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Foundations in Microbiology, 4/e
Kathleen Park Talaro, Pasadena City College
Arthur Talaro

Drugs, Microbes, Host: The Elements of Chemotherapy

Chapter Capsule

I. Antimicrobial Chemotherapy
A. Chemotherapeutic Drugs: Used in treatment of infections, control of microbes in the body.
1. Categories of antimicrobics
a. Antibiotics are chemicals derived from bacteria and molds, natural or semisynthetic (part natural, part synthetic).

b. Synthetic drugs are derived completely from industrial processes.

c. Drugs may be narrow-spectrum or broad-spectrum, microbicidal or microbistatic.
2. Scope: Types include antibacterial (largest number), antifungal, antiprotozoan, antihelminthic, antiviral.

3. Ideal qualities of antimicrobics
a. Selective toxicity, meaning high toxicity to microorganisms, low toxicity to animals.

b. Potency unaltered by dilution.

c. Stability and solubility in tissue fluids.

d. Lack of disruption to host’s immune system or microflora.

e. Exempt from drug resistance.
4. Route of administration: By mouth; parenteral (injection into vein, muscle); topical on skin, mucous membranes.

5. Major adverse results of chemotherapy
a. Toxicity ranging from slight, short-term damage to permanent debilitation.

b. Allergic reactions.

c. Disruption of normal microbial flora of body.

d. Superinfections by resistant species.

e. Drug resistance is a serious outcome that results when pathogens develop tolerance to drugs through mutation or transfer of resistance plasmids (R factors).
6. Special clinical approaches
a. Prophylaxis, administering antimicrobic drugs to prevent infections in highly susceptible persons.

b. Combined therapy, administering two or more antimicrobics simultaneously to circumvent drug resistance or to achieve synergism, the additive or magnified effectiveness of certain drugs working together.
7. Stages in selection of proper drug
a. Identification of microbe in vitro; testing antimicrobial sensitivity or susceptibility (determining the MIC).

b. Assessing the therapeutic index.

c. Final drug selection weighs potential effectiveness, toxicity, in vivo effects, spectrum, and the medical condition of the patient.
8. Perspectives in antimicrobic abuse: Drugs are overprescribed, overproduced, and used inappropriately on a worldwide basis, with unfortunate medical and economic consequences.
II. Antibacterial Antibiotics
A. Penicillins
1. Types/source: Beta-lactam–based drugs; from Penicillium chrysogenum mold; natural form is penicillin G; semisynthetic forms vary in spectrum and applications.

2. Mode of action: Bactericidal; blocks the completion of the cell wall, causes weak points and cell rupture.

3. Examples are narrow-spectrum penicillin and broad-spectrum ampicillin and methicillin.

4. Problems in therapy: Penicillins are not highly toxic, but cause of allergic reactions; bacterial resistance to some forms of penicillin occurs through beta-lactamase (for example, penicillinase).
B. Cephalosporins
1. Types/source: Natural and semisynthetic forms from Cephalosporium mold.

2. Mode of action: Similar to penicillins; inhibit peptidoglycan synthesis.

3. Specific uses/spectra
a. Effective against gram-positive cocci and gram-negative cocci and rods.

b. Broad-spectrum, especially for gram-negative enteric rods and gram-positive cocci.
4. Problems in therapy: Adverse blood and kidney reactions; superinfections; allergic reactions; bacterial resistance through cephalosporinases.
C. Aminoglycosides
1. Types/source/spectrum: Mostly narrow-spectrum, from Streptomyces.

2. Mode of action: Interference with the bacterial ribosome, inhibition of protein synthesis.

3. Examples
a. Streptomycin, narrow-spectrum, for tuberculosis therapy.

b. Gentamicin, for gram-negative enteric infections.
4. Problems in therapy: Toxic reactions to 8th cranial nerve, kidney damage, intestinal disturbances; drug resistance.
D. Tetracyclines and Chloramphenicol
1. Source/spectrum: Very broad-spectrum drugs originally from species of Streptomyces (now semi- or fully synthetic).

2. Mode of action: Interfere with translation (protein synthesis).

3. Examples
a. Tetracyclines very broad-spectrum against numerous types of gram-positives, -negatives, rickettsias, and mycoplasmas.

b. Chloramphenicol (chloromycetin) limited by toxicity; indicated for serious infections where there is no alternative.
4. Problems in therapy: Tetracycline may lead to hepatotoxicity, gastric disturbance, discoloration of tooth enamel in children, superinfections; chloramphenicol may damage bone marrow.
E. Erythromycin, Clindamycin, Vancomycin, Rifampin
1. Modes of action: Erythromycin and clindamycin disrupt protein synthesis; vancomycin interferes with early cell wall synthesis; rifampin inhibits RNA synthesis.

2. Specific uses/spectra
a. Erythromycin is extended spectrum treatment for penicillin-resistant bacteria.

b. Clindamycin used for intestinal infections by anaerobes.

c. Vancomycin applied in life-threatening staphylococcal infections.

d. Rifampin used for tuberculosis and leprosy.
3. Problems in therapy: Vancomycin is neurotoxic; clindamycin and erythromycin can harm the GI tract; rifampin is hepatotoxic; resistant bacteria occur for all.
F. Bacitracin and Polymyxin
1. Spectrum: Narrow-spectrum.

2. Mode of action
a. Bacitracin prevents synthesis of the cell wall of gram-positive bacteria.

b. Polymyxin has detergent action that disrupts cell membrane of gram-negative bacteria.
3. Specific uses
a. Bacitracin used in ointments with neomycin for skin infections.

b. Polymyxins used to treat Pseudomonas infection or in skin ointments.
4. Problems in therapy: Polymyxin can cause nephrotoxic and neuromuscular reactions; bacitracin is useful only for topical applications.
III. Synthetic Antibacterial Drugs
A. Sulfonamides (Sulfa Drugs)
1. Types/spectrum: All types have similar basic structure; commonest is sulfisoxazole; relatively broad-spectrum.

2. Mode of action: Acts as an antimetabolite, a metabolic analog that causes competitive inhibition, resulting in blockage in nucleic and amino acid synthesis.

3. Specific uses: Urinary tract infections, nocardiosis, burn and eye infections; often combined with trimethoprim.

4. Problems in therapy: Allergy and formation of crystals in kidney.
B. Miscellaneous
1. Trimethoprim, medication for urinary, respiratory, and gastrointestinal infections; a competitive inhibitor in nucleic acid synthesis; can cause bone marrow damage.

2. Dapsone, a major antileprosy drug, combined with rifampin.

3. Isoniazid (INH), an antituberculosis drug; blocks synthesis of cell wall of mycobacteria; may damage liver.

4. Fluoroquinolones (ciprofloxacin), promising new broad-spectrum drugs.
C. Drugs for Fungal Infections
1. Polyenes: Amphotericin B and nystatin, antibiotics that disrupt cell membrane by detergent action. Amphotericin is a key drug in systemic fungal infections; nystatin is used for skin and membrane candidiasis. Both are commonly nephrotoxic.

2. Azoles: Synthetic drugs that interfere with membrane synthesis; ketoconazole, fluconazole, and miconazole are used for various levels of infection; can cause liver damage.

3. Flucytosine: Synthetic inhibitor of DNA synthesis; used alone or in combination with amphotericin for systemic mycoses; may lower WBC count; fungal resistance.
D. Drugs for Protozoan Infections
1. Quinines: Types are chloroquine, primaquine, and quinine used to manage malaria depending on sensitivity and stage in the parasite’s cycle; can cause intestinal symptoms and eye disturbances; resistance and complexity of life cycle are main hurdles.

2. Others: Metronidazole (flagyl) for amebiasis, giardiasis, and trichomonas infections; suramin, melarsoprol, indicated in treatment of African trypanosomiasis; nitrifurimox, for acute South American trypanosomiasis.
E. Drugs for Helminth Infections
1. Mebendazole, thiabendazole, and praziquantel, all-purpose agents in treating intestinal roundworm, tapeworm, and some fluke infestations.

2. Pyrantel and piperazine, primarily for intestinal roundworms.

3. Niclosamide, for tapeworms.

4. Taken orally, cure occurs only upon incapacitation or death of worms and eggs followed by their expulsion in feces.
F. Drugs for Viral Infections

Most antivirals function intracellularly to block some part of virus multiplication; main drawbacks are resistance and toxicity.
1. Acyclovir and vidarabine are synthetic nitrogen bases that block synthesis of viral components in herpesviruses.

2. Amantadine, restricted to treating influenza A infections.

3. AZT and protease inhibitors are anti-AIDS drugs.

4. Interferon, a naturally occurring protein that can be useful in reducing symptoms of some viral infections and treating a few cancers.