Penicillin

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Penicillin
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Fading Miracle

• The Ecology of Antimicrobial Resistance

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Antibiotic Resistance

• Shnayerson and Plotkin, The Killers Within. The
  Deadly Rise of Drug-Resistant Bacteria.
• Levy, Stuart B, The Antibiotic Paradox How the
  misuse of antibiotics destroys their curative
  powers

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Multi-Drug Resistant TB
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MDR-TB Hotspots
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Antibiotic/Antimicrobial

• Antibiotic Chemical produced by a microorganism
  that kills or inhibits the growth of another
  microorganism
• Antimicrobial agent Chemical that kills or
  inhibits the growth of microorganisms

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Antimicrobial Agents

• Disinfectant antimicrobial agent used only on
  inanimate objects
• Chemotherapeutic agent antimicrobial agent that
  can be used internally

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Disinfection

• Pasteurization destruction of all
  disease-producing microorganisms or reduction in
  spoilage microorganisms
• Sterilization killing or removal of all living
  organisms and their viruses

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Antimicrobial Agents

• Bactericidal agent that kills bacteria
• Bacteriostatic agent that inhibits the growth
  of bacteria
• Selective toxicity A drug that kills harmful
  microbes without damaging the host

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Antimicrobial Resistance

• Relative or complete lack of effect of
  antimicrobial against a previously susceptible
  microbe

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Ehrlichs Magic Bullets
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Magic Bullets

• 1906 Paul Ehrlich discovered Salvarsan 606
• 1930s sulfa drugs discovered

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Alexander Fleming
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Penicillin Inhibition of Bacterial Growth
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Penicillium notatum
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Fleming Wins Nobel Prize
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Ernst Chain and Howard Florey
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Commercial Production

• Tale of a London Policeman

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Penicillin 1942
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Microbial Sources of Antibiotics
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Antibiotic Spectrum of Activity

• No antibiotic is effective against all microbes

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Modes of Antimicrobial Action
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Antimicrobial Agents
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Penicillinase (b Lactamase)
Figure 20.8
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Semisynthetic Penicillins

• Penicilinase-resistant penicillins
• Carbapenems very broad spectrum
• Monobactam Gram negative
• Extended-spectrum penicillins
• Oral penicillns
• Penicillins ?-lactamase inhibitors

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Inhibitors of Cell Wall Synthesis

• Cephalosporins
• 2nd, 3rd, and 4th generations more effective
  against gram-negatives

Figure 20.9
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Inhibitors of Cell Wall Synthesis

• Polypeptide antibiotics
• Bacitracin
• Topical application
• Against gram-positives
• Vancomycin
• Glycopeptide
• Important "last line" against antibiotic
  resistant S. aureus

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Antimicrobial Agents
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Antimicrobial Agents
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Measuring Antimicrobial Sensitivity
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Minimal Inhibitory Concentration

• Antimicrobial resistance increase in MIC

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Antimicrobial Resistance

• Relative or complete lack of effect of
  antimicrobial against a previously susceptible
  microbe
• Increase in MIC

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Horizontal Gene Transfer
A Transformation B Conjugation C
Transduction
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Antimicrobial Resistance in Biofilms

• 103-104 higher doses needed to kill biofilm
  compared with planktonic organisms
• Biofilm is a molecular filter?
• Low metabolism of cells?
• Reduces drug activity?

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Selection for Resistant Bacteria
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Antimicrobial Resistance Klebsiella pneumoniae
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Consequences of Antimicrobial Resistance

• Infections resistant to available antibiotics
• Increased cost of treatment

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Pseudomembraneous Colitis

• Normal colon non spore-forming anaerobes
  predominate
• Colon after antimicrobial treatment normal flora
  reduced
• Clostridium difficile increases (Gram
  spore-former)

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Pseudomembraneous Colitis

• C. difficile toxins induce diarrhea, ulceration
  of the colon, can cause death
• Pseudomembranes formed from dead cells, mucin
  and fibrin

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Pseudomembraneous Colitis

• Usually associated with clindamycin,
  cephalosporins, ampicillin also anti-tumor drugs
• Can be reversed with antibiotics to which C.
  difficile is sensitive
• 10-20 relapse rate

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What Factors Promote Antimicrobial Resistance?

• Exposure to sub-optimal levels of antimicrobial
• Exposure to microbes carrying resistance genes

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Inappropriate Antimicrobial Use

• Prescription not taken correctly
• Antibiotics for viral infections
• Antibiotics sold without medical supervision
• Spread of resistant microbes in hospitals due to
  lack of hygiene

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Nosocomial Antimicrobial Resistance
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Inappropriate Antimicrobial Use

• Lack of quality control in manufacture or
  outdated antimicrobial
• Inadequate surveillance or defective
  susceptibility assays
• Poverty or war
• Use of antibiotics in foods

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Antibiotics in Meat
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Shooting Antibiotics into Cattle
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Antibiotics in Meat
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Antibiotics in Foods

• Antibiotics are used in animal feeds and sprayed
  on plants to prevent infection and promote growth
• Multi drug-resistant Salmonella typhi has been
  found in 4 states in 18 people who ate beef fed
  antibiotics

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Antimicrobial Resistance
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MRSA

• Methicillin-Resistant Staphylococcus aureus
• Most frequent nosocomial (hospital-acquired)
  pathogen
• Usually resistant to several other antibiotics

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Proportion of S. aureus Nosocomial Infections
Resistant to Oxacillin (MRSA) Among Intensive
Care Unit Patients, 1989-2003
Source NNIS System, data for 2003 are incomplete
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Community Associated MRSA

• MMWR August 22 2003
• Methicillin-resistant Staphylococcus aureus
  infections among competitive sports participants
  Colorado, Indiana, Pennsylvania, and Los
  Angeles County, 2000-2003

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Vancomycin Use USA
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Antimicrobial Resistance

• Weinstein, Controlling Antimicrobial Resistance
  in Hospitals, EID http//www.cdc.gov/ncidod/eid/vo
  l7no2/weinstein.htm

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VRE
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VRE Mortality
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Ecology of Antimicrobial Resistance
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Proposals to Combat Antimicrobial Resistance

• Speed development of new antibiotics
• Track resistance data nationwide
• Restrict antimicrobial use
• Direct observed dosing (TB)

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Proposals to Combat Antimicrobial Resistance

• Use more narrow spectrum antibiotics
• Use antimicrobial cocktails

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Effects of Combinations of Drugs

• Synergism occurs when the effect of two drugs
  together is greater than the effect of either
  alone.
• Antagonism occurs when the effect of two drugs
  together is less than the effect of either alone.

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Effects of Combinations of Drugs
Figure 20.22
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The Future of Chemotherapeutic Agents

• Antimicrobial peptides
• Broad spectrum antibiotics from plants and
  animals
• Squalamine (sharks)
• Protegrin (pigs)
• Magainin (frogs)

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The Future of Chemotherapeutic Agents

• Antisense agents
• Complementary DNA or peptide nucleic acids that
  binds to a pathogen's virulence gene(s) and
  prevents transcription

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