Antimicrobial agents provide some of the most dramatic examples of the advances of modern medicine. Many infectious diseases once considered incurable and potentially lethal can now be treated effectively with antibiotics. The remarkably powerful and specific activity of antimicrobial drugs is due to their selectivity for targets that are either unique to prokaryote and fungal microorganisms or much more important in these organisms than in humans. Among these targets are bacterial and fungal cell wall-synthesizing enzymes (Chapters 43 and 48), the bacterial ribosome (Chapters 44 and 45), the enzymes required for nucleotide synthesis and DNA replication (Chapter 46), and the machinery of viral replication (Chapter 49). The special group of drugs used in mycobacterial infections is discussed in Chapter 47. Cytotoxic antiseptics and disinfectants are discussed in Chapter 50. The clinical uses of many antimicrobial agents are summarized in Chapter 51.
The major problem threatening the continued success of antimicrobial drugs is the development of resistant organisms. Antibiotic resistance mechanisms existed long before the clinical use of antibiotics, even resistance to synthetic drugs that were created in the 20th century. Because resistance mechanisms are already present in nature, an inevitable consequence of antimicrobial use is the selection of resistant microorganisms. Since the start of the antibiotic era, antibiotic use in patients and animals has fueled a major increase in the prevalence of drug-resistant pathogens. In recent years, highly resistant Gram-negative organisms with novel mechanisms of resistance have been increasingly reported. Some of these strains have spread over vast geographic areas as a result of patients seeking medical care in different countries.
Much attention has been focused on eliminating the misuse of antibiotics to slow the tide of resistance. Antibiotics are misused in a variety of ways, including use in patients who are unlikely to have bacterial infections, use over unnecessarily prolonged periods, and use of multiple agents or broad-spectrum agents when not needed. Large quantities of antibiotics have been used in agriculture to stimulate growth and prevent infection in livestock, and this has added to the selection pressure that results in resistant organisms. In December 2013, the U.S. Food and Drug Administration (FDA) announced a program to phase out the nontherapeutic use of antibiotics in livestock. In 2015, President Obama announced a 5-year National Action Plan with the goals of improving antimicrobial stewardship efforts, tools for diagnosing infectious diseases, and surveillance for resistant organisms. However, even if these programs are successful, it will take years before the benefits are apparent.
Antibiotic resistance has many negative consequences. The prevalence of resistant organisms drives the use of broader-spectrum, less efficacious, or more toxic antibiotics. Not surprisingly, infections caused by antibiotic-resistant pathogens are associated with increased costs, morbidity, and mortality. The Centers for Disease Control and Prevention estimates that every year in the United States at least 2 million people acquire infections due to and 23,000 people die from infections caused by resistant bacteria.
Unfortunately, as the need has grown in recent years, development of novel antibiotics has slowed. Several of the largest pharmaceutical companies have abandoned research and development in this area because of diminished success and profits; the resulting reduction in new drug introductions is shown in the figure below, which shows new systemic antibacterial agents approved by the FDA per 5-year period through 2012. Several new antimicrobial agents have been approved between 2013 and 2015; however, most are slight modifications of existing drugs. Some novel targets are under investigation. For example, tarocin was found to successfully inhibit teichoic acid, a structure essential for bacterial cell wall synthesis. When combined with a β-lactam antibiotic in a mouse model, tarocin effectively killed methicillin-resistant strains of Staphylococcus aureus that were resistant to either agent alone. These compounds have not yet been studied in humans. Pending the identification and development of new targets and compounds, we will have to rely on currently available families of drugs. In the face of continuing development of resistance, considerable effort will be required to maintain the effectiveness of these drug groups.
Decline in the number of new systemic antibacterial drugs approved by the FDA over a 30-year period. (Reproduced, with permission, from Boucher HW et al: 10 × '20 progress-development of new drugs active against Gram-negative bacilli: An update from the Infectious Diseases Society of America. Clin Infect Dis 2013;56:1685. By permission of Oxford University Press on behalf of the Infectious Diseases Society of America. Modified, with permission, from Spellberg B et al: Trends in antimicrobial drug development: Implications for the future. Clin Infect Dis 2004;38:1279. By permission of Oxford University Press.)