"Antibiotic resistance as a phenomenon is, in itself, not surprising. Nor is it new. 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.