Antimicrobial Therapy

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Antimicrobial Therapy
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Antimicrobial Therapy

• Chemotherapy
• Antimicrobial drugs act by interfering with the
  __________________, but they must do so
  ___________________(compared to a disinfectant
  which can work __________).

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Antimicrobial Therapy

• The advent of antimicrobial therapy has
  dramatically __________ the life span and quality
  of life for humans.
• More people have died ___________than have died
  from ___________.

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When did antimicrobial therapy originate?

• Many ancient cultures have used antimicrobials
  from ______________.
• First systematic attempt to find specific
  antimicrobials occurred in the __________.

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History of Chemotherapy

• 1910--_________, father of chemotherapy,
  discovered that Salvarsan could treat _______.
• 1935Discovered ___________.
• 1928-40_________________action from the mold,
  ___________, however many years passed before
  penicillin was purified and produced.

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Antimicrobial Drugs

• Antibiotic

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• Note more than half of the antibiotics produced
  are derived from __________, a bacteria found in
  soil, hence many researchers are looking for more
  possible antibiotics in __________, etc.

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Narrow-spectrum vs. Broad-spectrum antibiotics.
What is Penicillin?Note Is it easier to treat
prokaryotic or eukaryotic infections?
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What is the ideal antimicrobial?

• _____________ idea by Paul Ehrlich
• Selective toxicity--gt the ideal drug kills
  _______________________.
• Solubility in body fluids
• Selective toxicity
• Toxicity not easily altered
• ____________
• Stability maintenance of a constant, therapeutic
  concentration in blood and tissue fluids
• Resistance to microorganisms not easily acquired
• ________shelf life
• Reasonable cost

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The Action of Antimicrobial Drugs

• Bactericidal
• ___________
• Bacteriostatic
• __________
• Antimicrobial Drugs have Different Mechanisms
• 1.
• 2.
• 3. Inhibition of Protein Synthesis
• 4.
• 5.

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The Action of Antimicrobial Drugs
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Inhibition of Cell Wall Synthesis Note the
cell wall is a good, selective target since
eukaryotes dont have peptidoglycanExample
Penicillin, bacitractin, cephalosporin, vancomycin
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Actions of Antimicrobial Drugs (cont.)

• Inhibition of Protein Synthesis
• exploit difference in ribosomes
• prokaryotic ribosomes 70S ribosomes
• eukaryotic ribosomes 80S ribosomes
• Erythromycin, Streptomycin, Tetracycline,
  Chloramphenical
• some toxicity since mitochondria have 70S
  ribosomes
• Injury to the Plasma Membrane
• change in permeabiblity of plasma membrane causes
  loss of important metabolites from cell
• polymyxin

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Actions of Antimicrobial Drugs (cont.)

• Inhibition of Nucleic Acid Synthesis
• inhibit transcription, translation
• some toxicity because of interference
• Rifamycin, quinolone
• Inhibition of Essential Metabolite Synthesis
• drugs can work as competitive inhibitors of
  important enzyme reactions
• sulfanilimide

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Actions of Antimicrobial Drugs

• Treatment of eukaryotic pathogens is
  _____________because they are more similar to
  human cells.
• Need to target the few differences between cells.
• Sterols in cell membrane in fungi
• Treatment of viral pathogens is also difficult
  because viruses ____________the human cell.
• Need to target the viral multiplication cycle
• attachment, ________ uncoating, __________,
  maturation, release

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Bioavailability of Chemotherapeutics

• The chemical structure of a drug AND the mode of
  entry of a drug influence
• a)
• b)

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Tests to Guide Chemotherapy

• Disk-Diffusion Method

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The Effectiveness of Chemotherapeutic Agents

• Effects of Combinations of Drugs
• Note need to be careful of how you take the
  drug(grapefruit juice effect) and if you are
  taking any drugs that could interfere with the
  activity of the prescribed antibiotic(synergism
  or antagonism).
• The Future of Chemotherapeutic Agents
• Many diseases have become resistant to
  antibiotics.
• Chemicals produced by plants and animals are
  providing new antimicrobial agents.

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The Future of Chemotherapeutic AgentsMany
diseases have become resistant to antibiotics.
Some drugs are actually a combination of 2 drugs.
This nifty example shows an ingenious way to
start with one antibiotic and then if it is being
degraded a second one can be released.
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Antibiotic Resistance

• Nature
• What is antibiotic resistance?
• How do bacteria resist antibiotics?
• Sources
• How does antibiotic resistance originate?
• How is antibiotic resistance propagated?
• Clinical Significance
• How does antibiotic resistance affect us?
• How can we prevent antibiotic resistance?

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Antibiotic Resistance

• How is antibiotic resistance propagated?
• Bacteria transfer antibiotic resistance and we
  exacerbate the problem by adding selective
  pressure
• Clinical Significance
• How does antibiotic resistance affect us?
• Renders antibiotics ineffective and subjects us
  to serious consequences, perhaps death.
• How can we prevent antibiotic resistance?
• Use ICPs and antibiotics wisely

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What is Antibiotic Resistance?

• Antibiotic Resistance ____________________________
  ______
• Common example
• child is prescribed amoxicillin for an ear
  infection, however there is no improvement in
  condition. Why?

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How do Bacteria Resist Antibiotics?

• Here are a few examples of the mechanisms of
  resistance. Some bacteria may
• 1.
• Streptomycin targets bacterial ribosomes. If
  ribosomes change in structure, can streptomycin
  inhibit translation?
• 2.
• If antibiotics can not enter the cell, will they
  be effective?
• 3.
• If a beta-lactamASE (aka penicillinASE) enzyme is
  produced, what will happen to penicillin?

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Beta-lactamase breaks the beta-lactam ring and
renders penicillin inactive
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How does antibiotic resistance originate?

• Antibiotic resistance originates as a consequence
  of genetic change.
• Bacteria change their genetic makeup in 2 ways
• ____________ genetic change
• Mutations normally occur every million base
  pairs. Since microbes can multiply rapidly
  (GT20min) many genetic changes can occur.
• ________________ genetic change
• Microbes can transfer genetic information in many
  ways which we will review
• Some use Resistance plasmids (R plasmids or R
  factors)
• Some R plasmids carry 6-7 different resistance
  genes

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Resistance plasmids can carry many resistance
genes

• YIKES! We now have a super bug!

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Can antibiotic resistance be transferred?

• Yes! We transferred antibiotic resistance in
  lab! Remember how easy it was to transform
  bacteria with an ampicillin resistant plasmid and
  then select for the recombinant bacteria by
  plating on TSAampicillin?
• A reminder of the different ways bacteria
  transfer genetic information
• 1.
• 2.
• 3.
• 4.

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Transformation(______________________)

• If gene a or gene b codes for penicillinase will
  the new recombinant bacterium be killed by
  penicillin treatment?

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2. Transduction(______________________)

• If the purple or red gene is penicillinase, will
  the new recombinant bacterium be killed by
  penicillin?

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3. Conjugation(____________________________)

• If the red plasmid contains a penicillinase
  gene, will the recipient bacterium be killed by
  penicillin?

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How does antibiotic resistance originate?
Susceptible Bacteria
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• Bacteria have evolved numerous mechanisms to
  evade _________.
• Chromosomal mutations are an important source of
  ________ to some antimicrobials.

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• Acquisition of resistance genes or gene clusters,
  via ________, _________, or __________, accounts
  for most antimicrobial resistance among bacterial
  pathogens.
• These mechanisms also enhance the possibility of
  _______________.

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How are Antibiotic Resistant Strains Propagated?

• ________________causes pressure to select
  resistant strains.
• _______________, selective pressure decreases and
  antibiotic resistance genes may be _______.

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• Do antimicrobials cause mutations? __________.
• Once resistant strains of bacteria are present in
  a population, ____________.
• ________ antimicrobial selection pressure is one
  key to preventing _________ _________and ________
  the utility of available drugs for as long as
  possible.

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Clinical Implications in the Development of Drug
Resistant Staphylococcus aureus
Penicillin
Penicillin-resistant
S. aureus
1950s
S. aureus

• How do we treat S. aureus infections when they
  become completely resistant to our last line
  antibiotic, Vancomycin?

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How does Antibiotic Resistance affect us?(More
clinical implications)

• When microbes develop resistance to antibiotics
  we can no longer treat bacterial diseases.
• What other types of diseases do we have a
  difficult time treating?
• Complete antibiotic resistance will be equal to
  not having antibiotics at all.
• Before the discovery of antibiotics, millions of
  people died of diseases that we can treat today.
• Unfortunately, antibiotic resistance __________.

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Antibiotic Resistance is Prevalent and Rising
Methicillin-resistant Staphylococcus aureus(MRSA)
Vancomycin-resistant Enterococci (VRE)
Non-Intensive Care Unit Patients Intensive Care
Unit Patients
Source National Nosocomial Infections
Surveillance (NNIS) System

• Can hospitals be dangerous for patients?

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• The proportion of pathogens causing
  hospital-onset infections that are resistant to
  target antimicrobial drugs continues to
  __________ at an alarming rate!!
• Currently, more that _____of Staphylococcus
  aureus isolates causing infections in
  _________are resistant to methicillin more than
  _____are resistant in other hospital units.

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• Vancomycin-resistant enterococci (VRE) emerged in
  the late 1980s and are now _______ in many
  hospitals.
• In many hospitals, more than 25 of enterococcal
  infections are caused by vancomycin-resistant
  strains.

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How can we prevent antibiotic resistance?

• 1. Prevent infection
• _____________
• 2. Diagnose and treat infection effectively
• ____________
• Use effective antibiotics
• 3. Use antimicrobials wisely
• __________________
• Stop feeding antibiotics to livestock
• 4. Prevent transmission
• Wash your hands (Soap, alcohol gel)
• __________________

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• These 4 strategies ________, ______________,
  ___________, and _____________- form the
  framework for CDCs Campaign to Prevent
  Antimicrobial Resistance.

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• Clinicians and their patient care partners hold
  the solution to integrating these strategies into
  daily practice and optimizing the care and safety
  of all patients.

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Treat microbes with effective antibiotics
Choose the antibiotic that gives the largest zone
of inhibition.Would you choose the top or the
bottom chemical?
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Take the full course of antibiotics to decrease
resistance
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Selective media identifies genetic resistance.
Selective media identifies genetic resistance,
BUT does not create it. However, selection can
result in an ______________________.
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Wash your hands OR use an alcohol based hand rub!

• At home, should you wash your hands with
  anti-bacterial soap? Why or why not?

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• In this scanning electron micrograph, many
  bacteria are seen in a matrix of material that
  also contains a red blood cell.
• This biofilm developed within 24 hours of
  catheter insertion.
• Biofilms may promote development of
  antimicrobial-resistant infections in several
  ways

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• Serving as a _____ for deposition and growth of
  _________that then are released to cause
  ___________
• Creating a __________to antimicrobial diffusion,
  so that bacteria imbedded in the biofilm may be
  exposed to sub-inhibitory concentrations of
  _________________ ___________________

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• Providing a _________ in which bacteria can
  _____________.
• Biofilms cannot be _______ but some strategies
  may decrease the rate at which biofilms are
  formed and decrease bacterial colonization of
  biofilms.

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Are these bacteria resistant to antibiotics?
Scanning Electron Micrograph
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Want to know more about Antibiotic Resistance?

• Visit the following websites
• http//www.microbeworld.org/htm/cissues/resist/res
  ist0.htm
• http//www.cdc.gov/drugresistance/index.htm
• http//www.who.int/csr/resources/publications/drug
  resist/antibiotics.pdf
• http//www.fda.gov

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Closing Thoughts

• Does antibiotic resistance scare you?
• Luckily, we still have time to prevent the spread
  of antibiotic resistance.
• How can you help prevent the spread of antibiotic
  resistance?
• The good news
• Remember that most bacteria are beneficial and
  only a small proportion cause disease.