Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Section V λ Antimicrobial Agents

Chapter Summary

Basic Principles

λAntibacterial drugs can be either bactericidal or bacteriostatic. The effectiveness of bacteriostatic drugs depends on an intact host immune system. Antimicrobial agents may be administered singly or in combination. Some combinations induce synergy and/or delay emergence of resistance.

λAn antimicrobial agent should have maximal toxicity toward the infecting agent and minimal toxicity for the host. Table V-1-1 summarizes the four basic antibacterial actions demonstrated by antibiotics and the agents working by each of these mechanisms.

λMicrobial resistance can occur by the gradual selection of resistant mutants or more usually by R-factor transmission between bacteria. Table V-1-2 summarizes the common modes of resistance exhibited by microorganisms against the various classes of antimicrobial agents.

Inhibitors of Bacterial Cell-Wall Synthesis

λThe inhibitors of bacterial cell-wall synthesis are the beta-lactam antibiotics (the penicillins and cephalosporins; Figure V-1-1), the carbapenems, vancomycin, and aztreonam.

λThe mechanisms of action of penicillins, the bacterial modes of resistance to penicillins, the penicillin subgroups, their biodisposition, and side effects are provided. The subgroups discussed are the penicillins that are β-lactamase susceptible with a narrow spectrum of activity; β-lactamase–resistant penicillins that have a very narrow spectrum of activity; and β-lactamase–susceptible penicillins that have a wider spectrum of activity. The common penicillins and their susceptible organisms are listed for each subgroup.

λThe same parameters are considered for the cephalosporins. These have the same mode of action as the penicillins and also require an intact β-lactam ring structure for activity. There are four generations of cephalosporins. Each is considered in terms of range of activity, susceptibility to resistance, clinical usage, and specific antibiotics in that class.

λImipenem and meropenem have the same mode of antibacterial action as the penicillins and cephalosporins but structurally are carbapenems that have the β-lactam ring. Their clinical uses, routes of elimination, and side effects are considered.

λAztreonam is a monobactam inhibitor of early cell-wall synthesis. It is used primarily as an intravenous drug against gram-negative rods.

λVancomycin inhibits an early stage of cell-wall synthesis. It has a relatively narrow range of activity, but as yet, resistance is uncommon. Its use, excretion, and side effects are considered.

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Chapter 1 λ Antibacterial Agents

Chapter Summary (cont’d )

Inhibitors of Bacterial Protein Synthesis

λFigure V-1-2 illustrates the mechanisms of bacterial protein synthesis, and Table V-1-3 summarizes the places in the translatory sequence, as well as the mechanisms by which antibiotics operate to disrupt protein synthesis.

λThe aminoglycosides (e.g., gentamicin and tobramycin) inhibit initiation complex formation. Their uses and properties are discussed. Streptomycin is particularly useful in the treatment of tuberculosis and is the drug of choice for treating bubonic plague and tularemia. Neomycin is toxic and can only be used topically.

λThe tetracyclines block the attachment of aminoacyl tRNA to the acceptor site on the bacterial ribosome. They are broad-spectrum drugs with good activity against chlamydial and mycoplasmal species, as well as against other indicated bacteria. Doxycycline is of particular use in the treatment of

prostatitis, minocycline is useful for treating meningococcal carrier states, and demeclocycline is useful for treating the syndrome of inappropriate secretion of ADH (SIADH). Their biodisposition and side effects are discussed.

λChloramphenicol inhibits the activity of peptidyltransferase and is currently used primarily as a backup drug. Its activity, clinical use, and side effects are considered.

λThe macrolides (e.g., erythromycin, clarithromycin, and azithromycin) are translocation inhibitors. Their spectrums of activity, clinical uses, biodisposition, and side effects are considered. Clindamycin is not a macrolide but shares the same mechanism of action.

λLinezolid inhibits initiation by blocking formation of the N-formyl-methionyl- tRNA-ribosome-mRNA ternary complex. The clinical uses and side effects of this new drug are mentioned.

λQuinupristin and dalfopristin bind to the 50S ribosomal subunit, where they interfere with the interaction of aminoacyl-tRNA and the acceptor site and also stimulate its dissociation from the ternary complex. Their clinical use and side effects are discussed.

Antibiotics That Inhibit Folic Acid Synthesis and Nucleic Acid Metabolism

λThe sulfonamides compete with para-aminobenzoic acid (PABA) as shown in Figure V-1-3. The methods bacteria use to develop resistance to the

sulfonamides, their activity and clinical uses, biodisposition, and side effects are considered.

λTrimethoprim (TMP), a folate analog and inhibitor of dihydrofolate reductase (Figure V-1-3), is usually used together with sulfamethoxazole (SMX). The simultaneous inhibition of the tetrahydrofolate synthesis pathway at two steps has a synergistic effect and prevents the rapid generation of resistance. The clinical uses and side effects of TMP-SMX are discussed.

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