Year 2000 Infectious Diseases Report
World Health Organization
Introduction: Humanity at the crossroads Since their discovery, antibiotics have completely transformed humanity’s approach to infectious disease. Scourges that once struck terror into the hearts of millions—plague, whooping cough, cholera and scarlet fever—have been, or are on the verge of, being controlled. Improvements in sanitation, housing, nutrition along with the advent of widespread vaccination programmes have likewise led to a dramatic drop in once common communicable diseases that formerly laid-low entire populations.
Now, at the dawn of a new millennium, humanity is faced with yet another crisis. Formerly curable diseases such as gonorrhoea and typhoid are rapidly becoming untreatable, while old killers such as tuberculosis are now arrayed in the increasingly impenetrable armour of antimicrobial resistance.
This phenomenon is inevitable yet 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 healthcare.
Since 1970, no new classes of antimicrobials have been developed to combat infectious disease. As once affordable and effective medications crumble in the face of this growing threat, what few new drugs developed to replace them will become increasingly expensive and beyond the reach of those who need them most. We are dreaming if we believe that any new antimicrobials in development will breach the gap. At best, anti-infective drugs take some 20 years and millions of dollars to develop. No new breakthoughs are yet on the horizon.
Among poor people who never benifited from quality antimicrobials in the first placeHIV/AIDS, shigella dysentery, malaria, pneumonia and a host of other ailments will continue to cut swathes through populations already suffering from infectious diseases long considered curable in developed countries. Between 1985 and 1991, TB increased by 12 per cent in the Unites States of America, 30 percent in Europe and 300 per cent in Africa where HIV/AIDS runs rampant. Diptheria has likewise re-emerged in the former USSR and Eastern European nations, while cholera—now multi-drug resistant—continues to harry those living in areas disrupted by war, famine and inadequate nutrition and sanitation. These recent developments mean longer and more expensive treatment courses, longer stays in hospital, increased morbidity, increased infectiousness and greater strains on already over-burdened healthcare systems in resource-starved developing nations. The resultant loss of productivity holds devastating consequences for families already a hairsbreadth away from starvation.
In wealthy nations, high-tech medical interventions long taken for granted could well become procedures of the past as hospital-acquired ‘super bugs’ colonize previously safe havens for the sick. This burgeoning microbial cataclysm means interventions such as hip replacements, organ transplants and even simple dental procedures could one day be consigned to the oblivion of a medical dead end.
Chapter One A world without antibiotics
Although the Soldiery retreated from the Field of Death, and encamped out of the City, the Contagion followed, and vanquifh'd them; many in their Old Age, and others in their Prime, funk under its cruelties; of the Female Sex moft did; and hardly any children efcaped; and it was not uncommon to fee an Inheritance pafs fuccesffively to three or four Heirs in as many Days; The Number of Sextons were not fufficient to bury the Dead.
–Nathanial Hodges; Loimologia: an account of the 1665 London Plague (300 years before streptomycin)
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.
As recently as the 19th century, the average life span in both Europe and North America was fifty years or so 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 from any number of hostile pathogens. It was a world in which the likelihood of dying prematurely from infectious diseases was as high as forty percent, and where men routinely married up to four wives each—many of whom succumbed during childbirth with infections easily curable by today’s standards. In the early 1800s, outbreaks of puerpural sepsis—a streptococcal infection—was reponsible for the deaths of upwards of 70 percent of new mothers ‘lying in’ at hundreds of small hospitals flecking Europe. In one Italian infirmary not a single woman survived childbirth for one entire year. Not until physicians (who routinely bounced between morgue and maternity room) adopted hand washing in the late 1800s, did the death rate decline.
For the ancestors of those 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—as The Church fathers constantly intoned—transient, ephemeral and characterized by an endless cycle of grief and loss.
Wave after wave of epidemics kept humanity forever teetering on the edge of demographic collapse. From between the 14th and 15th centuries, Europe saw its population halved by successive outbreaks of smallpox, typhus, and the successive eruptions of the Black Death. In India, plague didn’t really take hold until 1896 when a mutant strain appeared out of Yunnan in China. By 1903 more than 1.3 million souls were expiring per annum. Overall, researchers estimate some 12.5 million people died of plague between 1896 to 1948 in India alone.
Cholera is another communicable disease that ran rampant throughout much of the last 1,000 years and continues to do so in many impoverished nations. Before the advent of European colonizers, references to cholera remained sketchy at best —although many historians and ethnographers speculate Vibrio cholerae was already entrenched throughout much of the Indian subcontinent long before the arrival of the Europeans. This is evidenced by a millennium-long practise of paying homage to the Goddess of Cholera—otherwise known as Oola Beebee or Ola Devi—who sits astride a vulture perched on the dessicated corpse of a cholera victim.
In 1783, British historians calculated that some 20,000 pilgrims to the holy site of Hardawar succumbed to cholera’s clammy grip. Within months the bacilli spread towards China, north to Russia (engaged in yet another interminable war with the Poles) and southwest to the Middle East. By 1831 cholera lapped up nearly half of the Haj faithful making the annual pilgrimmage to holy sites in Mecca and Medina—the fatal consequence of bathing and drinking at a single ritualistic source of contaminated water. Sucked dry and shedding vibrios, dying pilgrims crept homewards depositing bacteria along key tranportation 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 shrivelled corpses, orphans, economic ruin and contaminated water and food.
Infectious disease has also influenced the entire course of history. Up until last century’s Second World War, it was pestilence—and not warfare—that spirited off the bulk of Europe and Asia’s fighting men. 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 demoralised 93,000—who wound up straggling home just long enough to pass on the Rickettsia on neighbours and loved ones. The subsequent epidemic wiped out another two million, carrying off 250,000 civilians in Germany alone. In the New World, it wasn’t superior Spanish, firepower, nor their reliance on horses that resulted in the conquest and enslavement of the Amerindian. By far, 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 gutting the local indigenous population by 80 percent—thereby liberating them not only of their pagan beliefs, but their very lives. That same outbreak was also responsible for rubbing out 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 the flu 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 when one factors in the inroads European diseases made into a people entirely devoid of immunity. Conquistador and expedition scribe Bernal Diaz described the resultant carnage 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 ten years, historians estimate that Mexico’s population plummeted from some 25 million to 6,500,000—a drop of 74 percent. In North America, later events echoed those in Mexico but with one not-so-subtle difference. By the 1600s colonisers knew enough about epidemiology to maliciously inflict deadly diseases on locals by providing ‘gifts’ of blankets and clothing infested with both smallpox and typhus-bearing lice—thus hearkening in the first recorded acts of biological warfare.
If smallpox was Europe’s primary export to the New World; the New World hit back with syphilis. After indulging in the usual rape and pillage, Spanish conquistadors, troops and camp hangers-on returned to Europe only to scatter the seeds of yet another epidemic. This new sexually-transmitted contagion was characterized by genital ulcers and 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 Mauppassant are just a few who undoubtedly met an ugly end courtesy of the peripatetic spirochaete.
The end of the First world also saw seemingly innocuous ailments such as the ubiquitous, ‘touch of grippe’ metamorphosize 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 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 noted that the pandemic wiped out 20 million in India, while contemporary experts tag the total number of dead at 30 million—more than those killed in the 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 percent of the Islands’ people died, while in Canada entire Inuit villages sniffled and then fell silent under the deathly pall of influenza-related infections. To date, influenza has caused more deaths than HIV/AIDS.
On a more personal and immediate note; who alive in industrialized nations today doesn’t know a grandmother or great uncle who can’t describe how whooping cough, influenza or diptheria whittled away at friends and family? A few questions will invariably yield a mare’s nest of suffering and loss. During 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. In the developing world—where poverty and lack of access to healthcare remain oppressive reminders of human frailty—communicable disease continues to be an omnipresent threat to life and livelihood. The consistency of diminished life expectation within developing countries testifies to the huge burden of infectious disease. Owing to the absence of hard historical data, one can only extrapolate former conditions of overcrowding, poor sanitation and malnutrition once prevailing in Europe to developing nations today.
Increases in antimicrobial drug resistance in developing nations—for malaria, diarrhoel disease and acute respiratory infections—threatens to undermine declines in childhood mortality that had until recently been the pre-imminent public health success story of the last quarter century. Chapter Two Beating back the bugs: the discovery of microbials “I will lift up mine eyes to the pills,” carolled the British writer Malcolm Muggeridge in 1962. For those living in developed nations – whether they are willing to recognize it or not—Muggeridge’s paean to the power of pills is no hyperbole. The twentieth century has seen an almost complete transformation in the 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 smallpox, measles, typhoid fever, rubella, diptheria, tetanus, yellow fever, pertussis and polio. In developed nations the story has been somewhat different. Separated by poverty, geography, scarcity of antimicrobials, and a lack of political will on the part of governments more engaged with warfare than public health, individuals living in such areas have long been consigned to the healthcare margins. Nevertheless, the fact that these tools exist and are (still) effective consititutes the healthcare miracle of the last 500 years.
From German microbiologist Paul Ehrlich’s seminal theory of the ‘magic bullet’ as a metaphor for antibodies—the human body’s own natural arsenal of disease-fighting organisms—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 other contributions were the first use of arsenic (Salvarsan) in the treatment of syphilis and quinine for malaria. His discoveries were soon followed and improved upon by successive generations of dedicated and often courageous researchers and health professionals.
In 1928 British scientist Alexander Fleming first 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, scientists dubbed it a ‘miracle drug.’ Fleming’s discovery triggered a healthcare revolution unprecedented in the annals of medical science. From that one intitial specimen flowered an entire family of penicillin-based antibiotics; followed by streptomycins, tetracycline, quinolones, antifungals and, more recently, antivirals. These drugs—collectively known as antimicrobials—have saved the lives of millions, reduced illness, and allowed the development of high-tech medical advances such as organ transplants, hip replacements, implantations and other complex surgical procedures previously considered too hazardous due to post-operative infection.
In 1927 German scientist Gerhard Domagk upped the ante with his research into sulpha compounds. After being appointed research director of IG Farbenindustrie where he discovered that 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 likewise relieved of a persistent streptococcal infection. Prontosil was eventually used to treat puerperal fever—slashing the mortality rate from 20 to 4.7 percent. Domagk won the Nobel Prize in 1939, but was blocked by Adolf Hitler who banned Germans from accepting Nobel prizes after the 1935 peace prize went to a ‘dissident.’ The night of the awards ceremony saw him cooling his heels in a gestapo prison. The Nobel Insititute remained so impressed by his dicoveries that they belatedly awarded him the prize during a special 1947 ceremony in Sweden.
Progress followed hard on the heels of Domagk’s ground-breaking research.. Nineteen thirty eight saw a British team lead by A.J. Evans develop yet another sulphonamide—sulfadiazine 693, later called sulphanilamide—that also proved effective in treating streptococci, including pneumococci. Winston Churchill was among many who credit the drug with prolonging his life after falling ill with pneumonia during a critical juncture in the Second World War. In 1940 Russian émigré Selman Waksman isolated a fungus that eventually lead to the development of the anti-tuberculosis drug streptomycin—a discovery that garnered him the Nobel Prize. Tuberculosis’s knock-out punch (before multi-drug resistance helped it back on its feet) was finally delivered by pharmaceutical giants Squibb and Hoffmann-La Roche with the development of isoniazid. Like other anti-TB drugs the new drug easily encouraged resistance in the ever-resilient bacilli. In 1957, this dilemma was effectively solved when a Lepitit research team headed by Piero Sensi discovered another anti-TB faily of drugs later released under the name rifamycin. 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.
In the 1970s, antivirals sidled onto centre stage with the development of acyclovir —potent against herpes zoster (shingles), cold sores and genital herpes. This was another significant advance in that it marked the first time an antiviral successfully stymied pathogen replication without proving toxic to the host. Of these particularly hard-won antimicrobials, drug resistance is already nibbling away at medications that took decades to bring to the market. In clinical practice, micrbial resistance has turned up during treatments with idoxridine for the herpes simplex virus, keratitis, acyclovir therapy for mucocutaneous HSV infection, rimantidine treatement for influenza and ganciclovir treatment of CMV disease in AIDS patients.
Nowadays, the cache of antimicrobial weapons targeting infectious disease has swollen to an impressive arsenal of 150 compounds. The cost however, has been huge. Pharmaceutical companies routinely deploy some US$ 500 million on associated research and development for every new compound that hits pharmacy shelves. For every success, there are tens of thousands of failures. Every pathogen that develops resistance represents the effective dismantling of a legion of hopes, dreams and dollars.
Although the development of drugs have saved the lives and eased the suffering of millions living in North America, Europe and Japan, these gifts have not extended to those living in the developing world. Healthcare gains enjoyed in developed nations are limited by geography and wealth. The Dark Ages live on for the majority of those who call developing nations their home.
The bugs bite back: how resistance develops and spreads As early as half a century ago—just a few years after the discovery of penicillin— scientists began noticing the emergence of a penicillin resistant strain of Staphylococcus aureus, a common bacterium that is part of the human body’s normal bacterial flora. Resistant strains of gonorrhoea, shigella dysentery (a major cause of premature death in developing countries) and salmonella rapidly followed in staphylococcus’s wake.
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 developing countries and those co-infected with HIV/AIDS, but has appeared in locations as diverse as Eastern Europe, Africa and Asia among healthcare 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 islolates gathered around New Delhi were sensitive to cheap, first-line drugs furazolidone, ampicillin, cotrimoxazole and nalidixic acid. Now, ten years later, formerly effective drugs are useless in the battle to contain cholera epidemics.
In some areas of the world—most notably Southeast Asia—98 percent of all gonorrhoea cases are multi-drug resistant. The persistence of gonorrhoea in turn contributes to the sexual transmission of HIV. In India, 60 percent of all cases of visceral leishmaniasis—a sandfly borne parasitic infection—no longer respond to the very limited cache of first-line drugs; while in the developed world, as many as 60 percent of hospital-acquired infections are caused by drug-resistant microbes. These infections—most notably Vancomycin resistant enterococcus (VRE) and Methicillin resistant Staphylococcus aureas (MRSA) are now no longer confined to wards but have crept into the community at large.
Although most drugs are still active, the lengthening of resistance’s long shadow means many won’t be for long. In the case of tuberculosis, multi-drug resistance means medications that once cost a mere $20 US 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 under-used by patients who don’t complete courses (usually due to poverty) and misuse through over-prescribing.
Dedicated research, community mobilisation, education and the development of new antimicrobials, drug combination therapies and vaccines can go a long way towards slowing and possibly halting destructive inroads into healthcare systems around the world. If governments, NGOs, healthcare organizations, hospitals act sooner rather than later, we all still have a chance to slip through a window of opportunity that is rapidly snapping shut. Chapter Three On parole: resistance's big guns As quickly as new drugs are launched to smash humanity’s most intractable infectious enemies, the forces of resistance re-group and strike back with yet another counter-offensive.
PNEUMONIA and MENINGITIS More than any other infectious disease, pneumonia remains the number one killer worldwide. Statistics for 1999 show 3.5 million children 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 have, thus far, proven themselves wily opponents.
As many 70 percent of chest infections are resistant to one of the first-line antimicrobials. These numbers will only increase the longer co-ordinated action is delayed. Formerly, first-line medications were both effective and affordable. With the onset of resistance however, newer treatments are proving too costly for the vast majority 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 and often can be distinguished only by laboratory tests—costly and therefore unavailable in many parts of the world. The problem is that bacterial infections can kill, while 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 one hundred respiratory infections, only 20 percent require antibiotic treatment. This means 80 percent of patients are treated with medications they don’t need. Such unnecessary dosing leads drugs directly into the crosshairs of resistance. As WHO scientist Kim Mulholland recently asserted, “It is in the noses of children that most resistance develops.”
As well as preventing the onset of disease, vaccines also offer the best hope in combatting resistance by reducing the number of infected individuals and thereby minimizing transmission, infection and the need for treatment. While vaccines have been developed to combat both viral and bacterial pneumonias and almost every form of meningitis, much more work needs to be done to bring these life-saving immunization programs to impoverished populations.
DIARRHOEAL DISEASES Multi-drug resistance is also insinuating itself into microbes that cause diarrhoeal diseases. Combined, these infections claim the lives of more than two million children under the age of five each year. One such agent, the bacterium Shigella dysenteriae, is a highly virulent microbe that is resistant to almost every available drug—indiscriminately killing adults and children alike. The results of this growing crisis were illustrated most notably in the wake of the 1994 Rwanda civil war when bacterium ripped through vulnerable refugee populations already traumatized by war and loss. Left untreated, death can follow within days of infection. Ten years ago the shigella epidemic could easily be controlled with a cotrimoxazole—a drug cheaply available in generic form. Today, nearly all shigella are non-responsive to the drug, while resistance to ciprofloxacin—the last remaining drug—appears to be just around the corner. Shigella dysentery is rare in developed countries and thus, not a pressing concern to pharmaceutical companies searching for higher returns on research and development.
The bacteria that cause cholera and typhoid are also displaying their facility to 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 typhimurium—like Shigella, —is adept at accumulating cassettes of resistance genes, producing strains that withstand first, second and now, third-line drugs. Up until 1972, chloramphenicol was the treatment of choice for typhoid fever throughout much of the Indian sub-continent. 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 serious, and frequently relapsing, disease killing at least 10 percent of those infected.
HIV/AIDS and sexually transmitted infections HIV/AIDS and sexually transmitted infections are conspirators whose deadly pairing has contributed to sky-rocketing death rates in many developed and developing nations. At the end of 1999, an estimated 33.6 million indiviuals were living with HIV/AIDS worldwide. In Zimbabwe, up to 50 percent of pregnant women are infected with HIV while in Botswana, life expectancy has plummeted from 70 years to 50 in the last 25 years because of HIV/AIDS. Overall,some 2.6 million people died in 1999 as a result of infection with HIV.
Because of inadequate access to antiretroviral drugs, this bleak scenario will continue as the number of HIV-infected individuals move into the acute full-blown AIDS stage. For these people—particularly the bulk of those living in developing nations—the availability of HIV tests, and expensive life-prolonging drug cocktails are almost nonexistent. Moreover, in the developed world—where treatment is more readily available—these drug combinations are unlikely to remain viable for much longer due 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 which burst onto the scene a mere ten 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 antivirals that took years to develop at huge cost. HIV/AIDS is a particularly insidious disease because those infected become ‘reservoirs’ for TB, leishmaniasis, pneumonia, and other opportunistic infections, which have themselves developed resistance. These infections are transmissible to the population at large.
Gonorrhoea and other sexually transmitted infections are important co-factors in the transmission and spread of HIV. This is because the virus bonds to white blood cells collecting at inflamed sites around the uro-genital tract. Of the STIs—including chancroid, chlamydial infection and herpes simplex—gonorrhoea is the most resilient with a resistance rate that continues to outstrip new treatment strategies. Studies show that those co-infected with gonorrhoea and HIV shed the virus at nine-times the rate of individuals affected with the HIV alone. Gonorrhoea resistance first showed up in GIs during the Vietnam war and is now entrenched around the globe with MDR strains showing up in 60 percent 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 percent overall. Newer more expensive drugs—notably ciprofloxacin—are likewise showing an increasing failure rate.
As with all STIs, women remain particularly vulnerable because infections are requently asymptomatic until well after the damage has been done. In many nations, women are forced to seek treatment at STI disease clinics which are often located far from where they live, but which also carry a powerful stigma. Untreated, gonorrhoea greatly enhances the likelihood of infection with HIV, causes infertility, miscarriages, still births and blindness in newborn babies.
TUBERCULOSIS 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 grossly effected. Nevertheless, researchers assess the approximate number of drug resistant TB cases at between one and two per cent 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 apparently untouched by MDR TB—China, Iran and parts of Eastern Europe—report 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. An example of how infectious TB can be, occurred during the Kosovo crisis of 1999, when three otherwise healthy flight attendants came down with MDR strain during an emergency airlift of refugees to the USA. Of those sick with the multi-resistant strain, most will fail treatment with first-line drugs. Of those, many will eventually die—but not before inadvertantly spreading the resistant strain to the community at large.
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 Strategy (DOTS).Consistently applied, DOTS can cure disease in upwards of 95 percent 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 bug rallies. Currently, a single treatment course of six months for regular tuberculosis costs $US 30. With MDR TB the costs shoot upward to $US 10,000 and even more.
In the impoverished post-perestroika era of Eastern Europe and the Russian Federation, inadequate treatment—meaning poor monitoring, interrupted courses, expired or counterfeit drugs—corresponds to growing transmission rates of resistant TB organisms. 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 if they manifest ‘weakness’ of the respiratory tract. This unwitting use of a powerful drug in sub-therapeutic doses leads directly to resistance.
In addition, TB patients who are co-infected HIV, or have silicosis, are diabetic, or are immune-compromised in any way, are not only more vulnerable to resistant strains, but also become unwitting ‘pools’ of infectiousness that easily spills over into the general populace. The ability of HIV/AIDS to accelerate the onset of acute MDR TB holds serious implications for humanity at large. In crowded hospitals filled with immune-suppressed individuals, resistant TB has the potential to stalk relentlessly through a population; afflicting patients, healthcare workers and physicians alike. War, poverty, overcrowding (as in Russia’s prison system), mass migration and the breakdown of existing medical infrastructures all contribute to MDR TB’s development, transmission and spread.
MALARIA A mosquito-borne infection that kills an estimated one million yearly, and with an estimated 300 to 400 million new cases globally each year, malaria promises to be the pre-eminent threat to development in endemic regions well into the millennium.
Eighty percent of all malaria cases occur in tropical Africa. The most dangerous and predominant of the four types of malaria is Plasmodium falciparum. This parasite is responsible for up to 30 per cent of all hospital admissions and 800,000 childhood deaths in Africa each year.
Like other diseases once considered banished to the geopolitical margins, malaria is resurging in areas of the world formerly deemed disease free. In a 1999 report WHO warned of a, “a serious risk of uncontrollable resurgence of malaria” in Europe due to civil disorder, global warming, increased irrigation (canals are important breeding grounds for mosquitoes) and international travel. In the United Kingdom 1000 new cases of malaria each year are imported from malaria endemic regions to the South. In the former USSR, collapsing 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 choloroquine—the former treatment of choice—is now widespread in 80 percent 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. According to WHO figures, mefloquine resistance emerged in South East Asia almost as soon as it 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 combination medications at lower cost. Increasing surveillance to guide the proper use of these and more attention to alternative prevention strategies such as insecticide-impregnated 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.
VIRAL HEPATITIS Between them, the hepatitis B and C viruses 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 diseases —specifically HIV/AIDS—hepatitis is not only difficult to diagnose without access to expensive laboratory tests, but is also costly to treat. The two infections are easily transmissable through contaminated blood, injecting drug behavior, or—as in the case of hepatitis B—through sexual behavior and close contact between siblings.
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, fully 30 percent show viruses resistant to antiviral therapy after the first year of treatment. Secondly; although lamuvidine reduces the viral load by some 80 percent, the virus 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 170 million individuals infected with hep C, the prognosis is even more dire. Both treatments—ribovirin 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 hep B vaccine is currently on the market—and some governments are taking steps to incorporate it in national immunization strategies—hefty prices mean individuals can ill afford the required cash outlay. This grim situation must change. In China and Southeast Asia, maternal transmission of HBV is at an all time high. This means vulnerable newborns with immature immune response are at greater risk of fatal complications and are at increased risk of transmitting the debilitating virus to others. As of today, there is no vaccine for hep C. Hospital-acquired infections No populace 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 bugs.’ In the USA alone, some 14,000 individuals are infected and die each year from drug resistant microbes they picked up in hospital. Salmonella, Pseudomonas and Klebsiella are among the gram-negative bacteria manifesting high levels of resistance—most notably in developing nations. Other infections—such as Methicillin-resistant Staphyloccocus aureus (MRSA) and Vancomycin resistant enterococcus—are also wreaking havoc in hospital wards around the world. During the 1950s/60s most staph infections were penicillin sensitive. Now, at the threshold of the new millennium, almost all are not only resistant to penicillin, but also increasingly impregnable 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 medical crisis. In some hospitals, particularly in the USA, the preponderance of staph and enterococcus infections are showing intransigence. So far, the only drug that is available to treat MRSA is vancomycin—itself faltering in the face of a renewed attack by super bug vancomycin intermediate Staphyloccocus aureus, otherwise known as VISA. This emerging microbe is already showing levels of resistance that, while still manageable, is nonetheless threatening to catapult it into the incurable big leagues.
“Being left with only one effective drug for this serious infection is very disturbing,” says Walter Stamm, Professor of Medicine, at the University of Washington School of Medicine. “The big concern is this growing pool of VRE will transfer vancomycin resistance to Staph,” he states, adding this latest evolution leaves hospital patients particularly susceptible. Because hospitals and nursing homes typically have large numbers of ‘immuno-compromised’ patients— specifically those individuals who have recently undergone transplants, are taking cancer treatment or have been infected with HIV/AIDS—organisms usually considered harmless in the healthy proliferate uncontested by the body’s immune response. So far, current preventive methods emphasising 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 previously taken for granted—hip replacements, dental surgery, and cyst removals—could conceivably be consigned to medical limbo. The repercussions are almost unimaginable.
“The implication widespread drug resistant Staph aureus has on commonplace medical procedures is truly frightening,” Stamm asserts. “Many of the advances we’ve made in medicine including transplant technology, implantation, and critical care are all being compromised.” “If we can’t treat associated infections we won’t be able to use those advances.” An added concern is that hospital-borne infections rarely stay put. There is ample evidence that many infectious diseases began in hospital settings before migrating to the community at large. Already, both MRSA and VRE have spread outside the hospital and into otherwise healthy populations.
Other big disablers Leishmaniasis Leishamaniasis is another insect borne disease that is showing resistance to the highly toxic and heavy-metal based antimonials at rate of upwards of 64 percent 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 anemia. Left untreated the disease is 100 percent fatal. Like MDR TB, drug resistant leishmaniasis results when treatment courses are too short, are interrupted or are caused by treatment with 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 where treatment is frequently inconsistent due to limited medical access, inadequate diagnosis, black market drugs, and political discord. Active monitoring procedures that could reveal the true extent of the disease are hobbled by lack of available funds and civil unrest. In one study, WHO researchers conducting a house to house search discovered the actual rate of infection was 48 times that which had been initially reported.
In the state of Bihar in Nort West india, up to 70 percent of leishmania cases are non-responsive to current treatment while in Bangledesh, Brazil—and most particularly the Sudan—where 90 percent of all lesihmania cases originate, resistance continues to grow. In developed Mediterannean nations, drug resistant leishmaniasis continues to spread as the number of patients co-infected with HIV increases. Those infected with HIV or who are immune-suppressed in any way—as a result of cancer treatments or organ transplants—are likewise vulnerable. Any kind of immune suppression can potentially up the ‘parasitic load’ thereby increasing the likelihood of transmission through the bite of the ubiquitous sandfly. This cycle facilitates a destructive spiral of greater resistance, higher parasitic load and increased infection-producing potential. And no one is immune.
During the 1990 Gulf War, some 20 Coalition soldiers became seriously ill with visceral leishmanisis. 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, globalisation, increased travel, and climatic change places the parasitic infection solidly in the category of emerging diseases. “Because of the political situation in the Sudan no one wants to help Sudan.” “Sanctions against Sudan have only hurt the already traumatized population,” maintains WHO scientist Farrokh Modabber. “It has spread to the point where hundreds and thousands are dying.” Potential threats: common worms Another area where drug resistance poses a threat is in the treatment of food and soil-borne worms—also known as helminths. These remain a leading cause of chronic illness throughout much of the developing world. Currently, some two billion individuals are infected with soil-transmitted worms (hookworm, roundworm and whipworm) while schistosomiasis—otherwise known as bilharzia —infections continue to afflict another 200 million in sub-Sahara Africa alone.
These infestations lead to the weakening of the body’s defence system through blood-loss, malnutrition, tissue and organ damage. Systemic parasitic colonisation predisposes individuals to other diseases and/or eventual death from kidney or liver failure. So far, the treatment of helminthic infestations costs mere pennies per dose. Nevertheless, such interventions must be undertaken on a regular basis and encompass an entire population in order to prevent re-infection—particularly those in high-risk groups such as children and women of childbearing age.
Among livestock, resistance has already burgeoned into a huge problem—a result of continuous reliance on anthelminthic drugs and the widespread disinfecting of pastures to ward of the often economically disastrous effects of parasitic infestations. In humans such widespread use is not yet the norm. Nevertheless, resistance still poses a real threat—particularly in the face of WHO’s recently announced initiative to reduce infestation in human populations through expanded treatment programmes. This initiative is vital in order to decrease the substantial health and economic costs associated with widespread infestation. Unfortunately however, such programmes could potentially encourage the development of drug resistance unless undertaken alongside proper surveillance and treatment strategies designed to preserve the pool of non-resistant parasites.
ALLIANCES A major foe defeated: drug-resistant leprosy and the importance of building partnerships One stand-out success story penetrating the otherwise formidable forces of resistance lies in story of leprosy—a monstrously deforming and stigmatizing disease that once disfigured millions. From a biblical scourge of mythical proportions to its near-elimination in the 1990s, leprosy remains a 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 the world’s most abject victims.
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 bug and lead the way to cure and, researchers hope, elimination by 2005. No longer complacent, scientists are holding back three alternative drugs in the event that resistance recurs.
The good news for doctors and patients, is that the leprosy bacterium tends to be more lethargic than most, and is characterized by fairly low transmission and mutation rates. Tackling the issue of cost however, has been quite another matter. 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.
TRPANOSOMIASIS Known generally as sleeping sickness, African trypanomiasis is a flyborne protozoan now manifesting 20 percent resistance to melarsoprol, the only medication with a proven track record against both the acute and chronic forms of the African strains. Trypanosomiasis, which typically afflicts the, ‘poorest of the poor’ is characterized by enlarged lymph glands, blinding headaches, insomnia, edema, wasting, somnolence and coma. Left untreated, this crippling illness eventually causes death.
Owing to the remote location of outbreaks, poverty, and ongoing war in endemic countries, the actual scope of trypanosomiasis remains difficult to determine. 1998 WHO figures pin the number at an estimated 250,000 in the Democratic Republic of the Congo alone. According to some researchers, a total of 55 to 66 million individuals are at risk of infection each year. Reduced to low levels of prevalence in the 1960s, sleeping sickness has rebounded in the wake of continued civil disturbance and subsequent degradation of medical and public infrastructures that once nearly vanquished the disease through tsetse fly control.
Because of low profit potential and the difficulty in treating late stage-disease —which requires medications powerful enough to cross the ‘blood brain’ barrier without killing the patient—few drug companies are willing to expend the time and expense in developing new drugs.
A few older drugs still have a role to play provided they are made available to those in need. Pharmaceuticals giant Aventis recently granted WHO the right to licence eflornithine—originally developed as an anti-cancer drug—that has proven effective in treating the form of the disease caused by T. brucei gambiense. Although registered in 1990 under the US Food and Drug Administration (FDA) the drug languished because the market for its use was both small and because those who needed it could not afford it. As a result of negotiations between the manufacturer, WHO and Medecins Sans Frontieres—an NGO committed to delivering healthcare regardless of borders or conflict—discussions are underway to produce eflornithine under a five-year agreement. This is one example of how public health institutions and drug companies can work together to ensure equal access to medical treatment regardless of socio-economic status. Unfortunately, the more virulent T-brucei rhodesiense form of the disease is not curable with eflornithine.
One that got away: gonorrhoea's winning salvo For every success story, there are ten failures. Gonorrhoea is one example of how antimicrobial abuse has propelled a once curable nuisance into potentially life-threatening contagion. The development of antimicrobial resistance in gonorrhoea is one of the major health care disasters of the 20th century. Treatment failure means sufferers are far more likely to become infected with HIV and will shed the virus at nine times the rate of those infected with HIV alone.
In 1996, the WHO Gonococcal Antimicrobial Surveillance Programme (GASP) examined 8,421 samples collected from people infected with the disease throughout the Western Pacific region. Fifty-per cent of isolates were multi-drug resistant. Another study undertaken in Vietnam revealed a stunning 97 per cent resistance to penicillin; while Cambodia, Malaysia and Singapore showed between 94 and 96 per cent resistance to quinolones. In Australia, quinolone resistant gonorrhoea imported by travellers arriving home from Southeast Asia leapt 23 per cent between between 1994 and 1996. These numbers continue to rise.
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. The recommended dose is 250 mg, while 500 mg will most certainly eradicate any lingering infection. The reality, however, is that poverty forces both physicans and their patients to opt for lower doses of prescribed medications or choose cheaper, less effective alternatives in order to save money.
As one WHO researcher recently put it, “to prevent resistance you need to either provide no treatment or excellent treatment.” The former needs to be avoided. The latter is a challenge that must involve all sectors of the health sector and the community at large.
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. “... WHO's annual report on infectious diseases paints a comprehensive picture of the dwindling effect penicillin and other antibiotics have in fighting once simple bacterial infections... a disturbing report...” - CNN
“... The WHO report describes how almost all major infectious diseases are slowly becoming resistant to existing medicines...” - CNN
“... warns that if we continue current practices, effective protection provided by antibiotics will not be available 50 years from now...” - The New York Times
“... Most people alive today do not remember a world without anti-microbial agents, when the possibility of death lurked in every cough or upset stomach. If we do not reform our use of medicines, this is the world we might bequeath to our children...” - The New York Times
“... The report describes how the major infectious diseases are gradually becoming impervious to existing drugs, reducing the curative power of once life-saving medicines to that of a sugar pill...” - The New York Times
“... offers recommendations for curbing the spread of resistance before once-treatable infections become incurable...” - USA Today
“...If the current pattern continues, the world could be plunged back into the ‘pre-antibiotic era’...” - Los Angeles Times
“...Raising the specter of a return to a pre-antibiotic age, WHO warns that illnesses as common as strep throat and diarrhoea could become untreatable within 10 to 15 years...” - The Boston Globe
“...The most comprehensive—and perhaps the most alarming—account to date about the rise of resistant microbes...” - International Herald Tribune
“... a tough report ... highlights several cases in which microbes have mutated into strains resistant to commonly used drugs...” - Financial Times
“... points to the danger that increasing drug resistance among infectious bacteria poses to programmes to reduce the victims of killer diseases...” - The Guardian
“... (issues) a stark warning about the risk of drug-resistant diseases which threaten to return medicine to the dark days before the discovery of penicillin...” - The Independent