ABC: ATP binding cassette
AUC: area under the Cp-time curve
CCR5: chemokine receptor type 5
CD4: T-helper cells
Cp: plasma concentration
CPmax: peak plasma concentration
CYP: cytochrome P450
DHFR: dihydrofolate reductase
DHPS: dihydropteroate synthase
EC: effective concentration
ELF: epithelial lining fluid
Emax: maximal effect
HIV: human immunodeficiency virus
IC: inhibitory concentration
MALDI-TOF MS: matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
MEC: minimum effective concentration
MIC: minimum inhibitory concentration
PAE: postantibiotic effect
PCR: polymerase chain reaction
PrEP: preexposure prophylaxis
rpoB: RNA polymerase
ANTIMICROBIAL CHEMOTHERAPY: CLASSES AND ACTIONS
This chapter reviews the general classes of antimicrobial drugs, their mechanisms of action and mechanisms of resistance, and principles of drug selection. Chapters 57 through 68 present the pharmacological properties and uses of individual classes of antimicrobials.
Microorganisms of medical importance fall into four categories: bacteria, viruses, fungi, and parasites. The broad classification of antibiotics—a term we will use colloquially to encompass all manner of antimicrobial agents—follows this classification closely, so that we have antibacterial, antiviral, antifungal, and antiparasitic agents. However, there are many antibiotics that work against more than one category of microbes, especially those that target evolutionarily conserved pathways. Classification of an antibiotic can be performed along several dimensions, including the class and spectrum of microorganisms it kills, the biochemical pathway it interferes with, and the chemical structure of its pharmacophore.
Antimicrobial molecules should be viewed as ligands whose receptors are typically microbial proteins. The term pharmacophore, 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 inhibits the replication of or directly kills the microorganisms. The biochemical processes commonly inhibited include cell wall synthesis, cell membrane synthesis and function, ribosomal translation, nucleic acid metabolism, topoisomerase-mediated chromosomal conformational changes, viral proteases, viral integrases, viral envelope entry/fusion proteins, folate synthesis, and parasitic chemical detoxification processes. Recently, antisense antibiotics have been developed; these work by inhibiting gene expression in bacteria in a sequence-specific manner. Furthermore, interferon-based products work by inducing specific antiviral activities of the infected human cells.
TYPES AND GOALS OF ANTIMICROBIAL THERAPY
A useful way to organize the types and goals of antimicrobial therapy is to consider where antibiotics are initiated with respect to the disease progression timeline (Figure 56–1); therapy can be classified as primary prophylaxis, preemptive, empirical, definitive, or suppressive/secondary prophylaxis.
Categories of antimicrobial therapy in relation to disease progression.
Prophylaxis involves administering antibiotics to patients who are not yet infected or have not yet ...