The perils of irrational antibiotic use
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Mumbai: When the BMJ presented its 2014 best medical team of the year award to doctors of a Mumbai-hospital run by Fortis Healthcare Ltd for its antimicrobial stewardship programme, the prestigious UK medical journal was honouring an achievement all too rare in India.
For some five years, the team at Fortis Hospital at Mulund in Mumbai had rationalized the use of antibiotics to control microbial resistance, a phenomenon that has emerged as a serious concern in the medical world.
Unfortunately, the initiative by Fortis Healthcare was just an isolated case in a city that has reported the highest number of multi-drug-resistant tuberculosis, or TB (7,483) and hospital-acquired infection (23,000) cases in the past four years in India. The numbers for the rest of India are equally dismal.
Uncontrolled use of antibiotics in food and for treating diseases is rendering many of these medicines ineffective to prevent infectious diseases. The key culprits are a faulty treatment regime, lax regulations on medical practice, availability of irrational drug combinations in the market, and the greed of the food and drug industries, experts say.
Doctors are left with no options to control infectious diseases caused by drug-resistant bacteria or superbugs; inadequate measures to handle these patients in the community and hospitals cause the infections to spread rapidly. And awareness of the severity and magnitude of the problem remains low.
“Microbial resistance to standard antibiotic treatments is one of the biggest medical crises that the country is facing now, and all stakeholders including doctors, the drug industry, regulators and even patients are equally responsible for this unfortunate situation,” said Vijay Yewale, president of Indian Academy of Pediatrics (IAP), which has been holding a series of workshops for paediatricians and family physicians on the rational use of antibiotics.
The country’s first official circular on this was issued by the Central Drugs Standard Control Organization (CDSCO), the drug regulator, only in 2012. This circular, which cautioned about development and spread of antimicrobial resistance due to overuse and misuse of antibiotics, had estimated that 70-80% of prescriptions for antimicrobial drugs were probably advised unnecessarily by healthcare providers.
Antibiotic resistance is the ability of a microorganism—bacteria, fungi, parasites and viruses—to withstand the effects of an antibiotic. Since no new antibiotics are yet available in the market to kill the stronger microbes, judicious use of existing drugs and efficient management of already reported resistant cases are key to controlling the risks.
“Antibiotics are a precious weapon in our arsenal against infectious diseases,” said Aditya Vij, chief executive officer of Fortis Healthcare. “We need to conserve them through controlled use and pay utmost heed to the dictum: the right drug for the right bug.”
Except in a few hospitals, the situation hasn’t changed much in the country. India’s public healthcare system, including the premier medical institutions, and the huge number of regional hospitals and primary health centres, is neither equipped to handle the crisis, nor fully aware of the risks.
WHO’s latest Antimicrobial Resistance: Global Report on Surveillance, released in February, highlighted that the information on resistance surveillance received from some 129 member countries showed very high rates of resistance in bacteria that cause common infections, including urinary tract infection and pneumonia, among others.
The WHO report also said that multi-drug resistant TB is a growing concern in many countries. Other highlights of the report were identification of spreading bacterial resistance to artemisinin (a comparatively newer drug to treat malaria) and increasing levels of transmitted anti-HIV drug resistance.
Latest surveillance data has established that at least seven microbes that cause the most common infections in communities or hospitals or through the food chain have developed resistance to standard treatments involving antibiotics such as cephalosporins, fluoroquinolones, carbapenems, methicillin and penicillin.
These seven microbes include E.coli that causes urinary tract and blood stream infections; Klebsiella pneumoniae causing pneumonia, blood stream and urinary tract infections; Staphylococcus aureus that causes wound and blood stream infection; Streptococcus pneumoniae that causes pneumonia, meningitis and otitis; Non-typhoidal salmonella that causes food-borne diarrhoea and blood-stream infection; and Neisseria gonorrhoeae that causes gonorrhoea. These are in addition to the already established resistance of Mycobacterium tuberculosis and certain HIV strains.
National data on bacterial resistance to antibiotics is still not available in India, although efforts at hospitals and various communities have been under way for some time. A draft national policy for containment of antimicrobial resistance in India had recommended various measures including surveillance of antibiotic use in hospitals and the veterinary sector.
The policy, which was drafted in 2011 by a committee headed by the Directorate General of Health Services of the ministry of health and family welfare, had also recommended that all 536 drugs currently grouped under Schedule H (drug to be used in hospitals or under medical supervision) required to be dispensed on the prescriptions of a registered medical practitioner.
In order to put in place separate regulations to check unauthorized sale of antibiotics, the draft policy had also suggested creation of a separate schedule—Schedule H1 under the Drugs and Cosmetics Rules, 1950—to exclusively regulate the sale of antibiotics.
Suggestions included colour-coding of third-generation antibiotics and all newer molecules like Carbapenems (Ertapenem, Imipenem, Meropenem), Tigecycline and Daptomycin; restricting their access to only tertiary hospitals and curtailing the availability of fixed-dose combination of antibiotics in the market. This draft policy is still awaiting approvals.
“General microbial resistance is a much bigger issue in India, and it needs to be looked at from different perspectives, as there are multiple reasons that collectively contribute to this high risk issue,” said Mini Khetarpal, TB control officer at Brihanmumbai Municipal Corporation (BMC), which has tracked the highest number of drug-resistant TB cases in the country so far.
Poor patient compliance
Almost 90% of the reported drug-resistant cases in India might have been caused by irrational or unnecessary use of antibiotics and poor patient compliance, according to healthcare data compiled by various regional disease control agencies and medical associations, including the health wing of BMC and IAP.
While overuse is encouraged by unnecessary prescriptions by doctors and over-the-counter availability of antibiotics, poor patient compliance is caused by patients not completing the dosage or the treatment course and availability of irrational combinations of antibiotics.
“We don’t have any rules for prescribing antibiotics,” said Khetarpal.
“Doctors, especially general practitioners, liberally prescribe various kinds of antibiotics even for conditions such as common cold, infant diarrhoea and allergic cough,” said Yewale of IAP. “This is one of the primary reasons for microbial resistance in patients and it needs to be regulated through a prescription code for doctors.”
Irrational use, unfair trade
The Indian pharmaceutical market has about 2,000 brands of fixed-dose combinations in the antibiotics segment alone. Of these, at least 1,800 brands are irrational in terms of wrong or unnecessary composition of multiple drugs, according to 2007 market data compiled by CDSCO for a proposed ban on such combination brands manufactured by both small and large drug makers.
Fixed-dose combinations are drug formulations that combine two or more different molecules meant for treating different ailments or symptoms in a single tablet or capsule. But in some cases, such combinations may force an additional drug unnecessarily into the patient, which may create resistance, especially in the case of antibiotics.
For instance, there are at least 100 brands of combination of norfloxacin or ciprofloxacin (antibiotics) with metronidazole or tinidazole (anti-diarrhoeal drugs) in the Indian market.
The Indian Journal of Pharmacology had in 2006 reported that these combinations were irrational because a patient suffers only from one type of diarrhoea and using this combination adds to costs, adverse effects and may encourage drug resistance. But these combinations are still sold in the market.
A 2007 proposal by then drugs controller general of India (DCGI) M. Venkateswarlu to ban some 3,000 such combination brands was withdrawn in the wake of resistance and legal challenges from the industry.
“A strong nexus between the drug industry and doctors helps in the generation of a huge number of prescriptions of these brands even today,” said Yewale.
Even several Indian drug brands for combination therapy advised for treating TB using antibiotics such as rifampicin, isoniazid and pyrazinamide have received criticism from the scientific community; faulty combinations result in interaction of drugs within, diluting the potency or affecting the bioavailability of the drug, which leads to resistance.
Drugs in the food chain
Overuse of antibiotics by the food animal industry and veterinary surgeons for better output and treating infections in livestock is another major cause of antimicrobial resistance in humans. Antibiotics are added to animal feed or drinking water of cattle, hogs, poultry and other food-producing animals to help them gain weight faster or use less food to gain weight.
Although late, a June notification by the department of animal husbandry, dairying and fisheries under the agriculture ministry had declared that apart from the primary use for animal treatment, antibiotics are also being rampantly used as a feed premix for regular feeding of poultry and animals.
“This kind of regular feeding of antibiotics has serious consequences on human beings since the residue of these antibiotics accumulated in meat, milk and eggs, when consumed, may develop resistance to these drugs in them,” the circular said.
The agriculture ministry’s notification, which was endorsed by the DCGI, had asked enforcement agencies in all states to discourage the overuse of antibiotics by the industry and veterinary surgeons along with strict instructions to the drug industry to label antibiotics intended to be used in animals with a specific withdrawal period.
Withdrawal period in this context means the time gap required for the slaughter of animals or use of milk or eggs from the species after the treatment.
A July study of the Centre for Science and Environment (CSE) found the presence or high residue of six antibiotics in chicken samples collected from the National Capital Region: oxytetracycline, chlortetracycline, and doxycycline (class tetracyclines); enrofloxacin and ciprofloxacin (class fluoroquinolones); and neomycin (an aminoglycoside).
The Indian Federation of Animal Health Companies says it has always promoted the rational use of antibiotics by the food animal industry.
“Although the overuse of antibiotics in animals and passing off this to humans through meat consumption had been a major concern in the country, this has been under control after strict guidelines from the regulators,” Vijay Teng, joint secretary of the industry body representing veterinary drug makers in the country, and head of the animal health business at Intas Pharmaceuticals Ltd, said in an earlier interview.
CSE, which collected and tested some 140 samples of chicken meat from different areas in and around Delhi, had said the country had no means for controlling antibiotic sales and use in the poultry industry, and hadn’t fixed any limits for antibiotic residue in chicken.
This is the third in a series on antibiotic resistance.