Resisting resistance

By: Satya Sivaraman

Courtesy: Himal Southasian, August 2009

The rampant, often-frivolous use of antibiotics over the past half-century has made us dramatically more vulnerable today. A looming catastrophe … one our planet faces due to long-term human intervention in the natural world … the impacts of which are already being felt … though the real damage lies ahead, the issue could be ameliorated through urgent action to bring about policy and behavioural changes. Surely we are talking about global warming, the hot issue on everyone’s minds these days? No, in fact we are referring to an equally significant though vastly under-discussed threat confronting the world today: antibiotic resistance, the phenomenon of bacteria becoming immune to antibiotic medication.

While global warming is all about the damage wrought to macro-ecosystems by human excess, antibiotic resistance is the story of what we have done over the decades to the world’s micro-ecosystems. It is about the ways in which our entire planet seems to be developing resistance to the presence and activities of the human beings living on it, in the ways in which the largely invisible world of bacteria and viruses have become resistant to our attempts to control them. In other words, while global warming threatens to bring the skies down upon our heads, antibiotic resistance, silent and faceless, is crumbling the ground beneath our feet.

In fact, the problem of antibiotic resistance has been around since the historic discovery of penicillin – the so-called miracle drug – by Alexander Fleming in 1928. Penicillin came into mass production in 1943, and since then numerous classes of increasingly powerful antibiotics have been developed. Prior to Fleming’s discovery, people commonly died of a variety of bacterial infections; by conquering these, antibiotics were quickly established as the cornerstone of modern medicine. Today, from heart surgeries to organ transplants, no major surgical procedure is possible without the use of antibiotics to keep infections under control.

Yet within years of the introduction of penicillin, medical practitioners had already begun to notice that whatever bacterium the drug was supposed to eliminate was beginning to develop resistance. Over time, these bacteria increasingly refused to surrender and die off so easily. While this resistance was initially overcome by the discovery of new and more-powerful antibiotics, today we are faced with a situation in which almost all antibiotics in use have been matched by resistant bacteria. “The growing phenomenon of bacterial resistance is now threatening to take us back to a pre-antibiotic era,” says Otto Cars, an infectious-diseases specialist at Uppsala University, in Sweden. Without effective treatment and the prevention of bacterial infections, Cars warns, we risk rolling back some of the most important achievements of modern medicine.

Irrational, unmonitored

Resistance is a natural biological outcome of antibiotic use. The more we use these drugs, the more we increase the speed of emergence and selection of resistant bacteria, which in turn require newer and more-powerful drugs to control them. Meanwhile, the almost overwhelming complexity of factors influencing antibiotic consumption includes cultural conceptions, patient demands, diagnostic uncertainty, economic incentives, the level of training among health staff and pharmacists, as well as advertising to prescribers, consumers and providers from the pharmaceutical industry.

Studies from some developing countries show that several antibiotics tend to be prescribed at each consultation. The use of broad-spectrum antibiotic agents, as a substitute for precise diagnostics or to enhance the likelihood of therapeutic success, increases the chances of resistant bacteria emerging. In addition, counterfeit and substandard drugs contribute to sub-optimal concentrations of antibiotics, failing to control bacterial populations that are considered a risk factor for developing resistance. Today, it is estimated that over half of all antibiotics worldwide are purchased privately without prescriptions, from pharmacies and even street vendors. “While antibiotics have saved lives when rationally used, they have also resulted in serious adverse affects like producing resistant strains of bacteria, which have unfortunately remained unmonitored,” says Dr Mira Shiva, a veteran public-health activist based in New Delhi. She says the adverse affect of the irrational use of antibiotics has not only created problems for individual patients, but also for the community in general.

Following their success in human beings, antibiotics have also increasingly been used to treat and prevent diseases in animals, fish and plants. Perhaps more importantly, small, sub-therapeutic doses of antibiotics have also been shown to have growth-enhancing effects, and thus for decades have been intensively used in animal-rearing practices. In Europe till a few years ago and North America even today, antibiotic use in the livestock sector constitutes half of total consumption. In addition, according to a study conducted in 1987, more than 90 percent of the drugs used on animals in the US were being administered without veterinary consultation. And whether the patient is animal or human, the effects of such indiscriminate and unmonitored use is very similar. Emerging multi-resistant bacteria from farm animals or antibiotic pollution are then transmitted to humans mainly through the food chain or by direct contact.

Indeed, much antibiotic resistance has come about due to inadvertent ingestion. A potent example comes from earlier this year, when a group of Swedish researchers published findings of their 2006-2007 study of treated wastewater outside Patancheru, an industrial estate in the Indian city of Hyderabad. The water, flowing from the over 90 generic drug factories operating in the estate, contained some of the highest concentrations of antibiotics and other medicines ever found – anywhere in the world. The concentration of pharmaceuticals found in wastewater downstream from the Indian plants, for example, was 150 times the highest levels detected in the US. The Swedish team found 100 pounds of the antibiotic ciprofloxacin alone running down the Iskavagu stream every day. This was a potentially serious situation, given that the villagers use the water for agriculture, and livestock drink from the stream. The surrounding communities could easily become an intense laboratory for the growth and spread of resistant bacteria.

There is inadequate data on antibiotic resistance in Southasia today. However, it is estimated that a large proportion of the over one million young children and infants who currently die of respiratory diseases every year might have been affected by resistant strains of bacteria. Diarrhoea is another major killer in South Asia; in the 1980s, over a thousand deaths took place in West Bengal due to the emergence of resistance to common antibiotics against the diarrhoea-causing bacteria Shigella. Likewise, a few years back stool samples from nearly 8200 individuals in four slums of Karachi, collected as part of a surveillance study, also showed the presence of highly resistant strains of Shigella in almost 400 patients. Up to 89 percent of these were found to be resistant to commonly used antibiotics such as cotrimoxazole and ampicillin. This is no small point: Shigella is now recognised as a major public-health problem in developing countries, with the majority of cases and deaths occurring among children less than five years of age.

The burden of antibiotic resistance is also becoming significant in high-income countries such as England and Wales. Here, researchers have found that the ten times increase in deaths between 1993 and 2005 associated with infections with the common bacteria Staphylococcus aureus, which can lead to blood poisoning and prevent the healing of wounds, was almost completely caused by methicillin-resistant Staphylococcus aureus (MRSA). A recent survey in the US likewise found that, every year, 126,000 patients are hospitalised with MRSA infections, of whom about 5000 eventually die from the bacterium. Treatment and care for these patients is thought to cost more than USD 4 billion every year.

Potent commons

For many years, society’s medical needs for antibacterial drugs were met by the pharmaceutical industry, and the apparent symbiosis between the interests of the community and those of the industry prevailed. Today, we see a completely different scenario. While existing antibiotics are losing their effect at an alarming pace, the development of new antibiotics is declining. Resistance to antibiotics frequently leads to resistance to the whole class of drugs; thus new classes of drugs are required to treat resistant bacteria, not just new drugs in existing classes.

More than a dozen new classes of antibiotics were developed during the 1930s through the 1960s. Since then, however, there have only been two new classes developed. In the four years between 1983 and 1987, drug companies created 16 new antibiotics; but from 1998 until 2002, only seven new ones were created. Currently, antibacterial drugs constitute only 1.6 percent of all the drugs being developed. This contrasts to 5.4 percent of the pipeline that is dedicated to antiviral drugs.

According to a fact sheet produced by group Action on Antibiotic Resistance, pharmaceutical companies are not researching and producing new classes of antibiotics for several reasons. Among these: drug discovery for chronic diseases is more favourable because long-term treatment generates more revenue than the short-term treatment of antibiotics; and a large number of old antibiotics already exist, resulting in a high level of therapeutic competition for newly developed drugs. Research-and-development programmes focus on broad-spectrum antibiotics, which may be counter to public-health efforts to encourage ‘narrow spectrum’ use of such drugs.

Apart from new drugs, there is also a sore lack of efficient and affordable diagnostics, particularly in the developing world, as again, this is an area pharmaceutical companies do not find very profitable. With high-enough sensitivity and specificity to distinguish bacterial from viral diseases, and to identify resistance patterns in bacteria, such diagnostics would significantly help to reduce inappropriate antibiotic use and minimise delay to effective therapy, thereby saving lives.

Meanwhile, even as the knowledge of antibiotic resistance is continually increasing, the gap between what is known and what is done widens. “Although the essential components of control of antibiotic resistance have been well known for long, there has only been limited success in changing policies and efficiently responding to the problem,” researchers wrote recently in the British Medical Journal. In 1998, the World Health Assembly adopted a resolution urging the member states to take action on the problem of antimicrobial resistance. Two years later, the World Health Organisation (WHO) urged a massive effort to prevent the “health care catastrophe of tomorrow”, and shortly thereafter presented a global strategy for the containment of antimicrobial resistance, calling for a multidisciplinary and coordinated approach to the problem. However, sufficient financial and human resources were never provided. In 2005, member states initiated a new resolution to strengthen the WHO’s leadership role in containing antimicrobial resistance, but again very little has taken place since then to implement the resolution.

Part of the problem is the fact that although international collective action and coordination is essential, responsibility for health remains predominantly national. In many settings, major roadblocks for evaluating and implementing interventions are linked to both the poverty of patients and weak public-health systems. Also, few proven mechanisms exist for resistance control, and almost none have been developed for implementation in low-income countries. Measures that are routinely recommended to contain antibiotic resistance include regulation of over-the-counter sales of antibiotics, more cautious prescribing by clinicians, better compliance with treatment guidelines by patients, avoiding antibiotic pollution in the environment, improved hospital hygiene, prevention of infectious diseases and overall strengthening of public-health systems.

A key part of solving the problem of antibiotic resistance will be to find ways in which both to curb the needless use of antibiotics and to regulate their sales. In this situation, both patients and doctors are at fault: patients often demand antibiotics even when do not really need them, and doctors often hand them out without giving much thought to the long-term consequences. “Patients need information and knowledge to reduce expectations of antibiotics for minor infections, and physicians need better diagnostic tools to help improve their treatment decisions,” says Dr Sujit Chandy, of the Department of Pharmacology and Clinical Pharmacology at Christian Medical College, Vellore.

Particularly in the Southasian context, there is also a need to target the thousands of unregulated, informal pharmacies that constitute the source of antibiotics for a large section of the population. Until the infrastructure to efficiently abolish unsanctioned drug distribution becomes available, informal distributors need to be engaged in some way to curb sales of antibiotics and their excessive use. In addition, far more emphasis is required on the prevention of infectious diseases. Investments in solving basic problems – lack of safe drinking water, poor nutrition and dysfunctional sanitation – would go a long way towards curbing the needless use of antibiotics as quick-fix solutions to avoidable diseases (see box, “Bacteria control, Kerala-style”).

Within the medical world and particularly in the field of microbiology, there is today consensus building that we need a fundamentally changed view of the use of antibiotics. At one level, antibiotics constitute a powerful tool that must be looked upon as a common good, wherein the individual’s choice to use an antibiotic will affect the possibility of effectively treating bacterial infections for others. Antibiotic effectiveness can be thought of as a natural resource, like fisheries or forests, in that it is accessible to anyone who can purchase it. Yet all antibiotic use, appropriate or not, ‘uses up’ some of the effectiveness of that antibiotic, thus specifically diminishing our ability to use it in the future.

At the same time, many veteran microbiologists are now arguing that bacteria can no longer be looked upon as ‘enemies’ to be ‘vanquished’ with antibiotics. Apart from being impossible to achieve – as evidenced also from the phenomenon of antibiotic resistance – this warlike approach is also counterproductive. New understandings that are emerging of the microbial world are today giving startling insights into the sheer scale and importance of microbes to human evolution and survival as a species (see box, “Micro-organisms are the good guys”). The future may indeed lie in finding a way for human beings to discern better ways to navigate their way through the ocean of microbes in which we live – and, ultimately, to strike a critical balance between their own protection and bacterial resistance.

Satya Sivaraman is a writer, journalist and filmmaker based in New Delhi.

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