Drug resistance

Microbes and Antimicrobial Agents

Antimicrobial Discovery and Development

Until modern times, the major cause of death in mankind was infection due to microorganisms such as bacteria, fungi, parasites, and viruses. In low-resource settings, infectious diseases continue to be the major killer.

The fortuitous discovery of penicillin on a mouldy Petri dish in 1928 by Alexandar Fleming launched a new era in medicine. This natural compound, produced by the Penicillium fungus, was found to be toxic to bacteria, but safe for use in humans. The use of penicillin in World War II is credited with saving the lives of hundreds of thousands.

The discovery of penicillin was followed by a vigorous search for other natural or synthetic compounds which could be used to treat other microbial pathogens. For some organisms, the quest has been more challenging than for others. Bacterial cells differ from human cells in many fundamental ways, so there are more opportunities for new drug development. In contrast, fungi, parasites, and viruses share many pathways and structures with human cells, so researchers must contend with fewer target sites of action and greater risks of patient toxicity.

Antimicrobials are different from other medicines

Medicines like insulin and and antihypertensive medications are used to treat diseases of human physiology. They are used for their beneficial effects on human cells, and the good or harm caused is limited to the patient under treatment. The efficacy of these drugs is similar worldwide, and drugs will maintain their value for future generations.

In contrast, antimicrobial agents kill susceptible organisms with profound and lasting consequences. Antimicrobials are often described as "societal" drugs because of the broad consequences of individual antimicrobial use on patient contacts, the local community, and potentially microbial populations worldwide.

  • Antimicrobial resistance is driven by the decisions of patients, healthcare practitioners, farmers, and veterinarians
  • Antimicrobial use disrupts the balance of microbial populations, leading to a rise in resistant organisms and changes in patterns of infections
  • The efficacy of antimicrobials varies over time and from country to country in response to antimicrobial use patterns and movement of organisms between communities
  • Misuse of antimicrobials in the past and today threatens the welfare of future generations

Crisis in the development of new antimicrobials

The knowledge and technologies available today to support new drug discovery and development are far superior to the resources available to scientists in decades past. However, researchers and pharmaceutical manufacturers have significantly cut back on funds for the evaluation and clinical testing of new agents. Consequently, the number of new antimicrobials in the development pipeline has plummeted in the past decade raising concern for the availability of effective therapy options in the future.

A number scientific and economic disincentives to new drug development exist.

  • Limited market for new agents
    • Antimicrobials are typically used for a period of one to ten days, decreasing the financial incentive for new drug development.
    • To limit the development of resistance, newly introduced antimicrobials are often subject to use restrictions by hospital pharmacists and national drug authorities.
    • Many parasitic, tropical, and "orphan" diseases are infrequent in the developed world, the primary source of revenue for medicines manufacturers.
  • Biological challenges
    • The identification of previously unknown target sites for antimicrobial action has proved difficult.
    • Most "new" antimicrobials are chemical variants of older agents. Consequently resistance development can occur quickly.
  • Toxicities
    • Antimicrobials are generally relatively safe when compared to other medicines used to treat human disease. Consequently, the tolerance threshold for any documented or suspected toxicities for new agents is low. The risk that new compounds may be withdrawn from the market is a strong disincentive to new drug development.

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