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Fading Miracle

Penicillin
The Ecology of
Antimicrobial Resistance

Antibiotic Resistance Multi-Drug Resistant TB

• 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

MDR-TB Hotspots
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 Disinfection
• Disinfectant: antimicrobial agent • Pasteurization: destruction of all
used only on inanimate objects disease-producing microorganisms
• Chemotherapeutic agent: or reduction in spoilage
antimicrobial agent that can be microorganisms
used internally • Sterilization: killing or removal of all
living organisms and their viruses

Antimicrobial Agents Antimicrobial Resistance


• Bactericidal: agent that kills • Relative or complete lack of effect
bacteria of antimicrobial against a previously
• Bacteriostatic: agent that inhibits susceptible microbe
the growth of bacteria
• Selective toxicity: A drug that kills
harmful microbes without damaging
the host

Ehrlich’s Magic Bullets Magic Bullets


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

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Penicillin Inhibition of
Alexander Fleming
Bacterial Growth

Penicillium notatum Fleming Wins Nobel Prize

Ernst Chain and Howard


Commercial Production
Florey
• Tale of a
London
Policeman

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Penicillin
1942

Antibiotic Spectrum of Activity

Microbial
Sources
of
Antibiotics

• No antibiotic is effective against all


microbes

Modes of Antimicrobial Action Antimicrobial Agents


Antimicrobial Mechanism of Resistance
Action Mechanisms
Beta lactams: Block cell wall Inactivation,
penicillins, formation mutation
cephalosporins
Glycopeptides: Block cell wall Mutation of
vancomycin formation binding
molecules
Amino Block protein Inactivation
glycosides: synthesis
gentamycin

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Semisynthetic Penicillins
Penicillinase (β Lactamase)
• Penicilinase-resistant penicillins
• Carbapenems: very broad spectrum
• Monobactam: Gram negative
• Extended-spectrum penicillins
• Oral penicillns
• Penicillins + β-lactamase inhibitors

Figure 20.8

Inhibitors of Cell Wall Synthesis


Inhibitors of Cell Wall Synthesis
• Polypeptide antibiotics
• Cephalosporins – Bacitracin
• Topical application
– 2nd, 3rd,
and 4th
• Against gram-positives
generations more
effective against – Vancomycin
gram-negatives • Glycopeptide
• Important "last line" against antibiotic resistant S.
aureus

Figure 20.9

Antimicrobial Agents Antimicrobial Agents


Antimicrobial Mechanism of Resistance Antibiotics Mechanism of Resistance
Action Mechanisms Action Mechanisms
Tetracyclines Block protein Inactivation Rifampin Inhibits Mutation in
synthesis bacterial RNA binding
Macrolides Block protein Ribosome polymerase molecules
synthesis protection Trimethoprim Block Mutation in
Sulfonamide formation of binding
Quinolones Inhibit DNA Mutation in nucleic acids molecules
replication binding and f-met
molecules

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Measuring Antimicrobial Minimal Inhibitory
Sensitivity Concentration

• Antimicrobial
resistance =
increase in MIC

Horizontal Gene Transfer


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

A = Transformation; B = Conjugation; C = Transduction

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 Antimicrobial Resistance:
Bacteria Klebsiella pneumoniae

Consequences of
Pseudomembraneous Colitis
Antimicrobial Resistance
• Infections • Normal colon: non spore-forming
resistant to anaerobes predominate
available • Colon after antimicrobial treatment:
antibiotics normal flora reduced
• Increased cost • Clostridium difficile increases
of treatment (Gram + spore-former)

Pseudomembraneous Colitis Pseudomembraneous Colitis


• C. difficile toxins induce diarrhea, • Usually associated with
ulceration of the colon, can cause clindamycin, cephalosporins,
death ampicillin; also anti-tumor drugs
• Pseudomembranes formed from • Can be reversed with antibiotics to
dead cells, mucin and fibrin which C. difficile is sensitive
• 10-20% relapse rate

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What Factors Promote Inappropriate Antimicrobial
Antimicrobial Resistance? Use
• Prescription not taken correctly
• Exposure to sub-optimal levels of • Antibiotics for viral infections
antimicrobial
• Antibiotics sold without medical
• Exposure to microbes carrying supervision
resistance genes
• Spread of resistant microbes in
hospitals due to lack of hygiene

Nosocomial Antimicrobial
Resistance

Inappropriate Antimicrobial
Antibiotics in Meat
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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Shooting Antibiotics into Cattle Antibiotics in Meat

Antibiotics in Foods Antimicrobial Resistance


Antimicrobials Microbes

• Antibiotics are used in animal feeds


Beta lactams E. coli, K. pneumoniae,
and sprayed on plants to prevent N. gonorrhoeae, S.
infection and promote growth aureus, S. pneumoniae
• Multi drug-resistant Salmonella Vancomycin E. faecalis, S. aureus
(partial)
typhi has been found in 4 states in
Multiple Drugs M. tuberculosis, P.
18 people who ate beef fed aeruginosa, S. typhi,
antibiotics Shigella spp., S.
aureus, V. cholerae

Proportion of S. aureus Nosocomial


MRSA Infections Resistant to Oxacillin (MRSA)
Among Intensive Care Unit Patients,
• Methicillin-Resistant 1989-2003*
Staphylococcus aureus
• Most frequent nosocomial (hospital-
acquired) pathogen
• Usually resistant to several other
antibiotics

*Source: NNIS System, data for 2003 are incomplete

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Community Associated MRSA Vancomycin Use USA
• MMWR August 22 2003
• Methicillin-resistant Staphylococcus
aureus infections among competitive
sports participants – Colorado, Indiana,
Pennsylvania, and Los Angeles County,
2000-2003

Antimicrobial Resistance VRE

• Weinstein, Controlling Antimicrobial


Resistance in Hospitals, EID
http://www.cdc.gov/ncidod/eid/vol7no2/weinst
ein.htm

VRE Mortality

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Ecology of Antimicrobial
Resistance

Proposals to Combat Proposals to Combat


Antimicrobial Resistance Antimicrobial Resistance

• Speed development of new • Use more narrow spectrum


antibiotics antibiotics
• Track resistance data nationwide • Use antimicrobial cocktails
• Restrict antimicrobial use
• Direct observed dosing (TB)

Effects of Combinations of
Effects of Combinations of
Drugs
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.

Figure 20.22

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The Future of The Future of
Chemotherapeutic Agents Chemotherapeutic Agents
• Antimicrobial peptides • Antisense agents
– Broad spectrum antibiotics from plants – Complementary DNA or peptide nucleic acids
and animals that binds to a pathogen's virulence gene(s) and
• Squalamine (sharks) prevents transcription
• Protegrin (pigs)
• Magainin (frogs)

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