M T Ch20 Antimicrobial Drugs SS10 s

7/27/2019 M T Ch20 Antimicrobial Drugs SS10 s

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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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Copyright 2006 Pearson Education, Inc., publishing as Benjamin Cummings

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


8/24Copyright 2006 Pearson Education, Inc., publishing as Benjamin Cummings

Inhibition of Protein Synthesis by Antibiotics

Figure 20.4



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



Retention of Penicillin G

Figure 20.7



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



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



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

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M T Ch20 Antimicrobial Drugs SS10 s