Page 807 - Basic _ Clinical Pharmacology ( PDFDrive )

SECTION VIII CHEMOTHERAPEUTIC DRUGS

INTRODUCTION TO ANTIMICROBIAL to have bacterial infections, use over unnecessarily prolonged
AGENTS periods, and use of multiple agents or broad-spectrum agents
when not needed. Large quantities of antibiotics have been used
Antimicrobial agents provide some of the most dramatic exam- in agriculture to stimulate growth and prevent infection in live-
ples of the advances of modern medicine. Many infectious dis- stock, and this has added to the selection pressure that results in
eases once considered incurable and potentially lethal can now resistant organisms. In December 2013, the U.S. Food and Drug
be treated effectively with antibiotics. The remarkably powerful Administration (FDA) announced a program to phase out the
and specific activity of antimicrobial drugs is due to their selec- nontherapeutic use of antibiotics in livestock. In 2015, President
tivity for targets that are either unique to prokaryote and fungal Obama announced a 5-year National Action Plan with the goals
microorganisms or much more important in these organisms of improving antimicrobial stewardship efforts, tools for diagnos-
than in humans. Among these targets are bacterial and fungal ing infectious diseases, and surveillance for resistant organisms.
cell wall-synthesizing enzymes (Chapters 43 and 48), the bacte- However, even if these programs are successful, it will take years
rial ribosome (Chapters 44 and 45), the enzymes required for before the benefits are apparent.
nucleotide synthesis and DNA replication (Chapter 46), and Antibiotic resistance has many negative consequences. The prev-
the machinery of viral replication (Chapter 49). The special alence of resistant organisms drives the use of broader-spectrum,
group of drugs used in mycobacterial infections is discussed in less efficacious, or more toxic antibiotics. Not surprisingly, infec-
Chapter 47. Cytotoxic antiseptics and disinfectants are discussed tions caused by antibiotic-resistant pathogens are associated with
in Chapter 50. The clinical uses of many antimicrobial agents increased costs, morbidity, and mortality. The Centers for Disease
are summarized in Chapter 51. Control and Prevention estimates that every year in the United
The major problem threatening the continued success of anti- States at least 2 million people acquire infections due to and 23,000
microbial drugs is the development of resistant organisms. Anti- people die from infections caused by resistant bacteria.
biotic resistance mechanisms existed long before the clinical use Unfortunately, as the need has grown in recent years, develop-
of antibiotics, even resistance to synthetic drugs that were created ment of novel antibiotics has slowed. Several of the largest phar-
in the 20th century. Because resistance mechanisms are already maceutical companies have abandoned research and development
present in nature, an inevitable consequence of antimicrobial use in this area because of diminished success and profits; the resulting
is the selection of resistant microorganisms. Since the start of the reduction in new drug introductions is shown in the figure below,
antibiotic era, antibiotic use in patients and animals has fueled a which shows new systemic antibacterial agents approved by the
major increase in the prevalence of drug-resistant pathogens. In FDA per 5-year period through 2012. Several new antimicrobial
recent years, highly resistant Gram-negative organisms with novel agents have been approved between 2013 and 2015; however,
mechanisms of resistance have been increasingly reported. Some most are slight modifications of existing drugs. Some novel tar-
of these strains have spread over vast geographic areas as a result of gets are under investigation. For example, tarocin was found to
patients seeking medical care in different countries. successfully inhibit teichoic acid, a structure essential for bacterial
Much attention has been focused on eliminating the misuse of cell wall synthesis. When combined with a β-lactam antibiotic in a
antibiotics to slow the tide of resistance. Antibiotics are misused mouse model, tarocin effectively killed methicillin-resistant strains
in a variety of ways, including use in patients who are unlikely of Staphylococcus aureus that were resistant to either agent alone.

793