Expand Document  |  Expand Chapter  |  Full TOC  |  Printable HTML version
Essential Drugs Monitor No. 028-029 (2000)
(2000; 36 pages) [French] [Spanish] View the PDF document
Table of Contents
View the documentEditorial - Antimicrobial resistance: A global threat
View the documentNewsdesk
View the documentAntimicrobial resistance
View the documentLetters to the editor
View the documentNational drug policy
View the documentNewsdesk
View the documentAccess
View the documentDRUG INFORMATION
View the documentResearch
View the documentCourses & meetings
View the documentNetscan
View the documentPublished lately
View the documentTraditional medicine
View the documentWorld trade
 

Antimicrobial resistance

Antimicrobial resistance: the facts

Over the past decade, there has been a dramatic upsurge world wide in the spread of drug-resistant microbes. Major infectious diseases such as tuberculosis, pneumonia and malaria are becoming increasingly difficult and expensive to treat, as microbes develop resistance to many of the medicines available. How widespread is the problem? How does drug resistance develop? And what is WHO doing to contain this threat? Rosamund Williams, Coordinator, Anti-infective Drug Resistance and Containment at WHO explains.

Antimicrobial resistance is on the increase - threatening our ability to treat some of the infectious diseases that cause most deaths. Diseases such as tuberculosis (TB), which was once thought to be under control, are becoming increasingly difficult to treat as medicines become less effective - steadily depleting the arsenal of drugs available.

Infectious diseases still account for 45% of deaths in low-income countries and for almost one in two premature deaths worldwide. And most of these deaths (about 90%) are due to no more than six diseases: acute respiratory infections (mainly pneumonia), diarrhoeal disease, HIV/AIDS, TB, malaria and measles. Antimicrobial resistance is today challenging our ability to treat effectively at least four of these infections: acute respiratory infections, diarrhoeal disease, malaria and TB.


DECLINING RESPONSE TO ANTIMALARIAL DRUGS

Source: The Southeast Journal of Tropical Medicine and Public Health, Mekong Malaria, Volume 30, Supplement 4, p 68, 1999

Chloroquine, for example - once the first-line treatment for malaria - is no longer effective in 81 of the 92 countries where the disease is a public health problem. In some regions, over half of all cases of streptococcal pneumonia are resistant to penicillin. And over 20% of new TB cases are now multidrug-resistant.

To make matters worse, resistance is already emerging to anti-HIV drugs. There are reports of resistance to all currently marketed antiretroviral drugs. And resistance is also widespread among sexually-transmitted infections, such as gonorrhoea, that enhance the spread of HIV.

But the problem does not end there. Hospital-acquired (nosocomial) infections, which account for 40,000 deaths a year in the United States alone, are almost always caused by drug-resistant microbes. Foodborne infections are also on the increase - promoting growing concern about drug resistance in pathogens such as Salmonella and Campylobacter. Meanwhile, tropical diseases, such as leishmaniasis (see box p.8) and African trypanosomiasis, which haunt the poor and marginalised communities of the world, are becoming increasingly difficult to treat among people also infected with HIV. Treatment with the usual (and sometimes only) drug is increasingly ineffective.

How widespread is the problem?

Drug resistance is a global problem - affecting both developing and developed countries. Its spread is helped by the enormous increase in global travel and trade.

Documented examples include:

• cases of drug-resistant gonorrhoea acquired by tourists visiting South-East Asia and transmitted among communities in Australia;

• outbreaks of multidrug-resistant TB in Western Europe traced back to Eastern European countries where TB control is poor;

• two outbreaks of MRSA (methicillin-resistant Staphylococcus aureus) hospital infection in Canada involving patients who acquired the strain in India.

In addition, cases of drug-resistant malaria occur among travellers returning to developed countries from malaria-endemic countries where resistance is high. These drug-resistant infections will not spread in developed countries provided there are no mosquito vectors. But global warming could change all that.

What is antimicrobial resistance?

When antimicrobial resistance occurs, it is the microbe (bacterium, virus, fungus or protozoan) that is resistant; not the drug, nor the patient. Species of bacteria that are normally resistant to penicillin, for example, can develop resistance to these drugs either through mutation (vertical transmission) or through acquisition from other bacteria of resistance genes (horizontal transmission). This dual means of acquiring resistance explains why the resistance trait can spread rapidly and replace a previously drug-susceptible population of bacteria.

Are antimicrobial drugs to blame?

No. Antimicrobial drugs do not cause resistance. But the process is accelerated when antimicrobials are misused. What happens is that natural selection - a natural biological process - favours the survival of microbes that develop resistance genes by chance when exposed to antimicrobials. All uses of antimicrobials - both appropriate and inappropriate - apply a selective pressure on microbial populations. However, the more antimicrobials are used, the greater this pressure will be. Thus it is critical to gain maximum benefit from the curative effects of antimicrobials - especially in developing countries, where they are not only misused, but often under-used due to financial constraints. At the same time, it is also essential to minimise the opportunities for resistance to emerge. In practice this means using antimicrobials both widely and wisely - neither too little, nor too much, and never inappropriately. Inappropriate prescribing practices - including the wrong choice of drug and incorrect dosage or length of treatment - poor compliance with treatment, and the use of low quality (sometimes counterfeit) drugs all contribute to the emergence of drug-resistant microbes.

How does resistance develop?

If a person develops an acute infection such as pneumonia with a drug-susceptible strain of Streptococcus pneumoniae, for example, and is treated promptly with penicillin, the bacteria will be killed and the infection resolved before resistance has time to emerge. However, in the treatment of chronic infections such as TB and HIV/AIDS - especially if treatment compliance is poor - drug-resistant mutants have time to emerge and multiply and replace the drug-susceptible population of microbes. Under these circumstances, it is likely that the treatment outcome will be poor.


THE PARADOX OF CONTROLLING DRUG RESISTANCE

Source: World Health Organization/CDS

So why is it that the microbes involved in acute infections have also become resistant to many of the first-line drugs available? The problem is that antimicrobial drugs not only kill the microbe being targeted, they also “treat” other normally harmless microbes (“normal flora”) in the body as well. For example, Streptococcus pneumoniae, as well as causing otitis, pneumonia and meningitis, is also carried by many people, especially children, as part of their normal throat flora, without causing any symptoms. So every time they take an antimicrobial - for whatever reason - their streptococci are exposed. If a mutant emerges, it will have a selective advantage and can spread to other people. A similar process occurs when salmonella bacteria are exposed to antimicrobials incorporated into animal feed. While these bacteria may not cause the animal any harm, they can be spread to humans through the food chain.


PENICILLIN-RESISTANT PNEUMOCOCCI IN THE 1990s

Source: Collected from published data

What is multidrug-resistance?

There are many different classes of antimicrobials, and microbes have devised ways to resist the action of each and every one. In addition, a single microbial cell can carry resistance genes to a whole series of totally unrelated antimicrobial drugs. Over time, the dysentery-causing bacterium Shigella, for example, has become resistant to each successive class of antimicrobials used in treatment. As a result, it has a string of genes, each coding for resistance to a different antimicrobial. To make matters worse, this string of genes can be transmitted from one bacterial cell to another. Thus a previously susceptible Shigella can, in one fell swoop, acquire five or six resistance genes.


IT’S CHEAPER TO TREAT PATIENTS RIGHT THE FIRST TIME

Source: World Health Organization/CDS

Why is antimicrobial resistance spreading so fast?

Although mutations are rare events (about one in a million bacteria may show a mutation which might lead to resistance), microbes multiply very rapidly - thereby enabling a single mutant to rapidly become dominant. Microbes also spread readily from person to person. Thus one patient infected with a resistant strain may be an important source of spread, not only of the infection, but of a resistant infection. This is demonstrated in hospitals, where one patient infected with MRSA, for example, is often the source from which many others become infected or colonised.

Thus in taking action to contain resistance, both the emergence of resistance and the spread of resistant strains need to be considered.

TACKLING THE PROBLEM

Can antimicrobial resistance be halted?

No. But it can be contained. Antimicrobial resistance is a natural biological phenomenon - the response of microbes subjected to the selective pressure of antimicrobial drug use. The main priority should be to prevent infection in the first place. After that, containment of the problem is the best we can aim for. And since it is antimicrobial use that drives resistance, the focus of any containment strategy should be on minimising any unnecessary, inappropriate or irrational use of antimicrobial drugs. Many groups of people play a role in determining how and where antimicrobials are used:

• patients and the general public;
• all groups of prescribers and dispensers;
• hospital managers and health care professionals;
• users of antimicrobials in agriculture;
• national governments;
• pharmaceutical, diagnostic and “surveillance” industries;
• international agencies, NGOs, professional societies.

All of these groups need to be engaged in developing and implementing a resistance containment action plan.

What is WHO doing?

WHO has taken the lead in developing a Global Strategy for the Containment of Antimicrobial Resistance. The strategy is designed to reduce the emergence of resistance and slow the spread of resistant infections, in an effort to reduce the mortality, morbidity, and high costs associated with antimicrobial resistance. The strategy is based on published evidence, expert opinion, and the deliberations of other expert bodies. It includes a review of the factors responsible for the emergence and spread of resistance and of the interventions that have been tested or proposed to address the problem. The strategy provides a framework of interventions for implementation. It also highlights the gaps in current knowledge and the many outstanding research needs. Foremost among these is the need to develop new drugs to combat drug-resistant infections, and to develop a new environment of incentives and public-private partnerships to address the challenges of antimicrobial resistance.

RESISTANCE CAN BE EFFECTIVELY TREATED

Ideal drug usage involves:

• The correct drug
• Administered by the best route
• In the right amount
• At optimum intervals
• For the appropriate period
• After an accurate diagnosis

Problems occur in both developed and developing countries when antimicrobials are:

• Not equitably available
• Used by too many people
• To treat the wrong disease
• In the wrong dosage
• For the wrong period of time
• Not in the correct formulation or strength

Antimicrobial resistance is not a new or surprising phenomenon. All micro-organisms have the ability to evolve various ways of protecting themselves from attack BUT over the last decade or so:

• Antimicrobial resistance has increased
• The pace of development for new and replacement antimicrobials has decreased

RESISTANCE MEANS THAT:

People can’t be effectively treated
People are ill for longer
People are at greater risk of dying
Epidemics are prolonged
Others are at greater risk of infection

Source: World Health Organization/CDS

The example of leishmaniasis

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 people each year in 61 countries in East Africa, India and the Mediterranean basin. The sandfly-transmitted parasite attacks the spleen, liver and bone marrow and is characterised by fever, severe weight loss and anaemia. Left untreated, the disease is fatal. 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 life. 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 parallel-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 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 is spreading 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.

War, globalisation, increased travel and climatic change places this parasitic infection solidly in the category of emerging diseases with rapidly-evolving resistance.

Source: WHO. Overcoming antimicrobial resistance. Geneva: World Health Organization; 2000.


A female patient with Leishmania aethiopica infection

Photo: WHO/TDR

For further details contact: Dr Rosamund Williams, Communicable Diseases Cluster, Anti-infective Drug Resistance and Containment, World Health Organization, 1211 Geneva 27, Switzerland.

Who contributes to misuse of antimicrobials?

KATHLEEN HOLLOWAY*

* Dr Kathleen Holloway is a Medical Officer in the Department of Essential Drugs and Medicines Policy at the World Health Organization.

Antimicrobial resistance is a natural consequence of antimicrobial use, which kills the sensitive organisms leaving the resistant ones to survive and multiply (selection of resistance). Overuse and misuse of antimicrobials do not help patients, they merely add to the problem of resistance and waste resources.

Prescribers

There is a wide variation in the prescribing of antimicrobials and other drugs. In primary health care 30 - 60% of patients receive antibiotics (see Figure 1), perhaps twice what is clinically needed. Misuse is common and may take the form of incorrect dosage or inappropriate prescription. In Tanzania, 91% of antibiotics were prescribed with incorrect dosage1 and in India over 90% of prescriptions did not have dose specifications.2 Inappropriate prescription of antibiotics has been reported to occur for viral respiratory tract infections in 97% of cases in China3 and 81% of cases in Ghana.4 Inappropriate prescription of antibiotics for childhood diarrhoea commonly occurs, as reported in Pakistan. Here private general practitioners were found to prescribe significantly more antibiotics (41% of paediatric cases) than paediatricians (36% of paediatric cases) in the public hospitals.5

Hospital prescribers are often the role models for primary health care prescribers. Unfortunately, antimicrobials are misused just as much in hospitals as in primary health care, as shown in Table 1.


Figure 1 - Percentage of primary health care patients receiving antibiotics

Source: Managing Drug Supply, 2nd ed. Quick JD, Rankin JR, Laing RO, O’Connor RW, Hogerzeil HV, Dukes MN, Garnett A, eds. Hartford CT: Kumarian Press; 1997.

Why do providers prescribe antimicrobials too often and unnecessarily? There are many causes including:

• lack of knowledge or information, leading to uncertainty about the diagnosis and the most appropriate drug(s), and fear of poor patient outcome

• patient demand

• earning a living through selling medicines.

Many prescribers in developing countries have little access to good quality information about diagnosis and drugs. Standard treatment guidelines are often unavailable and health workers are often unsupported and unsupervised. Frequently, drug company representatives are doctors’ only source of information. Such information may well be biased, particularly with regard to how effective their company’s drug is compared to rival drugs of the same class. Uncertainty of the diagnosis, fear of poor patient outcome, (and in industrialised countries, fear of litigation), lead to overpresciption of antibiotics. In many developing countries, the diagnostic process is often inadequate to arrive at a diagnosis with any certainty (Figure 2).

Table 1 - Inappropriate use of antibiotics in teaching hospitals

Country

Inappropriate use (%)

Type/department

Canada 1977

42%

Surgical ward - injections, antibiotics

 

50%

Gynaecology ward

 

12%

Medical ward

USA 1978

41%

All patients

Australia 1979

86 - 91%

Prophylaxis

Canada 1980

30%

Paediatric medical cases

 

63%

Paediatric surgical cases

Australia 1983

48%

All departments

Kuwait 1988

39%

Paediatric inpatients

Australia 1990

64%

Patients on vancomycin

Thailand 1990

91%

All departments

South Africa 1991

54%

Gynaecology inpatients

 

22 - 100%

Unrestricted antibiotics

Thailand 1991

41%

All departments

 

79.7%

Surgical prophylaxis

 

40.2%

Documented infection

Source: Hogerzeil HV. British Journal of Clinical Pharmacology 1995;39:1 - 6.

Patient demand or prescriber perception?

Even if prescribers are certain of their diagnoses (and none of them will be all the time), they are still greatly influenced by patients’ demands. Many traditional practitioners are now prescribing allopathic medicines instead of herbal or other kinds of medicines because this is what patients want. In Tanzania 60% of health workers admitted to prescribing inappropriate drugs demanded by socially influential patients, to avoid being labelled “difficult”.6 Many people in India believe in ‘tonics’ and will not return to a doctor unless he or she prescribes according to their wishes. Even though doctors may know that ‘tonics’ are ineffective, they prescribe them because they are dependent on the patient returning for their livelihood.7 In Europe, over 50% of mothers interviewed in a study expected to receive antibiotics for most respiratory infections.8

Prescribers citing patient demand as a cause of irrational prescribing has been reported in many countries. And patient demand for specific drugs has been widely observed by researchers. However, the degree to which prescribers are influenced by their patients is unknown and probably varies according to the skills and confidence of the prescriber. There is some evidence that it is a prescriber’s perception of patient demand, rather than actual patient demand, during the consultation process that may affect the prescribing decision.9,10

Effects of dispensing doctors

Many prescribers, as well as drug retailers, earn their living by selling medicines and not by charging a consultation fee. It has been shown in many countries that prescribers who earn money from dispensing medicines consistently prescribe more drugs than those who do not make money from dispensing. In a study in Zimbabwe11 dispensing doctors prescribed antibiotics to 58% of their patients compared to non-dispensing doctors who prescribed antibiotics to 48% of their patients. In China, after the ‘socialist market economy’ reforms of the late 1970s, drug sales became an important source of income for providers, including health worker salary supplements. Once drug sales formed part of health worker salaries, greater polypharmacy was observed, and the average prescription was found to cost two to six times the average per capita daily income.12 Selling high cost items, such as antibiotics, may earn dispensing prescribers more profit, but unfortunately many patients cannot afford such drugs and may buy incomplete courses. In a study in the Philippines 90% of antibiotic purchases were for 10 or fewer capsules, which in most circumstances would be less than a full course.

In conclusion, antibiotics are often prescribed irrationally (over-prescription and inappropriate prescription) and this contributes to the development of antimicrobial resistance. However, prescribers may have very rational reasons for prescribing irrationally and it is not just a question of lack of knowledge. Only by understanding the reasons underlying inappropriate prescribing can one design effective interventions to change such behaviour.


Figure 2 - Adequacy of diagnostic process

Sources: Thaver et al, Social Science and Medicine 1998. Guyon et al, WHO Bulletin 1994. Krause et al, Tropical Medicine and International Health 1998. Bitran, Health Policy and Planning 1995. Bjork et al, Health Policy and Planning 1992, Kanji et al, Health Policy and Planning 1995.

References

1. Gilson L, Jaffar S, Mwankusye S, Teuscher T. Assessing prescribing practice: a Tanzanian example. International Journal of Health Planning and Management 1993;8: 37 - 58.

2. Uppal R, Sarkar U, Giriyappanavar Cr, Kacker V. Antimicrobial drug use in primary health care. Journal of Clinical Epidemiology 1993;46(7):671 - 673.

3. Hui L, Li X.S, Zeng X.J, Dai Y.H, Foy H.M. Patterns and determinants of use of antibiotics for acute respiratory tract infection in children in China. Paediatric Infectious Disease Journal 1997;16(6):560 - 564.

4. Bosu W.K, Afori-Adjei D. Survey of antibiotic prescribing patterns in government health facilities of the Wassa West District of Ghana. East African Medical Journal 1997;74(3):138 - 142.

5. Nizami S, Khan I, Bhutta Z. Drug prescribing practices of general practitioners and paediatricians for childhood diarrhoea in Karachi, Pakistan. Social Science and Medicine 1996;42(8):1133 - 1139.

6. Mnyika K.S, Killewo J.Z.J. Irrational drug use in Tanzania. Health Policy and Planning 1991;6(2):180 - 184.

7. Nichter M, Pharmaceuticals, health commodification and social relations: ramifications for primary health care, Anthropology and International Health, South Asian Case Studies 1989; Section 3, No.9:233 - 277. (Kluwer Academic Publishers).

8. Branthwaite A, Pechere J-C. Pan-European survey of patients’ attitudes to antibiotics and antibiotic use. Journal of International Medical Research 1996;24(3): 229 - 238.

9. Britten N, Ukoumunne O. The influence of patients’ hopes of receiving a prescription on doctors’ perceptions and the decision to prescribe: a questionnaire survey. British Medical Journal 1997;315:1506 - 1510.

10. Paredes P, de la Pena M, Flores-Guerra E, Diaz J, Trostle J. Factors influencing physicians’ prescribing behaviour in the treatment of childhood diarrhoea: knowledge may not be the clue. Social Science and Medicine 1996;42(8):1141 - 1153.

11. Trap B, Hansen E.H, Hogerzeil H.V. Prescribing by dispensing and non-dispensing doctors in Zimbabwe. Copenhagen: Royal Danish School of Pharmacy; 2000. (Unpublished study).

12. Shao-Kang Z, Sheng-Ian T, You-de G, Bloom G. Drug prescribing in rural health facilities in China: implications for service quality and cost. Tropical Doctor 1998;28:42 - 48.

Problems from antimicrobial use in farming

KLAUS STÖHR*

* Dr Klaus Stöhr is a Scientist at the World Health Organization, Communicable Diseases Cluster, Animal and Food-Related Public Health Risks, Department of Communicable Disease Surveillance and Response.

Following their success in human medicine, antimicrobials have been increasingly used to treat disease in animals, fish and plants. They also became an important element of intense animal husbandry because of their observed growth enhancing effect, when added in sub-therapeutic doses to animal feed. Some growth promoters belong to groups of antimicrobials (for example, glycopeptides and streptogramins), which are essential drugs in human medicine for the treatment of serious, potentially life-threatening bacterial diseases. These include Staphylococcus or Enterococcus infections.

The widespread use of antimicrobials in farming is of serious concern as some of the newly emerging resistant bacteria in animals are transmitted to humans, mainly from food of animal origin or through direct contact with farm animals. Treating disease caused by these resistant bacteria in humans is more difficult and costly and, in some cases, available antimicrobials are no longer effective. The best-known examples are diseases caused by the foodborne pathogenic bacteria Salmonella and Campylobacter and the commensal (harmless in healthy persons and animals) bacteria Enterococcus. Research has shown that resistance in these bacteria is often a consequence of using certain antimicrobials in agriculture.

More studies are needed, however, as the impact of the widespread distribution of non-metabolised antimicrobials through manure and other effluents into the environment is still unknown. And information is also scarce on the type and amount of antimicrobials used in the expanding aquaculture sector. Based on the lessons learned from species living on land, there is an urgent need to review current practices to identify potential hazards. This also applies to other uses of antimicrobials, in plant protection and in industry, for example.


A butcher’s stall in the Dominican Republic. There is increasing evidence of the problems caused by feeding antimicrobials to farm animals

Photo: WHO/PAHO/A. Waak

Scale of use

The total amount of antimicrobials used in food animals is not precisely known, although it is estimated that about half of the antimicrobials produced globally are used in farming, particularly in pig and poultry production.

In Europe, all classes of antimicrobial licensed for disease therapy in humans are also registered for use in animals, a situation comparable with other regions in the world, although comprehensive registration data are much more difficult to obtain. National statistics on the amount and pattern of antimicrobial use, in human medicine or anything else, exist in only a few countries.

An average of 100 milligrams of antimicrobials are used in animals in Europe to produce one kilogram of meat for human consumption. Statistics from other regions are scarce, but increased meat production in many developing countries is mainly due to intensified farming, which is often coupled with greater antimicrobial use for both disease therapy and growth promotion.

Factors contributing to overuse

• Education on antimicrobial resistance and prudent antimicrobial use is lacking amongst dispensers and prescribers of antimicrobials, and in many countries, people who are inadequately trained dispense them. One study reported that more than 90% of the drugs used in animals in the United States in 1987 were administered without professional veterinary consultation. Inappropriate doses and combinations of drugs are frequently used in animals. And antimicrobials administered to animal flocks and herds in their feed causes problems of inaccurate dosing, and the inevitable treatment of all animals irrespective of health status.

• Empiric treatment predominates because of the widespread lack of diagnostic services, particularly in developing countries. In many places, it is uncommon to submit clinical specimens and samples from sick animals, due to the costs involved, time restrictions and the limited number of laboratories.

• Drug sales constitute a significant portion of veterinarians’ income in some countries and may lead to unnecessary prescribing.

• In many countries, including several developed ones, antimicrobials are available over-the-counter and may be purchased without prescription.

• Inefficient regulatory mechanisms or poor enforcement, with lack of quality assurance and marketing of substandard drugs, are important contributory factors. Discrepancies between regulatory requirements and prescribing/dispensing realities are often wider than in human medicine.

• Antimicrobial growth promoters are not considered drugs and are licensed, if at all, as feed additives.

• As in human medicine, pharmaceutical industry marketing of antimicrobials influences veterinarians’ and farmers’ prescribing behaviour and use patterns. There are currently few countries with industry codes or government rules for overseeing advertising practices for antimicrobials for non human use.

• There is a significant increase in intensive animal production, particularly in countries with economies in transition where all the factors listed here are present. When animal production appears to benefit from the use of antimicrobials, economic incentives may take precedence over the possible transfer of resistance to humans, and the potential negative impact on human health.

Examples of the consequences of overuse

♦ Shortly after the licensing and use of fluoroquinolone, a powerful new class of antimicrobials, in poultry, fluoroquinolone-resistant Salmonella and Campylobacter isolations from animals, and soon afterward from humans, became more common. Community and family outbreaks, as well as individual cases, of Salmonellosis and Campylobacteriosis resistant to treatment with fluoroquinolones have since been reported from several countries.

♦ With the emergence of vancomycin-resistant strains of Staphylococcus and Enterococcus bacteria in many hospitals around the world, the question arose if the use of those antimicrobial agents in agriculture could have compounded the worsening problem. Vancomycin-resistant Enterococci were isolated in animals, food and non-treated volunteers in countries where vancomycins were also used as growth promoters in animals. By 1997 all European countries had banned vancomycin, and after this the prevalence of resistant Enterococci in animals and food, particularly in poultry meat, fell sharply.

How to tackle the problem

WHO, the UN Food and Agriculture Organization, the Office International des Epizooties and 14 other international governmental and nongovernmental organizations and professional societies have developed a framework of recommendations to reduce the overuse and misuse of antimicrobials in food animals for the protection of human health. (For further information see: http://www.who.int/emc/diseases/zoo/who_global_principles.html).

What the various stakeholders need to do

Responsibilities of regulatory and other relevant authorities

All antimicrobials used in food animals should be reassessed in relation to their propensity to cause antimicrobial resistance in bacteria which can be transmitted to humans. Priority should be given to those products considered most important in human medicine.

After the licensing of veterinary antimicrobials, surveillance of resistance to antimicrobials belonging to classes considered important in human medicine should be conducted. In this way emergence of antimicrobial resistance will be detected in time to allow corrective strategies to be implemented as part of an efficient post-licensing review.

Authorities should ensure that all antimicrobials for disease control in animals are classified as prescription-only medicines.

Distribution/sales/marketing

Enforcement policies should be designed to ensure compliance with laws and regulations on the authorisation, distribution and sale, and use of antimicrobials. They should aim at preventing the illicit manufacture, importation, and sale of antimicrobials, and at controlling their distribution and use.

Special attention should be paid to the distribution and sale of counterfeit, sub-potent and misbranded veterinary antimicrobials. Enforcement action should be taken to stop such distribution and sale by relevant authorities, in coordination with the exporting country, if appropriate.

Antimicrobial growth promoters

Use of antimicrobial growth promoters that belong to classes of antimicrobial agents used (or submitted for approval) in humans and animals should be terminated or rapidly phased-out in the absence of risk-based evaluations.

Surveillance of antimicrobial resistance

Programmes to monitor antimicrobial resistance in animal pathogens, zoonotic agents (for example, Salmonella spp. and Campylobacter spp.), and bacteria known to be indicators of antimicrobial resistance (for example, Escherichia coli and Enterococcus faecium) should be implemented on bacteria from animals, food of animal origin and humans.

Surveillance of antimicrobial use

Information on the amounts of antimicrobials given to food animals should be made publicly available at regular intervals, be compared to data from surveillance programmes on antimicrobial resistance, and be structured to permit further epidemiological analyses.

Prophylactic use of antimicrobials

Use of antimicrobials for prevention of disease can only be justified where it can be shown that a particular disease is present or is likely to occur. The routine prophylactic use of antimicrobials should never be a substitute for good animal health management.

Prophylactic use of antimicrobials in control programmes should be regularly assessed for effectiveness and whether use can be reduced or stopped. Efforts to prevent disease should continuously be in place, aimed at reducing the need for the prophylactic use of antimicrobials.

Education and training

Veterinary undergraduate, postgraduate and continuing education should be evaluated to ensure that preventive medicine, prudent antimicrobial use and antimicrobial resistance are given high priority. The effectiveness of this training should be continuously monitored.

Education strategies emphasising the importance and benefits of prudent use principles must be developed and implemented to provide relevant information on antimicrobial resistance for producers and stakeholders. Emphasis must also be given to the importance of optimising animal health through implementation of disease prevention programmes and good management practices.

The public should be informed of the human health aspects of antimicrobial use in food animals, so that they can support efforts to control antimicrobial resistance.

Research

Stakeholders should identify research priorities to address public health issues of antimicrobial resistance from antimicrobial use in farming. Governments, universities, research foundations and industry should give high priority to supporting research in these areas.

Promoting resistance?

JOEL LEXCHIN*

* Dr Joel Lexchin is an emergency physician in Toronto, Canada, and the Secretary-Treasurer of the Medical Lobby for Appropriate Marketing. He is also a co-author of Drugs of Choice: A Formulary for General Practice.

The Autumn 1996 issue of Health Horizons, the magazine of the International Federation of Pharmaceutical Manufacturers Associations, ran a two-page feature entitled “International Mobilization Against New and Resistant Diseases.” This article highlighted the efforts being made by international organizations and the pharmaceutical industry to deal with the threat of increasing antibiotic resistance. What the article didn’t mention was that some in the industry can also play a role in promoting bacterial resistance to currently available medications.

According to one company, ciprofloxacin is “an appropriate choice for your [doctors’] patients at risk.” This was the message in an advertisement that appeared in the 3rd October 2000 issue of the Canadian Medical Association Journal. “Appropriate” for whom? To answer that question readers had to notice a small asterisk after the word “risk” and then look down to the bottom of the page, where in small print they found the definition. “Appropriate” for what? Once again in small type was the answer; ciprofloxacin should be used in “challenging” respiratory tract infections. Challenging was never defined. In the same advertisement the company claimed that it supports the appropriate use of antibiotics.

Advertisements that do not give clear information or that give it in print that requires the use of a magnifying glass are not supportive of appropriate use of medications. The message in the ad for ciprofloxacin is that doctors should feel free to use this medication as a first line agent any time they are worried about their patients, or think that there is something unusual going on. Ciprofloxacin is a good first choice for a limited number of problems but not for most respiratory tract infections. The Australian Schedule of Pharmaceutical Benefits restricts the use of this antibiotic in these situations and the same is true in some Canadian provinces.

Another recent Canadian journal advertisement, this time for azithromycin, had a young baseball pitcher, his face determined, ready to release the ball with the message “tough on acute otitis media, easy on kids.” The message in this case was that doctors and their young patients need a powerful medication to deal with otitis media and that azithromycin fits the bill. However, this does not reflect the growing consensus that otitis media, at least in children older than two years, should not be treated with antibiotics unless the child fails to improve after 48 hours.

What these advertisements do is to promote, as first line choices, the use of antibiotics that should be kept in reserve, and promote the use of antibiotics for conditions that will probably resolve without any intervention. Both situations represent inappropriate use of antibiotics and clearly have the potential to lead to increased resistance.

The other common feature of these advertisements is that they are for new, expensive antibiotics; drugs that can generate large profits for companies, if sales volumes are large. What doctors do not see is advertising for older, less expensive antibiotics, even though these drugs are the ones that are the most appropriate. When was the last time there was an ad for penicillin for streptococcal pharyngitis or for trimethoprim for a urinary tract infection?

This scenario is not limited to Canada, the situation is, if anything, worse in other parts of the world. The Medical Lobby for Appropriate Marketing (MaLAM) has received a number of examples of inappropriate antibiotic promotion in developing countries. Advertisements in 1994 and 1995 in the Philippines advocated the use of lincomycin for tonsillitis/pharyngitis and clindamycin in upper respiratory tract infections. The most likely cause of any of these conditions is a viral infection where antibiotics are useless. Once again, antibiotics are being advertised for conditions that do not require them.

1997 advertising claims in India for clarithromycin used the words “paediatric suspension... speed,... strength,... spectrum,... safety” without any qualification. In MaLAM’s opinion it would have been reasonable for readers of this ad to interpret those words to mean that clarithromycin has clinically important advantages over alternative antimicrobials and thus was a first line antibiotic for common childhood infections. As MaLAM pointed out, authoritative sources did not recommend clarithromycin as the treatment of choice for paediatric otitis media, pharyngitis or sinusitis. The parallels with the Canadian example of the advertisement for ciprofloxacin are clear; the advertisements are encouraging the overuse of second-line drugs.

A couple of American studies, spanning almost a quarter of a century, make the point that the concern about promotion leading to the misuse of antibiotics is more than just a theoretical problem. The first of these, published in the early 1970s, showed that more appropriate use of the antibiotic chloramphenicol was related to infrequent use of journal ads to learn about usefulness of new drugs, and disapproval of detailers as sources of prescribing information for new drugs.1 The second study came out in 1996. In this case, researchers presented a group of primary care doctors with three case scenarios, two of which involved infectious diseases, and asked them to choose between four treatment options of equal efficacy but with widely varying costs. The more credibility that doctors attached to information coming from sales representatives the higher the physician’s cost of prescribing.2

In many cases in developing countries doctors lack sources of objective information about antibiotics. These doctors are totally reliant on promotional material from companies, with all of the biases that this material entails. In the mid 1980s physicians practicing in a peripheral health centre in Sri Lanka where polypharmacy, multiple antibiotic therapy and the use of mixtures of unproven efficacy were common, were totally dependent on, and positive towards, drug information from drug companies.3

Drug companies are now racing to bring out new, more powerful antibiotics to combat drug resistance, and we should welcome these medications. But if the industry is sincere about wanting to do something about resistance then it should start by monitoring its promotional practices more closely.

References

1. Becker MH, Stolley PD, Lasagna L, McEvilla JD, Sloane LM. Differential education concerning therapeutics and resultant physician prescribing patterns. Journal of Medical Education 1972;47:118 - 27.

2. Caudill TS, Johnson MS, Rich EC, McKinney WP. Physicians, pharmaceutical sales representatives, and the cost of prescribing. Archives of Family Medicine 1996;5:201 - 6.

3. Tomson G, Angunawela I. Patients, doctors and their drugs: a study at four levels of health care in an area of Sri Lanka. European Journal of Clinical Pharmacology 1990;39:463 - 7.

Antibiotic use and bacterial resistance to antibiotics in children in a Vietnamese community

In 1999 a household survey was conducted in one agricultural district in sub-tropical north Viet Nam. This district has 32 community health stations, one district hospital, three licensed private pharmacies, a few private practitioners, about 16 drug outlets and 362 villages. The researchers randomly selected 200 children, aged 1 - 5 years, within 166 households, from the 225 households in five villages (out of 67 villages where there is a surveillance programme). Nasopharygeal and throat specimens were collected from each child, and their carers were interviewed to obtain drug use information. Researchers explained the purpose of the study to each household and obtained permission to collect the specimens.

A standardised questionnaire was developed, piloted and then used by four experienced local interviewers. They asked questions about the types of antibiotics which had been used, how long for, where they were purchased, and what they knew about them. At the same time, microbiologists from Hanoi University collected nasopharygeal (posterior nares) and throat (tonsillar) swabs. The swabs were immediately placed in charcoal transport medium, and transported to the laboratory for culture, species identification and susceptibility testing.

Table 1
Prevalence of antibiotic resistant (R) and intermediate susceptible (I) strain of H. influenzae, S. pneumoniae and M. catarrhalis

 

H. influenzae

S. pneumoniae

M. catarrhalis

 

n = 74

n = 62

n = 27

Antibiotics

R

I

R

I

R

I

Ampicillin

18%

6%

-

-

19%

30%

Chloramphenicol

24%

0%

25%

3%

15%

4%

Ciprofloxacin

6%

6%

0%

80%

0%

19%

Erythromycin

4%

49%

23%

3%

-

-

Gentamicin

0%

2%

3%

95%

0%

0%

Loracarbef

2%

0%

-

-

0%

4%

Penicillin V

24%

60%

6%

5%

54%

31%

Tetracycline

32%

32%

88%

2%

13%

0%

Trimethoprim/Sulphonamide

44%

3%

32%

12%

59%

19%

Vancomycin

-

-

2%

2%

-

-

Number of susceptibility tested strains susceptibility tested (n). Antibiotic not tested (-).

Ignoring treatment guidelines

It was found that 82% of the children had at least one symptom of acute respiratory infection during the four weeks prior to interview, and that of these children 91% had been treated with antibiotics. Thus, 75% of all the children (both with and without symptoms) had

been treated with antibiotics. On average antibiotics were given for 3.9 days and ampicillin was the commonest choice; this is contrary to the national treatment guidelines, which recommend cotrimoxazole for acute respiratory infection.

When deciding which antibiotic to use, 67% of carers used a pharmacy, 11% decided themselves, and 22% followed a doctor’s prescription. The carers were asked what drug information they paid attention to when treating their children, and replied as below:

daily dosage

87%

how to take the drug

2%

(e.g. with water)

 

total dosage

12%

contraindictions

8%

expiry date

3%

antibiotic resistance

1 person

Eighty percent of the antibiotics were purchased from small shops and pedlars, 18% from community health stations and 2% from a national hospital pharmacy.


Figure 1 - Antibiotic consumption amongst children

Eighty-two percent of the 200 children had symptoms of ARI four weeks preceding the study (left pie chart) and seventy-five percent of these children had used antibiotics within this four week period (right pie chart). As some antibiotics were used in combination, the percentages total more than 100%.

A disturbing level of resistance

One hundred and sixty-three isolates from 145 children were susceptibility tested. The carrier rate for S. pneumoniae was 50%, for H. influenzae 39%, and for M. catarrhalis 17%. In 74% of the 145 children resistant pathogens were found. Resistance to one or more antibiotics was shown in 68% (50/74) of H. influenzae isolates, 90% (56/62) of S. pneumoniae isolates, and 74% (20/27) of M. catarrhalis isolates. The prior consumption of ampicillin or pencillin was associated with a significantly greater ampicillin or penicillin resistance, odds ratio 2.3 (p<0.05). Multi-drug resistance to a combination of trimethoprim/sulphonamide, tetracycline, chloramphenicol, penicillin V and ampicillin was found in 26% of H. influenzae isolates. Multi-drug resistance was found in 31% of S. pneumoniae isolates. Almost all S. pneumoniae isolates were resistant to both tetracycline and trimethoprim/sulphonamide and about half were resistant to chloramphenicol and/or erythromycin.

The authors conclude that there is a serious public health problem in the Vietnamese community. A majority of children will suffer acute respiratory infection symptoms within any one month. They will be treated inappropriately with antibiotics, which are contributing to significant levels of resistance.

Source: Larsson M, et al. Antibiotic medication and bacterial resistance to antibiotics: a survey of children in a Vietnamese community. Tropical Medicine and International Health 2000;5(20):711 - 721.

Working to decrease costs of anti-TB drugs

MARCOS ESPINAL, RAJESH GUPTA, MARIO RAVIGLIONE*

* The authors work for the World Health Organization, Communicable Diseases Cluster, in Strategy Development and Monitoring for Endemic Bacterial and Viral Diseases, Communicable Disease Control, Prevention and Eradication.

Among infectious diseases tuberculosis (TB) remains a leading cause of adult mortality.1 Over the last decade, the rising spectre of multidrug-resistant TB (MDR-TB) began to threaten global TB control efforts. MDR-TB is defined as disease caused by Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. There is evidence that short-course chemotherapy with first-line anti-TB drugs used to treat drug-susceptible cases is not as effective to cure MDR-TB cases.2 In some areas of the world (especially countries of the former Soviet Union and eastern Europe), rates of MDR-TB among new and previously-treated cases are so high that they are considered “international public health emergencies” given the possibility of international spread.3,4

To respond to the challenge, WHO and several partners have launched pilot projects to manage MDR-TB within programme conditions in settings of limited resources. However, one of the greatest obstacles to providing treatment to patients infected with MDR-TB has been the high cost of the second-line anti-TB drugs needed for the management of MDR-TB.5 Over the last three years, open market prices for these second-line anti-TB drugs have been as high as US$ 15,000 for an 18-month treatment regimen. In contrast, the first-line anti-TB drugs needed for management of drug-susceptible TB cost as little as US$ 11 for a six-month treatment regimen.6 In order to decrease the cost of these drugs, the WHO Working Group (specially created to deal with MDR-TB) has negotiated with both the research-based and generic pharmaceutical industry. Negotiations have resulted in a preferential price decrease in the cost of treatment regimens of up to 90% in comparison to the open market price. These preferential prices were partially achieved through global procurement of drugs. Consolidating the market into a single-demand source not only allowed for some market forces to arise, but also for industry members to conduct more accurate demand forecasts that, previously, had been very difficult.

At the same time, in order to protect against the misuse of drugs and creation of resistance to these drugs (the last line of chemotherapeutic defence against TB), these preferentially priced drugs are only released to those projects adhering to standard scientific guidelines as determined by an independent body called the

Green Light Committee.7 This Committee, housed in WHO, is currently comprised of six institutions: Centres for Disease Control and Prevention, Harvard Medical School, Médecins Sans Frontières, the National TB Programme - Peru, Royal Netherlands TB Association and WHO (serving as a permanent member and secretariat). Most of the work conducted by the Green Light Committee is performed via videoconference, teleconference and e-mail. All decisions are made by consensus.8

Overall, the process has worked well due to the joint efforts of all institutions involved. Pilot projects have benefited from the procurement process and the negotiations, which, by virtue of the mechanism described, guarantee that high-quality anti-TB drugs provided at preferential prices are used in the best possible, controlled manner. This method of procurement helps to ensure the scientific integrity of the pilot projects and should be explored for use in other infectious diseases, including HIV/AIDS.


A patient in Tanzania suffering from TB, a disease which is becoming increasingly common and increasingly resistant to drug treatments

Photo: WHO/O.Harrer

References

1. Raviglione MC, Snider DE Jr, Kochi A. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 1995;273(3): 220 - 26.

2. Espinal MA, et al. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcome in six countries. JAMA 2000;283 (19):2537 - 2545.

3. WHO, International Union Against Tuberculosis and Lung Disease. Anti-tuberculosis drug resistance in the world: the WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance, Report No. 2. Geneva: World Health Organization; 2000. WHO/TB/2000. 278.

4. Harvard Medical School and Open Society Institute. The global impact of drug-resistant tuberculosis. Programme in Infectious Disease and Social Change. 1999.

5. WHO. Procurement of second-line anti-tuberculosis drugs for DOTS-Plus Pilot Projects. Proceedings of a

meeting. Gupta R, Brenner JG, Henry CL, et al, eds. Geneva: World Health Organization; 2000. WHO/CDS/TB/2000.276.

6. Khatri. Personal Communication. 2000.

7. WHO. Guidelines for establishing DOTS-Plus Pilot Projects for the management of multi-drug-resistant tuberculosis. Geneva: World Health Organization; 2000. WHO/CDS/TB/2000.279.

8. WHO. DOTS-Plus and the Green Light Committee. Geneva: World Health Organization, 2000. WHO/CDS/TB/2000.283.

How Chile tackled overuse of antimicrobials

LUIS BAVESTRELLO AND ANGELA CABELLO*

* Dr Luis Bavestrello is a clinical pharmacologist and Head of the Infectious Diseases Department, Dr Gustavo Fricke Hospital, and Angela Cabello is a pharmaceutical chemist in the Pharmaceutical Unit, Dr Gustavo Fricke Hospital, Alvarez 1532, Viña del Mar, Chile. Tel/fax: + 56 32 652450.

In 1998, the Pan American Infectious Diseases Society and the Pan-American Health Organization carried out a study in Chile on trends in antimicrobials use during the previous 10 years.1 The study revealed a significant increase in antibiotic consumption, expressed in terms of DDD (defined daily dose) per 1,000 population per day over the 10 years, based on annual sales data for antibiotics in terms of both grams consumed and units of sale.2 Noteworthy findings included increases in sales of amoxicillin (+ 498%), oral cephalosporins (+ 309%) and oral fluoro-quinolones (+ 473%) between 1988 and 1997. The only antibiotic with declining consumption was chloramphenicol (-18%). See Tables 1 and 2.

These findings were submitted to the Chilean Ministry of Health, and meetings arranged to study what to do about the problem. Health Ministry staff met with scientific associations, the body regulating drug manufacture and prescribing, the Institute of Public Health and the

Committee on Health of the National Congress. Professional organizations of physicians and chemists, and the National Department of Consumer Affairs were also consulted, with a view to informing the general public before adopting any potentially unpopular measures. This was necessary because people were accustomed to purchasing antibiotics without a prescription, and even individual tablets in Chile’s pharmacies.

Table 1
Percentage increases in consumption of selected antibiotics and groups of antibiotics, 1988 - 1997

Antimicrobial

1988
DDD/1000
pop. per day*

1997
DDD/1000
pop. per day

Variation
% increase

cloxacillin

0.39

0.417

7

ampicillin

0.54

0.613

14

amoxicillin

0.87

5.204

498

clavul. amoxicillin

0.0025

0.414

16460

cotrimoxazole

0.965

1.163

20

cephalosporins

0.064

0.262

309

fluoroquinolones

0.049

0.281

473

* Defined Daily Dose per 1,000 population per day


These children playing happily in Chile stand to benefit from the country’s actions to minimise antimicrobial resistance

Photo: WHO/PAHO/C. Gaggero

Hitting the headlines

At the end of September 1999, after this consultative process, the Ministry of Health acted to control antibiotics, by making them available only through chemists and on prescription. Compliance with the measure was encouraged by distributing leaflets in private chemists, displaying posters and by extensive coverage on radio and television news programmes. In addition, the attention of the pharmaceutical chemists responsible for the technical management of pharmacists was drawn to the increase in antibiotic consumption over the previous 10 years.

Three months after the Ministry’s action an evaluation study showed a downturn in consumption. This further study, entitled “Preliminary evaluation of the impact of the measures to regulate outpatient consumption of antimicrobials in Chile”, involved a comparison between the same two quarters of two years, one immediately before the introduction of the measure, the other immediately after. The study showed a decline in consumption of 36% in amoxicillin, 56% in ampicillin and 30% in erythromycin between the last quarter of 1998 and the same quarter of 1999.

Expenditure dropped by US$ 6,483,883 between 1998 and 1999, representing a saving for the population as shown in Table 4.

Studies reveal that the Ministry of Health’s control measures introduced after consultation with scientific, professional and consumer associations, and with Parliament, had a clear impact on the sale and consumption of antibiotics in Chile. As a result, in Chile antibiotics may now only be purchased by prescription. This has reduced self-medication and the concomitant threat of microbial resistance.

Table 2
Annual sales of packs of antimicrobials in private pharmacies in Chile, by antimicrobial group, 1988 - 1997

Year

Macrolides

Penicillin: broad spectrum

Penicillin: M-R Spectrum

Cephalosporin

Cotrimoxazole

Tetracycline

Chloramphenicol

Fluoroquinolone

1988

765,800

3,199,000

3,488,600

 

1,409,800

836,500

392,600

 

1989

798,400

3,373,700

3,797,800

185,200

1,457,000

851,400

457,100

 

1990

989,235

3,633,271

3,379,425

214,084

1,478,396

870,288

398,428

 

1991

1,053,390

4,104,949

3,354,194

221,457

1,717,625

1,028,031

402,170

 

1992

1,118,807

4,368,913

3,240,031

247,261

1,578,412

914,297

278,566

 

1993

1,435,275

5,151,850

3,289,910

322,135

1,752,653

883,301

298,809

240,167

1994

1,400,078

5,090,712

3,250,074

367,539

1,543,922

844,178

276,392

269,452

1995

1,615,879

6,213,139

3,548,893

505,036

1,532,223

1,016,890

320,594

307,376

1996

1,818,824

6,858,590

3,676,448

537,154

1,550,226

979,917

341,639

335,728

1997

2,076,073

7,799,949

4,035,888

563,902

1,692,889

1,055,055

330,348

414,625

... = No data available
Source: International Marketing System

Table 3
Changes in consumption by DDD/1000 pop./per day between the last quarter of 1998 and the same quarter of 1999 (immediately after the introduction of the Ministry of Health regulation)

Antimicrobials

4th quarter 1998

4th quarter 1999

Variation (%)

clarithromycin

0.366

0.446

21.8

azithromycin

0.342

0.353

3.2

erythromycin

0.536

0.370

-30.9

amoxicillin

4.639

2.943

-36.5

ampicillin

0.391

0.182

-53.4

clavulanic amoxicillin

0.459

0.443

-3.5

cloxacillin

0.424

0.338

-20.3

phenoxymethylpenicillin

0.184

0.111

-39.7

cotrimoxazol

0.913

0.633

-30.7

tetracycline

0.499

0.340

-31.8

ciprofloxacin

0.317

0.386

21.8

Table 4
Dollar sales of groups of antimicrobials by private pharmacies in Chile, 1998 - 1999

Group of antimicrobials

1998

1999

Difference (US$)

macrolides

14,763,740

12,448,627

2,315,113

broad spectrum penicillins

13,747,242

11,227,954

2,519,288

oral cephalosporin

4,488,543

4,193,849

294,694

fluoroquinolone

4,075,818

4,115,261

-39,443

med.-nar. spect. penicillin

4,121,100

3,275,517

845,583

cotrimoxazole

2,316,260

1,767,612

548,648

Total

43,512,703

37,028,820

6,483,883

Source: International Marketing System

This Chilean example shows that given political will, determination, consultation and public education, effective measures that save lives - by promoting rational use of antibiotics - and money are possible.

References

1. PAHO. Resistencia antimicrobiana en las Américas: Magnitud del problema y su contención. Editores Salavtierra-González R, Benguigui Y. OPS/HCP/HCT/163/2000 pp.234 - 240.

2. Bavestrello L, Cabello A. Estudio del consumo de antimicrobianos en la comunidad. Chile, diez años después. Rev Chil Infect (1999);16(3):185 - 190.

Nepal: an economic strategy to improve prescribing

Apre-post with control study was conducted in 33 health facilities (10 - 12 per district) in three districts in Eastern Nepal1. In 1992 all three districts charged the same flat fee per prescription, covering all drugs in whatever amounts. In 1995 the control district charged the same fee, but the other two districts had instituted new fee systems. One district charged a single fee per drug item (1-band item fee), whatever the drug, but covering a full course of the drug. A second district charged a higher fee per expensive item (e.g. antibiotics and injections) and a lower fee per cheap item (e.g. vitamins), each fee covering a full course of the drug. All the fees were priced so as to cost patients about 25% of average daily household income for two drug items. Prescribing was monitored in all health facilities before and after the fee systems were changed.

Table 1 shows that both item fees were associated with significantly better prescribing quality than the prescription fee. The percentage of patients receiving antibiotics decreased and the proportion of prescriptions conforming to standard treatment guidelines increased in both item fee districts as compared to the prescription fee district. The 1-band fee was associated with a greater reduction in cheap vitamins and tonics, and the 2-band fee with a greater reduction in expensive injections.

Reference

1. Holloway KA, Gautam BR. The effects of different charging mechanisms on rational drug use in eastern rural Nepal. Paper presented at the First International Conference on Improving Use of Medicines; 1997 April 1 to 4; Chiang Mai, Thailand. Available on the Web at: www.who.int/dap-icium/posters/4e2_Text.html

Table 1
The effects of different kinds of user fee on prescribing quality in Nepal

Fees system

Control flat fee/Px
n=12

1-band fee/drug item
n=10

2-band fee/drug item
n=11

Av. no. items/Px

2.9 → 2.9 (0%)

2.9 → 2.0 (-31%)

2.8 → 2.2 (-21%)

% Px with antibiotics

66.7 → 67.5 (+0.8%)

63.5 → 54.8 (-8.7%)

60.7 → 54.3 (-6.4%)

% Px with injections

23.4 → 20.0 (-3.4%)

19.8 → 16.1 (-3.7%)

21.8 → 14.9 (-6.9%)

% Px with vitamins or tonics

27.0 → 22.1 (-4.9%)

26.5 → 8.4 (-18.1%)

23.5 → 15.8 (-7.8%)

% Px conforming to STGs

23.5 → 26.3 (+2.8%)

31.5 → 45.0 (+13.5%)

31.2 → 47.7 (+16.5%)

Av. cost/ Px (NRs)

24.3 → 33.0 (+35.8%)

27.7 → 28.0 (+1.1%)

25.6 → 24.0 (-6.3%)

Px = prescription

Containing drug resistance through hospital infection control

NIZAM DAMANI*

* Dr Nizam Damani is Clinical Director and Consultant Microbiologist, Craigavon Area

Hospitals are a crucial component of the antimicrobial resistance problem world wide, because highly vulnerable patients often require prolonged antibiotic therapy, and the problem of cross infection arises.

Every hospital should make containment and control of multi-resistant micro-organisms a high priority, and it requires a team approach. The first step is to establish an active and effective infection control committee with responsibility for formulating, implementing and auditing an infection control programme throughout the hospital.

The microbiology laboratory’s role

A good diagnostic microbiology laboratory service is essential. Laboratories should use internationally recognised protocols to identify organisms and antibiotic sensitivity, and their range of diagnostic facilities should cover non bacterial and unusual infections. Close liaison with clinicians, the infection control team and the drug and therapeutics committee is essential. Laboratories should serve as an important source of local surveillance data both for the hospital and the community.

Antibiotic prescribing: a crucial element

Hospital drug and therapeutics committees should be responsible for the promotion of rational prescribing, drug use monitoring and cost containment. They must regularly review antibiotic use, conduct audits and give doctors feedback to influence prescribing habits. Committees should also approve the use of newer antimicrobial agents, which should be restricted to agreed clinical conditions.

Doctors must be trained to take responsibility for rational prescribing and to justify their antimicrobial use. Their prescribing policy must be evidence-based and should reflect local antibiotic resistance surveillance data. This can be achieved by having a written hospital formulary, and an antibiotic policy that is regularly updated and has broad input and consensus among all involved.

Infection control measures

Barrier precautions are vital to prevent the spread of multi-resistant microorganisms in hospitals. These include isolating patients with multi-resistant organisms, and ensuring that staff adheres to hand hygiene procedures and use of appropriate personal protective equipment. It is important for infection control measures to be based on the local epidemiology and be tailored to suit individual needs.

Hospitals should have a written disinfectant policy with procedures to ensure adequate decontamination of equipment and the environment. Internationally recommended sterility checks must be carried out on a regular basis. As multi-resistant organisms can survive in the environment for prolonged periods, and may act as a reservoir for infection, the hospital environment should be kept clean, dry and dust free.

Therapeutic devices, such as urinary and intravenous catheters, are not only responsible for the majority of hospital-acquired (nosocomial) bacteraemias, but also for cross infection/outbreaks of multi-resistant organisms. Urinary catheters should be inserted only when necessary and removed when no longer required. All hygiene precautions must be followed. The use of antibiotics should be restricted to patients who show clinical signs of infection.

The majority of primary blood stream infections are associated with the use of intravascular devices. Again the best prevention is to insert an intravascular line only if necessary and to keep it in place for a minimum period. The routine use of antibiotics to prevent catheter-associated and intravenous line infection is not recommended.

A universal challenge

The control and containment of multi-resistant micro-organisms represents a universal challenge requiring national and international efforts, as ease of long distance travel no longer limits spread. Every hospital should devote adequate resources to an infection control programme or health and health care resources could suffer.


No one is more vulnerable to multi-drug resistance than people admitted to hospital wards

Photo: WHO/PAHO/A.Waak

Hospital, 68 Lurgan Road, Portadown, Co. Armagh BT63 5QQ, Northern Ireland, UK. Tel: + 44 128 38 33 4444 ext. 2654, fax: + *****************.

References

1. WHO. Recommendations for the control of meticillin-resistant Staphylococcus aureus (MRSA). Geneva: World Health Organization; 1996. WHO/EMC/LTS/96.1.

2. The Hospital Infection Control Practices Advisory Committee. Recommendations for preventing the spread of Vancomycin resistance. Morbidity and Mortality Weekly Report 1995;44:1 - 13.

3. Global consensus conference on infection control issues related to antimicrobial resistance: Final recommendations. American Journal of Infection Control 1999; 27:503 - 513.

4. The Hospital Infection Control Practices Advisory Committee. Guidelines for isolation precautions in hospitals. American Journal of Infection Control 1996;24:24 - 52.

5. Shlaes DM, Gerding DN, John JF, et al. Society of Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: Guidelines for prevention of antimicrobial resistance in hospitals. Infection Control and Hospital Epidemiology 1997;18:279 - 291.

6. Goldman DA, et al. Strategies to prevent and control the emergence and spread of antimicrobial-resistant micro-organisms in hospitals. Journal of American Medical Association 1996; 275:234 - 240.

Changing prescriber behaviour

TRAINING AND TREATMENT GUIDELINES IMPROVE PRESCRIBING IN UGANDA

A randomised controlled trial to test the impact of standard treatment guidelines (STGs) plus training and supervision on rational prescribing was carried out in 127 health units in Uganda. Prescribing was monitored in all facilities both before and after the interventions. In a control group of 42 health units, no intervention was introduced. In a second group of 42 health units, the national standard treatment guidelines were disseminated but no training or supervision was conducted. In a third group of 29 health units, the national standard treatment guidelines were introduced and on-site training on therapeutic problems conducted. In a fourth group of 14 health units, the same was done as for the third group but, in addition, four supervisory visits were conducted over a six-month period.

Table 1 shows how prescribing changed in the different groups. Prescribing quality, (as judged by the percentage of prescriptions conforming to standard treatment guidelines) did not improve when only guidelines were disseminated, but greatly improved if dissemination was accompanied by training and supervision. The intervention used was not only directed at antibiotic prescribing, but other aspects of prescribing also. This may account for why the changes in prescribing quality (percentage of prescriptions conforming to treatment guidelines) were much greater than for antibiotic use alone (percentage of prescriptions containing antibiotics).

Table 1
Randomised controlled trial in Uganda

Randomised group

n

% prescriptions
containing antibiotics

% prescriptions
conforming to STG

Control group

42

53.0 → 58.0%

+5.0%

24.8 → 29.9%

+5.1%

Dissemination of STG

42

51.6 → 57.8%

+6.2%

24.8 → 32.3%

+7.5%

STG + on-site training in therapeutic problems

29

51.7 → 50.7%

-1%

24.0 → 52.0%

+28.0%

STG + on-site training in therapeutic problems + 4 supervisory visits in 6 months

14

54.3 → 54.3%

0%

21.4 → 55.2%

+33.8%

Reference

Kafuko J.M, Zirabumuzaale C, Bagenda D. Rational drug use in rural health units of Uganda: effect of national standard treatment guidelines on rational drug use. Final report. Kampala: UNICEF, Uganda; 1996.

Prioritising interventions to contain antimicrobial resistance

KATHLEEN HOLLOWAY*

* Dr Kathleen Holloway is a Medical Officer in the Department of Essential Drugs and Medicines Policy at the World Health Organization.

Just as there are many actors and activities that contribute towards antimicrobial resistance, so there are many potential strategies to contain the growth and spread of resistance. The WHO Global Strategy to contain resistance, (which will be published in 2001 and will be available on the Web via http://www.who.int/emc/amr), identifies 64 interventions in total. Of these, 44 interventions are aimed at improving the use of antimicrobial drugs in humans at the national level or below, (i.e. excluding interventions concerning animal use, new vaccine and drug development and international measures).

Critical decisions

No country in the world is implementing all of these recommended interventions and most would find it impossible to do so. Therefore, all countries will need to prioritise the interventions and choose which ones to implement first and which to implement later. Developing countries in particular will need to prioritise and choose only those interventions that, in their local contexts, are both feasible and likely to have the greatest impact. This article discusses the problem of how to choose which interventions will be both feasible and have a significantly large impact. Two methods are described. The first method was used in two WHO Regional Offices and one country, whilst the Global Strategy was being developed. From the problems encountered using the first method, a second method was developed and used at WHO Headquarters in finalising the present draft of the Global Strategy.

Table 1
Agreed list of interventions to contain antimicrobial resistance

Target group

Recommended interventions

A
Patients and the public

1. Education on appropriate use
2. Education on hygiene
3. Discourage self-medication

B
Prescribers and dispensers

1. Training
2. Guidelines and formularies
3. Monitoring and supervision
4. Regulation of professionals
5. Educate prescribers about promotion

C
Health systems

1. Therapeutic committees
2. Infection control committees
3. Guidelines for antimicrobial use
4. Antimicrobial use surveillance
5. Laboratory network and epidemiological resistance surveillance

D
Government policies, strategies and regulations

1. National AMR task force with budget
2. Drug policies e.g. essential drugs list, standard treatment guidelines
3. Registration of all drug outlets
4. Antimicrobials by prescription-only
5. Dispensing of antimiocrobials by licensed staff only
6. Quality assurance system
7. Drug licensing to include resistance data
8. Undergraduate and postgraduate training on AMR
9. Access to evidence-based drug information
10. Cut perverse rational drug use economic incentives
11. Monitor and supervise drug promotion
12. Monitor and link AMR and drug use data

E
Pharmaceutical industry

1. Incentives for industry to do research and development
2. Monitor and supervise drug promotion
3. Production according to Good Manufacturing Practice standards

F
Non-human antimicrobial use

1. Surveillance of resistance and use
2. Phase-out growth promoters
3. Educate farmers and vets

THE REGIONS’ PRIORITISATION PROCESS

Step one: deciding who participates in the process

A list of participants was agreed locally. In the Regional Office for the Eastern Mediterranean (EMRO) and the Regional Office for South-East Asia (SEARO), participants were WHO staff members. In Nepal they were from the Ministry of Health, academic institutions and local NGOs. All health disciplines concerned with antimicrobial use and/or resistance were invited, including all those concerned with communicable diseases, health systems, essential drugs and primary health care.


A pharmacy in Colombia. Ensuring good dispensing practices is seen as a high priority in the fight against antimicrobial resistance

Photo: WHO/PAHO/A.Waak

Step two: developing a list of interventions

EMRO participants developed a list of interventions starting from those recommended in the WHO draft Global Strategy. SEARO and Nepali participants also agreed to use this list (see Table 1).

Step three: voting on the proposed interventions

Each intervention was scored according to:

(1) the importance or relevance of any impact it might have, and
(2) the feasibility of implementation.

It was agreed that “relevance” would take into account whether an intervention would impact on the diseases of particular concern locally, and that “feasibility” would take into consideration both cost of implementation and the political context. The scoring was as follows:

0 = not feasible or no relevant impact
1 = medium feasibility or medium relevant effect
2 = good feasibility or very relevant effect

Step four: collating the voting data

All the participants’ scores for likely relevant impact and feasibility for each intervention were added up and then plotted on a matrix. Interventions that were likely to have the greatest impact and be feasible appeared in the top right-hand corner of the chart and were judged to be of highest priority. Those interventions that appeared in the bottom left-hand corner of the chart were judged less feasible and relevant. For example, in a group of 11 people, the maximum score an intervention could receive for either importance or feasibility was 22 (11 participants awarding a maximum of two points). The points plotted on the matrix would therefore be 22 for importance and 22 for feasibility.

Diverse views

The graphs below (figures 1 - 3) indicate the priority given to different interventions. Comparison shows how the various regions agreed and disagreed on which interventions should have highest priority. The reasons for differences in the priorities between these three groups may have been due to different priorities in different areas, but were also in large part due to the different expertise of participants in the different groups. For example, in SEARO there was no one specialising in health systems or drug regulation, in Nepal microbiologists were poorly represented, as were agriculturalists in both EMRO and SEARO.

The most feasible and important interventions agreed by everyone included:

• training of prescribers and dispensers, and the use of guidelines and formularies;

• establishing infection control committees, guidelines for antimicrobial use, and surveillance of antimicrobial use in hospitals;

• developing national drug policies, essential drugs lists and standard treatment guidelines;

• ensuring undergraduate and postgraduate training on antimicrobial resistance;

• ensuring drugs are produced according to Good Manufacturing Practice standards.

The least feasible and important interventions agreed by everyone included:

• ensuring that antimicrobials are dispensed by licensed staff and only with a prescription;

• cutting perverse economic incentives to prescribe antibiotics - for example the problem of dispensing prescribers earning more money from selling antibiotics than from other drugs;

• monitoring and linking data concerning antimicrobial resistance and antimicrobial use;

• monitoring and supervising drug promotion both for human and animal use;

 

• phasing out growth promoters in animal use.

Priorities in the WHO Global Strategy for Containment of Antimicrobial Resistance

Although all interventions were classified into fundamental, high, medium and low, only the first two categories are shown below. Within the two priority groupings shown here, interventions are not ranked.

Fundamental interventions

Make containment of antimicrobial resistance a national priority including:

• creating a national task force;

• allocating resources to implement interventions to contain antimicrobial resistance;

• developing indicators to monitor and evaluate the impact of an antimicrobial resistance strategy;

• designating or developing reference microbiology laboratory facilities.

These would coordinate effective, epidemiologically-sound, surveillance of antimicrobial resistance among common pathogens in the community, hospitals and other health care facilities.

High priority interventions

1. Patient education on:

• the importance of measures to prevent infection such as immunization, vector control, use of bed-nets;

• simple measures that may reduce transmission of infection in the household and community, such as hand washing, food hygiene.

2. Prescriber and dispenser (including drug seller) education on:

• the importance of appropriate antimicrobial use and containment of antimicrobial resistance;
• disease prevention (including immunization) and infection control issues.

3. Targeted undergraduate and postgraduate education programmes for all prescribers, dispensers and other health care workers, and veterinarians, on accurate diagnosis and management of common infections.

4. Development, updating and use of standard treatment guidelines and treatment algorithms to foster appropriate use of antimicrobials.

5. Infection control programmes with responsibility for effective management of antimicrobial resistance in hospitals.

6. Diagnostic laboratories that provide:

• microbiology laboratory services which are appropriately matched to the level of the hospital (e.g. secondary, tertiary);

• appropriate diagnostic tests, bacterial identification, antimicrobial susceptibility tests of key pathogens, with adequate quality assurance, and timely, relevant reporting of results.

7. Limiting the availability of antimicrobials to prescription-only status, except in special circumstances where they may be dispensed on the advice of a trained health care professional.

8. Ensuring that only antimicrobials meeting international standards of quality, safety and efficacy are granted marketing authorisation.

PRIORITISING INTERVENTIONS FOR THE WHO GLOBAL STRATEGY

As a result of the diverse views obtained from the regions, a different process of prioritisation was conducted for the draft Global Strategy, in order to produce some concrete practical advice for Member States.

Experts in the fields of drug use, clinical microbiology and other related disciplines from all over the world were invited to a workshop in Geneva. Participants were divided into three working groups, with each considering interventions aimed at a particular target audience:

Group 1: Prescribers and dispensers
Group 2: Hospitals
Group 3: Health systems

For each target audience, the interventions were prioritised according to their relative merits and ranked according to sequence and importance of implementation. This complex task required consideration of multiple factors relating to each intervention including:

• overall importance of the intervention to improving the appropriate use of antimicrobials and containing antimicrobial resistance;

• likely impact, allowing for the expected cost of implementation;

• complexity of implementation, considering the capacity of various health care systems and political realities;

• time required for implementation and the expected lag period before outcomes could be expected;

• the accuracy with which most health care systems could assess the efficacy of each intervention;

• the interrelationship between various interventions, including the need to undertake some interventions in a logical sequence.

As a result of this process, interventions were ranked as high, medium and low, and consideration was given to whether the ranking would vary according to a national health system’s level of development.

Once interventions for each target audience were ranked, the interventions were then ranked according to their overall importance and timing (sequence) of implementation, without consideration of their target audience. This was done by all the participants in a plenary session (see box). It was recognised that some priorities might vary depending on the health care system in which they would be implemented. However, this did not impact to any significant extent on the priority given to the majority of very high priority interventions.

Although it was not planned to address issues relating to consumers and drug promotion at this workshop, in fact they were also considered. This was because participants, particularly in Group 1, felt that prescribers and dispensers could not be considered separately from consumers.


Figure 1 - Prioritisation of interventions by the 11 members of EMRO antimicrobial resistance task force


Figure 2 - Prioritisation of interventions by 15 health officials in Nepal


Figure 3 - Prioritisation of interventions by 7 staff members of SEARO

The figures should be viewed in conjunction with Table 1, as the different shapes and colours on the three graphs each represent one of the six target groups (A - F) listed in the Table. For example, a green circle signifies D - interventions involving government policies, strategies and regulations. The numbers within each shape correspond to the different recommended interventions in each of the target groups. So there are 12 green circles on the map numbered 1 to 12, corresponding to the numbered list of interventions under D in Table 1. Their position on the graph is dependent on the scores participants awarded them. For example, D10 - cutting perverse rational drug use economic incentives - appears in the bottom left-hand corner of the graph, showing that it received the lowest scores for both importance and feasibility.

The dotted green cross lines signify where the average score (1 point for both importance and feasibility awarded by each person in the group) would appear.

INTERVENTIONS FOR MAXIMUM IMPACT

Comparison of the priorities identified at country, regional and international levels shows many similarities. The interventions agreed by everyone to be both high priority and feasible are:

1. training prescribers and dispensers, and using guidelines and formularies;

2. establishing infection control committees and guidelines for antimicrobial use;

3. developing national drug policies, essential drugs lists and standard treatment guidelines;

4. ensuring undergraduate and postgraduate training on antimicrobial resistance;

5. ensuring that drugs are produced according to good manufacturing practice standards and are of adequate quality.

Interestingly, regional staff felt that surveillance of antimicrobial use in hospitals was feasible and important, and gave it higher priority than the experts invited to Geneva did. On the other hand, while the Geneva group felt that restricting antimicrobials to prescription-only status was very important, regional staff felt that it was not feasible.

There is no hard evidence as to which interventions are most important and have the greatest impact, and expert opinion varies. Nevertheless the two different processes of prioritisation identified the five interventions listed above. Everyone agreed that these interventions were feasible and would have the greatest impact on antimicrobial resistance if adequately implemented.


A leaflet from the UK’s public education campaign on the correct use of antibiotics

Department of Health, UK

Useful websites on antimicrobial resistance

APUA-Alliance for the Prudent Use of Antibiotics
http://www.antibiotic.org (see also EDM No.24 p.20)

AR InfoBank-WHO Antimicrobial Resistance Information Bank
http://oms2.b3e.jussieu.fr/arinfobank

BUBL Catalogue of Internet Resources - Infectious Diseases
http://bubl.ac.uk/link/i/infectiousdiseases.htm

Center for Adaptation Genetics and Drug Resistance
http://www.healthsci.tufts.edu/labs/Sblevy/home.html

Center for Complex Infectious Diseases
http://www.ccid.org/

Centers for Disease Control, Drug Resistance Homepage
http://www.cdc.gov/drugresistance/

CIA. The global infectious disease threat and its implications for the United States. 1999
http://www.odci.gov/cia/publications/nie/report/nie99-17d.html

EARSS-European antimicrobial resistance surveillance system
http://EARSS.rivm.nl

Eurosurveillance
http://eurosurv.org/

Global Polio Eradication Initiative
http://www.polioeradication.org

Infectious Disease News
http://www.slackinc.com/general/idn/idnhome.htm

International Society for Infectious Diseases
http://isid.organize-it.com/

Johns Hopkins University - Infectious Diseases
http://www.hopkins-id.edu/index_id_links.html

Karolinska Institute, Sweden
http://micf.mic.ki.se/Diseases/

National Foundation for Infectious Diseases, USA
http://www.nfid.org/

Project Icare: Intensive Care Antimicrobial Resistance Epidemiology
http://www.sph.emory.edu/ICARE/

Roll Back Malaria
http://www.rbm.who.int/

Stop TB Initiative
http://www.stoptb.org

The Hot Zone: Emerging Infectious Diseases Reports and Web Sites
http://www.qis.net/~edwardmc/eid.htm

UK Public Health Laboratory
http://www.phls.co.uk/

US National Center for Infectious Diseases
http://www.cdc.gov/ncidod/eidtopics.htm

Washington University Infectious Disease Division, USA
http://www.id.wustl.edu/

WHO Communicable Diseases Home Page
http://www.who.int/health-topics/idindex.htm

WHO/TDR (Special Programme for Tropical Disease and Research)
http://www.who.int/tdr

Selected references

Coast J, Smith RD, Millar MR. An economic perspective on policy to reduce antimicrobial resistance. Soc Sci Med 1998;46:29 - 38.

Fidler DP. Legal issues associated with antimicrobial drug resistance. Emerg Infect Dis 1998;4:169 - 77.

Finch RG, Williams RJ. Eds. Antibiotic resistance. Clin Infect Dis 1999;5(2).

Goldmann DA, Huskins WC. Control of nosocomial antimicrobial-resistant bacteria: a strategic priority for hospitals worldwide. Clin Infect Dis 1997;24 (Supplement 1):S139 - 45.

Hart CA, Kariuki S. Antimicrobial resistance in developing countries. BMJ 1998;317:647 - 650.

Institute of Medicine. Antimicrobial resistance: issues and options. Workshop report. Washington D.C.: National Academy Press; 1998. http://books.nap.edu/books/0309060842/html/R1.html#pagetop

Pittet D et al. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Lancet 2000;356: 1307 - 1312.

Polk HC Jr, Christmas AB. Prophylactic antibiotics in surgery and surgical wound infections. Am Surg 2000;66:105 - 11.

UK Standing Medical Advisory Committee Sub-Group on Antimicrobial Resistance. The path of least resistance. London: Department of Health; 1998. http://www.open.gov.uk/doh/smac.htm

WHO. World Health Assembly 1998. Emerging and other communicable diseases: antimicrobial resistance. WHA51.17, agenda item 21.3. http://www.who.int/emc/

WHO. Anti-tuberculosis drug resistance in the world. The WHO/International Union Against Tuberculosis and Lung Disease global report on anti-tuberculosis drug resistance surveillance 1994 - 97. Geneva: World Health Organization; 1997. WHO/TB/97.229.

WHO. Guidelines for the management of drug-resistant tuberculosis. Geneva: World Health Organization; 1997. WHO/TB/96.210.

WHO. Integrated management of childhood illnesses: A WHO/UNICEF initiative. WHO Bulletin 1997;75 (Supplement 1).

WHO. The medical impact of the use of antimicrobials in food animals: Report and proceedings of a WHO meeting, Berlin, Germany, 13 - 17 October 1997. Geneva: World Health Organization; 1997. WHO/EMC/ZOO/97.4.

WHO. Treatment of tuberculosis: guidelines for national programmes; 2nd ed. Geneva: World Health Organization; 1997. WHO/TB/97.220.

WHO. Use of quinolones in food animals and potential impact on human health. Report and proceedings of a WHO meeting, Geneva, Switzerland, 2 - 5 June 1998. Geneva: World Health Organization; 1998. WHO/EMC/ZDI/98.12.

WHO. Basis for the development of an evidence-based case-management strategy for MDR-TB within the WHO’s DOTS Strategy. Geneva: World Health Organization; 1999. WHO/TB/99.269.

WHO. Containing antimicrobial resistance. Review of the literature and report of a WHO workshop on the development of a global strategy for the containment of antimicrobial resistance. Geneva, Switzerland, 4 - 5 February 1999. Geneva: World Health Organization; 1999. WHO/CDS/CSR/DRS/99.2. www.who.int/emc/WHO_docs/general.htm

WHO. WHO report on infectious diseases. Removing obstacles to healthy development. Geneva: World Health Organization; 1999. WHO/CDS/99.1. http://www.who.int/infectious-disease-report/

WHO. Anti-tuberculosis drug resistance in the world. Report no. 2. Prevalence and trends. The WHO/International Union Against Tuberculosis and Lung Disease global report on anti-tuberculosis drug resistance surveillance. Geneva: World Health Organization; 2000. WHO/CDS/TB/2000.278.

WHO. Global tuberculosis control: WHO Report 2000. Geneva: World Health Organization; 2000. WHO/CDS/TB/2000.275.

WHO. Guidelines for establishing DOTS-Plus pilot projects for the management of multidrug-resistant tuberculosis (MDR-TB). Geneva: World Health Organization; 2000. WHO/CDS/TB/2000.279.

WHO. Management of the child with a serious infection or severe malnutrition: guidelines for care at the first-referral level in developing countries. Geneva: World Health Organization; 2000. WHO/FCH/00.1.

WHO. World Health Organization report on infectious diseases 2000. Overcoming antimicrobial resistance. Geneva: World Health Organization; 2000. WHO/CDS/2000.2. http://www.who.int/infectious-disease-report-2000

WHO. Surveillance standards for antimicrobial resistance. Geneva: World Health Organization; 2000. CDS/CSR/DRS 2000.2 (in preparation).

Pioneers of antimicrobial resistance


Paul Ehrlich, 1854 - 1915

A German medical scientist renowned for his pioneering work in haematology, immunology and chemotherapy, Ehrlich won the 1908 Nobel Prize for his discovery of the first effective treatment for syphilis. As well as his research into early chemotherapy, Ehrlich also developed “side chain theory” a hypothesis that provided the first plausible description of the body’s own immunological response to destructive pathogens.


Louis Pasteur, 1822 - 1895

Considered one of the greatest French biologists of the nineteenth century, Pasteur devoted his life to solving practical problems in industry, agriculture and medicine. Pasteur was the first to discover that fermentation and putrefaction only took place in the presence of living organisms. With further research he developed the technique of pasteurization that not only revolutionized the dairy industry, but food processing as well.


Selman Waksman, 1888 - 1973

A Ukrainian-born biochemist, Selman Waksman played a major role in initiating a calculated, systematic search for antibiotics among microbes. His discovery of streptomycin - effective in the treatment of tuberculosis - garnered him the Nobel Prize in 1952.


Sir Alexander Fleming, 1881 - 1955

Honoured with a Nobel Prize for his discovery of penicillin, Fleming transformed medical science with the development of the world’s first antibiotic. While working with Staphylococcus bacteria in 1928, the Scottish bacteriologist noticed a bacteria-free circle around a mould growth contaminating a culture of staphylococci. Upon further investigation he discovered a substance that prevented bacterial replication even when diluted 800 times. In 1943 he was elected fellow of the Royal Society and knighted in 1944.


Robert Koch, 1843 - 1910

A 1905 Nobel Prize honoree, Koch was the first scientist to identify the organism that causes tuberculosis, Koch is considered the founder of modern bacteriology because he successfully isolated several disease-causing bacteria and discovered the animal vectors of a number of major diseases including anthrax. Through his many experiments, Koch discovered how to obtain microorganisms from animals, and how to culture those same samples. It was Koch who discovered that cholera is primarily a water-borne disease.


John Enders, 1897 - 1985

American microbiologist and Nobel laureate John Enders led a research team which developed a technique for growing viruses in cultured cells. He showed that poliomyelitis viruses grew in both brain and cultured tissues and in this way caused cell destruction.

John Enders went on to demonstrate the safety of cultured viruses in producing immunity, and proved that measles could be prevented through vaccination.

 

to previous section
to next section
 
 
The WHO Essential Medicines and Health Products Information Portal was designed and is maintained by Human Info NGO. Last updated: August 29, 2014