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8/2/2019 antibioticslecturemay2010-110703092455-phpapp02

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Antimicrobial Drugs

Fading Miracle?

BLS 206 Lecture

Hoza, A . S


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Ehrlichs Magic Bullets

1906: PaulEhrlich discoveredSalvarsan 606

1930s: sulfa drugs

discovered


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Fleming and Penicillin


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TERMINOLOGIES


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Chemotherapy

The use of drugs to treat a disease

Selective toxicity:

A drug that kills harmful microbeswithout damaging the host

Terminologies


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Antibacterial spectrumRange of activity of an antibiotic

A broad spectrumAntibiotic that can inhibit wide range of G- positive and G-negative bacteria e.g. Carbapenems, 3-4th generationcephalosporins, quinolones

A narrow spectrumAntibiotic that is active only against a limited number ofbacteria e.g. penicillin G, 1-2nd generation cephalosporins,oxazolidone

Terminologies


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Bacteriostatic activityLevel of antimicrobial activity that inhibits the

growth of bacteria

Minimum inhibitory concentration (MIC)

The lowest concentration that inhibits the growthof bacterial population

Bactericidal activity

Minimum bactericidal concentration (MBC)The lowest concentration that kills 99.9% ofthe bacterial population


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Antibiotic synergismCombination of antibiotics have enhanced activity

when tested together compared with each antibioticalone (e.g. 2 + 2 = 6)e.g. ampicillin+gentamicin in entercoccal carditis

Additive effectCombination of antibiotics has an additive effect(e.g. 2 + 2 = 4)

e.g. combination of two -lactam antibioticsAntibiotic antagonism

Combination in which the activity of one antibiotic

interferes with the activity of the other (e.g. 2 + 2 < 4)

Antibiotic combinations


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Effects of Combinations of 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.


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Effects of Combinations of Drugs


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Combined antibacterial therapy


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Antibiotic/Antimicrobial

Antibiotic:

Chemical produced by a microorganism that

kills or inhibits the growth of anothermicroorganism

Antimicrobial agent:

Chemical that kills or inhibits the growth ofmicroorganisms


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Antimicrobial Agents Disinfectant:

antimicrobial agent used only on inanimateobjects

Chemotherapeutic agent:

antimicrobial agent that can be used internally

Bactericidal:

agent that killsbacteria

Bacteriostatic:

agent that inhibits the growth of bacteria


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Microbial

Sources ofAntibiotics


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Antibiotic Spectrum of Activity

No antibiotic is effective against all microbes


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Mechanisms of Antimicrobial Action

Bacteria have their own enzymes for Cell wall formation

Protein synthesis

DNA replication

RNA synthesis

Synthesis of essential metabolites


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Mechanisms of Antimicrobial Action

Viruses use host enzymes inside host cells

Fungi and protozoa have own eukaryotic enzymes

The more similar the pathogen and host enzymes,the more side effects the antimicrobials will have


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Modes of Antimicrobial Action


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Basic mechanisms of antibiotics


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Basic mechanisms of antibiotic action

(1) Disruption of bacterial cell wall

-lactam antibioticsPenicillins, cephalosporins and cephamycins,carbapenems and monobactams, -lactamase inhibitor/-lactam combinations

Glycopeptides Vancomycin

PolypeptidesBacitracin, polymyxins

Drugs used for treatment of mycobacterial infectionsIsoniazid, ethinamide, ethambutol, cycloserine


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Bacterial cell wall of G+ (A) and G- (B) bacteria


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Gram-positive and Gram-negative bacteria


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2. Inhibition of protein synthesis

Acting at 30S ribosomesAminoglycosides

Tetracyclines

Acting at 50S ribosomesChloramphenicol

Macrolides

Clindamycin

Streptogramins

Oxazolidones


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3. Inhibition of nucleic acid synthesis

Acting on DNA replicationQuinolones

Metronidazole

Acting on RNA synthesisRifampin

Rifabutin


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4. Antimetabolites

Sulfonamides

Dapsone

Trimethoprim

Paraaminosalicylic acid


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Antimicrobial Agents


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Penicillin (over 50 compounds)

Share 4-sided ring ( lactam ring)

Natural penicillins

Narrow range of action

Susceptible to penicillinase ( lactamase)

Antibacterial Antibiotics Inhibitors of Cell WallSynthesis


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Prokaryotic Cell Walls

Gram positive cell

wall

Gram negative cell

wall


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Penicillins

Figure 20.6


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Penicillinase (b Lactamase)

Figure 20.8


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Penicilinase- resistant penicillins

Carbapenems: very broad spectrum

Monobactam: Gram negative

Extended- spectrum penicillins

Penicillins + b-lactamase inhibitors

Semisynthetic Penicillins


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Cephalosporins

2nd, 3rd, and 4th

generations moreeffective againstgram-negatives

Other Inhibitors of Cell Wall Synthesis

Figure 20.9


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Polypeptide antibiotics

Bacitracin

Topical application

Against gram-positives

Vancomycin

Glycopeptide

Important "last line" against antibiotic resistant

S. aureus



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Antibiotics effective againstMycobacteria:

interfere with mycolic acid

synthesis or incorporation

Isoniazid (INH)

Ethambutol


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Broad spectrum, toxicity problems

Examples

Chloramphenicol (bone marrow)

Aminoglycosides: Streptomycin, neomycin,gentamycin (hearing, kidneys)

Tetracyclines (Rickettsias & Chlamydia; GI tract)

Macrolides: Erythromycin (gram +, used inchildren)

Inhibitors of Protein Synthesis


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Polymyxin B (Gram negatives)

Topical

Combined with bacitracin and neomycin(broad spectrum) in over-the-counter

preparation

Injury to the Plasma Membrane


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Rifamycin

Inhibits RNA synthesis

Antituberculosis

Quinolones and fluoroquinolones

Ciprofloxacin

Inhibits DNA gyrase

Urinary tract infections

Inhibitors of Nucleic Acid Synthesis


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Sulfonamides (Sulfa drugs)

Inhibit folic acid synthesis

Broad spectrum

Competitive Inhibitors

Figure 5.7


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Antifungal Drugs

Fungi are eukaryotes

Have unique sterols in

their cell walls

Pathogenic fungi are

often outside the body


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Antiviral Drugs

Viruses are composed of nucleic acid, proteincapsid, and host membrane containing virus proteins

Viruses live inside host cells and use many hostenzymes

Some viruses have unique enzymes for DNA/RNA

synthesis or protein cutting in virus assembly

Figure 20.16a


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Antiviral DrugsNucleoside and Nucleotide Analogs

Figure 20.16a


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Figure 20.16b, c

Analogs Block DNA Synthesis

A i i l D E I hibi


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Inhibit assembly

Indinavir (HIV)

Inhibit attachment

Zanamivir (Influenza)

Inhibit uncoating

Amantadine (Influenza)

Antiviral Drugs Enzyme Inhibitors


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Interferons

prevent spread of viruses to new cells (Viralhepatitis)

Natural products of the immune system in viralinfections

Antiviral Drugs Enzyme Inhibitors


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Antiprotozoan Drugs

Protozoa are eukaryoticcells

Many drugs areexperimental and their

mode of action is unknown


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Antihelminthic Drugs

Helminths aremacroscopicmulticellular eukaryoticorganisms:

tapeworms,

roundworms,

pinworms,

hookworms


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Prevent ATP generation (Tapeworms)

Alters membrane permeability (Flatworms)

Neuromuscular block (Intestinal roundworms)

Inhibits nutrient absorption (Intestinal roundworms)

Paralyzes worm (Intestinal roundworms)

Antihelminthic Drugs


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Measuring Antimicrobial Sensitivity

E Test

MIC: Minimal

inhibitoryconcentration


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Measuring Antimicrobial Sensitivity: Disk Diffusion


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Penicillin

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