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.

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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

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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 β-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 β-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.