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Ch 20
Antimicrobial
Drugs
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SLOs
Describe the history ofchemotherapy.
Name the microbes that producethe most antibiotics.
Describe problems of chemo-therapy for viral, fungal,
protozoan, and helminthicinfections.
Define: Therapeutic index,antibiotic, activity spectrum,bacteriostatic, -cidal
Identify five modes of action ofantimicrobial drugs.
Describe the mechanism of action
of penicillin and the mechanismof resistance to penicillin.
Compare penicillin,
cephalosporin, and
vancomycin
Briefly explain the modes of
action of some antifungal
drugs.
Explain the modes of action ofsome antiviral drugs.
Explain the modes of action of
some antiprotozoan and
antihelminthic drugs.
Describe the Kirby Bauer test.
Describe mechanisms of drug
resistance.
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Antimicrobial Drugs
Chemotherapy: The use of drugs to treat adisease.
Antimicrobial drugs: Interfere with the growth ofmicrobes within a host.
Antibiotic: Of biological origin. Produced by amicrobe, inhibits other microbes.
Chemotherapeutic agent: synthetic chemicals
Today distinction blurred many newer"antibiotics" are biological products that are
chemically modified or
chemically synthesized
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Paul Ehrlichand SahachiroHata developedSalvarsan
(Arsphenamine) against
syphilis in 1910: The
concept of chemotherapy totreat microbial diseases was
born.
Sulfa drugs (sulfanilamide)discovered in 1932
against Gram+ bacteria
The History of Chemotherapy
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The History of Chemotherapy cont.
Fig 20.1
1928: Fleming discoveredpenicillin
1940: Howard Florey and ErnstChain performed first clinical
trials of penicillin.
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Features of Antimicrobial Drugs
Selective toxicity: Drug kills pathogens withoutdamaging the host.
Therapeutic index: ratio between toxic dose and
therapeutic dose or ratio of LD50 to ED50High therapeutic index less toxic
Antimicrobial action Bacteriostatic vs. bactericidal
Activity Spectrum Broad-spectrum vs. narrow-spectrum
Tissue distribution, metabolism, and excretion BBB; Unstable in acid; half-life duration
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The Action of Antimicrobial Drugs
FoundationFig 20.2
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Inhibition of Protein Synthesis by Antibiotics
Figure 20.4
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Antibacterial AntibioticsInhibitors of Cell Wall Synthesis: Penicillin
Natural and semisynthetic penicilins contain -lactam ring
Natural penicillins produced by Penicillium are effectiveagainst Gram + cocci and spirochetes
Semisynthetic penicillins: made in laboratory by addingdifferent side chains onto -lactam ring penicillinaseresistant and broader spectrum of activity
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Retention of Penicillin G
Figure 20.7
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Penicillin cont.
Penicillinase (-lactamase): bacterial enzyme thatdestroys natural penicillins
Penicillinase resistantpenicillins: methicilin replacedby oxacilin and nafcilin due to MRSA
Extended-spectrum penicilins: Ampicilin, amoxicilin;new: carboxypenicilins and ureidopenicillins (also goodagainst P. aeruginosa)
Fig 20.8
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Cephalosporins
Fungi of genusCephalospor ium 4 Generations ofcephalosporins
1. First-generation: Narrow spectrum, gram-positive
2. Second-generation: Extended spectrum includes
gram-negative3. Third-generation: Includes pseudomonads; mostly
injected, some oral.
4. Fourth-generation: Most extended spectrum
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Cephalosporins cont.
Structure and mode of action resembles penicilins
1. More stable to
bacterial -
lactamases thanpenicilins
2. Broader
spectrum usedagainst penicillin-
resistant strains
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Vancomycin
Glycopeptide from Streptomyces
Inhibition of cell wall synthesis
Used to kill MRSA
Emerging Vancomycinresistance: VRE and VRSA
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Antifungal Drugs
Polyenes, such as nystatin and amphotericin B,for systemic fungal infections. Inhibition ofergosterol synthesis fungicidal. Nephrotoxic
Griseofulvin from Penicillium. Systemic/oral.
Binds to tubulin ForTineae
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Antiviral Drugs
Nucleoside analogs inhibit DNA synthesis
Acyclovirand newer derivatives: Selective inhibitionof herpes virus replication. Acyclovir conversion tonucleotide analog only in virus infected cells
very little harm to uninfected cells!
Fig 20.16
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Mechanism of Action of Acyclovir
Fig 20.16
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HIV protease cleaves viral polypeptide
into functional proteins
Protease inhibition HIV cannot mature
and noninfectious viruses are produced.
Antiviral Drugs for Treating HIV/AIDS:
HAART
1. NRTIs and NNRTIs
2. Protease Inhibitors
3. Fusion Inhibitors
4. Integrase Inhibitors
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Antiprotozoan and Antihelminthic Drugs
Examples ofAnt iprotozoan:
Chloroquine: Malaria
Quinacrine: Giardia
Metronidazole (Flagyl): Vaginitis, anaerobic bacteria
Examples ofAnt ihelminth ic :
Niclosamide and praziquantel: Tapeworm
Mebendazole: broadspectrum antihelmintic
Ivermectin: nematodes, mites, lice . . .
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Antibiotic Assays to Guide Chemotherapy
Agar Disk Diffusion Method determinessusceptibility of an organism to a series ofantibiotics: Kirby-Bauer test
More sophisticated methods available for clinicallabs
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Drug Resistance
Penicillin G resistance ofS. aureus from 3% to >
90%
Multidrug-resistant S. aureus = MRSAor super-bug
Vancomycin-resistance
Multi drug resistant TB = MDR-TB
Evolut ion o f drug resistance: Vertical evolution due to spontaneous
mutation
Horizontal evolution due to gene transfer??
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Antibiotic Resistance
A variety of mutations can lead to antibioticresistance
Mechanisms of antibiotic resistance
1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3.Alteration of drug's target site
4. Rapid ejection of the drug Resistance genes are often on plasmids or
transposons that can be transferred between
bacteria.
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Resistance to Antibiotics
Fig 20.20
Read Clinical Foc s
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Antibiotic Resistance
Misuse of antibiotics selects for resistance mutants.
Misuse includes
Using outdated or weakened antibiotics
Using antibiotics for the common cold and other
inappropriate conditions
Using antibiotics in animal feed
Failing complete the prescribed regimen
Using someone else's leftover prescription
ANIMATION Antibiotic Resistance: Origins of Resistanceand Forms of Resistance
Read Clinical Focus:
Antibiotics in Animal Feed
Linked to Human Disease (p. 577)
http://localhost/var/www/apps/conversion/tmp/scratch_4/antibiotic_origins.html