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ANTIMICROBIAL CHEMOTHERAPY

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Microorganisms of medical importance fall into 4 categories: bacteria, viruses, fungi, and parasites. Likewise, antibiotics are broadly classified as (1) antibacterial, (2) antiviral, (3) antifungal, and (4) antiparasitic agents. Antimicrobial molecules should be viewed as ligands whose receptors are microbial proteins. 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. 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.

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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

The relationship between antimicrobial concentration and effect on a population of organisms is modeled using the standard Hill-type curve for receptor and agonist (see Chapters 2 and 3), characterized by 3 parameters: the inhibitory concentration 50, or IC50 (also termed EC50), a measure of the antimicrobial agent's potency; the maximal effect, Emax; and H, the slope of the curve, or Hill factor. In antimicrobial therapy, the relationship is often expressed as an inhibitory sigmoid Emax model, to take into account the control bacterial population without treatment (Econ) as a fourth parameter (Equation 48–1 and Figure 48–1), where E is the effect as measured by microbial burden.

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Figure 48–1

Inhibitory sigmoid Emax curve.CFU, colony-forming unit.

Graphic Jump Location
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(Equation 48-1) Image not available.

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THE PHARMACOKINETIC BASIS OF ANTIMICROBIAL THERAPY

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PENETRATION OF ANTIMICROBIAL AGENTS INTO ANATOMIC COMPARTMENTS. In many infections, the pathogen causes disease not in the whole body, but in specific organs. Antibiotics are often administered far away from these sites of infection. Therefore, in choosing an antimicrobial agent for therapy, a crucial consideration is whether the drug can penetrate to the site of infection.

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For example, the antibiotic levofloxacin achieves skin tissue/plasma peak concentration ratio of 1.4, epithelial lining fluid to plasma ratio of 2.8, and urine-to-plasma ratios of 67. In clinical trials with levofloxacin, the failure rate of therapy was 0% in patients with urinary tract infections, 3% in patients with pulmonary infections, and 16% in patients with skin and soft tissue infections. Clearly, the poorer the penetration into the anatomical compartment, the higher the likelihood of failure. Penetration of a drug into an anatomical compartment depends on the physical barriers that the molecule must traverse, the chemical properties of the drug, and the presence of multidrug transporters. The physical barriers are usually due to layers of epithelial and endothelial cells, and the type of junctions formed between these cells. Penetration across ...

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