A REQUIM FOR ANTIBIOTICS
By
Dr. Gladstone A.D’COSTA
Member, National Executive Committee, Voluntary Health Association of India
The Lancet of 11th August 2010 reported that a bacterium resistant to all antibiotics had been identified and the inherent dangers of such bacteria were described. The origin of the bug was stated to be, at least in part, in India and the opinion expressed that “NDM-1 will likely spread worldwide.”
The Lancet is not a journal to be taken lightly; but the resultant uproar in this country focussed largely on the organism being named after Delhi, thereby missing the wood for the trees. The serious implications of the findings were lost in the cacophony of protest that followed; but the noise had barely died down when a new threat emerged. Researchers from Spain have tied up with SGPGI, Lucknow, to study yet another resistant organism; this time, it was salmonella (with the rmtC gene), which can cause severe diarrhoea and death. Once again the organism was found in patients most of whom had recently travelled to India. A further complication came from a Chennai study; an organism had been identified with both the NDM1 and the armA (which is similar to the rmtC) genes; which is serious because the organism is also resistant to all known antibiotics.
Recently there was a spurt of upper respiratory tract infections along the west coast, including Goa, which caused an irritating dry hacking cough which lasted in some cases, for weeks. Most physicians felt it was a viral infection, though to my knowledge no specific causative organism was identified. Yet the sale of azithromycin (an antibiotic) in one pharmacy alone doubled between mid- December and mid-January at the peak of such cases. This incident illustrates the attitude of both patients and physicians in their approach to the use of antibiotics. Patients expect a prescription for antibiotics, indeed often demand it even when there is no justification for it; and physicians are more than willing to prescribe it to “keep the customer happy.” The process of identifying the cause of the infection is too time consuming, expensive, and often inconclusive. Hence a best guess choice (often choices) is made by the physician. If there is no relief within a few days, either the antibiotic or the doctor is changed. Paradoxically such overuse is often matched by under-use. If the patient feels better in a few days, treatment is stopped prematurely for financial reasons. Hence the outburst by Abdul Ghafur in the Lancet “The overuse of antibiotics is embedded in our Indian gene. Why should we Indians worry? We can always depend on honey, yoghurt and cow’s urine. At any rate within a few years, these products may be more useful than antibiotics!”
Antibiotic resistant infections cause an estimated 100,000 deaths annually in the US alone, and are predicted to rise even further. This alarming situation has developed within a span of 60 odd years since penicillin was first introduced. How is it that after the initial advantage in the battle against infections, we are now in danger of loosing the war? After all, NDM-1, rmtC, and armA will join a growing list of resistant organisms headed by MRSA (Methicillin Resistant Staph. aureus). In the past, resistant strains did not matter because research by pharmaceutical companies produced newer and more potent antibiotics. An estimated 200 new drugs were developed in 30 years, each more potent and toxic than the previous one.
Eventually hard economic realties hit the industry. In the period 1983-1987, 16 totally new drugs (as opposed to minor molecular variations) were approved. Since 2008 there have been only two. Only 5 of the 13 biggest pharmaceutical companies are actively engaged in antibiotic research; the rest have abandoned the field for more lucrative markets. This is certainly not because of lack of knowledge, expertise or clinical material. Deep sea exploration has turned up organisms that we never new existed.
The explanation lies in the balance sheets.
When a new antibiotic is introduced, it is patented, and restricted to difficult infections in an attempt to preserve its efficacy. Sales figures naturally remain suppressed, till the patent runs out or the physicians start overusing the drug against all rational recommendations. Further, when used judiciously the drug is usually prescribed for short periods like a week or two. Compare that with a new anti-cancer or anti-diabetic drug; the drug is used widely as soon as it is introduced and for months, years, or the rest of the patients life. The sales returns for such drugs can be up to twenty times the sales figures for antibiotics. In short it pays to research and introduce drugs for chronic diseases, rather than antibiotics; even though infections are more common than cancer, diabetes or heart disease.
A further disincentive is the research restrictions. The conditions under which penicillin was introduced were dramatically different from the FDA restrictions of today. There were no such rigorous stipulations such as double blind studies or placebo controls. Today, the drug has to be tested in a sufficient number of patients to qualify for acceptance. In severe and rare infections, this is not always practical or feasible. Further it has to be tested against a known remedy to prove an advantage. Vancomycin resistant enterococcus infections of the bowel and urine, is thought to affect 26,000 hospital patients annually in the US according the Centre for Disease Control and Prevention. However, research was abandoned because of inadequate sample sizes and clinical material.
Yet when there are adequate financial incentives, there is no dearth of initiative, ingenuity or talent. As a result of the anthrax scare in 2001, there was a huge spurt in research in anthrax even though most practicing physicians have never seen a case in their entire clinical careers. The National Institute of Allergy and Infectious Diseases spent $94 million in 2009, researching anthrax and plague; because they were potential agents of bioterrorism. In contrast only $16 million was spent researching antibiotics for resistant infections. Such financial enthusiasm was feasible only because the government guaranteed purchase of any approved final product, as part of its counter-terrorism campaign.
If we are to prove Abdul Ghafur wrong when he predicted a day when honey, cows’ urine and yoghurt will be more effective than antibiotics, we will have to change our mind-set and implement what the BMJ terms “antibiotic stewardship programs”. Our future survival depends on it because antibiotics will gradually get more expensive and have an ever decreasing spectrum of utility. The initiative must come from both the physician as well as the patient. Prescriptions have to be more rational and evidence based. Numerous studies have established that between 20- 50% of antibiotic usage is inappropriate by virtue of the drug, dose, duration or redundancy. Public education programs must sell the concept that patients are doing more harm than good by demanding antibiotics, or changing doctors and/or antibiotics willy nilly. The authorities must come down more dramatically and heavily on unauthorized over the counter sales of scheduled drugs whose unbridled usage contributes to the problem. Finally there must be adequate incentives provided for exploring alternative pathways for research by the pharmaceutical companies such as tax breaks, increased patent period discretion and guaranteed sales to encourage continued research. There are newer pathways like using other organisms, just waiting to be developed.
Otherwise we really will have to depend on cows’ urine in the foreseeable future.
