An Emptying Quiver: Antimicrobial Drugs and Resistance

has shadowed the success of infectious disease therapy. In his 1945 Nobel Prize acceptance speech, Alexander Fleming noted the danger of resistance: “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.... Moral: If you use penicillin, use enough” (1). Sixty years later, our understanding of resistance has grown vastly more sophisticated and the proliferation of new antimicrobial drugs has engendered an equally varied collection of resistance mechanisms (Figure). Resistance is now an important problem in virtually all areas of infectious diseases, including viral, bacterial, fungal, and parasitic diseases. In a 2003 Institute of Medicine report, Microbial Threats to Health, antimicrobial resistance was noted as a paramount microbial threat of the twenty-first century (2). Some strains of pathogenic bacteria are now resistant to essentially all available antimicrobial drugs, and some remain susceptible to only one. At the same time, what once was an apparent deluge of antimicrobial drug development is now barely a trickle. The lack of new drug classes is a consequence of difficulties in discovery of new compounds that has persisted for many years. In addition, pharmaceutical companies are finding in industrialized nations more potent markets for other disease treatments and lower profit in nonindustrialized countries (3,4). This trend is reflected in the absence of any novel class of antibacterial drug approved for use in the United States between 1968 and 2000. Indeed, most of the new drugs approved since 1968 have been chemical modifications of existing drugs. However, since 2000, two new drug classes have been approved by the U.S. Food and Drug Administration (5,6). Whether this trend will continue is unclear and does not obviate the need for more new classes. Barring the arrival in the near future of new antimicrobial drugs that are effective against disparate organisms, we are left with imperfect tools to control drug resistance. With a notable exception, vaccines have not been produced that address the problem of resistance (7). Infection control in healthcare settings, which is essential for preventing transmission of susceptible and resistant microorganisms alike, remains imperfect. Reducing the discretionary use of antimicrobial drugs when possible is helpful, but even if we use these drugs with exquisite precision, resistance will continue to evolve and spread. Ensuring adherence to multidrug regimens to prevent emergence of resistance requires uninterrupted drug supplies and is vulnerable to human inconstancy. Finally, efforts to modify behavior An Emptying Quiver: Antimicrobial Drugs and Resistance