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  • 1. Chapter 12 Drugs, Microbes, Host: The Elements of Chemotherapy Chapter Summary This chapter discusses the use of antimicrobial agents for the treatment of diseases. It examines the development of chemotherapy and the origins of the antimicrobial drugs. The mechanism of drug action is discussed and the development of drug resistance is introduced. The chapter is very inclusive concerning the treatment of antibiotic, antifungals, and antiviral drugs. The toxicity of these chemotherapeutic agents on the human cell is also considered. Chapter Outline I. Principles of Antimicrobial Therapy A. The Terminology of Chemotherapy 1. Prophylaxis 2. Chemotherapeutic 3. Antimicrobial chemotherapy 4. Antibiotics a. Synthetic b. Semisynthetic 5. Antimicrobic 6. Narrow or broad spectrum B. Drug, Microbe, Host — Some Basic Interactions C. The Origins of Antimicrobial Drugs 1. Bacteria Streptomyces and Bacillus 2. Molds Penicillium and Cephalosporium II. Interactions Between Drug and Microbe A. Mechanisms of Drug Action 1. Antimicrobial Drugs That Affect the Bacterial Cell Wall: Penicillins and Cephalosporins 2. Antimicrobial Drugs That Affect Nucleic Acid Synthesis a. Sulfonamides i. Competitive inhibition ii. Structural or metabolic analogs iii. Compete with natural PABA (para-aminobenzoic acid) b. Other Nucleic Acid Inhibitors i. Trimethoprim ii. Chloroquine and malaria iii. Antiviral AZT and Acyclovir 3. Drugs That Block Translation a. Chloramphenicol b. Erythromycin 4. Drugs That Disrupt Cell Membrane Function a. Polymyxins b. Amphotericin B III. Survey of Major Antimicrobic Drug Groups A. Antibacterial Drugs 1. Penicillin and Its Relatives: from Penicillium chysogenum a. Subgroups and Uses of Penicillins b. Penicillin G and V 37
  • 2. c. Mezlocillin and Azlocillin 2. The Cephalosporin Group of Drugs: from mold Cephalosporium acremonium a. Subgroups and Uses of Cephalosporins i. Many are administered parenterally ii. Second generation Cefaclor and Cefonacid for Enterobacter Proteus {ch.20, p.616} and Haemophilus iii. Third generation Keflex for beta-lactamase producers b. Other Beta-Lactam Antibiotics 3. The Aminoglycoside Drugs: from Streptomyces and Micromonospora a. Subgroups and Uses of Aminoglycosides b. Gentamicin for Escherichia coli, Pseudomonas and Salmonella and Shigella 4. Tetracycline Antibiotics a. Subgroups and Uses of Tetracycines b. Mycoplasma pneumonia and cholera 5. Chloramphenicol: from Streptomyces venezuelae 6. Erythromycin, Clindamycin, Vancomycin: from Streptomyces a. Erythromycin: for Mycoplasma pneumoniae, legionellosis , Chlamydia, and Mycobacterium MAC b. Clindamycin c. Vancomycin for Clostridium d. Rifampin: for Neisseria meningitides 7. The Bacillus Antibiotics: Bacitracin and Polymyxin 8. New Classes of Antibiotics a. Fosfomycin b. Synercid B. Synthetic Antibacterial Drugs 1. The Sulfonamides, Trimethoprim, and Sulfones: for Pneumocystis (carinii) jirovecci pneumonia 2. Miscellaneous Antibacterial Agents a. Isoniazid for Mycobacterium tuberculosis b. Fluoroquinolones C. Agents to Treat Fungal Infections 1. Amphotericin B 2. Nystatin 3. Azoles 4. Flucytosine D. Antiparasitic Chemotherapy 1. Antimalarial Drugs: Quinine and Its Relatives: for Plasmodium 2. Chemotherapy for Other Protozoan Infections a. Metronidazole (Flagyl) b. Entamoeba histolytica c. Giardia lamblia and Trichomonas vaginalis E. Antihelminthic Drug Therapy F. Antiviral Chemotherapeutic Agents 1. 3 Major Modes of Action a. Inhibition of Virus Entry i. Fuzeon, Amantidine, Tamiflu b. Inhibition of Nucleic Acid Synthesis i. Acyclovir, AZT, Nevirapine c. Inhibition of Viral Assembly/Release i. Protease Inhibitors - Saquinavir IV. The Acquisition of Drug Resistance 38
  • 3. A. How Does Drug Resistance Develop?: Resistance Factors B. Specific Mechanisms of Drug Resistance 1. Drug Inactivation Mechanisms a. Beta-lactamases destroy Penicillins and Cephalosporins b. Staphylococcus aureus c. Neisseria gonorrhoeae and PPNG (penicillinase producing NG) 2. Decreased Drug Permeability or Increased Drug Transport a. Multidrug resistant pumps b. Staphylococcus, Streptococcus, Pseudomonas, Escherichia coli 3. Change of Drug Receptors a. Penicillin resistance in Streptococcus pneumoniae b. Methicillin resistance in Staphylococcus aureus 4. Changes in Metabolic Patterns C. Natural Selection and Drug Resistance V. Characteristics of Host/Drug Reactions: side effects A. Toxicity to Organs B. Allergic Responses to Drugs C. Suppression and Alteration of the Microflora by Antimicrobics: superinfections VI. Considerations in Selecting an Antimicrobial Drug A. Identifying the Agent B. Testing for the Drug Susceptibility of Microorganisms 1. Kirby-Bauer method 2. Minimum inhibitory concentration (MIC) 3. The MIC and Therapeutic Index: ratio of dose toxic to humans to MIC C. The Art and Science of Choosing an Antimicrobic Drug D. An Antimicrobial Drug Dilemma Key Terms and Phrases prophylaxis Rifampin concentration chemotherapy bacitracin antimicrobial Polymyxins antibiotic Trimethoprim synthetic isoniazid antimicrobic fluoroquinolones narrow-spectrum amphotericin B broad-spectrum nystatin selectively toxic imidiazoles sulfonamides flucytosine competitive inhibition antiparasitic metabolic analog antiviral drug resistance azidothymidine beta-lactamase amantadine parenterally interferon actinomycetes acyclovir penicillin side effects cephalosporin allergy aminoglycosides flora chloramphenicol superinfection erythromycin in vitro clindamycin Kirby-Bauer Vancomycin minimum inhibitory 39
  • 4. Topics for Discussion This chapter always generates a lot of discussion. The chemotherapeutic agents are always a subject of concern for the college student. Many of them will currently be on one of the medications that you are discussing in class. I usually take the opportunity to investigate the reasoning behind the prescription, if it is applicable. This always leads to a good session on the development of resistant bacteria. The other major discussion will probably be about the antiviral agents. Students are very hopeful for the development of more antiviral medications and this is an interesting topic for them to develop critical concepts about how they would suggest the research of these agents proceed. Discuss the wide range of drugs used for AIDS patients. 40