SCIENTIFIC BASIS OF ANTIMICROBIAL CHEMOTHERAPY
An important revolution in human understanding of nature was the germ theory of disease based on the work of Louis Pasteur and Robert Koch, which linked specific microorganisms to specific diseases (Koch, 1876; Pasteur, 1861). Modern chemotherapy is predicated on this idea, radical in its time. The germ theory developed considerably in the 20th century, with identification and characterization of many microbial pathogens and their pathogenic mechanisms and the introduction of antimicrobial drugs. With the use of these drugs came issues of appropriate regimens, drug resistance, drug interactions, and toxicity.
Although the antimicrobials are a large group of diverse structures with myriad mechanisms of actions against bacteria, viruses, fungi, and parasites, we can, nonetheless, develop generalizations about important issues surrounding the use of antimicrobial agents. This chapter reviews the general classes of antimicrobial drugs, their mechanisms of action, mechanisms of resistance, and patterns of kill by different classes of the drugs. It also discusses principles for the selection of an appropriate antibiotic, dose, dose schedule, and type of antibiotic therapy. The pharmacological properties and uses of individual classes of antimicrobials are discussed in Chapters 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59.
Classes and Actions of Antimicrobial Agents. Microorganisms of medical importance fall into four categories: bacteria, viruses, fungi, and parasites. The first broad classification of antibiotics follows this classification closely, so that we have (1) antibacterial, (2) antiviral, (3) antifungal, and (4) antiparasitic agents. Within each of these major categories, drugs are further categorized by their biochemical properties. Antimicrobial molecules should be viewed as ligands whose receptors are microbial proteins. The term pharmacophore, first introduced by Ehrlich, defines that active chemical moiety of the drug that binds to the microbial receptor. The microbial proteins targeted by the antibiotic are essential components of biochemical reactions in the microbes, and interference with these physiological pathways kills the microorganisms. To the extent that an antimicrobial agent targets a protein that is not widely expressed in other bacteria, the drug will be relatively selective in its antimicrobial effect. The biochemical processes commonly inhibited include cell wall synthesis in bacteria and fungi, cell membrane synthesis, synthesis of 30s and 50s ribosomal subunits, nucleic acid metabolism, function of topoisomerases, viral proteases, viral integrases, viral envelope fusion proteins, folate synthesis in parasites, and parasitic chemical detoxification processes. Classification of an antibiotic is based on:
the class and spectrum of microorganisms it kills
the biochemical pathway it interferes with
the chemical structure of its pharmacophore
Because antimicrobial agents are ligands that bind to their targets to produce effects, the relationship between drug concentration and effect on a population of organisms is still modeled using the standard Hill-type curve for receptor and agonist (Chapters 2 and 3), characterized by three parameters: the inhibitory concentration 50, ...