antimicrobial therapy. the advent of antimicrobial therapy has dramatically increased the life span...
TRANSCRIPT
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Antimicrobial Therapy
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Antimicrobial Therapy• The advent of antimicrobial
therapy has dramatically increased the life span and quality of life for humans.
• More people have died of infection in wartime than have died from swords or bullets.
• Today, doctors are worried that we are dangerously close to a postantibiotic era where the drugs we have are no longer effective
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The Origins of Antimicrobial Drugs• Naturally occurring antimicrobials
– Metabolic products of bacteria and fungi
– Microbes produce antibiotics (their weapons) to reduce competition for nutrients and space
• Derived from:– bacteria in the genera Streptomyces
and Bacillus– molds in the genera Penicillium and
Cephalosporium
• Antibiotic= a substance produced by microorganisms that in small amounts inhibits another microorganism.
Penicillium
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Origins of Antimicrobial Therapy
• Many ancient cultures have used antimicrobials from plants and trees.
• First systematic attempt to find specific antimicrobials occurred in the early 1900’s.
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History of Chemotherapy• 1910--Paul Erhlich, “father of
chemotherapy”, discovered that Salvarsan could treat syphilis
• 1935—Sulfa drugs were discovered
• 1928-40—Alexander Fleming discovered antimicrobial action from the mold, Penicillium notatum, however many years passed before penicillin was purified and produced.
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What is the ideal antimicrobial?• Selective toxicity: drug kills the
pathogen without damaging the host
• Solubility in body fluids• Toxicity not easily altered by
bacteria• Non-allergenic• Stability: maintenance of a
constant, therapeutic concentration in blood and tissue fluids
• Resistance by microorganisms not easily acquired
• Long shelf life• Reasonable cost
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The Action of Antimicrobial Drugs
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Inhibition of Cell Wall Synthesis
Penicillin's effect on the Gram negative bacterial cell wall
• The cell wall is a good, selective target since eukaryotes don’t have peptidoglycan
• Examples: Penicillin, bacitractin, cephalosporin, vancomycin
• Penicillins and cephalosporins inhibit the peptide crosslinks that hold the carbohydrate units together. Similar to taking a blow torch and cutting links in a chain link fence.
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Inhibition of Cell Wall Synthesis: Penicillin
• Inhibits cell wall synthesis • Produced by the mold,
Penicillium chrysogenum– A diverse group (1st, 2nd , 3rd
generations)• Natural (penicillin G and V)• Semisynthetic (ampicillin,
Augmentin)
– Structure• Beta-lactam ring
Treat streptococci, meningococci, and spirochete infections
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The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive.
Inhibition of Cell Wall Synthesis: Penicillin
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Injury to the Plasma Membrane
• Change in permeability of plasma membrane causes loss of important metabolites from cell
– Interact with membrane phospholipids– Distorts the cell surface– Leakage of proteins and nitrogen bases
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Inhibition of Protein SynthesisExploit difference in ribosomes: •Drugs specifically bind to 70S and not 80S because of specific shape ribosomes•Erythromycin, Streptomycin, Tetracycline, Chloramphenical•Some toxicity since mitochondria have 70S ribosomes
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Inhibition of Nucleic Acid Synthesis
• Inhibition of DNA replication• Inhibition of transcription of
RNA– Modes of action include:
• Binds and cross-links the double helix
• Other quinolones – inhibits DNA unwinding enzymes
• Analogs of purines and pyrimidines that mimic natural bases
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Inhibition of Folic Acid Synthesis
• Sulfonamides (sulfa drug) and trimethoprim– Competitive inhibition preventing the metabolism
of DNA, RNA, and amino acid
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Antibiotic Spectrum• Broad-spectrum drugs: effective against more than
one group of bacteria. Ex. tetracycline antibiotics• Narrow-spectrum drugs: target a specific group Ex.
polymyxin
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Biofilm Effects on Antibiotic Treatment • Biofilms are unaffected by the
same antimicrobials that work against them when they are free living– penetration of the biofilm– different phenotype is expressed
by biofilm bacteria, giving them different antibiotic sensitivity
• Strategies for treating biofilm infections– interrupting quorum sensing
signals– adding DNase to antibiotics helps
with penetration– impregnating devices with
antibiotics
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Bioavailability Effects on Antibiotic Treatment
• The chemical structure of a drug AND the mode of entry of a drug influence:
• concentration of drug in blood
• time of drug in blood
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Actions of Antimicrobial Drugs
• Treatment of eukaryotic pathogens is more difficult 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 find protection inside the human cell.
• Limited drugs available • Difficult to maintain selective toxicity• Effective drugs – target viral replication cycle
– Entry– Nucleic acid synthesis– Assembly/release
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Drug and Host Interaction
• Be cautious of toxicity to organs• Some drugs can cause allergic reactions
– (especially penicillin and sulfa drugs)
• Many times, drugs will suppress or alter the normal microflora – (good to take extra sources of live cultures(like
Lactobacillus acidophilus found in yougurt and milk) to replenish flora
• Need Effective drugs—be mindful to use the best drug for the job.
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Testing for Drug Susceptibility
• Will the treatment kill the pathogen?• What concentration of antimicrobial is needed
for Minimal Inhibitory Concentration (MIC)• Natural selection of bacteria
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Serial-Dilution Test-Review• The minimum inhibitory concentration (MIC) is the
concentration required to inhibit growth of a specific isolate in vitro under standardized conditions.
• It is determined by finding the lowest dilution without visible growth during serial dilution testing. This will vary for individual isolates.
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Tests to Guide Chemotherapy
• Disk-Diffusion Method (Kirby-Bauer technique)
• Same as testing disinfectants
• Zone of inhibition surrounding the discs is measured and compared with a standard for each drug
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Tests to Guide Chemotherapy• E test uses a strip that contains a gradient of
antimicrobial• Indicates the concentration of antimicrobial needed
to inhibit growth
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The Effectiveness of Chemotherapeutic Agents• Effects of Combinations of Drugs
• 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.
Synergy between dalfopristin (right) and quinupristin (left) against a staphylococcal strain resistant to both.
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The MIC and Therapeutic Index
• In vitro activity of a drug is not always correlated with the in vivo effect
• Failure of antimicrobial treatment is due to:– the inability of the drug to diffuse into that body
compartment (brain, joints, skin)– resistant microbes in the infection that didn’t make it
into the sample collected for testing– an infection caused by more than one pathogen
(mixed), some of which are resistant to the drug
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The MIC and Therapeutic Index
• Therapeutic index: the ratio of the dose of the drug that is toxic to humans as compared to its minimum effective (therapeutic) dose:
– the smaller the ratio, the greater the potential for drug reactions
– TI = 1.1 is a risky choice– TI = 10 is a safer choice– the drug with the highest therapeutic index has the
widest margin of safety
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The MIC and Therapeutic Index • The physician must take a careful
history before prescribing an antibiotic– preexisting conditions that might
influence the activity of the drug, Ex. Alcoholism, intestinal damage
– history of allergy to a certain class of drugs
– underlying liver or kidney disease, our filters!
– infants, the elderly, and pregnant women require special precautions
– intake of other drugs can result in increased toxicity or failure of one or more drugs. Ex. Birth control!
– genetic or metabolic abnormalities– site of infection, route of administration,
cost
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How Does Drug Resistance Develop?• Resistance to penicillin developed
in some bacteria as early as 1940• In the 1980s and 1990s scientists
began to observe treatment failures on a large scale
• Microbes become newly resistant to a drug after one of the following occurs– spontaneous mutations in critical
chromosomal genes– acquisition of entire new genes or
sets of genes via horizontal transfer from another species
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Development of Drug Resistance
• Chromosomal drug resistance– usually results from spontaneous random
mutation– can be the result of a phenotypic, rather than a
genotypic change; slowing or stopping of metabolism so that the microbe can’t be harmed by the antibiotic
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Development of Drug Resistance• Resistance through horizontal transfer
– Resistance (R) factors: plasmids containing antibiotic resistance genes (some have 6-7 resistance genes!)
– Can be transferred through conjugation, transformation, or transduction
– Plasmids encoded with drug resistance are naturally present in microbes before they have been exposed to an antibiotic
– Transposons that have duplicated and inserted genes for drug resistance into plasmids
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Resistance plasmids can carry many resistance genes
• YIKES! We now have a “super bug”!
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Resistant StrainsRare
xx
Resistant Strains Dominant
Antimicrobial Exposure
xxxx
xx
xx
xx
Antibiotic Resistant Strain Propagation
• Antimicrobial exposure causes pressure to select resistant strains.
• Without antibiotics, selective pressure decreases and antibiotic resistance genes may be lost.
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Intermicrobial transfer of plasmids containing resistance genes
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S. aureus
Penicillin
1950s
Penicillin-resistant
S. aureus
Clinical Implications in the Development of Drug Resistant Staphylococcus aureus
• How do we treat S. aureus infections when they become completely resistant to our last line antibiotic, Vancomycin?
Methicillin
1970s
Methicillin-resistant S. aureus (MRSA)
Vancomycin-resistant
enterococci (VRE)
Vancomycin
1990s
1997
Vancomycin
intermediate-resistantS. aureus (VISA)
Vancomycin Resistant S. aureus
1997
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Mechanisms Associated with Drug Resistance
1. Drug inactivation2. Decreased
permeability3. Activation of drug
pumps4. Change in drug
binding site5. Use of alternate
metabolic pathways
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Beta-lactamase breaks the beta-lactam ring and renders penicillin inactive
•Penicillins-Original penicillin was narrow-spectrum and susceptible to microbial counterattacks-Molecule has been altered and improved upon over the years-Later penicillins overcome the limitations of the original molecule
Synthetic Advances in Antibiotics
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The Future of Chemotherapeutic Agents
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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New Approaches to Antimicrobial Therapy • Using bacteriophages
– Eastern European countries use mixtures of bacteriophages as medicine, but these drugs have never been approved for use in the West
– Biophage-PA used to treat ear infections caused by Pseudomonas aeruginosa biofilms
– Other researchers are incorporating bacteriophages into wound dressings
– Advantage to bacteriophage is their narrow specificity; only infect one species of bacterium
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0
10
20
30
40
50
60
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Per
cen
t R
esis
tan
ce
Methicillin-resistantStaphylococcus aureus(MRSA)
0
5
10
15
20
25
30
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Per
cen
t R
esis
tan
ce
Vancomycin-resistantEnterococci (VRE)
Non-Intensive Care Unit Patients
Intensive Care Unit Patients
Antibiotic Resistance is Prevalent and Rising
Source: National Nosocomial Infections Surveillance (NNIS) System
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Preventing Antibiotic Resistance• Prevent infection
• Stay healthy • Diagnose and treat infection effectively
• Don’t treat viral infections with antibiotics
• Use effective antibiotics• Use antimicrobials wisely
• Take full course of antibiotics• Stop feeding antibiotics to
livestock• Prevent transmission
• Wash your hands • Isolate infections
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Take the full course of antibiotics to decrease resistance
Preventing Antibiotic Resistance
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Preventing Antibiotic Resistance
Antibiotics are sold world wide without a prescription
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Development of Drug Resistance
• A wide variety of soil bacteria can not only survive in the presence of many antibiotics, but can use the antibiotics as fuel
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Development of Drug Resistance• A large population of natural
environmental bacteria exists with antibiotic resistance capabilities that might be transferred to disease-causing bacteria
• Non-disease-causing flora of humans and animals can also harbor antibiotic resistance genes that can jump into pathogenic bacteria with which they share space Yep, it’s a cow peeing