Meeting

Issues of Resistance: Microbes, Vectors, and the Host

When:: Wednesday, February 06, 2002 - Thursday, February 07, 2002 (9:00 AM)

Topic(s):: Diseases, Global Health, Public Health
Activity:: Forum on Microbial Threats
Board(s):: Board on Global Health

Resistance in microbesâ€”bacterial, viral, or protozoanâ€”to therapeutics is not surprising or new. It is, however, an increasing challenge as drug resistance accumulates and accelerates, even as the drugs for combating infections are reduced in power and number. Today some strains of bacterial and viral infections are treatable with only a single drug, some no longer have effective treatments. The disease burden from multi-drug resistant strains of tuberculosis, malaria, hepatitis, and HIV is growing in both developed and developing countries.

Infections caused by resistant microbes fail to respond to treatment, resulting in prolonged illness and greater risk of death. Treatment failures also lead to longer periods of infection, which increase the numbers of infected people moving in the community and thus expose the general population to the risk of contracting a resistant strain of infection. When infections become resistant to first-line antimicrobials, treatment has to be switched to second- or third-line drugs, which are nearly always much more expensive and sometimes more toxic as well, e.g. the drugs needed to treat multidrug-resistant forms of tuberculosis are over 100 times more expensive than the first-line drugs used to treat non-resistant forms. In many countries, the high cost of such replacement drugs is prohibitive, with the result that some diseases can no longer be treated in areas where resistance to first-line drugs is widespread. Most alarming of all are diseases where resistance is developing for virtually all currently available drugs. Even if the pharmaceutical industry were to step up efforts to develop new replacement drugs immediately, current trends suggest some diseases will have no effective therapies within the next ten years.

More recently, the challenges of resistance are compounded by growing concerns about the possible use of biological weapons leading to large-scale disease outbreak or exposure. The ability to respond effectively to such exposures could be significantly compromised by the introduction of drug-resistant pathogens. The use of prophylactic drugs or therapies on large populations may also contribute to the development of drug resistance and thus increase both the immediate and longer-term challenges of treating infectious diseases.

A number of trends in human behavior increasingly contribute to the emergence of resistance to antimicrobial agents. Host behaviors such as noncompliance with recommended treatment and self-medication are among the most complicit problems associated with the development of resistance. Noncompliance with treatment occurs when individuals forget to take medication, interrupt the treatment as they begin to feel better, or are unable to afford a full course of therapy. Self-medication with antimicrobials almost always involves unnecessary, inadequate, and ill-timed dosingâ€”creating an ideal environment for microbes to adapt rather than be eliminated. In many countries, antimicrobials are readily available to consumers without a medical prescription. Both noncompliance and self-medication are complicated in some countries by the availability of low quality antimicrobials (particularly antibiotics) that are poorly manufactured, counterfeit products, or expired.

Another factor contributing to the rise in antimicrobial resistanceâ€”over-prescribing by physiciansâ€”has been heavily influenced by patient expectations and demands. Growing patient awareness (not necessarily accompanied by understanding) of antimicrobial agents (largely from direct-to-consumer marketing) sets up an expectation when being treated that they should receive such treatments, even in the absence of appropriate indications. Multiple factors such as diagnostic uncertainty, lack of opportunity for patient follow-up, and lack of knowledge regarding optimal approaches on the part of the physician may influence the response to patient demands.

Hospitals are fertile breeding grounds for antimicrobial resistance. The combination of highly susceptible patients, intensive and prolonged antimicrobial use, and cross-infection among patients has resulted in nosocomial infections that are highly resistant to available therapeutics. Ultimately, these infections are expensive to treat and extremely difficult to eradicate. Failure to practice simple infection control measures, such as hand washing and glove changing after patient contact, commonly causes the spread of infection in hospitals.

The overuse of antimicrobials in animals is contributing to the development of drug-resistant microbes (largely bacteria) that are subsequently transmitted to humans, usually through food products. It has been estimated that 50 percent of all antimicrobial production is directed to food-producing animals. Beyond the problem of human infection by drug-resistant foodborne bacteria (such as salmonella and camphylobacter), concern is growing about the role that the accumulation of subtherapeutic levels of antimicrobials from animal products might play in contributing to the emergence of resistance pathogens within the human host. Because antimicrobials have proven to be excellent growth promotion supplements in many food animals, their perception as a beneficial contribution to production has so far outweighed the concerns for growing drug resistance.

These trends are currently outpacing scientific discovery to counter resistant pathogens. However, one promising aspect of such factors in the emergence of resistance is their amenability to change, which may be accomplished through public education, appropriate training, political action, and domestic and international regulation.

Beyond the development of resistance in microbes, the ever-increasing resistance of disease vectors to biological and chemical pesticides looms as another complicating factor in efforts to control and eliminate the emergence of infectious diseases. Resistance to insecticides has appeared in the major insect vectors from every genus (e.g., mosquitoes, sand flies, ticks, fleas, and lice). Resistance has developed to every chemical class of insecticide, including microbial drugs and insect growth regulators. Insecticide resistance is predicted to have an increasing and profound affect on the reemergence of most vector-borne diseases. And where resistance has not contributed to disease emergence, it is expected to threaten disease control. Malaria control programs that already face complex challenges presented by multi-drug resistant strains of the disease are additionally undermined by vector mosquito populations that show increasing resistance to the pyrethroid-treated bed nets used to reduce malaria transmission.

Resistance is a natural response of microbes and other organisms to selective pressure from antimicrobial and other biological and chemical countermeasures. Adaptive mechanisms in the organisms permit survival and the development of genetic resistance. While the emergence of resistance cannot be eliminated, the rate and extent of its occurrence can be contained. In order to contain the threats posed to human health by resistance, it is important to determine the magnitude and trends of resistance and to define the relative importance of different contributing factors, such as therapeutic, behavioral, economic and social, and health systems factors, as well as veterinary and agricultural misuse. Based on this understanding it may be possible to develop effective methods to contain resistance in different settings.

Through invited presentations and participant discussion, the Forum workshop explored the causes and consequences of the resistance phenomenon. The Forum discussion also examined the scientific evidence supporting current and potential strategies for containment of resistance in microbes, vectors, and animal and human hosts. The methods and measures of a response for industry, federal regulation, domestic and international public health, federal and academic research, and the private healthcare sector were addressed. Issues that were considered in defining the challenges and crafting a response include:

Challenges

Existing disincentives for new research and production of antibacterials and antivirals
Biological and chemical pesticide resistance in vectors for infectious diseases
The challenge of nosocomial infections and the role of hospital prescribing in spreading resistance
Transfer of resistance in animal microbes to human pathogens and the resulting risk of human disease
Vaccine-resistant microbes
The contribution of behavioral factors and therapeutic compliance to the emergence of resistance
The cost of resistance (disease burden from human and vector resistance)

Response: Containment Measures and Options for the Future

Globally-integrated surveillance of resistant pathogens and vectors coupled with prediction tools for resistance pharmacodynamics
The application of genomics research in the detection of genes associated with the development of resistance
Regulating the rational use of antibiotics, antibacterials, and antivirals in humans and animals (role of physicians, public health, veterinary public health, animal husbandry/food production industry, federal agencies)
Lessons learned from chemotherapeutic resistance
Setting priorities for drug discovery: the role of medicinal chemistry and collaborative research
Novel and emerging technologies to combat resistance (feasibility and access for laboratories and developing countries)
Education and risk communication regarding the imprudent use of drugs

The summary of this workshop was released in April 2003.