treatment center in the entire world. Its chief TB physician, Dr. Michael Iseman, the pre-eminent expert in the United States of America on diagnosis and the treatment of the disease, admitted that MDR-TB was highly contagious and extremely lethal. Despite radical treatment, including surgical removal of TB filled lungs, more than half the patient never recovered from the disease; rest either fell into life -long tuberculosis state or died. None of the Iseman’s 107 patients were HIV positive.
In 1991-92 scientists developed an ingenious way to ‘see’ drug- resistant strains in the laboratory using the luciferase chemical found in fireflies to light up resistance genes, identifying 500 genetically distinct tuberculosis strains, and figuring out how the bacteria managed to hide inside CD (T-helper) cells of the immune system. In addition to the tubercle and leprosy bacilli, the genus Mycobacterium contains about 50 species that exits naturally as environmental saprophytes. These are also opportunistic organisms.
Environmental Mycobacteria and particularly associated with water, and are found in swamps, ponds, rivers, and estuaries. Some species including Mycobacterium and Mycobacterium gordonae prefer free water, while Mycobacterium and Mycobacterium xenopi have colonized piped water supplies. They are also found in compost and on plants. They are readily transmissible to men in potable water, by inhalation of aerosols, or by traumatic inoculation. Infection of man by environment Mycobacteria is widespread and common, resulting in immunologically effected contact manifesting as cross- reactions on tuberculin testing.
As they are of environmental origin, the prevalence of disease caused by these Mycobacteria in man is unaffected by tuberculosis control measures designed to break the cycle of person-to-person transmission. Thus, although the incidence of such disease remains fairly constant, it is rising relative to tuberculosis in recent years, especially because of immuno- suppression, notably by AIDS and to some extent by rising trend of diabetes.
The environment Mycobacteria cause four main types of disease: chronic pulmonary, lymphadenitis, post-inoculation, and disseminated.
Chronic pulmonary disease occurs in patients with predisposing local lung lesions such as industrial dust disease, old tuberculosis cavities, cancer, cystic fibrosis and bronchiectasis or generalized autoimmune or immunosuppressive disorders. Most patients are middle aged or elderly and men are much more frequently affected than women. Since there are no diagnostically reliable clinical differences between pulmonary environmental Mycobacterial disease and tuberculosis, diagnosis therefore depends on the isolation and identification of the causative organism by way of taking two pure cultures from specimens taken at least one week apart.
Lymphadenitis attributable to non-tubercle Mycobacterium, is principally a disease of young people, which about half the cases occurring in children under the age of five years FANC (Fine Needle Aspiration for Cytology) or excision biopsy is mandatory for accurate diagnosis.
Post-inoculation Mycobecterioses is characterized by large skin ulcers ie Buruli ulcers. The natural habitat of Mycobacterium marinum, the cause of swimming-pool granuloma or fish tank granuloma, is water; it enters cuts and abrasions acquired while indulging in aquatic activities such as swimming and tending to tropical fish-tanks. Infected with Mycobacterium marinum may lead to Tenosynovitis, Carpal Tunnel Syndrome, Osteomyelitis and Dissemination.
Most other cases of post-inoculation disease are caused by the rapid growers Mycobacterium chelonae and Mycobacterium fortuitum. The most common lesions are post injection abscesses, which may occur sporadically or in mini-epidemics due to contaminated multi-dose vaccines or other injectable materials. Abscesses may develop from 1 to 12 months after injection and may enlarge to 7cm or more in diameter. They tend to be very chronic and to remain localized, but multiple abscesses with spreading cellulitis may develop in insulin dependent diabetics. Trauma to cornea predisposes infection to Mycobacterium chelonae and Mycobacterium fortuitum, in which corneal grafting is usually required. More serious infections have followed accidental inoculation during surgical operations.
Disseminated Mycobacterium disease is associated with HIV infection, congenital immune deficiencies in young people and in renal transplant recipients. Mycobacterium species involved are Marium-intracellulare complex Mycobacterium haemophilum. The disease emerges from dormant foci infection in the lymphatic tissue of the alimentary or respiratory tract acquired many years previously. Diagnosis is made by culture of sputum and blood or biopsies of liver, lymph nodes and bone-marrow.
The treatment of environmental or atypical Mycobacterium infection is fairly different from that of Mycobacterium tubercle-infection, depending on proper diagnosis made especially after culture of organism in a reliable laboratory set up. Therefore, the backing of a laboratory facilitating culture of Mycobacterium species is mandatory in controlling what seems to be TB epidemic.
So far the Extra Pulmonary Tuberculosis cases are either ignored or undiagnosed probably due to lack of understanding the disease syndrome by majority of medical practitioners from Government and private sector, in absence of proper medical teaching/training facilities in most of the medical institutions of our country. The most common organ system involved in Extra Pulmonary Tuberculosis are lymphatic, pleural, genitourinary, bone joint, disseminated (miliary), meninges- Central Nervous System, peritoneal, Gastro Intestinal System, and pericardial, that manifests in feverishness with more extensive disease prominently including miliary, pleural and genitourinary disease. Diagnosis is problematic in most forms of Extra Pulmonary Tuberculosis due to relative paucity of bacilli. Histopathology of involved tissues, sophisticated makers including the polymerase chain reaction tuberculostearic acid level, or antibody assay appear to be useful apart from tissue culture in establishing the diagnosis although they are not widely available.
Most bacteriological relapses after the completion of chemotherapy are due to drug susceptible organisms. If such relapse occurs during the course of therapy, it is almost certain that the patient is not taking the drugs. Persistence or recurrence of positive culture in patient known to be taking drugs is much more likely to be associated with the emergence of drug resistance. This can occur if an inadequate regimen has been prescribed or the patient fails to take all the drugs regularly, thereby allowing the number of susceptible organisms decrease. The regime must be changed if acquired resistance emerges and drug susceptibility has enabled suitable retreatment regimes to be selected.
There is no absolute definition of drug resistance. Clinically drug resistance is divisible into ‘initial’ or ‘primary’, the patient who claim that they have never received anti-tuberculosis chemotherapy and ‘acquired’ or ‘secondary’ when it occurs during chemotherapy and is due to the selection of drug resistant mutants.
Cultures of susceptible tubercle bacilli contain certain bacteria with a range of drug susceptibilities including a few drug resistant mutants. The aim of susceptibility testing is not to detect these mutants but to determine whether a patient infected with given strain is likely to respond to treatment with a drug at its usual therapeutic concentration. A change of regimen should be considered only if the patient fails to respond to prescribed treatment regimen after first six week therapy.
The only clinical role of pre -treatment susceptibility testing is for selection of the best regimen for a patient who is not responding to primary chemotherapy, but the culture susceptibility testing in case of primary treatment failure is of paramount importance and essential from any point of view.
So the acumen of clinical competence depends upon a reliable laboratory backing. Ideally susceptibility tests should not be done only if the reliability and consistency of their result can be guaranteed by careful standardization and quality control. Susceptibility testing is of vital utility especially, one in research to elucidate the mechanisms of drug action & two to study the epidemiology of drug resistance in a community so that anti-tuberculosis programs can be planned and three to determine the pattern of acquired resistance to guide retreatment of patients whose primary chemotherapy has failed.
Among the more common errors that contribute to the evolution of multi drug resistance is failure to recognize and cope with non-adherence in a timely manner, failure to identify an individual at high risk for pre-existing drug resistance resulting in use of an inadequate initial regimen. It is vital that clinicians realize that responsibilities are not complete when they have established the diagnosis and initiated chemotherapy for their patients. Contact investigation of the home, work place, school or other congregate facilities may well reveal active cases or newly infected persons who are at substantial risk for TB. Priority must be given to investigation where infants or AIDS patients have been exposed due to their compressed incubation period for potentially lethal forms of tuberculosis. Certain groups within the infected population are at greater risk than others e.g., persons with HIV with newly diagnosed infectious tuberculosis, recent converters, persons with abnormal chest radiographs that show fibrotic lesions likely to represent old healed tuberculosis, intravenous drug users known to be HIV sero-negative, persons with medical conditions that been reported to increase the risk of TB especially in case where immune system is as stress like in Diabetes Mellitus.
A number of practitioners from various streams of medicine with doubtful competence to treat a disease syndrome like tuberculosis, Diabetes, Coronary Artery Disease or any other congenital Heart-Disease of young stressing human in immune defense system with tuberculosis, second opinion of a specialist physician must be sought in these types of cases. A better co-operation and co-ordination is mandatory between public and government medical and healthcare system.
Finally some solutions are offered. Fear, without potential mitigating solutions, can be very volatile. It has throughout history, prompted life -long imprisonment of the victims of a disease. Perhaps less onerously, it can lead to inappropriate expenditures of money and human resources aimed at staving off a real or imagined enemy. What is required overall is a new paradigm in the way people think about disease. Rather than a view that sees humanity’s relationship to the microbes as a historically linear one, tending over the centuries toward-ever-decreasing risk to humans, a far more challenging perspective must be sought, allowing for a dynamic, nonlinear state of affairs between Homo-sapiens and the microbial world, both inside and outside their bodies. “We must embrace complexity, seek ways to describe and comprehend an ever-changing ecology we cannot see, but nonetheless, by which we are constantly affected”. Preparedness demands understanding. To comprehend the interactions between Homo-sapiens and the vast and diverse microbial world, perspectives must be forged that meld such disparate fields as medicine, environmentalism, economic development, cultural anthropology, human rights law, entomology, virology, bacteriology, evolutionary biology and epidemiology. Nature isn’t benign.
The bottom lines; the units of natural selection-DNA, sometimes RNA elements are by no means neatly packaged in discrete organisms. They all share the entire biosphere. The survival of the human species is not a preordained evolutionary program. Abundant sources of genetic variation exist for microbes to learn new tricks, not necessarily confined to what happen routinely, or even frequently.
Now the time has come to retrospect. A sincere introspection is needed to analyze the factors responsible for the failure of National Tuberculosis Program of 1962. We can’t move ahead unless we are ready to learn from are past mistake. Medical Science is a continuous phenomenon and there is no hope for personal inhibition, ego and prejudices. Explosion of AIDS, and the saga of endemic malaria; the unconquered parasite, are example lessons to be learnt for medical scientist in India. And tuberculosis is no exemption.
There is a plenty of good medical talent in private sector, and I think it will not be a bad idea to involve some willing personal from private medical sector to evolve a viable and effective strategy to control tuberculosis and other mycobacterial diseases. People responsible to implement RNTCP (Revised National Tuberculosis Control Program) must endorse the views of independent thinker physicians and must accommodates their views in their policies and planning, rather than imposing there self- satisfied ideas. Their bureaucratic attitude has done enough damage; now the crisis has deepened enough that they ensure to take entire fraternity in proper confidence.
There is not much difference between RNTCP from old National Tuberculosis Program, except that the drug supply has been made compulsorily incessant under RNTCP, and the compliance accountability has been bestowed in DOT (direct Observation Therapy) providers; again an idea lifted from the lady volunteers working in slums in New York. This is a good omen.
But to rely on only first five drug regimen is not enough to check-mate the mycobacterial problem. There may be financial constraints on account of public health with Governments of India, but the minimum facility of culture and susceptibility testing cab be provided; so that the resistant cases can be isolated, first to prevent them from spreading mutant lethal strains to healthy and immuno-comprised patients and second to stop unnecessary administration of useless drugs thus curtailing useless expenditures. Once aware of their health status, MDR-TB patients can try to avail the best possible therapy at their own expense, if they can afford.
Under RNTCP, number of laboratories and treatment centers has been increased. More advanced drugs to treat drug resistant have been made available including the latest ones like Bedaquiline, Pretomanid, Delamanid apart from Rifabutane, Rifapantene, Ethiomide, Protheomide, Cyclocerine etc: though inevitable doubt keep on persisting that how long and for how many patients government can maintain the continuous supply. Moreover, supply of sub- standard molecules made locally using Reverse Transcriptase method will not made tentative incursion and then continuous supply will not replace the standard quality in connivance of politicians and administration. Therefore these reserved drugs effective in curing drug resistant tuberculosis patients need to be protected from misuse.
Secondly but most importantly, only 38% of tuberculosis patients demonstrate Acid Alcohol Fast Bacilli in their sputum. Moreover the inability of general pathologists to identify beaded or bamboo structured bacilli is an additional problem in effective control of Tuberculosis infested population.
Therefore, this undue emphasis to be sputum positive for a patient to avail treatment is useless and unscientific policy. Disease syndrome caused by mycobacterium species are highly misnomer and sticking to a rigid policy is virtually harmful. It has to be diagnosed with high clinical acumen and sometimes only clinical evaluation of mycobacterium diseases is much more precise than the rigid criteria of being sputum positive as in RNTCP is going to be as futile an exercise as National TB program in past. Moreover, mycobacteria are extremely rare to be found in case of extra-pulmonary disease syndrome, though extra pulmonary diseases syndrome, though extra pulmonary diseases caused by mycobacterial species are not that contagious as pulmonary diseases are, but the overall epidemiological impact can be not be ignored.
Physicians of substance can be identified and invited on a long terms basis from private sector in evolving an effective policy for treatment and TB eradication program. These physicians should be entrusted to manage the complicated pulmonary and extra-pulmonary tuberculosis as well as atypical mycobacterium disease syndromes in their respective area of working. These second and third generation Anti-TB drugs should be prescribed by selected physicians only, because protection of second and third generation molecules in treatment of tuberculosis and in atypical Mycobacterium infections is mandatory. It is a specialized medical job. Indiscriminate use of second and third line drugs will render these molecules microbe resistant like the first generation drugs.
Unless misuse or under use or quackery with anti-tuberculosis drugs are not controlled by making tuberculosis a compulsory referral disease, I don’t see any viable solution to control the TB menace, especially in XDR-TB cases, forget about eradicating it.
One can’t take solace in saying that TB is predominantly a disease of slums and poor. The population living in slums, below poverty line interacts with every class of society every day in various spheres of life activities, thus exposing any one to the lethal mutant strains of XDR-TB. The most important points of vulnerability in the public health system are that the individual who failed therapy could become carriers of chronically active XDR-TB cases for a life time.
For further questions/ comments/ critique:
Contact: drrakeshshrivastava@gmail.com or call at 091 – 0755- 4254542, 4249973, +919893054254
