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INTRODUCTION

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The mode of action of antimicrobials on bacteria is the focus of this chapter. Resistance to antibacterial agents, and strategies to minimize resistance, are also addressed here. Specific information about pathogenic bacteria can be found in Chapters 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, and 41; a complete guide to the treatment of infectious diseases is beyond the scope of this book.

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Natural materials with some activity against microbes were used in folk medicine in earlier times, such as the bark of the cinchona tree (containing quinine) in the treatment of malaria. Rational approaches to chemotherapy began with Ehrlich's development of arsenical compounds for the treatment of syphilis early in the 20th century. Many years then elapsed before the next major development, which was the discovery of the therapeutic effectiveness of a sulfonamide (prontosil rubrum) by Domagk in 1935. Penicillin had been discovered in 1929 by Fleming, but could not be adequately purified at that time; this was accomplished later, and penicillin was produced in sufficient quantities so that Florey and colleagues could demonstrate its clinical effectiveness in the early 1940s.

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Sulfonamides and penicillin were the first effective antibacterial agents

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Since that time, numerous new antimicrobial agents have been discovered or developed, and many have found their way into clinical practice. Thanks to these medicines, the human experience in industrialized nations is dramatically different today than it was in the preantibiotic era. However, this success has come at the cost of rising antimicrobial resistance. In order to be good antimicrobial stewards, all clinicians must understand the ways in which these drugs work, the ways in which bacteria evolve in response to antibiotics, and strategies for their judicious use.

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Antimicrobial resistance is a critical challenge for modern medicine

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ANTIBACTERIAL AGENTS AND THERAPY

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GENERAL CONSIDERATIONS

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Clinically effective antimicrobial agents exhibit selective toxicity toward the microbe rather than the host, a characteristic that differentiates them from the disinfectants (see Chapter 3). In most cases, selectivity is explained by action on microbial processes or structures that differ from those of mammalian cells. For example, some agents act on bacterial cell wall synthesis (an organelle not present in eukaryotes), and others on the 70 S bacterial ribosome (but not the 80 S eukaryotic ribosome). Some antimicrobials, such as penicillin, are essentially nontoxic to the host, unless hypersensitivity develops. For others, such as the aminoglycosides, the effective therapeutic dose is relatively close to the toxic dose; as a result, control of dosage and blood levels must be much more precise.

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Ideally, selective toxicity is based on the ability of an antimicrobial agent to attack a target present in bacteria but not humans

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