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Antimicrobial Chemotherapy


CLASSIFICATION

Antimicrobials can be classified by at least three different schemes:

  1. Effects on cells
  2. Range of activity
  3. Sites of activity
This page will examine these different classification schemes and describe several examples of each type of antimicrobial. The mechanisms by which organisms become resistant to these agents will also be discussed. Finally, toxicologic properties of antimicrobial chemotherapy will be described.
1. Antimicrobial Effects on Cells

Antimicrobials can be divided into two classifications based upon their effects on target cells. Drugs that actually kill microorganisms are termed bactericidal. Drugs that only inhibit the growth of microorganisms are termed bacteriostatic. The decision to use a bactericidal or bacteriostatic drug to treat infection depends entirely upon the type of infection. For example, bactericidal drugs will only kill cells that are actively growing. Bacteriostatic drugs, in comparison, will only inhibit the growth of cells; ultimate elimination of the organisms is dependent upon host phagocytic activity. Some examples of bactericidal and bacteriostatic drugs are listed below.


2. Range of Activity

Antimicrobials can also be classified by their range of activity. In general, five classifications can be described. The first of these is termed narrow spectrum. Narrow spectrum drugs, as the name implies, are only active against a relatively small number of organisms. In general, narrow spectrum antibiotics are effective against Gram-positive organisms. The second classification is termed moderate spectrum. These drugs are generally effective against the Gram-positives and most systemic, enteric and urinary tract Gram-negative pathogens. The beta-lactam antibiotics (penicillin, ampicillin, cephalosporins, etc.) belong in a third classification, narrow and moderate spectrum because some members are only effective against Gram-positive organisms while other members can also kill certain Gram-negative bacteria. A fourth classification is termed broad spectrum. These drugs are effective against all prokaryotes with two exceptions: Mycobacteria (see below) and Pseudomonas. The fifth group includes those drugs that are effective against Mycobacteria. The following table details some examples of these antimicrobials.

Range of Activity Organisms Affected Example Antibiotics
Narrow Spectrum Gram-positives (Actinomyces, Corynebacteria, Bacillus, Clostridium, Pyogenic cocci, Spirochetes) Macrolides (Erythromycin)
Polypeptides (Polymyxin)
Moderate Spectrum Gram-positives plus systemic, enteric and urinary tract Gram-negatives Sulfonamides
Aminoglycosides
(Streptomycin, Gentamycin, Tobramycin)
Narrow/Moderate Spectrum Gram-positives plus Gram-negatives Beta-lactams
(Penicillin, Ampicillin, Cephalosporins)
Broad Spectrum All prokaryotes except Mycobacteria and Pseudomonas Chloramphenicol
Tetracycline
Anti-mycobacterial Mycobacteria Isoniazid
Ethambutol
Streptomycin
Rifampin

3. Sites of Activity

A third means of classifying antimicrobials is by their site of activity within the target cell. Further, antimicrobials may affect either the integrity or the synthesis of these sites. The various cellular targets include the cell wall, the plasma membrane, the nucleic acids and proteins. The following table lists these sites and gives examples of antimicrobials acting against them.

Site of Activity Example Antibiotics
Inhibition of cell wall integrity Lysozyme
Inhibition of cell wall synthesis
1. Biosynthetic enzymes (cytoplasmic) Fosfomycin, Cycloserine
2. Membrane-bound phospholipid carrier Bacitracin
3. Polymerization of subunits Beta-lactams
4. Combine with wall substrates Vancomycin
Inhibition of membrane integrity Surfacants, Polyenes, Polypeptides
Inhibition of membrane synthesis None
Inhibition of nucleic acid integrity Alkylating, Intercalating agents (mitomycin, chloroquin)
Inhibition of nucleic acid synthesis
1. Metabolism of DNA 5-Fluorocytosine, Acyclovir, NTP analogs
2. Replication of DNA Nalidixic acid, Novobiocin, Nitroimadazoles
3. Synthesis of RNA Rifampin
Protein integrity Phenolics, Heavy metals
Protein synthesis
1. 30S Subunit Streptomycin, Kanamycin, Tetracycline
2. 50S Subunit Chloramphenicol, Macrolides (Clindamycin, Erythromycin)
3. Folate metabolism Sulfonamides, Trimethoprim

RESISTANCE MECHANISMS

The problem of antibiotic resistance is becoming increasingly apparent as more and more strains of pathogenic microorganisms are untreatable with commonly used antimicrobials. This problem can be attributed to a variety of factors including overuse of antibiotics in agriculture and medicine and misuse of antibiotics by consumers. In addition, antibiotic resistance is often plasmid-borne, which means that resistance can be readily transferred from one organism to another. There are several mechanisms for antibiotic resistance and these relate to the sites of antimicrobial activity. These mechanisms include:

  1. Altered receptors for the drug
  2. Decreased entry into the cell
  3. Destruction or inactivation of the drug
These mechanisms and some examples are outlined in the following table.

Altered Receptors  
1. Beta-lactams Altered Penicillin Binding Proteins
2. Macrolides Methylation of 2 adenine residues in 23S RNA of the 50S subunit
3. Rifampin Single amino acid change in RNA polymerase -subunit
4. Sulfonamide/trimethoprim Altered synthetase binds pABA preferentially/altered reductase for TMP
5. Nalidixic acid Altered gyrase
6. Streptomycin Altered S12 protein in 30S subunit
Decreased Entry  
1. Tetracycline Normally biphasic, active transport reduced
2. Fosfomysin (chromosomal) Glucose-6-phosphate transport reduced
Destruction/Inactivation  
1. Chloramphenicol acetyltransferase Acetylates chloramphenicol
2. Beta-lactamase Cleaves -lactam ring
3. Aminoglycosides Acetylation or phosphorylation as drug passes membrane

TOXICOLOGY

While antimicrobials can be life-saving, they also pose certain dangers to the patient. Some antibiotics are relatively safe; others should only be used if there is no other means of controlling an infection. The following table lists some side effects/dangers of antimicrobial chemotherapy.

Side effects/Toxic effects Examples
Overgrowth of pathogens Intestinal (C. difficile), Vaginal (Candida)
Depression of intestinal symbiotes Several
Nephrotoxicity Polypeptides, Aminoglycosides
Ototoxicity - 8th cranial nerve Aminoglycosides
Ophthalmic toxicity Ethambutol
Aplastic anemia Chloramphenicol
Hypersensitivity Penicillin
Bone seeking Tetracycline

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