The History of Medicine
As early as half a century ago – just a few years after penicillin was put on the market – scientists began noticing the emergence of a penicillin-resistant strain of Staphylococcus aureus, a common bacterium that claims membership among the human body's normal bacterial flora. Resistant strains of gonorrhoea, dysentery-causing shigella (a major cause of premature death in developing countries) and salmonella rapidly followed in the wake of staphylococcus 20 to 25 years later.
From that first case of resistant staphylococcus, the problem of antimicrobial resistance has snowballed into a serious public health concern with economic, social and political implications that are global in scope and cross all environmental and ethnic boundaries. Multi drug-resistant tuberculosis (MDR-TB) is no longer confined to any one country or to those co-infected with HIV, but has appeared in locations as diverse as eastern Europe, Africa and Asia among health care workers and in the general population. Penicillin-resistant pneumococci are likewise spreading rapidly, while resistant malaria is on the rise, disabling and killing millions of children and adults each year. In 1990, almost all cholera isolates gathered around New Delhi (India) were sensitive to cheap, first-line drugs furazolidone, ampicillin, co-trimoxazole and nalidixic acid. Now, 10 years later, formerly effective drugs are largely useless in the battle to contain cholera epidemics.
In some areas of the world – most notably South-East Asia – 98% of all gonorrhoea cases are multi drug-resistant which in turn contributes to the sexual transmission of HIV. In India, 60% of all cases of visceral leishmaniasis – a sandfly-borne parasitic infection – no longer respond to an increasingly limited cache of first-line drugs; while in the industrialized world, as many as 60% of hospital-acquired infections are caused by drug-resistant microbes. These infections – the most recent of which are vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), are now no longer confined to wards but have crept into the community at large.
Although most drugs are still active, the lengthening shadow of resistance means that many of them may not be for long. In the case of tuberculosis, the emergence of multi drug-resistant bacteria means that medications that once cost as little as US$ 20 must now be replaced with drugs a hundred times more expensive. Other diseases are likewise becoming increasingly impervious as currently effective drugs continue to be underused by patients who do not complete courses, and misused through indiscriminate and over-prescribing.
How Resistance Develops and Spreads
Environment and society. Twenty years ago physicians in industrialized nations believed that infectious disease were a scourge of the past. With industrialization came improved sanitation, housing and nutrition, as well as the revolutionary development of disease-fighting antimicrobials. Populations living in those nations were not only enjoying an unprecedented decrease in mortality and morbidity, but a corresponding increase in life expectancy. In the developing world – where poverty and ongoing civil disturbance offset often modest health care gains – people could nevertheless look forward to a time when an increased quality of life might one day lead to a relatively disease-free future. The tools were there.
Confident in this pharmacopoeia, major drug manufacturers turned away from intensive antibacterial research, and concentrated their energies on seeking cures for heart disease, Alzheimer's and other chronic diseases – thus effectively closing the door on further research into new drugs designed to combat bacterial infections. Indeed, since the early 1980s, significant breakthroughs have been largely confined to the development of antiviral agents targeting the ever-widening HIV epidemic.
Microbiology. Researchers soon discovered that pathogens develop resistance to antimicrobials through a process known as natural selection. When a microbial population is exposed to an antibiotic, more susceptible organisms will succumb, leaving behind only those resistant to the antimicrobial onslaught. These organisms can then either pass on their resistance genes to their offspring by replication, or to other related bacteria through "conjugation" whereby plasmids carrying the genes "jump" from one organism to another. This process is a natural, unstoppable phenomenon exacerbated by the abuse, overuse and misuse of antimicrobials in the treatment of human illness and in animal husbandry, aquaculture and agriculture. Disease – and therefore resistance – also thrives in conditions of civil unrest, poverty, mass migration and environmental degradation where large numbers of people are exposed to infectious diseases with little in the way of the most basic health care. Our challenge is to slow the rate at which resistance develops and spreads.
The Poverty Paradigm: Drug Access and Resistance
More than any other issue, poverty and inadequate access to drugs continue to be a major force in the development of resistance. In many developing nations drugs are freely available – but only to those who can afford them. This means that most patients are forced to resort to poor quality counterfeit, or truncated treatment courses that invariably lead to more rapid selection of resistant organisms. A patient infected with a resistant strain may endure prolonged illness (often resulting in death) and hospital stays which in turn result in lost wages, lost productivity, family hardship and increased infectiousness. Treatment with second and third-line drugs is costly, more often toxic to the patient, and increasingly ineffective owing to the speed with which mutant organisms develop resistance. In India, the past five years has seen 20% of typhoid isolates become resistant to ciprofloxacin, a relatively recent and expensive third-line drug.
Misdiagnosis and Resistance
Misdiagnosis is just another symptom of weak public health systems in industrialized and developing nations. Overworked and under-informed physicians and healthcare workers are ill-equipped to deal with the large number of patients pouring through clinic and office doors. Increased pressure inevitably leads to "defensive" and unnecessary prescribing as a means of forestalling potential complications. A dearth of proper diagnostic facilities and laboratories in poorer nations means physicians and healthcare workers are forced to engage in the kind of symptom-based guesswork that often leads to misdiagnosis and the increased likelihood of prescribing the wrong medication. In many developing countries poverty and a lack of information forces patients to purchase single doses of drugs taken only until the patient feels better. Health workers may also be responsible. In a study undertaken in Viet Nam in 1997, researchers discovered that more than 70% of patients were prescribed inadequate amounts of antimicrobials for serious infections, while another 25% were given unnecessary antibiotics. In China, researchers found that 63% of antimicrobials selected to treat proven bacterial infections were simply the wrong choice, while in Bangladesh 50% of drugs dispensed in one hospital unit were inappropriate. The same is true in North America where it is estimated that physicians in both Canada and the United States over-prescribe antibiotics by 50%.
Counterfeit drugs are also a problem that directly contributes to antimicrobial resistance. A US$ 21 billion industry – which comprises an estimated 5% of all antibiotics sold worldwide, bogus drugs claim the lives of victims whose health, families and livelihood could have been spared with proper medication and the necessary government controls.
Resistance flourishes wherever antibiotics are abused, misused and dispensed at levels lower than treatment guidelines dictate. This means that instead of wiping out the infection altogether, medications kill only non-resistant organisms – leaving their tougher counterparts to replicate and spread resistance genes.
Between 1992 and 1994, as many as 51% of counterfeiting cases uncovered by WHO (70% of which were discovered in developing countries) revealed that forged drugs carried no active ingredient whatsoever. Among the counterfeits, yet another 17% contained the wrong ingredient, while an additional 11% contained weaker than recommended concentrations of active medication. Indeed, some of these, so-called "medications" contained poisons capable of causing severe disability or death. Overall, only 4% of counterfeits contained the same quantity and quality of medication as their authentic counterparts.
Today, no one knows to what extent drug counterfeiting has spread. What is clear, however, is that in the wake of globalization and the increasing power of organized crime, the problem of counterfeiting grows ever more acute.
Dubious Pay-offs and High-priced Prescriptions
Owing to fears of resistance, many health workers are avoiding narrow-spectrum drugs that treat specific complaints in favour of broader-spectrum antibiotics that have wider applications. In countries where health care providers earn only subsistence wages, unethical pharmaceutical companies sometimes pay a commission for recommending more expensive broader-spectrum medications when cheaper narrow-spectrum alternatives would suffice. The end result is a smaller, more highly-priced pool of antimicrobials combating a larger number of infectious diseases. This troubling development accelerates the natural process of resistance, and results in only a small percentage of the world's population benefiting from new research.
Advertising for Resistance
At the other end of the spectrum, patient demand for antimicrobials – sometimes the result of TV, internet, magazine or newspaper advertising – also spurs the development of resistance. In a 1997 study undertaken in Europe, physicians cited patient pressure as the number one reason why they prescribed the wrong antibiotics. In the United States, 95% of physicians surveyed had seen an average of seven patients in the previous six months who had requested specific drugs as a result of advertising. Of physicians questioned, 70% admitted that patient pressure forced them to prescribe drugs they might otherwise have avoided. In a 1995 study undertaken in Peru, two-thirds of those health workers surveyed claimed that their primary source of information came from medical journals. Researchers concluded otherwise, and wrote that advertising appeared to be a key information source. The authors went on to say that this factor "tended to promote irrational drug use".
Misinformation also plays a role. In the Philippines, many people believe the anti-TB drug isoniazid is a "vitamin for the lungs" and will dose children accordingly. Unwitting use of powerful drugs at subtherapeutic doses leads directly to the development of multi drug-resistant bacteria.
Lack of Education
Even in industrialized nations, antimicrobial resistance is given only cursory coverage in medical schools or is confined to specialist training. In developing nations, an acute shortage of qualified health care workers means that patients must rely on their own judgement, or that of underqualified doctors, paramedics and other health care workers.
Many drug dispensers are likewise under-educated and under-informed. In a study of 40 randomly selected healthcare facilities in Ghana, only 8% of drug dispensers had received formal training. At most clinics surveyed, trained dispensers were notable only by their absence. These factors are particularly significant when one considers that in many countries the majority of patients purchase antimicrobials and other drugs without visiting a health worker first. Another study found that drug retailers in seven sub-Saharan African nations often advised consumers to purchase non-essential drugs without adequate explanation – and without any suggestion that individuals consult a health worker prior to their purchase. This combination of poverty and ignorance is the perfect spawning ground for antimicrobial resistance.
Resistance and Hospitals
Most health workers cut their professional teeth in the hospital setting. Unfortunately, when it comes to prescribing practices, teaching hospitals sometimes unwittingly promote the type of irrational dispensing that contributes to drug resistance. No matter how thorough under-graduate teaching is, once on the ward, junior doctors tend to follow the habits of their supervisors. The same holds true for other trained health workers.
In an analysis of 10 studies undertaken at teaching hospitals worldwide, researchers determined that between 40% and 91% of antibiotics prescribed were inappropriate. The survey also revealed that health care workers often disregarded basic hygiene practices – such as hand-washing and/or changing gloves – before and after patient visits.
Inadequately cleaned equipment is also a major determinant in the spread of infectious disease. In one study, researchers surveying health clinics in United Republic of Tanzania discovered that some 40% of presumed sterile reusable needles and syringes were contaminated with bacteria. Inadequate training, monitoring and education on basic hygiene has serious implications, not only for the hospital population itself, but also for the community at large.
Antimicrobial Resistance and Food
Another source of resistance lies in our food supply and is related to infectious agents that live in what we eat and drink. Since the discovery of the growth-promoting and disease-fighting capabilities of antibiotics, farmers, fish-farmers and livestock producers have used antimicrobials in everything from apples to aquaculture. Currently, only half of all antibiotics produced are slated for human consumption. The other 50% are used to treat sick animals, as growth promoters in livestock, and to rid cultivated foodstuffs of various destructive organisms. This ongoing and often low-level dosing for growth and prophylaxis inevitably results in the development of resistance in bacteria in or near livestock, and also heightens fears of new resistant strains "jumping" between species. Vancomycin-resistant Enterococcus faecium (VRE) is one particularly ominous example of a resistant bacterium appearing in animals that may have "jumped" into more vulnerable segments of the human population.
The emergence of VRE in food can be traced to the widespread use of avoparcin (the animal equivalent of the human antibiotic vancomycin) in livestock. Moreover, with livestock production increasing in developing countries, reliance on antimicrobials is likewise expanding – often without guidelines in those nations where antibiotics are sold without prescription. With the trends toward globalization and the relaxing of trade barriers, inadequate standards and enforcement in one nation means all others are vulnerable.
Often bacteria that are harmless to livestock are fatal to humans. This is true of a number of outbreaks that have taken the medical community by surprise. One example occurred in Denmark in 1998, when strains of multi drug-resistant Salmonella typhimurium struck 25 people, killing two. Cultures confirmed that the organisms were resistant to seven different antibiotics. Epidemiologists eventually traced the micro-organism to pork and to the pig herd where it originated. In 1998, 5 000 people in the United States learned the hard way about antimicrobial resistance when they fell ill with multi drug-resistant campylobacteriosis caused by contaminated chicken. The same drugs that eventually failed them had also been used in the poultry that turned up on their plates.
Globalization and Resistance
International travel and trade also play a role in the development of resistance. A microbe originating in Africa or South-East Asia can arrive on North American shores within 24 hours. One example occurred in Canada where health care authorities traced two outbreaks of MRSA to a small village in North India. In the United States, published reports show that the majority of multi drug-resistant typhoid cases originate in six developing countries. While outbreaks of drug-resistant tuberculosis in western Europe have been shown to originate in countries further east, drug resistance is not merely an issue of immigration. Drug-resistant tuberculosis in eastern Europe is due primarily to lax TB control (lack of DOTS implementation), lack of political will by some governments, and little enforcement of effective guidelines within health care institutions.