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Study Outline
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  1. Introduction
    1. Chemotherapeutic agents are chemical agents used to treat disease
    2. Antibiotics are microbial products or their derivatives that kill or inhibit susceptible microorganisms
    3. Synthetics-drugs that are not microbially synthesized
  2. The Development of Chemotherapy
    1. Paul Ehrlich (1904-1909)-aniline dyes and arsenic compounds
    2. Gerhard Domagk, and Jacques and Therese Trefouel (1939)-sulfanilamide
    3. Ernest Duchesne (1896) discovered penicillin; however, this discovery was not followed up and was lost for 50 years
    4. Alexander Fleming (1928) accidentally discovered the antimicrobial activity of penicillin on a contaminated plate; however, follow-up studies convinced him that penicillin would not remain active in the body long enough to be effective
    5. Howard Florey and Ernst Chain (1939) aided by the biochemist, Norman Heatley, worked from Fleming's published observations, obtained a culture from him, and demonstrated the effectiveness of penicillin
    6. Selman Waksman (1944)-streptomycin; this success led to a worldwide search for additional antibiotics, and the field has progressed rapidly since then
  3. General Characteristics of Antimicrobial Drugs
    1. Selective toxicity-ability to kill or inhibit microbial pathogen with minimal side effects in the host
      1. Therapeutic dose-the drug level required for clinical treatment of a particular infection
      2. Toxic dose-the drug level at which the agent becomes too toxic for the host (produces undesirable side effects)
      3. Therapeutic index-the ratio of toxic dose to therapeutic dose: the larger the better
    2. Drugs with narrow spectrum activity are effective against a limited variety of pathogens; drugs with broad-spectrum activity are effective against a wide variety of pathogens
    3. Chemotherapeutic agents can occur naturally, be synthetic, or semisynthetic (chemical modifications of naturally occurring antibiotics)
    4. Drug can be cidal (able to kill) or static (able to reversibly inhibit growth)
    5. Minimal inhibitory concentration (MIC) is the lowest concentration of the drug that prevents growth of a pathogen; minimal lethal concentration (MLC) is the lowest drug concentration that kills the pathogen
  4. Determining the Level of Antimicrobial Activity
    1. Dilution susceptibility tests-a set of broth-containing tubes are prepared; each tube in the set has a specific antibiotic concentration; a standard number of test organisms is added to each
      1. The lowest concentration of the antibiotic resulting in no microbial growth is the MIC
      2. Tubes showing no growth are subcultured into tubes of fresh medium that do not contain antibiotic to determine the lowest concentration of the drug from which the organism does not recover; this is the MLC
    2. Disk diffusion tests-disks impregnated with specific drugs are placed on agar plates inoculated with the test organism; clear zones (no growth) will be observed if the organism is sensitive to the drug; the size of the clear zone is used to determine the relative sensitivity according to tables prepared for the various available drugs; zone width is a function of initial concentration, solubility, and diffusion rate of the antibiotic
    3. Measurement of drug concentrations in the blood can be done using microbiological, chemical, immunological, enzymatic, and/or chromatographic assays
  5. Mechanisms of Action of Antimicrobial Agents
    1. Inhibition of cell wall synthesis
    2. Inhibition of protein synthesis
    3. Inhibition of nucleic acid synthesis
    4. Disruption of cell membranes
    5. Inhibition of metabolic activities (antimetabolites)
  6. Factors Influencing the Effectiveness of Antimicrobial Drugs
    1. Drug's ability to reach the site of infection-this is greatly influenced by the mode of administration (e.g., oral, topical, parenteral), but can also be influenced by exclusion from the site of infections (e.g., blood clots or necrotic tissue protects bacterium)
    2. Susceptibility of pathogen-influenced by growth rate and by inherent properties (e.g., whether or not pathogen has target of the drug)
    3. Factors influencing drug concentration in the body-must exceed the pathogen's MIC for the drug to be effective; this will depend on
      1. Amount of drug administered
      2. Route of administration
      3. Speed of uptake
      4. Rate of clearance (elimination) from the body
    4. Drug resistance has become an increasing problem
  7. Antibacterial Drugs
    1. Sulfonamides or sulfa drugs-structural analogues of metabolic intermediates; they inhibit folic acid synthesis in bacteria (humans don't synthesize folic acid, so are not affected); resistance is increasing and many patients are allergic to these drugs
    2. Quinolones-inhibit bacterial DNA gyrase, thereby disrupting replication, repair, and other processes involving DNA
    3. Penicillins-inhibit cell wall synthesis; many types have been identified or synthesized; they differ in spectrum of activity and administration route; resistance is an increasing problem; some patients are allergic to these antibiotics
    4. Cephalosporins-inhibit cell wall synthesis, broad spectrum of activity; they can be given to some patients with penicillin allergies
    5. Tetracyclines-inhibit protein synthesis; broad spectrum
    6. Aminoglycosides-inhibit protein synthesis; quite toxic to patients
    7. Erythromycin and other macrolides-inhibit protein synthesis; broad spectrum
    8. Vancomycing and teicoplanin-glycopeptide antibiotics that block peptidoglycan synthesis I. Chloramphenicol-inhibits protein synthesis; it has a broad spectrum but is toxic
  8. Drug Resistance
    1. Mechanisms of drug resistance
      1. Prevent entrance of drug (e.g., alter drug transport into cell)
      2. Pump the drug out of the cell once it has entered
      3. Enzymatic inactivation of the drug-chemical modification of the drug by cellular enzymes can render it inactive before it has a chance to damage the cell
      4. Alteration of target enzyme or organelle-modification of the target so that it is no longer susceptible to the action of the drug
      5. Use of alternative pathways and increased production of the target metabolite have been used by some organisms to minimize the effects of the drug
    2. The origin and transmission of drug resistance
      1. Spontaneous mutations in chromosomal genes; these are then inherited by progeny of the resistant mutant
      2. Transfer of R plasmids
      3. Superinfection-growth of drug-resistant pathogens as the result of extensive drug treatment
      4. Several strategies can be used to discourage emergence of drug resistance (e.g., administration of high doses, simultaneous treatment with two different drugs, limited use of broad-spectrum antibiotics
      5. Drug resistance has become an increasing problem; new drugs are constantly being developed and new treatment methods (e.g., phage treatment of bacterial infections) are being explored
  9. Antifungal Drugs
    1. Fungal infections are more difficult to treat than bacterial infections, because the greater similarity between fungi and host limits the ability of a drug to have a selective point of attack; furthermore, many fungi have detoxification systems that inactivate drugs
    2. Superficial mycoses are infections of superficial tissues and can often be treated by topical application of antifungal drugs such as miconazole, nystatin, and griseofulvin, thereby minimizing systemic side effects
    3. Systemic mycoses are more difficult to treat and can be fatal; however, amphotericin B and flucytosine have been used with limited success; amphotericin B is highly toxic and must be used with care; flucytosine must be converted by the fungus to an active form, and animal cells are incapable of this; some selectivity is possible, but severe side effects have been observed with both drugs
    4. Drug resistant fungal strains are also beginning to emerge
  10. Antiviral Drugs
    1. Selectivity has been a problem because viruses use the metabolic machinery of the host
    2. Antiviral drugs target specific steps of life cycle, especially enzymes that function in the life cycle (e.g., amantadine, vidarabine, acyclovir, and azidothymidine)
    3. Human interferon is used to treat some viral infections

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