A Message From the
Since their discovery, antibiotics have completely transformed humanity's approach to infectious disease. Today, the use of antibiotics combined with improvements in sanitation, housing, and nutrition alongside the advent of widespread vaccination programmes, have led to a dramatic drop in once common infectious diseases that formerly laid low entire populations. Scourges that once struck terror into the hearts of millions plague, whooping cough, polio and scarlet fever have been, or are, on the verge of being controlled. Now, at the dawn of a new millennium, humanity is faced with another crisis. Formerly curable diseases such as gonorrhoea and typhoid are rapidly becoming difficult to treat, while old killers such as tuberculosis and malaria are now arrayed in the increasingly impenetrable armour of antimicrobial resistance.
This phenomenon is potentially containable. It is a deepening and complex problem accelerated by the overuse of antibiotics in developed nations and the paradoxical underuse of quality antimicrobials in developing nations owing to poverty and a resultant dearth of effective health care.
Last year's infectious diseases report, "Removing Obstacles to Healthy Development," demonstrated that communicable diseases remain a significant cause of disability, are responsible for continued high mortality and primarily afflict the world's most vulnerable populations.
This year's report focuses on the issue of drug resistance and how this disturbing development is closing the windows of opportunity to treat infectious diseases. By developing a global strategy to contain resistance and building alliances involving all healthcare providers countries, governments, international organizations, non-governmental organizations and both the private and public health care sectors we have an opportunity to launch a massive effort against infectious diseases that perpetuate poverty. Used wisely and widely, the drugs we have today can be made available to the world's poorest to prevent the health care catastrophes of tomorrow.
This is our challenge and must be our goal.
Dr Gro Harlem Brundtland
Table of Contents
Preface: Our Window of Opportunity
Chapter 1: A World Without Antibiotics
Chapter 2: The Discovery of Antimicrobials
Chapter 3: Factors Contributing to Resistance
Chapter 4: The Big Guns of Resistance
Chapter 5: Call to Action
Preface: Our Window of Opportunity is Closing
We are the first generation ever to have the means of protecting itself from the most deadly and common infectious diseases. Today, we possess the knowledge to prevent or cure diseases such as malaria, tuberculosis, HIV, diarrhoeal diseases, pneumonia and measles.
Smallpox eradication and a reduction of deaths due to measles has been made possible by the introduction of widespread immunization campaigns. And while there are still no effective vaccines to prevent infection from other leading killers (tuberculosis, malaria, HIV, diarrhoeal diseases and pneumonia), control and containment using existing interventions is well within our reach. Within the past two decades, the scientific community has developed successful strategies and products to counter threats posed by infectious diseases in both wealthy and poorer nations.
In all countries, these diseases can be prevented or treated with tools and medicines that usually cost a few dollars often mere cents. Because of advances in the use of anti-malarials and insecticide-treated bednets, malaria deaths are no longer common in Viet Nam. Mexico has achieved a five-fold reduction in diarrhoeal deaths through the use of oral rehydration. Increased condom use and health education have enabled Thailand and Uganda to reduce the spread of HIV. The effective use of antibiotics in parts of India has resulted in a seven-fold decrease in tuberculosis deaths.
Previous generations once prayed for these life-saving drugs, interventions and control strategies. But now that they are available, the world has been slow to put them to wide use. In disease endemic countries, global efforts have remained embarassingly modest. Only 3% of Africa's children have bednets. Effective anti-TB medicines and treatment strategies reach only 25% of the world's TB cases and only half of developing countries have adopted the effective Integrated Management of Childhood Illnesses (IMCI) package.
The underuse and misuse of recent health breakthroughs has been catastrophic for people living and working in developing countries. Two out of every three deaths among young people in the poorest countries of Africa and Asia continue to result from just a handful of illnesses. Each year worldwide, more than 11 million people die from these preventable or curable afflictions. Most deaths are among young parents and children.
The Threat of Antimicrobial Resistance is Growing
We are now beginning to pay for our neglect a price over and above the tragedy and suffering infectious diseases inflict on millions of people annually. Our failure to make full use of recently discovered medicines and products means that many will slip through our grasp.
This is evident in wealthy countries which have exclusively focussed efforts on fighting disease within their own borders, while failing to help eliminate them globally. Proliferating elsewhere, many bacteria, viruses and parasites mutate, become drug resistant and venture back to wealthy countries via modern transportation.
Resistance is also seen where health workers have exclusively focussed on providing drugs for their patients while inadvertently failing to take time to ensure proper diagnosis, prescription and adherence to treatment.
Antimicrobial resistance is a natural biological phenomenon. But it becomes a significant public health problem where it is amplified many-fold owing to human misuse and neglect. Drug resistance is the most telling sign that we have failed to take the threat of infectious diseases seriously. It suggests that we have mishandled our precious arsenal of disease-fighting drugs, both by overusing them in developed nations and, paradoxically, both misusing and underusing them in developing nations. In all cases, half-hearted use of powerful antibiotics now will eventually result in less effective drugs later.
This report describes the growing threat of antimicrobial resistance. It documents how once life-saving medicines are increasingly having as little effect as a sugar pill. Microbial resistance to treatment could bring the world back to a pre-antibiotic age.
The Window of Opportunity is Closing
Before long, we may have forever missed our opportunity to control and eventually eliminate the most dangerous infectious diseases. Indeed, if we fail to make rapid progress during this decade, it may become very difficult and expensive if not impossible to do so later. We need to make effective use of the tools we have now.
The eradication of smallpox in 1980, for example, happened not a moment too soon. Just a few years' delay and the unforeseen emergence of HIV would have undermined safe smallpox vaccination in populations severely affected by HIV.
While many exciting research efforts are currently underway, there is no guarantee that they will yield new drugs or vaccines in the near future. Since 1970, no new classes of antibacterials have been developed to combat infectious diseases. On average, research and development of anti-infective drugs takes 10 to 20 years. Currently, there are no new drugs or vaccines ready to emerge from the research and development pipeline.
Moreover, for the major infectious killers, research and development funding continues to be woefully inadequate. A very small percentage of all global health research and development funding is currently devoted to finding new drugs or vaccines to stop AIDS, acute respiratory infections (ARI), diarrhoeal diseases, malaria and TB. The pharmaceutical industry reports that it costs them a minimum of US$ 500 million just to bring one drug to market. Combined funding for research and development into ARI, diarrhoeal diseases, malaria and TB last year was under that amount.
A Massive Effort is Required
Although prevention through vaccination continues to be the ultimate weapon against infection and drug resistance, no vaccines are available to prevent five of the six major infectious killers. Yet it is a needless tragedy that 11 million people perish each year awaiting the advent of newer miracle drugs and vaccines. Prevention and treatment strategies using tools available now can be provided to populations throughout the world to help eliminate high-burden diseases of poverty.
We need not stand by helplessly watching antimicrobial resistance increase and drug effectiveness decrease. As this report shows, resistance can be contained. When an infection is addressed in a comprehensive and timely manner, resistance rarely becomes a public health problem. The most effective strategy against antimicrobial resistance is to get the job done right the first time to unequivocally destroy microbes thereby defeating resistance before it starts.
Today - despite advances in science and technology - infectious disease poses a more deadly threat to human life than war. This year at the onset of a new millennium the international community is beginning to show its intent to turn back these microbial invaders through massive efforts against diseases of poverty diseases which must be defeated now, before they become resistant. When diseases are fought wisely and widely, drug resistance can be controlled and lives saved.
Back to Table of Contents
Chapter 1: A World Without Antibiotics
'Although the Soldiery retreated from the Field of Death, and encamped out of the City,
the Contagion followed, and vanquish'd them; many in their Old Age, and others in their
Prime, sunk under its cruelties; of the Female Sex most died; and hardly any children
escaped; and it was not uncommon to see an Inheritance pass successively to three or four
Heirs in as many Days; the Number of Sextons were not sufficient to bury the Dead.'
Nathanial Hodges; Loimologia: an account of the 1665 London Plague
Throughout history, humanity has fallen victim to pandemics of cholera, plague, influenza, typhoid, tuberculosis and other infectious maladies so widespread, most people rarely made it into middle age. Other (seemingly more banal ailments) such as ear, skin and throat infections often resulted in deafness, disfigurement and/or death due to blood poisoning and other complications.
As recently as the 19th century, the average life span in Europe and North America was around 50 years and marked by the steady if predictable loss of family, friends, spouses and colleagues. The habit of enquiring after another's health was a meaningful and entrenched nicety based on the ever-present threat of sudden death due to pestilence, accidents or random infection caused by any number of hostile pathogens. It was a world in which the likelihood of dying prematurely from infectious diseases was as high as 40%, and where women routinely succumbed during childbirth to infections easily curable by today's standards.
In developing nations the situation was even worse with one caveat; unlike industrialized nations, conditions in developing nations never really improved. In poorer nations today infectious diseases both major and seemingly minor further contribute to premature death and the ongoing misery of underprivileged populations.
Helpless Against Diseases
For previous generations living in industrialized nations, frequent illness replete with fears of sudden (or slow) death marred a life that was already "nasty, brutish and short". Such an existence could well have been the miserable consequence of being born in the first place. Few people escaped debilitating disease, disfiguring skin conditions or the likelihood of pain and suffering caused by any number of cunning microbes. Life was transient, ephemeral and characterized by an endless cycle of grief and loss.
In Europe, wave after wave of epidemics kept humanity forever teetering on the edge of demographic collapse. Between the 14th and 15th centuries, the continent saw its population halved by successive outbreaks of smallpox, typhus, and the ever-present menace of the Black Death (plague). In India, plague didn't appear to take hold until 1896 when a strain appeared out of Yunnan in China. By 1903 more than 1.3 million Indians were dying every year. Overall, historians estimate that between 1896 and 1948 12.5 million people died of plague on the subcontinent alone. In 1783, British historians calculated that some 20 000 pilgrims to the Indian holy site of Hardawar succumbed to cholera. Within months the bacilli spread outwards towards China, north to Russia and southwest to the Middle East. By 1831, cholera infected nearly half of the Haj faithful making the annual pilgrimage to sacred sites in Mecca and Medina the fatal consequence of drinking from a single ritualistic source of contaminated water. Dehydrated and shedding vibrios, dying pilgrims crept homewards depositing bacteria along key transportation routes. The great ports of Alexandria and Istanbul were soon staggering under a cholera epidemic that subsequently radiated outwards throughout the entire North African littoral, into the Balkans, up the Danube and onwards towards Hungary leaving behind a trail of corpses, orphans, economic ruin and contaminated water and food.
In the early 1800s, outbreaks of puerperal sepsis a streptococcal infection were responsible for the deaths of upwards of 70% of new mothers "lying in" at hundreds of small hospitals flecking Europe. In one Italian infirmary it was reported that not a single woman survived childbirth over an entire year. Not until health workers (who routinely moved between morgue and maternity room) adopted hand-washing in the late 1800s, did the death rate decline.
The end of the First World War saw seemingly innocuous ailments such as the ubiquitous "touch of grippe" metamorphose into grim harbingers of contagion and death. In the fall of 1918, a tidal wave of influenza rolled over Europe, Asia, Australia, North and South America killing millions and devastating entire economies. A viral infection, influenza today rarely kills on its own but erodes the lining of the respiratory tract thereby allowing secondary "super" infections (often bacterial) to take hold.
British demographer Kingsley David once suggested that influenza wiped out 20 million in India, while contemporary experts tag the total number of dead worldwide at 30 million more than those killed in the Great War itself. Among the world's aboriginal peoples most notably the Inuit of northern Canada the epidemic exacted a harsh and bitter toll. Formerly isolated from the disease, such populations suffered the most.
In Samoa, 25% of the islands' people died, while in Canada entire Inuit villages sickened and then fell silent under the deathly pall of influenza-related infections.
A Destroyer of Empires
It is arguable whether war or the devastation wrought by infectious disease has had a greater historic influence on political boundaries. Up until the Second World War, it was pestilence and not warfare that claimed the lives of Europe's soldiers. Napoleon Bonaparte can lay blame for his ignominious retreat from Moscow not on the Russians, nor even the Russian winter. By far, his deadliest opponent was typhus; a louse-borne infection that reduced a healthy Grande Armee of 655 000 to a pitiful and demoralized 93 000 who wound up straggling home and surviving just long enough to pass the rickettsia on to neighbours and loved ones. The subsequent epidemic killed another two million, carrying off 250 000 civilians in Germany alone.
In the New World, it was not superior Spanish firepower, nor their reliance on horses that resulted in the conquest and enslavement of the Amerindians. By far the greatest allies of the self-proclaimed, "liberators of the heathens" were smallpox, influenza and measles. Formerly unknown in the Americas, the first recorded smallpox epidemic hit the fledgling colony of Santo Domingo in 1495, destroying 80% of the local indigenous population. That same outbreak was also responsible for the deaths of hundreds of Spanish soldiers after the battle of Vega Real in 1495.
In 1515, another flare-up in Puerto Rico spared the Spanish but extirpated the locals. By the time Hernando Cortes and his rogue's army of mercenaries and missionaries set foot on Mexico's shores, smallpox, measles and influenza had already insinuated themselves as a kind of microbial fifth column among the local population. How a ragtag army of 300 men (albeit armed with muskets, riding horses and unbridled greed) could defeat the highly organized and warlike Aztecs can never be satisfactorily explained except by factoring in the inroads European diseases made into a people entirely devoid of immunity. Conquistador and expedition scribe Bernal Diaz described the resultant carnage from infectious disease thus: "We could not walk without treading on the bodies and heads of dead Indians. The dry land was piled with corpses." In the space of 10 years, historians estimate that Mexico's population plummeted from some 25 million to 6.5 million owing to epidemics of infectious disease a drop of 74%. In North America, later events echoed those in Mexico but with one not-so-subtle difference. By the 1600s, colonizers knew enough about epidemiology to maliciously inflict deadly diseases on locals by providing "gifts" of blankets and clothing infested with smallpox and typhus-bearing lice the first recorded acts of biological warfare.
Terrible Old Visitors Who Won't Go Away
Today's most virulent killers have been at work for centuries. Malaria and acute respiratory infections have killed multitudes throughout much of human history. Indeed, forensic archaeologists discovered TB bacteria hiding out in the tissue of mummies thousands of years old.
If smallpox was Europe's primary export to the New World, the New World may well have hit back with syphilis. After engaging in rape and pillage, Spanish conquistadors, troops and camp-followers sailed home to Europe only to scatter the seeds of yet another epidemic. This new sexually transmitted contagion was characterized by genital ulcers that progressed to rash, dementia and hideous abscesses that gnawed away at flesh and bone. Henry VIII, Sir Randolph Churchill (Winston's father), Schopenhauer and Guy de Maupassant were just a few who may have met an ugly end courtesy of the peripatetic spirochaete.
We're Vulnerable Without Effective Medicines
Most people alive in industrialized nations today know a grandmother or great uncle who can describe how whooping cough, influenza or diphtheria whittled away friends and family. In previous epochs and still today in many developing nations a simple bladder infection could lead to death by kidney failure; minor skin conditions such as impetigo could end in scarring and lifelong disfigurement; and killers such as measles, tuberculosis and pneumonia stalked uncontested though the streets, offices and homes of every city and hamlet around the world.
Today, the situation in developing nations remains as grim as that of previous generations in industrialized nations. In impoverished regions of the world, almost everyone knows a relative who suffers from infectious diseases of poverty such as simple diarrhoea, respiratory infections, tuberculosis, malaria or AIDS.
In the developing world where poverty and inadequate access to healthcare remain oppressive reminders of human frailty infectious disease continues to be an omnipresent threat to life and livelihood. Owing to the absence of hard historical data, one can only extrapolate former conditions of overcrowding and poor health once prevailing in Europe to developing nations today.
Back to Table of Contents
Chapter 2: The Discovery of Antimicrobials
"I will lift up mine eyes to the pills."
Malcolm Muggeridge describing the age of modern medicine in a 1962 newspaper column.
For those living in industrialized nations Muggeridge's paean to the power of pills is no hyperbole. The 20th century has seen an almost complete transformation in our understanding and treatment of infectious disease. Successful medications have reconfigured our approach to most bacterial and fungal infections while effective vaccines have been developed against infections such as smallpox, measles, typhoid fever, rubella, diphtheria, tetanus, yellow fever, pertussis and polio.
In developing nations the story has been tragically different. Separated by poverty, geography, scarcity of antimicrobials and a lack of political will on the part of governments whose priorities may not be public health, individuals living in such areas have long been consigned to the health care margins. Nevertheless, the fact that these tools against infection exist and are still effective constitutes the health care miracle of the last 500 years.
Apart from smallpox vaccines, quinine and penicillin, few of these breakthroughs have been accidental discoveries, stumbled upon by chance. Instead, they are the result of dedicated scientific effort and vast amounts of money, time and human labour expended over decades.
Magic Bullets and Miracle Drugs
From German microbiologist Paul Ehrlich's seminal theory of the "magic bullet" as a metaphor for cures wrought by heavy metals (eventually used as a widespread treatment for parasitic and sexually-transmitted infections) to the discovery and eventual release of penicillin, the history of antimicrobial research is replete with victories won against almost insurmountable odds. Among Ehrlich's contributions was the first use of arsenic (Salvarsan) in for the treatment of syphilis and the first description of the body's immunological response to infectious organisms.
In 1928, British scientist Alexander Fleming pushed the frontiers even further when he observed the antibiotic effects of a mould that later became known as penicillin. The product of this seemingly humble fungus proved so effective in fighting infections formerly deemed fatal, that scientists dubbed it a "miracle drug". Fleming's discovery triggered a health care revolution unprecedented in the annals of medical science. From that one initial specimen flowered an entire family of penicillin-based antibiotics.
Later discoveries included streptomycins, tetracycline, quinolones, antifungals, antiparasitics and, more recently antivirals. These drugs collectively known as antimicrobials have saved the lives of millions, reduced illness, and allowed the development of complex surgical procedures previously considered too hazardous due to post-operative infection. At the same time antimicrobials have prevented disability such as deafness, blindness, and disfigurement from such diseases as leprosy and elephantiasis.
In 1927 German scientist Gerhard Domagk upped the ante with his research into sulfa compounds after he discovered a brilliant red dye, known as Prontosil red, cured mice injected with lethal doses of haemolytic streptococci. From mice, Domagk graduated to his own daughter whom he successfully relieved of a persistent streptococcal infection. Prontosil was eventually used to treat puerperal fever slashing the mortality rate from 20% to 4.7% in Germany. The Nobel Institute was so impressed by his discoveries that it belatedly awarded him the prize during a special 1947 ceremony in Sweden after the Second World War.
Progress followed hard on the heels of Domagk's ground-breaking research. In 1938 a British team led by A.J. Evans developed yet another sulfonamide sulfadiazine 693, later called sulfanilamide that also proved effective in treating streptococci including pneumococci. Winston Churchill - among many - can credit the drug with prolonging his life after falling ill with pneumonia at a critical juncture during the Second World War. In 1940, Russian émigré Selman Waksman isolated a fungus that eventually led to the development of the anti-tuberculosis drug streptomycin a discovery that garnered him the Nobel Prize. Many scientists believed that tuberculosis had finally been conquered with the development of isoniazid. Like other anti-TB medications however, the new drug easily encouraged resistance in the ever-resilient bacilli. In 1957, this dilemma was solved when a Lepetit research team headed by Piero Sensi discovered another anti-TB family of drugs later released under the name rifampicin. Used in combination with streptomycin and isoniazid in a strategic long-term therapy, this chemotherapeutic triad has successfully (that is, until recently) contained a dreaded disease once characterized as "galloping" consumption.
A Lull in the Action
After a flurry of discoveries between 1930 and 1970, the past 30 years have witnessed fewer discoveries in the fight against infectious killers. The 1970s brought acyclovir potent against herpes zoster (shingles), cold sores and genital herpes. This was the first time an antiviral successfully stymied pathogen replication without proving toxic to the host.
With the advent of HIV, the discovery and development of antiretrovirals has meant yet another leap forward in the fight against contagious diseases. The introduction of zidovudine (AZT) in 1985 was followed a decade later by the first protease inhibitor.
Nowadays, the cache of antimicrobial weapons targeting infectious disease has swollen to an impressive arsenal of more than 150 compounds. The cost, however, has been huge. Pharmaceutical companies routinely spend some US$ 500 million on research and development for every new compound that makes it to market. For every success, there are many failures. Every pathogen that develops resistance represents the dismantling of a legion of hopes, dreams and dollars.
Today drug resistance is already nibbling away at medications that took decades to develop. In clinical practice, microbial resistance has turned up during treatments with idoxuridine for herpes simplex, keratitis, acyclovir for mucocutaneous HSV infection, rimantidine for influenza and ganciclovir for CMV disease.
It's not a Breakthrough Unless it's Widely Available
Although antimicrobial drugs have saved the lives and eased the suffering of millions, health care benefits have not extended fully to those in the developing world. Extreme poverty, poor sanitation, malnutrition, inadequate drug access, poor health care delivery and ongoing conflicts represent major obstacles to healthy development.
Back to Table of Contents
Chapter 3: Factors Contributing to Resistance
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.
Back to Table of Contents
Chapter 4: The Big Guns of Resistance
"This enquiry has been an alarming experience, which leaves us convinced that
resistance to antibiotics and other anti-infective agents constitutes a major threat to
public health and ought to be recognized as such more widely than it is at the present
Lord Soulsby, U.K. House of Lords Select Committee on Science and Technology, 1998
As quickly as new drugs are launched to smash humanity's most intractable infectious enemies, the forces of resistance regroup and strike back with yet another counter-offensive.
More than any other infectious disease, pneumonia remains the number one killer worldwide. Statistics for 1998 show that 3.5 million people died as a result of the disease. The majority of all acute respiratory infections (ARIs) occur in developing countries where poverty and inadequate medical care contribute to high mortality rates. The primary microbial culprits, Streptococcus pneumoniae and Haemophilus influenzae have, thus far, proven themselves wily opponents. In lab samples as many as 70% of chest infections are resistant to one of the first-line antimicrobials. These numbers will only increase the longer action is delayed. Formerly, first-line medications were both effective and affordable. With the onset of resistance however, newer treatments are proving too costly to the vast majority of those living in poor developing nations. This alarming situation is due, in part, to widespread confusion over the difference between viral and bacterial respiratory infections. Both forms present the same clinical symptoms that can often only be distinguished by laboratory tests expensive and therefore unavailable in many parts of the world. While bacterial infections can kill, treating viral illness with antibiotics is not only ineffective but contributes to the development of resistance. This is particularly true when it comes to treating children. Recent studies undertaken by WHO indicate that for every 100 respiratory infections, only 20% require antibiotic treatment. This means that 80% of patients are treated with unnecessary medications thereby leading drugs directly into the sight lines of resistance.
As well as preventing the onset of disease, vaccines also offer the best hope in combating resistance by reducing the number of infected individuals and thereby minimizing transmission, infection and the need for treatment. While vaccines have been developed to prevent some viral and bacterial pneumonias, much more work needs to be done to bring these life-saving immunizations to impoverished populations.
Multi drug-resistance is also occurring in microbes that cause diarrhoeal diseases. Combined, these infections are believed to have claimed the lives of more than 2.2 million people in 1998. One such agent, the bacterium Shigella dysenteriae, is a highly virulent microbe that is resistant to almost every available drug killing adults and children alike. The results of this growing crisis were illustrated most notably in the wake of the 1994 civil war in Rwanda when the bacterium spread through vulnerable refugee populations already traumatized by war and loss. Left untreated, death can follow within days of infection. Ten years ago a shigella epidemic could easily be controlled with co-trimoxazole a drug cheaply available in generic form. Today, nearly all shigella are non-responsive to the drug, while resistance to ciprofloxacin the only viable medication left appears to be just around the corner. Shigella dysentery is rare in developed countries, and thus, not a pressing concern to pharmaceutical companies favouring higher returns on research and development.
The bacteria that cause cholera and typhoid are also revealing the ease with which they acquire resistance. In treating people with cholera, fluid replacement is paramount, but antibiotics (especially tetracycline) play an important public health role in limiting the spread of epidemics. Salmonella typhi like shigella, is adept at accumulating cassettes of resistance genes, producing strains that withstand first-line, second-line and now, third-line drugs. Up until 1972, chloramphenicol was the treatment of choice for typhoid fever throughout much of the Indian subcontinent. By 1992 two-thirds of reported cases were chloramphenicol-resistant, thereby necessitating treatment with expensive quinolones that are themselves losing effectiveness. Without proper treatment, typhoid is a seriousand frequently relapsing disease that kills up to 10% of those infected.
At the end of 1999, an estimated 33.6 million individuals were living with HIV worldwide. In Zimbabwe, up to 50% of pregnant women are infected with HIV, while in Botswana life expectancy has plummeted from 70 to 50 years in the past 25 years because of AIDS. Worldwide, some 2.6 million people died in 1999 as a result of infection with HIV.
Because of inadequate access, infected individuals are often unable to obtain antiretroviral drugs. This bleak scenario will continue as a growing number of HIV-infected individuals develop AIDS. For these people particularly the bulk of those living in developing nations the availability of HIV tests and expensive life-prolonging drug cocktails are largely non-existent until now. Moreover, in the industrialized world where treatment is more readily available drug combinations are under increasing pressure to remain viable owing to both resistance and toxic side-effects. A small but growing number of patients are showing primary resistance to zidovudine (AZT) as opposed to "secondary" resistance where viruses grow increasingly insensitive to antivirals over the course of the patient's illness. This is also true for protease inhibitors that became available a mere 10 years ago. A growing body of evidence indicates that when HIV develops resistance to one protease inhibitor it quickly becomes insensitive to the entire family of drugs, thus outwitting antiretrovirals that took years to develop at huge cost. AIDS is a particularly insidious disease because those infected become reservoirs for TB, leishmaniasis, pneumonia and other opportunistic infections some of which have themselves developed resistance. These infections are transmissible to the population at large.
Tuberculosis is yet another ancient killer that is not only staging a major comeback, but is becoming increasingly resistant to anti-TB drugs. Exact figures for MDR-TB are hard to pin down as surveillance remains uneven in nations most affected. Nevertheless, researchers assess the approximate number of multi drug-resistant TB cases at between 1% and 2% of current global tuberculosis figures. This apparently low figure may suggest that there is less cause for alarm unless the overall prevalence of TB estimated to be 16 million cases is recognized. Fears will continue as nations where MDR-TB went previously unreported China, The Islamic Republic of Iran and parts of eastern Europe reveal a growing caseload. Recent reports of global trends in MDR-TB are particularly chilling when one considers that tuberculosis is transmitted by tiny particles suspended in the air.
Adding to the resistance crisis is the length of TB treatments (a minimum of six months), with non-compliance common in those living in nations unable or unwilling to adopt the WHO-recommended Directly Observed Treatment, Short-course (DOTS). Consistently applied, DOTS can cure disease in upwards of 95% of drug-susceptible cases even in impoverished nations. This strategy not only ensures a cure by directly supervising and adapting drugs to patient needs, but also minimizes the development of resistance by preventing treatment failure. Treatment failures occur when patients are either dosed with poor quality drugs, have limited access to, or are non-compliant with existing therapies. Insufficient treatment results in a roller-coaster ride of brief reprieves followed by relapses that grow ever more impregnable to available medications each time the TB organism rallies Currently, a single treatment course of six months for regular tuberculosis costs as little as US$ 20. With MDR-TB, the costs shoot upward to US$ 2 000, or even more.
In the post-Perestroika era of eastern Europe and the Russian Federation, inadequate treatment i.e. poor monitoring, interrupted courses, or a reliance on expired or counterfeit drugs corresponds to growing transmission rates of resistant TB organisms.
In addition, patients who are infected with HIV, have silicosis, are diabetic, or are immune-compromised in any way, are more vulnerable to TB exposure and become unwitting pools of infectiousness that easily spills over into the general population.
The ability of HIV to accelerate the onset of acute MDR-TB has serious implications for humanity. In crowded hospitals filled with immuno-suppressed individuals, resistant TB has the potential to stalk relentlessly through a population, afflicting patients, health care workers and physicians alike. War, poverty, overcrowding, mass migration and the breakdown of existing medical infrastructures all contribute to MDR-TB's development, transmission and spread.
A mosquito-borne infection that killed an estimated 1.1 million people in 1998, and with an estimated 300 to 400 million new cases globally each year, malaria promises to be a pre-eminent threat to development in endemic regions well into the new millennium.
Like other diseases once considered banished to the geopolitical margins, malaria is reappearing in areas of the world formerly deemed disease-free. In a 1999 report WHO warned of "a serious risk of uncontrollable resurgence of malaria" in Europe owing to civil disorder, global warming, increased irrigation (canals are important breeding grounds for mosquitoes) and international travel. In the United Kingdom, 1 000 new cases of malaria are imported each year from malaria-endemic countries. In the former USSR, weakening public infrastructures have triggered large-scale epidemics in central Asian republics, while in Turkey numbers have increased tenfold since the disease was believed nearly defeated in 1989.
Resistance to chloroquine the former treatment of choice is now widespread in 80% of the 92 countries where malaria continues to be a major killer, while resistance to newer second and third-line drugs continues to grow. Unfortunately, many of these new drugs are not only expensive and have serious side effects, but most will be eventually rendered ineffective by the malaria organism's complex epidemiology and facility for rapid mutation. Mefloquine resistance emerged in South-East Asia almost as soon as the drug became a treatment option.
The challenge is to use already existing antimalarials more effectively to better control the disease. This means improving access to appropriate drugs and providing combinations of medications at lower cost. Increasing surveillance to guide the proper use of drugs, and more attention to alternative prevention strategies such as insecticide-treated bednets is also vital. A renewed commitment to research and development of newer, more effective medications is likewise critical to the containment of drug-resistant malaria.
Between them, the hepatitis B and C viruses are thought to infect some 520 million individuals each year. Both diseases can cause chronic illness, and may eventually lead to death from liver cancer or other complications. Like many viral infections e.g. HIV hepatitis is not only difficult to diagnose without access to expensive laboratory tests, but is also costly to treat. The two infections are easily transmissible through contaminated blood, injecting drug use, or as in the case of hepatitis B through sexual behaviour or any close contact .
Both hepatitis B and C are showing high levels of resistance to already inadequate treatment options. Lamivudine a drug recently developed to treat hepatitis B is hampered by several serious drawbacks. Firstly, of those patients taking the drug over a long period of time, fully 30% show resistance to antiviral therapy after the first year of treatment. Secondly, although lamivudine reduces the virus by some 80%, it rebounds more vigorously once treatment stops. This is one example of how quickly resistance can consign a promising new antiviral to the darkness of the medicine cabinet.
For the estimated 170 million individuals infected with hepatitis C, the prognosis is even more dire. Both treatments ribavirin and interferon are prohibitively expensive, not always effective and have potentially damaging side-effects. Even in developed nations, few governments will bankroll treatments when results remain troublingly inconsistent.
So far, the greatest hope lies in the development of vaccines and in increased funding for widespread immunization programs. Although a hepatitis B vaccine is currently on the market (and some countries are taking steps to incorporate it into national immunization strategies) lack of government commitment is responsible for continued high rates of infection. This grim situation must change. In China and South-East Asia, maternal transmission of hepatitis B is at an all-time high. This means vulnerable newborns with immature immune response are at greater risk of fatal complications and are more likely to transmit the debilitating virus to others. As of today, there is no vaccine for hepatitis C.
No population is more vulnerable to multi drug-resistance than those admitted to hospital wards. Of the resistant organisms now proliferating around the world, none carry more potential for destruction and threaten existing medical interventions than the emergence of hospital-acquired "super-infections". In the United States alone, some 14 000 individuals are infected and die each year from drug-resistant microbes picked up in hospital. Salmonella, Pseudomonas and Klebsiella are among the bacteria manifesting high levels of resistance most notably in developing nations. Other infections for instance methicillin-resistant Staphyloccocus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) are also wreaking havoc in hospital wards around the world. During the 1950s and 1960s most staphylococcus infections were penicillin-sensitive. Now, at the beginning of the new millennium, almost all are not only resistant to penicillin, but also increasingly impervious to each successive drug developed to breach the gap.
From what used to be considered mere medical curiosities, these resistant infections have exploded into a major healthcare crisis. In some hospitals particularly in the United States most staphylococcus and enterococcus infections are increasingly intractable. So far, the only drug available to treat MRSA is vancomycin itself faltering in the face of a renewed attack by vancomycin-intermediate Staphyloccocus aureus, otherwise known as VISA. This emerging microbe is already showing levels of resistance that, while still manageable, are nonetheless threatening to catapult it into the drug-resistant big leagues.
Because hospitals and nursing homes typically hold large numbers of immuno-compromised patients specifically those individuals who have recently undergone transplants, are taking cancer treatment or have been infected with HIV organisms usually considered harmless in healthy individuals proliferate uncontested by the body's immune response. So far, current preventive methods emphasizing hygiene and aggressive infection-control measures have reaped only dubious benefits and at best, only slowed the spread of resistant bacteria. This means that commonplace medical procedures once previously taken for granted hip replacements, dental surgery and cyst removals could conceivably be consigned to medical limbo. The repercussions are almost unimaginable.
An added concern is that hospital-acquired infections rarely stay put. Ample evidence would suggest that many resistant infections erupted in hospital settings before migrating to the community at large. Already, both MRSA and VRE have spread outside the hospital to affect healthy populations.
Leishmaniasis is an insect-borne disease that is showing resistance to the highly toxic, heavy metal-based antimonials at rates of 64% in some developing nations. Currently, visceral leishmaniasis otherwise known as Kala-azar afflicts 500 000 individuals each year in 61 countries in the Mediterranean basin, East Africa and India. The sandfly-transmitted parasite attacks the spleen, liver and bone marrow and is characterized by fever, severe weight loss and anaemia. Left untreated, the disease is fatal. Like MDR-TB, drug-resistant leishmaniasis results when treatment courses are too short, interrupted, or consist of poor-quality or counterfeit drugs. Once infected, victims remain vulnerable to potentially fatal flare-ups throughout their lifetime. As with most infectious diseases, resistant strains flourish in areas where poverty is high, surveillance is low and treatment frequently inconsistent due to limited medical access, inadequate diagnosis, the availability of black-market drugs, and political discord. Active monitoring procedures that could reveal the true extent of the disease are hindered by lack of available funds and civil unrest. In one study, WHO researchers conducting a house-to-house search discovered that the actual rate of infection was 48 times that which had been initially reported.
In the state of Bihar in north-western India, up to 70% of Leishmania cases are non-responsive to current treatments, while in Bangladesh, Brazil and particularly Sudan (where 90% of all cases originate), resistance continues to grow. In developed Mediterranean nations, drug-resistant leishmaniasis continues to spread as the number of patients co-infected with HIV increases. Those infected with HIV or who are immuno-suppressed in any way (as a result of cancer treatments or organ transplants) are likewise vulnerable. Any kind of immuno-suppression can potentially increase the number of parasites in the blood, thereby giving rise to the likelihood of transmission through the bite of the sandfly. This cycle facilitates a destructive spiral of greater resistance, higher parasitic levels and increased infection-producing potential.
Conflicts, civil upheaval and climatic change also play a role in the spread of leishmaniasis. During the 1990 Gulf War, some 20 Coalition soldiers became seriously ill with the infection. In Brazil and Turkey, visceral leishmaniasis was virtually unknown until fairly recently. In war-torn Sudan, where the disease has been endemic for centuries, researchers have discovered leishmania inexorably marching north. War, globalization, increased travel, and climatic change places the parasitic infection solidly in the category of emerging diseases with rapidly-evolving resistance.
Gonorrhoea is one example of how antimicrobial abuse has propelled a once-curable nuisance into a potentially life-threatening contagion. The development of antimicrobial resistance in gonorrhoea is one of the major health care disasters of the 20th century.
Gonorrhoea and other sexually transmitted infections (STIs) are important co-factors in the transmission and spread of HIV. This is because HIV bonds to white blood cells collecting at inflamed sites around the urinogenital tract. Studies show that those co-infected with gonorrhoea and HIV shed HIV at nine times the rate of individuals affected with HIV alone.
Of the STIs including chancroid and chlamydial infection gonorrhoea is the most resilient with a resistance rate that continues to outstrip new treatment strategies. Gonorrhoea resistance first showed up in GIs during the Viet Nam war and is now entrenched around the globe with MDR strains appearing in 60% of those infected each year. In most of South-East Asia, resistance to penicillin has been reported in nearly all strains at a rate of 98% overall. Newer, more expensive drugs notably ciprofloxacin are likewise showing an increasing failure rate. Owing to resistance gonorrhoea has become a driving force in the HIV epidemic.
Economics play a significant role in the development of gonorrhoeal resistance. For example, a 125 mg dose of ciprofloxacin may cure gonorrhoea, but will likely kill only those organisms susceptible to the medication, leaving a small number of resistant organisms that cause no symptoms. The recommended dose is 250 mg, while 500 mg will most certainly eradicate any lingering infection. The reality, however, is that poverty forces both health care providers and their patients to opt for lower doses of prescribed medications or choose cheaper, less effective alternatives in order to save money.
As with all STIs, women remain particularly vulnerable because infections are frequently asymptomatic until well after the damage has been done. In many nations, women are forced to seek treatment at STI disease clinics that are often located far from where they live, since the clinics carry a powerful stigma. Untreated, gonorrhoea greatly enhances the likelihood of infection with HIV, causes infertility in both men and women, miscarriages, still births and blindness in newborn babies.
Because levels of resistance vary widely from one nation to the next indeed, from clinic to clinic WHO no longer recommends a single, first-line treatment for gonorrhoea. Instead, each nation must make decisions according to its own resistance situation a quandary, given that many cannot afford surveillance and must instead rely on proxy data gathered by wealthier neighbours.
Another area where drug resistance poses a threat is in the treatment of food-borne and soil-transmitted helminths also known as worms. These remain a leading cause of chronic illness throughout much of the developing world. Currently, some two billion people are infected with soil-transmitted worms (hookworm, roundworm and whipworm) while schistosomiasis otherwise known as bilharzia infections afflict another 200 million in sub-Saharan Africa.
These infections lead to a weakening of the body's defence system through blood-loss, malnutrition, tissue and organ damage. Systemic parasitic colonization predisposes individuals to other diseases and/or eventual death from kidney or liver failure. So far, the treatment of helminthic infections costs a few cents per dose. Nevertheless, such interventions must be undertaken on a regular basis and encompass an entire population in order to prevent re-infection particularly among those in high-risk groups such as women of childbearing age and children.
Among livestock, resistance in helminths has already burgeoned into a huge problem a result of continuous reliance on anthelminthic drugs and the widespread disinfecting of pastures to ward off the often economically disastrous effects of parasitic infections. In humans, resistance has not yet emerged, but remains a real threat that could seriously undermine current treatment programmes.
Back to Table of Contents
5: Call to Action:
A Massive Effort to Provide Proper Treatment
"Antibiotic resistance as a phenomenon is, in itself, not surprising. Nor is it
It is, however, newly worrying because it is accumulating and accelerating, while the world's tools for combating it decrease in power and number."
Joshua Lederberg, Nobel Prize winner
Despair may be an understandable reaction as resistant microbes continue to proliferate despite the immense effort and billions of dollars that have gone into a century of research and development. The battle, however, is far from lost. Better treatment strategies, immunization programmes, improved hygiene, nutrition, enhanced vector control and initiatives targeting poor and disrupted populations have gone a long way towards reducing the spread of drug-resistant infectious diseases. Critical investments of time, effort, money, cooperation, flexibility, philanthropy and personal commitment on the part of individuals, governments, NGOs, large pharmaceutical companies and private and public organizations can halt the spread of this growing problem.
Inadequate health services, inadequate drug supplies, non-adherence to treatment strategies and dubious drug quality all favour the emergence of resistance. In peoples who enjoy wide access to antimicrobials and wise dispensing in approved treatment strategies health can be improved and the evolution of resistance contained. Without wiser and wider use, effective antimicrobials now taken for granted, will be rendered increasingly impotent against a burgeoning population of resistant microbes.
The beneficial effects of wise and wide use have been clearly demonstrated. In some regions of China anti-TB drugs are widely available to all patients diagnosed with TB. At the same time, these drugs are provided wisely through the WHO-recommended DOTS strategy an effective case-management system that helps ensure that patients take quality anti-TB drugs in the right dosage for the appropriate length of time. A recent study has shown that TB resistance in those areas of China implementing DOTS, is one-third lower than in regions that have opted out. The Stop TB Initiative an alliance of concerned governments, non-governmental organizations, international organizations, and financial institutions is mobilizing resources and promoting DOTS expansion worldwide.
Roll Back Malaria is another "wisely and widely" initiative, based on the principle that antimalarials must be made widely available in order to prevent the 1.1 million deaths the infection causes every year while, at the same time, promoting rational use of quality antimalarials. Currently, Roll Back Malaria is developing surveillance strategies designed to detect increased drug resistance to further enable countries to respond wisely to the threat of resistance before it reaches a critical level.
WHO's Wisely and Widely Points for Action
1. Adopt WHO Strategies and Policies
For most diseases, WHO has established effective strategies specifically targeting disease prevention, treatment and control among the most important are WHO policies on immunization.
Vaccination is the most logical and effective means to contain resistance by preventing infection in the first place. For those diseases for which no vaccine exists, other effective tools are available but still largely untapped. For ARIs, diarrhoeal diseases and malaria in children, WHO has developed the Integrated Management of Childhood Illness (IMCI). For the treatment of TB, WHO recommends use of the DOTS strategy.
Despite the relatively low cost of these and other WHO-recommended interventions, many countries have yet to adopt them as an integral part of national health care strategies. Of equal concern are nations that have adopted WHO recommended interventions as policy, but have yet to fully implement them. Practical and lifesaving policies and interventions are only effective if properly implemented and maintained.
Antimicrobial resistance surveillance another critical tool in the fight against antimicrobial resistance identifies and tracks resistance trends in specific infections and geographical locations. In order to assure maximum impact, WHO recommends that surveillance data be analysed and distributed to health-care workers in order to assist them in prescribing drugs appropriately. Surveillance data is essential in updating national lists of essential drugs, treatment guidelines and infection control policies. WHO surveillance standards and disease-specific guidelines provide invaluable blueprints for the development and strengthening of national surveillance planning.
WHO's Global Strategy for the Containment of Antimicrobial Resistance is another strategy that offers a series of recommendations aimed at enabling countries to define and implement national policies designed to maintain antimicrobial efficacy.
2. Educate Health Workers and the Public on the Use of Medicines
Educating the public and health care sectors on the wiser use of antimicrobial drugs is imperative to halt the spread of resistance. Governments, professional societies and teaching institutions must keep healthcare priorities up-to-date by supplying necessary information on the selection of correct drugs, dosages, and optimum treatment durations necessary for effective patient management. Education programmes must also be tailored to the needs of specific groups be they village healers, market vendors, street dispensers, health care workers, paramedical assistants, midwives, nurses, dentists, doctors or others involved in primary care. WHO recommendations, described in the booklet Rational drug use: consumer education and information, discusses practical issues and dilemmas related to the responsible use of antimicrobials.
Educating consumers and the community on the judicious use of antimicrobials is also critical in tackling the problem of drug resistance. Patients need to recognize the value of antimicrobials, how to use them and how not to use them; the importance of taking them as required, and avoiding them when unnecessary. A 1997 study in Peru revealed that public education resulted in decreased antibiotic misuse in the treatment of simple diarrhoea.
In Canada, researchers found that antimicrobial use declined by 4% in 1999 after widespread media and government campaigns warning Canadians of the dangers of antimicrobial resistance. However interventions such as these are more challenging when applied on a global scale - illiteracy and funding shortfalls make it difficult for poorer nations to implement educational programmes. Sadly, it is those very nations that are hardest hit by infectious diseases.
Advertising is another potent means of educating both the public and health care workers. At best, material that promotes specific medications in a responsible way can be an invaluable source of information. At worst, irresponsible attempts to increase medicine sales and profits results in the dissemination of information calculated to mislead often desperate consumers into spending hard-earned cash on unnecessary and sometimes harmful medications. In addition, irresponsible advertising sometimes persuades prescribers to dispense expensive second and third-line drugs that should normally be kept in reserve.
This need not be the case. Both pharmaceutical companies and governments must join forces to ensure that existing guidelines for responsible advertising and promotion are followed.
Educating prescribers on advertising tactics is another approach. In the Philippines, medical students who underwent a four-hour programme on the critical evaluation of drug promotional materials showed significantly more "media savvy" when queried on guideline violations in drug advertising.
3. Contain Resistance in the Hospital
People in their homes ingest the majority of antimicrobial drugs. The most intensive use of these drugs however, occurs in hospitals where over-crowded conditions and large numbers of sick people drive the emergence of multi-resistant pathogens such as MRSA.
Therefore it is imperative that hospitals act quickly to mobilize the professional expertise of administrators, clinicians, pharmacists, microbiologists and other health care providers to find creative solutions to tackle the problem of antimicrobial resistance. Developing and implementing new policies and practices ensuring the wise use of antimicrobials is a vital first step. Stepped-up strategies designed to monitor drug use and increase resistance surveillance is equally imperative. For maximum efficacy, hospitals must ensure results are delivered back to health care professionals to provide up-to-date diagnostic and prescribing guidelines.
WHO also encourages hospitals to form drugs and therapeutics committees aimed at establishing treatment guidelines. These encourage drug-use monitoring and infection-control thereby preventing the transmission and spread of resistant organisms.
4. Reduce the Use of Antimicrobials in Livestock
Growing evidence reveals the impact of drug resistance on human health. In 1997 WHO recommended antimicrobials normally prescribed for humans be prohibited as growth promoters in animals.
Furthermore, WHO recommended that antimicrobials not be used as an alternative to high-quality animal hygiene. Evidence shows that farmers who stopped relying on antimicrobials as growth promoters in livestock have experienced no economic repercussions provided animals were given enough space, clean water and high-grade feed.
In 1998, the European Union followed WHO recommendations and banned the use of antimicrobials prescribed for the treatment of human infections as growth promoters in animals. Recent studies would appear to offer testimony to the wisdom of such legislation. In Germany and Denmark preliminary research appears to confirm that the ban of avoparcin as a growth promoter in chicken has led to a decrease in the prevalence of vancomycin-resistant enterococci in both poultry and the community at large.
Though bans on antimicrobial use on animals seem to be effective, other non-medical uses of antimicrobials need to be carefully monitored for their potential impact on human health.
5. Increase Research for new Drugs and Vaccines
Encouraging the research community to develop new compounds is essential as once-effective treatments become impotent in the face of ever-evolving resistant microbes. Even our best efforts will only slow the pace at which resistance emerges. Thus, development of new antimicrobials and alternative approaches (such as vaccines) is vital. Current public and private sector investment in vaccines, drugs and other products to prevent or treat major infectious diseases in developing countries has been less than 2% of total health research expenditures throughout the world. Incentives are needed to encourage pharmaceutical companies to discover and develop new compounds, as well as intensify research into dosage regimens calculated to minimize the likelihood of selecting for resistance.
Effective vaccination programmes prevent people from getting sick in the first place and thus minimize the need for drugs, which in turn reduces the selection and spread of resistant microbes. Vaccination is also the most cost-effective means of controlling disease as evidenced by the success of smallpox and polio eradication programmes - both of which highlight mass immunization strategies. Such has been the commitment to polio eradication, that wars and conflicts have been suspended for national immunization days.
Nevertheless, investments of time and capital needed to develop new vaccines are substantial. The risks of failure are huge. Moreover, not every infectious disease lends itself to this type of prevention. In those diseases for which vaccines are currently lacking, but where their development is feasible, efforts must be intensified. At the same time, research for new antimicrobial drugs, and for simpler diagnostic tests that permit more targeted use of antibiotics, must be increased.
WHO is now actively promoting joint funding for research into new drugs, vaccines and diagnostics in addition to the development of ethical treatment guidelines with the input of both the private and public health care sectors. These strategies are designed to reduce costs enough to minimize financial risk thus enabling large pharmaceutical companies to take over the manufacturing and distribution of effective medications.
Private and non-profit organizations are also contributing. In 1999 the Gates Foundation earmarked US$ 100 million specifically for malaria, TB and HIV vaccine research, and has donated an additional US$ 750 million for the Global Alliance on Vaccines and Immunization (GAVI) to distribute vaccines to needy children. The Gates Foundation has also provided
US$ 50 million for the development of new drugs for TB and malaria the latter through the new Medicines for Malaria Venture (MMV). MMV is an example of how public and private institutions can join forces to develop new drugs and fight drug resistance. This Swiss-based non-profit organization is dedicated to developing a new antimalarial drug every five years. Initial co-sponsors of MMV include: the Gates Foundation, WHO, the International Federation of Pharmaceutical Manufacturers Associations (IFPMA), the World Bank, the Department for International Development in the United Kingdom, the Swiss Agency for Development and Co-operation, the Global Forum for Health Research, the Rockefeller Foundation and the Roll Back Malaria partnership. The mandate of this new venture is to provide funding for the discovery and development of drugs to treat illness among poor populations.
Another innovative public/private sector partnership between the UNDP, World Bank, WHO Special Programme for Research and Training in Tropical Diseases (TDR ), the Japanese government, and the Japanese pharmaceutical industry involves screening pharmaceutical compounds discovered by Japanese companies for antimalarial activity.
In response to the growing need for new treatment strategies to address the increasing threat of drug-resistant malaria, four pharmaceutical companies (Knoll, Novartis, Scanpharm and Scherer) have banded together with TDR to study the efficacy of rectal suppositories containing artesunate for the prevention of childhood malaria deaths. Drug combinations have long been recognised as critical in combating multi drug-resistant malaria. Studies are now being developed by TDR in association with Novartis and SmithKline Beecham to systematically analyse combination malaria treatment.
6. Build Alliances and Partnerships to Increase Access to Antimicrobials
Inadequate access to essential antimicrobials results in inappropriate treatment which in turn hastens the development of resistance. Successful attempts to increase access to existing antimicrobials in a coordinated manner are dependant on creative private and public sector collaboration. Implementation can only be assured through alliances that involve governments, international organizations and non-governmental organizations (NGOs).
The story of the fight against leprosy a deforming and stigmatizing disease that once disfigured millions is illuminating. Nearly eliminated in the 1990s, the retreat of this ancient scourge is a particularly fine example of how public health institutions, NGOs, communities, private donors and pharmaceutical giants can work together to fight resistance and ease the suffering of thousands of people.
It wasn't until the 1950s that effective treatment for leprosy was introduced into vulnerable populations. By the 70s, the organism had launched a major counter-offensive and had effectively disarmed and rendered obsolete the sulpha drug dapsone. By the 1980s, two drugs rifampicin and clofazamine cleared the way for viable treatment alternatives. The organism developed resistance to all three drugs when prescribed singly but in combination with dapsone, these new medications effectively trounced the leprosy bacilli and led the way to cure and researchers hope elimination by 2005. Wiser for the experience, scientists are holding back three alternative drugs in the event that resistance recurs. The only outstanding issue however is cost. Fortunately, a solution involving the private and public sectors working in tandem with corporate interests means patients need wait no longer. Blister packs containing multi-drug therapies are now being distributed to patients free of charge. Thanks to WHO-sponsored research grants, Nippon Foundation funds, and donations of medication from the Swiss pharmaceutical Novartis, leprosy is on the way out.
The costs of treating resistant TB places an enormous burden on poor countries. As the prevalence of MDR-TB increases there is a pressing need to identify the most cost-effective treatment regimens. WHO has recently partnered the Eli Lilly Company and Médecins sans Frontières to form a Green Light Committee aimed at reviewing research proposals designed to evaluate the most cost-effective treatment of multi drug-resistant TB. Applicants will be offered concessionally-priced second-line anti-TB drugs for approved projects.
A unique partnership between TDR and Aventis, the company that developed eflornithine, could spell relief for thousands suffering the effects of African Trypanosomiasis, also known as sleeping sickness.
Earlier this year Aventis donated the licence for eflornithine to WHO. Through TDR, the organization will license production to another pharmaceutical company (possibly within a developing country) to produce and market the drug. In partnership with Aventis, Médecins Sans Frontières and WHO, existing stocks will be made available at no cost to those countries most in need.
These are just a few examples of how public health institutions and pharmaceutical companies can work together to ensure equal access to medical treatment regardless of socio-economic status. Owing to the assistance and generosity of corporations and non-profit organizations, these and other crippling infectious diseases can now be tackled with existing drugs before resistance becomes an uncontrollable problem.
7. Increase Availability of Essential Drugs
In 1977 WHO developed the Model List of Essential Drugs to encourage rational drug use. The intent is to provide a blueprint on essential drugs required for national governments to treat specific complaints. Over the years, this document has been revised regularly and now serves as a guide for more than 120 countries.
Essential drug policies when adopted in conjunction with educational programmes, effective follow-up, development of national standard treatment guidelines and mechanisms to ensure the supply of high-quality drugs significantly increase wider availability of quality drugs as well as encourage their wiser use.
Analysis has shown that individuals living in nations that have adopted essential drug policies enjoy greater drug access yet resort to significantly fewer injections and antimicrobial prescriptions when confronted with possible infections. A retrospective survey of prescribing practices in Ethiopia determined that health care providers who relied on the essential drugs list discouraged the unnecessary dispensing of non-essential drugs. To further bolster national efforts, WHO has recently released an Internet guide to assist Member States in accessing reliable information on pharmaceutical products.
8. Make Effective Medicines Available to Poor People
The discovery and development of antimicrobial drugs has brought enormous health gains to those fortunate enough to benefit from their availability yet too many are still missing out. To address this divide, we must all work to substantially increase funds to provide life-saving drugs and health technologies in developing countries thus enabling the poor to take control of their own health. It is now possible to strike a blow at the diseases of poverty, thereby reducing deaths caused by the highest burden diseases in low-income countries by 50% within the next decade.
These diseases include malaria, tuberculosis, infections related to high-risk pregnancy, childhood infections, HIV, diarrhoeal diseases, acute respiratory infections and measles. A massive effort is needed to ensure that life-saving medicines and other interventions are made available through effective health services before drug resistance reduces options still further. These products include diagnostics for malaria, essential antimicrobials, oral rehydration therapy in addition to mosquito nets, condoms, and vaccines. Beneficiaries will include public and private health care organizations including non-governmental organizations that have shown a demonstrable ability to use such interventions effectively in the fight against poverty and ill health.
Back to Table of Contents
In the last century medical advances and enhanced knowledge of the origins and causes of disease have led to an unprecedented increase in longevity and quality of life for those fortunate enough to enjoy access to drugs and vaccines.
With those gifts has come a kind of complacency that could well lead humanity into the same straits as the fabled hare who slept while the turtle crept, and thereby lost the race.
Be it medical interventions or a bounty of medications that have transformed our experience of life into something other than the precarious existence of our ancestors, humanity still has much to learn about the wise and wide use of antimicrobial drugs.
We need to use our resources wisely; to widen access to appropriate medications to encompass all people regardless of race, gender, or socio-economic status while at the same time reserving these precious compounds to treat only those diseases for which they are specifically required. We need to continue the fight to end conditions of poverty, ignorance, greed and social injustice that force individuals and health care providers into decisions that will ultimately bring about our own downfall. The potential of drug resistance to catapult us all back into a world of premature death and chronic illness is all too real.
Our grandparents lived during an age without antibiotics. So could many of our grandchildren. We have the means to ensure antibiotics remain effective, but we are running out of time. Our window of opportunity to help those impoverished by infectious diseases is closing.
Back to Table of Contents