"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 time."
– 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.