Foundations in Microbiology Seventh Edition

Transcription

1 Lecture PowerPoint to accompany Foundations in Microbiology Seventh Edition Talaro Chapter 12 Drugs, Microbes, Host The Elements of Chemotherapy Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

2 Can You Remember? Who was Louis Pasteur Components of a virus, properties of viruses, two main virus structures Phases/ steps in animal virus multiplication cycle (in detail) What factors limit virus host range The two kinds of persistent infections The name of viruses that cross the placenta The name of the largest and most complex group of viruses, one of which has been eliminated by vaccination The difference between HSV-1 and HSV-2. What causes herpes recurrence The name of the virus that causes both chicken pox and shingles Which virus causes mono (kissing disease) and a cancer What hepatitis means. The three hepatitis viruses. How each is transmitted What is human papillomavirus. What are hemagglutinin and neuraminidase; with which virus they are associated The difference between antigenic drift and antigenic shift 2 A serious complication from measles

3 12.1 Principles of Antimicrobial Therapy Administer a drug to an infected person that destroys the infective agent without harming the host s cells Antimicrobial drugs are produced naturally or synthetically 3

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6 Origins of Antimicrobial Drugs Antibiotics are common metabolic products of aerobic bacteria and fungi Bacteria in genera Streptomyces and Bacillus Molds in genera Penicillium and Cephalosporium By inhibiting the other microbes in the same habitat, antibiotic producers have less competition for nutrients and space 6

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8 12.2 Interactions Between Drug and Microbe Antimicrobial drugs should be selectively toxic drugs should kill or inhibit microbial cells without simultaneously damaging host tissues As the characteristics of the infectious agent become more similar to the vertebrate host cell, complete selective toxicity becomes more difficult to achieve and more side effects are seen 8

9 Mechanisms of Drug Action 1. Inhibition of cell wall synthesis 2. Breakdown of cell membrane structure or function 3. Inhibition of nucleic acid synthesis, structure or function 4. Inhibition of protein synthesis 5. Blocks on key metabolic pathways 9

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12 The Spectrum of an Antimicrobic Drug Spectrum range of activity of a drug Narrow-spectrum effective on a small range of microbes Target a specific cell component that is found only in certain microbes Broad-spectrum greatest range of activity Target cell components common to most pathogens (ribosomes) 12

13 Antimicrobial Drugs That Affect the Bacterial Cell Wall Most bacterial cell walls contain peptidoglycan Penicillins and cephalosporins block synthesis of peptidoglycan, causing the cell wall to lyse Active on young, growing cells Penicillins that do not penetrate the outer membrane and are less effective against gram-negative bacteria Broad spectrum penicillins and cephalosporins can cross the cell walls of gram-negative bacteria 13

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15 Antimicrobial Drugs That Disrupt Cell Membrane Function A cell with a damaged membrane dies from disruption in metabolism or lysis These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes Polymyxins interact with phospholipids and cause leakage, particularly in gram-negative bacteria Amphotericin B and nystatin form complexes with sterols on fungal membranes which causes leakage 15

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17 Drugs That Affect Nucleic Acid Synthesis May block synthesis of nucleotides, inhibit replication, or stop transcription Chloroquine binds and cross-links the double helix; quinolones inhibit DNA helicases Antiviral drugs that are analogs of purines and pyrimidines insert in viral nucleic acid, preventing replication 17

18 Drugs That Block Protein Synthesis Ribosomes of eukaryotes differ in size and structure from prokaryotes; antimicrobics usually have a selective action against prokaryotes; can also damage the eukaryotic mitochondria Aminoglycosides (streptomycin, gentamycin) insert on sites on the 30S subunit and cause misreading of mrna Tetracyclines block attachment of trna on the A acceptor site and stop further synthesis 18

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20 Drugs that Affect Metabolic Pathways Sulfonamides and trimethoprim block enzymes required for tetrahydrofolate synthesis needed for DNA and RNA synthesis Competitive inhibition drug competes with normal substrate for enzyme s active site Synergistic effect the effects of a combination of antibiotics are greater than the sum of the effects of the individual antibiotics 20

21 Figure 12.6 (a) 21

22 Figure 12.6 (b) 22

23 Antiviral Chemotherapeutic Agents Selective toxicity is almost impossible due to obligate intracellular parasitic nature of viruses Block penetration into host cell Block replication, transcription, or translation of viral genetic material Nucleotide analogs Acyclovir herpesviruses Ribavirin a guanine analog RSV, hemorrhagic fevers AZT thymine analog HIV Prevent maturation of viral particles Protease inhibitors HIV 23

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25 Interferons (INF) Human-based glycoprotein produced primarily by fibroblasts and leukocytes Therapeutic benefits include: Reduces healing time and some complications of infections Prevents or reduces symptoms of cold and papillomavirus Slows the progress of certain cancers, leukemias, and lymphomas Treatment of hepatitis C, genital warts, Kaposi s sarcoma 25

26 12.4 The Acquisition of Drug Resistance Adaptive response in which microorganisms begin to tolerate an amount of drug that would ordinarily be inhibitory; due to genetic versatility or variation; intrinsic and acquired Acquired resistance: Spontaneous mutations in critical chromosomal genes Acquisition of new genes or sets of genes via transfer from another species Originates from resistance factors (plasmids) encoded with drug resistance, transposons 26

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28 Mechanisms of Drug Resistance Drug inactivation by acquired enzymatic activity penicillinases Decreased permeability to drug or increased elimination of drug from cell acquired or mutation Change in drug receptors mutation or acquisition Change in metabolic patterns mutation of original enzyme 28

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30 Natural Selection and Drug Resistance Large populations of microbes likely to include drug resistant cells due to prior mutations or transfer of plasmids no growth advantage until exposed to drug If exposed, sensitive cells are inhibited or destroyed while resistance cells will survive and proliferate. Eventually population will be resistant selective pressure natural selection Worldwide indiscriminate use of antimicrobials has led to explosion of drug resistant microorganisms 30

31 Figure A model of natural selection for drug resistance 31

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33 12.5 Interactions Between Drug and Host Estimate that 5% of all persons taking antimicrobials will experience a serious adverse reaction to the drug side effects Major side effects: Direct damage to tissue due to toxicity of drug Allergic reactions Disruption in the balance of normal florasuperinfections possible 33

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37 12.6 Considerations in Selecting an Antimicrobial Drug Identify the microorganism causing the infection Test the microorganism s susceptibility (sensitivity) to various drugs in vitro when indicated The overall medical condition of the patient 37

38 Identifying the Agent Identification of infectious agent should be attempted as soon as possible Specimens should be taken before antimicrobials are initiated 38

39 Testing for Drug Susceptibility Essential for groups of bacteria commonly showing resistance Kirby-Bauer disk diffusion test E-test diffusion test Dilution tests minimum inhibitory concentration (MIC) smallest concentration of drug that visibly inhibits growth Provide profile of drug sensitivity 39

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43 The MIC and Therapeutic Index In vitro activity of a drug is not always correlated with in vivo effect If therapy fails, a different drug, combination of drugs, or different administration must be considered Best to chose a drug with highest level of selectivity but lowest level toxicity measured by therapeutic index the ratio of the dose of the drug that is toxic to humans as compared to its minimum effective dose High index is desirable 43

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