Indian Journal for the Practising Doctor

Gaash, B

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Dr Bashir Gaash, MD, Phd, DCH, is a public health practitioner with a particular interest in emergence of resistance to commonly used antibiotics
Contact: Cell: 9419089018
Email: gaashb_10(at)yahoo.co.in

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Pharmaco-epidemiology, among other things, monitors trends of antibiotic use and the emergence of resistance to commonly used antibiotics. In our place, the concept has not taken up yet and rampant misuse of antibiotics is a rule, with dramatic emergence of multi-drug resistant typhoid, pneumonia, urinary tract infection, reproductive tract infection and nosocomial infections. Here we discuss the problem in an international and Indian perspective.

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Introduction

The accidental discovery of the first antibiotic by Alexander Fleming¹ in 1928 revolutionized the therapy of infection, and saved millions of lives especially during the two World Wars. The dramatic impact was attributable to lack of primary resistance among microbes and scarcity of antibiotics with a high cost which necessitated extraordinary prudence in their use.

Then came a time when, with progressively falling costs and increasing availability of antibiotics, prescribing became less judicious. The global pharmaceutical industry was quick to take advantage of the declining costs of production, expanding world markets especially in developing countries, and gullibility of the prescribers. Every week a new antibiotic started to be pumped into the market leaving no time for doctors to fully get acquainted with new products while, at the same time, providing ample chances to microorganisms to develop different means of resistance to guarantee their survival.

Global scenario

Currently, antimicrobials are the most widely used category of drugs in the world. In 2004, the World Health Organization reported the figure for unwarranted antibiotics prescriptions standing at roughly 50%. Overuse and misuse of antibiotics was particularly high (50% to almost 100%) in upper respiratory infections, most of which are generally viral and self-limited. A WHO study of antibiotic use in 13 low-, middle- and high-income countries from 1992 to 1996 revealed that antibiotics were wrongly prescribed for approximately 30% of cases of URTI. Studies have revealed the existence of compulsive antibiotic prescribing all over the world³.

Developed world: Contrary to expectations, antibiotic misuse and overuse is common not only in developing countries but also in the developed world. A large study in the USA found that 51% of patients with colds and URTI were receiving antibiotics and estimated that over 20% of all antibiotic prescriptions were clinically useless⁴. In addition, it was found that only 20-25% of antibiotic use in USA was based on the results of culture and sensitivity tests.

A 2003 article by Ronning et al⁵ reviewed antibacterial usage in 16 European countries. This study demonstrated that the antibiotic use was higher than required, largely irrational and generally empirical. In Italy, a mere 2% of antibiotic use was determined by culture and sensitivity. A European study presented at the 14th European Congress of Clinical Microbiology and Infectious Diseases held in Prague in May 2004⁶ reported that 36% of the children with symptoms reported use of antibiotics within 2 weeks, most frequently for acute respiratory infections (ARI) and diarrhoea-like syndromes.

In Australia, it was found that, even with ‘antibiotic guidelines’ in place, less than 50% of antibiotic treatment in the wards of teaching hospitals in Melbourne complied with the recommendations. In far-flung centres in that country, more than 90% of surgical prophylaxis was found to be inappropriate⁷.

The situation of drug overuse or irrational use in developing world is particularly alarming.

China: A comparative study of antibiotic use in 35 countries showed that the overall rate for the use of antibiotics for upper respiratory tract infection in 1997 was as high as 97% in China⁸ Multicentric studies showed that over 70% of patients were prescribed antibiotics in Indonesia and Pakistan.

Indonesia: A WHO-World Bank supported study found an antibiotic overuse of 43% in Indonesia. While only 46% of the under fives received oral rehydration salts (ORS) for the treatment of diarrhea, 73% of them received oral antibiotics. For patients aged over five years, the respective figures were 36% and 91%. In terms of mild upper respiratory infection treatment, 75-86% of patients received antibiotics.⁹

Pakistan: In Pakistan, the average number of drugs per prescription was 3.5, with antibiotics accounting for 76% of the prescribed drugs. Almost 75% of antibiotics were given by injection. Even at the rural health service levels, antibiotics were prescribed to 78% patients, 74% receiving them parenterally. The antibiotic prescription frequency in case of children aged 1-15 was as high as 84%.¹⁰

The over-prescribing of antibiotics and injections is confirmed by the breakdown of prescribing for the 10 most frequently diagnosed diseases (Fig 1), which also reveals gross irrationality in antibiotic prescribing.

Fig 1: Most frequent indications for antibiotic use in Pakistan¹⁶

Nepal: In Nepal, over 50% of antibiotics prescribed in 1996 were found to be unnecessary. Studies performed between 1997 and 199911, 12 reported a prevalence of 61% antimicrobial use in intensive care units. Results of studies performed in 2004-0513 were no different. Analysis of prescriptions showed that 50.2% of the patients received an antimicrobial, and that 84.5% of the antimicrobials were used without obtaining bacteriological evidence of infection. Combination therapy was not uncommon: the prescribing frequency of combination antimicrobials was 14.6%, of which 84.4% of the combination prescriptions were for ampicillin + cloxacillin. Almost 62% of the antimicrobials were prescribed by the parenteral route. Almost 30% of the antibiotics prescribed were for lower respiratory tract infections, mainly for COPD followed by pneumonia.

Approximately 71% of the patients receiving an antimicrobial were from the medical side while 29.5% were surgical patients.

Antimicrobials were used for prophylaxis in 30.9% and for non-bacteriologically proven infection in 51%. The most commonly prescribed antimicrobials were metronidazole, ampicillin, combination of ampicillin and cloxacillin and gentamicin. This profile closely resembled that used in Pakistan.

Studies on prophylaxis showed metronidazole, ampicillin+cloxicillin, gentamicin, ampicillin and cefotaxime, in that order, to be the most frequently prescribed antibiotics. It is noteworthy that prophylactic use of antimicrobials has a very high potential of easy abuse and overuse with consequent costly and dangerous implications.

Retrospective analysis of case records showed that, in 26.2% cases, the use of the antimicrobials was irrational. Common examples of illogical prescribing were prescription of a third generation cephalosporin where a cheaper antimicrobial would have been satisfactory, use of a cocktail of antimicrobials with overlapping spectrums for abdominal infections, and use of antimicrobials in cases of cerebrovascular accidents, acute confusional states, etc. Costly antimicrobial combinations and newer antimicrobials were used where an older antimicrobial would have worked satisfactorily.

A study of antibiotic practices in 35 countries of the world14, 15 presented at the 1st International Conference for Improving the Use of Medicines (ICIUM) in Thailand held in 1997 showed that, on an average, 45% of patients were prescribed antibiotics (Half of them parenterally). However, in Indonesia (1990), Pakistan (1998) and West Bengal, India, (1999) rates in excess of 70% were observed. Analysis of data from Uzbekistan, Pakistan, Indonesia and Eritrea revealed that 75%- 99% of patients diagnosed with an upper respiratory tract infection (URTI) received antibiotics.

In Eritrea, for example, it was confirmed that 75% of the adults and children diagnosed with URTI were prescribed antibiotics even though the cause of the infection may have been viral.

Fig 2: Results of a 35-country study – Percentage of patients receiving antibiotics

Oman: Study of sub-speciality prescribing at hospital facilities in Oman (Muscat and Dhofar) revealed that 14-29% of patients were prescribed antibiotics. Suburban PHCs revealed a frequency of 21-23% and urban PHCs 25%. The highest antibiotic prescribing was seen in medical and ENT sub-specialities. The methodology used a large sample size of 600 prescriptions per facility. Antibiotic utilization studies in Sudan and Jordan showed that the respective percentage of prescriptions involving antibiotics was as high as 63% and 60.9%. The comparative figures for Nigeria (48%), Zimbabwe (29%), Lebanon (17.5%) and Yemen (46%) were lower.^17-21

Uzbekistan: Studies in Uzbekistan2²² found that at least 21% of prescriptions contained an antibiotic. The respective frequency of antibiotic prescribing for upper and lower respiratory infections was as high as 93.5% and 78.9%, of which 79% and 54.8% were given by injections. Significantly, 30.2% diarrhoeal patients were prescribed antibiotics along with other largely unnecessary drugs.

Peru: In Peru, a study²³ conducted jointly by IHCAR, Karolinski Institute (Sweden), Institute of Tropical Medicine, Peru University, and University of Florence (Italy) showed that 71% of 6-72 month old children receiving antibiotics had their antibiotics prescribed by a health care professional, 8% had consulted a pharmacist and 19% had selfmedicated without consulting a health care supplier. It was surprising to find that children whose caregivers have consulted a health care provider were more likely to be treated with antibiotics than children who had been exclusively self-medicated by their caregivers. About 28% of the children with upper ARI-like symptoms were treated with antibiotics. A higher percentage of the children with ARI-diarrhoea mixes (38%), lower ARI (50%) and diarrhoea (44%) received antibiotics.

India²⁴: Being a populous country with rampant corruption and lax controls, India is an ideal country for multinational companies to pump in their newly developed but poorly researched drugs including antibiotics.

Utilization studies and prescription audits in Goa have shown that antibiotics constitute about 39% of drugs prescribed to outdoor patients²⁵; 30% in indoor perinatal patients²⁶; and 22% in rural hospitals²⁷.

Medical activists in India have been raising their fingers at the rampant misuse of antibiotics for quite sometime now²⁸. Overprescribing of antibiotics has been widely reported^29,30 The use of single injection of tetracycline to a febrile child has been highlighted even in the press.³¹

A recent survey in Goa revealed that polypharmacy was the norm, with 80% of prescriptions having more than one medicine, (many patients receiving 5 or more preparations simultaneously). Antibiotics (with analgesics) were included in almost a quarter of prescriptions32. The average frequency of antibiotic prescribing in the neighbouring Pune was found to be 43%³³.

In a north Indian study of 2400 prescriptions, antibiotics were found to be widely and inappropriately used by practitioners³⁴. A study of 2953 prescriptions from PHCs in south India revealed that patients received an average of 2.71 drugs and that antibiotics (with analgesics and antihistamines) were the most commonly used drugs accounting for more than 80% of the drugs prescribed²⁹.

In Andhra Pradesh, 60% of drugs (particularly antibiotics and vitamins) prescribed in rural areas and 47% of them in urban areas, were non-essential, compared to 47% in urban areas³⁵.

Studies also revealed that in the majority of cases antibiotic prescribing was empirically directed at the putative site of infection. Since the meager culture facilities are available in a very small number of hospitals in India, empirical antibiotic use is rampant³⁶. The distressing fact is that where these are available, they are infrequently requested and when advised, often the results are not considered for decision making.

Although antibiotic use is rampant in medical outpatients and wards, surgeons don’t lag behind. In spite of several available guidelines for the appropriate use of antimicrobials in perioperative patients, the fear of high morbidity and mortality associated with intra-abdominal infections and surgical site infections has led to misuse of antimicrobials in the perioperative period. Studies³⁷ show that the third/fourth generation cephalosporin plus an anti-anaerobic agent were preferred (84% cases) for treating intraabdominal infections. Approximately 55% of the surgeons prescribed a single antibiotic for clean surgeries. A combination of two or three antimicrobial agents was preferred in clean contaminated (42.3%) and dirty (46.9%) surgeries respectively. Third generation cephalosporins (particularly ceftriaxone and cefotaxime) were the commonly prescribed antibiotics (80%) for all surgeries. However, in majority of cases antibiotics were prescribed for durations longer than recommended in standard guidelines.

A recent (2007) study at the Jawahar Lal Nehru Medical College, AMU, revealed that the most commonly prescribed drugs by general surgeons were antibiotics (93%) – mostly ceftriaxone and amikacin. (Salman MT et al. Drug Prescribing Pattern in Surgical wards of a Teaching Hospital in North India. Ind J Pract Doctor 2008;IV(5):5+

Unnecessary medication: Globally, the figure for unwarranted antibiotics prescriptions stands at roughly 50%. According to figures gathered by surveys presented to WHO in 2000, about 60% of antibiotics in Nigeria were prescribed unnecessarily. In Nepal, over 50% of antibiotics prescribed in 1996 were not needed and 40% of medicine expenditure in the same year was wasted due to inappropriate prescriptions. Retrospective analysis of case records in Nepal in 2003 showed that, in 26.2% cases, the use of the antimicrobials was irrational

The World Health Organization pointed out that nearly 2 out of every 3 antidiarrhoeal preparations sold in 12 countries in Latin America in 1990 contained an antibiotic. Similarly, a survey carried out in 1989 showed that nearly one out of two antidiarrhoeal products in Third World countries contained an unnecessary antibiotic.

The conclusions drawn at the consultative group discussion²³ in Peru were that the results suggested ever increasing potential of irrational use of antibiotics for children, including short courses, over-prescribing, and self medication.

In a north Indian study of 2400 prescriptions, antibiotics were found to be widely and inappropriately used by practitioners.³⁴

Study of emergency room prescriptions in private hospitals in Manila showed that over 90% of patients who received antibiotics did not really need them.

Side effects: Antibiotics can potentially do the same to the host what they do to the bacterium. For example, trimethoprim can depress folic acid in both the microorganism and the host. Many antibiotics can lead to adverse effects through multiple means: chloramphenicol depresses bone marrow in all the recipients but may drastically do so in a person with idiosyncrasy. A State Food and Drug Administration (SFDA; China’s drug watchdog) survey revealed that nearly 50% of the total side-effect reports from drugs were for prescribed antibiotics. Experts there believe that many of the 20 million people with hearing disabilities in China might be suffering because of the irrational use of antibiotics⁸. In the 1960s and 1970s, nationwide abuse of acheomycin is said to have resulted in damage to the teeth of a generation of Chinese people.⁸

Recently, fluoroquinolones are being blamed for multiple adverse effects which may be long lasting. The sufferers have hosted their web sites to denounce what they call ‘floxing’.

In addition to development of resistance, superinfection may result from overuse or prolonged administration of broad spectrum antibiotics. Many wide spectrum antibiotics are recognized to cause death of the normal intestinal and vaginal flora. Fungal infections are linked to overuse of such expensive antibiotiocs as cephalosporins^37a.

Problem of Resistance: Irrational use (overuse, misuse, prolonged use) of antimicrobials are contributing to growing resistance to treatment for the very diseases that contribute most to the burden of illness in low-income countries. The irrational use of pharmaceutical drugs, contributing to increasing resistance was particularly discussed at the 9-day long World Health Assembly in May 2005³⁸. The World Health Organisation says that anti-microbial resistance is one of the world’s most serious public health problems; a major cause being the wrong use of medicines.

The World Health Assembly in May 2005 warned that the anti-microbial resistance was rapidly increasing, with resistance of up to 70-90% to original first-line antibiotics for dysentery (shigella), pneumonia (pneumococcal), gonorrhoea, and hospital infections (staph. Aureus).

Global antimicrobial resistance prevalence rates:

• Malaria (chloroquine resistance in 81 out of 92 countries);
• Tuberculosis (0-17% primary multi-drug resistance);
• HIV/AIDS (0-25% primary resistance to at least one antiretroviral drug);
• Gonorrhoea (5-98% penicillin resistance);
• Pneumonia and bacterial meningitis (0-70% penicillin resistance in streptococcus pneumonia); diarrhoea: shigellosis (10-90% ampicillin resistance, 5-95% cotrimoxazole resistance);
• Hospital infections (0-70% resistance of staphylococcus aureus to all penicillins and cephalosporins).

WHO country data 2002-03

On a global scale resistance to penicillin treatment was estimated to be between 5% and 98% for gonorrhoea and between 12% and 55% for pneumonia and bacterial meningitis^39,40

In Bangladesh⁴¹, resistance to ampicillin in the treatment of shigellosis diarrhoea is estimated to be over 90%. In addition, resistance to treatment with nalidixic acid increased from less than 10% in 1987 to over 90% in 1992.

Overuse of chloroquine for the treatment of malaria led to widespread resistance which is now established in 81 of the 92 countries where the disease is endemic – substantially raising the costs of treatment with second- and third-line antimalarial medicines⁴². This was a matter of great concern at the 2nd International Conference on Improving Use of Medicine (Chang Mai), sponsored by WHO, the Thai Network for Rational Use of Drugs (ThaiNRUD), Management Sciences for Health, the Centre for International Health, Boston University School of Public Health; Harvard Medical School and the International Network for the Rational Use of Drugs.

Economics of Antibiotic Overuse:

Currently, antimicrobials are the most widely used category of drugs in the world, accounting for over one-quarter of hospital drug costs2.

Studies found in Indonesia that, in terms of cost, antibiotics ranked highest, followed by cough and cold medicines, and analgesics. Drugs for the treatment of diarrheal diseases and respiratory conditions accounted for 68% of all under-five health centre drug costs and 38% of all over-five drug costs.⁴³ The observed treatment cost was Rp. 512 per case (4 times the expected cost). Antibiotics accounted for 60-63% of URI treatment costs.

About 40% of medicine expenditure in Nepal in 1996 was wasted due to inappropriate antibiotic prescriptions. Such avoidable wastage has great implications for an economically weak, resource-poor country with a high burden of infectious diseases.

Drugs in the present day world have come to mean money for the manufacturer as well as prescriber and retailer. According to the WHO, the global sales of prescription drugs in 2000 were $282.5 billion. This has to be borne in mind that all this money has to come from the pocket of a patient, who is often poor and financially drained, or from the resource-less governments of poor countries, antibiotics and other essential drugs have to be procured at the cost of food, child education and family welfare.

A joint 1992 study by the National University of Malaysia and the Health Ministry conducted at six government hospitals found that, alhough the WHO Essential Drug List recommends only 20 antibiotics, yet there are over 200 antibiotic preparations sold in Malaysia. Thus, it does not surprise to learn that the 1993 imports of antibiotics cost the country over RM85 million (up 100% since 1982) – with penicillins taking up 28% of the total. Antibiotics made up 14% of all medicinal and pharmaceutical products produced or imported into that country.

In Australia, drug companies spend A$200 million every year just to market their products. The sum represents almost A$10,000 a year spent on attempting to win each of Australia’s 21,000 GPs. This is 50% more than allowed by law in the UK for marketing.

In Japan, there are an estimated 43,000 drug salesmen and almost as many wholesaler representatives. An average Japanese doctor receives 450 sales calls a year. Returns for drug companies are enormous: In 1988, Japan’s market for injectable antibiotics amounted to about £1.7 billion; cephalosporins accounting for 71% of the total compared to about 24-55% in the US and Europe.

In Britain the pharmaceutical industry also realises the importance of bringing new products to the attention of GPs. As a result, about two million visits are paid by sales representatives, with the average GP receiving some 62 visits a year.

To top them all, drug promotion costs in the US were $15.7 billion in 2000. This far exceeded the entire WHO budget in that year to discourage aggressive drug promotion.

The aggressive campaigning by pharmaceutical companies has paid off. Data on trends in medicine use show that globally the average number of drugs used increased from 1990 to 2003 from 2.2 to 2.7 per patient between 1990 and 2003. Only 40-50% of patients were treated in compliance with standard treatment guidelines; in other words 50-60% of antibiotic use in the world is either because of our innocence or the drug companies’ shrewdness.

Quinolones (fluoroquinolones) which are among the latest antibiotics to be developed in the 1980s, accounted for 15% of the world antibiotic market in 1990. Americans spend US$700,000 a day on just one type, ciprofloxacin. In 1989, ciprofloxacin was the 4th most commonly prescribed antibiotic in the US – with over 5 million prescriptions at a cost of US$248 million. The sales soared only because of heavy promotion. In the first half of 1988, ciprofloxacin was the 2nd most advertised product.

A WHO Expert Committee has suggested that a reserve list of fewer antibiotics like the thirdgeneration cephalosporins, quinolones and vancomycin be set aside for specific indications such as infections caused by organisms resistant to standard drugs and not be available for unrestricted use. However, the former two products are widely used as first-line antibiotics by doctors including specialists in private practice.

The cost of excessive promotion is met by huge profit margins of life-saving drugs like antibiotics. According to WHO, profit margins for expensive drugs like cephalosporins make up a large part of a hospital’s income in developed countries. The value of this discount scheme is estimated at £7 billion each year!

The promotion for medicine, especially antibiotics, according to the Research Institute for Tropical Medicine, Manila, is heaviest in developing countries⁴⁴. This, on the one hand, increases the cost of drugs, particularly antibiotics, and on the other hand, puts the prescriber under social or economic pressure to unnecessary use of the adverstised antibiotics.

According to the Working Group on Health and Development (WEMOS) in Amsterdam, 75 products (including many antibiotics) which had been pulled out or banned in one or more European countries were identified in the Third World in 1991. This proves that multinational companies forced to withdraw certain products considered to be dangerous, ineffective or unnecessary turn to the developing world for profiteering. They resort to aggressive campaigning to make up for their loss of business in the developed world.

Though WHO has come out with an Essential Drug List (EDL) of 250 preparations, in India alone the drug market has 70,000 preparations. Most of these drugs comprise of antibiotics, vitamins and anti-inflammatory analgesics.

Jammu and Kashmir State is a considered a huge consumer of drugs, required or not. One guess puts the number of drug companies operating in the State at a whopping 9000!. People of Kashmir Valley are particularly fond of medicines, and have been made habitually tolerant to polypharmacy.

An average prescription has 4-5 different drugs. Antibiotics are prescribed freely, and in absence of Drugs and Cosmetic Act, can be purchased from any pharmacy at will. Majority of children still receive one or two antibiotics for diarrhea, though ORS use has not been more than 38%⁴⁵. All cases of ARI are managed by giving the latest antibiotics. Doctors compete with each other in prescribing the most recently introduced, albeit very costly, antibiotics. Often the freshly introduced antibiotic is prescribed within the first 10 minutes of introduction. Salesmen (called medical representatives) try all means to fulfill their sale targets, and more often than not the doctor may not even get a chance to go through the company leaflet describing the prescribed drug.

The doses are often substandard and durations shorter or much longer than those recommended. The consequences have been the rapidly increasing resistance among commonly found organisms. One study⁴⁶ conducted by us found that majority of the uropathogens had already developed resistance to most commonly used drugs including norfloxacin, co-trimoxazoile, and ampicillin. Multi-drug resistant community-acquired pneumonia and typhoid are common in the Valley.

Drug prescribing in Kashmir has taken shape of a racket where every stake holder, except the patient, is benefitted. Promotion is vehemently aggressive, and the nexus between pharmaceutical companies and the prescribers is keeping the environment favourable for flourishing substandard drug (called here Number 2) trade.

There is an urgent need to enforce the Essential Drug List of the WHO in public as well as private medical practice. The Government must take the lead by purchasing generic drugs for hospitals and peripheral health outlets. Private medical setup will either follow or can be made to fall in line through legislation and legal enforcement.

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