Antimicrobial%20Medications

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Antimicrobial Medications

• Chapter 21

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History and Development ofAntimicrobial Drugs

• Discovery of antimicrobial drugs
• Paul Erlich (1909)found the first pharmaceutical
  effective for treatment of syphilis Salvarsan
• Arsphenamine highly toxic
• Sulfonamide was the first sulfa drug
• In vitro derivative of Prontosil dye
• effective against streptococcal infections
• Bayer Labs, 1939 Nobel prize in Medicine

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History and Development ofAntimicrobial Drugs

• Discovery of antibiotics
• Penicillin discovered by Alexander Fleming
• Identified mold Penicillium that produced a
  bactericidal substance that was effective against
  a wide range of gram microbes
• Inhibits cell wall synthesis
• Mass production of penicillin during WWII
• Streptomycin (1943) isolated from soil bacterium
  Streptomyces griseus by Selman Waksman
• Bacteriostatic
• Inhibits protein synthesis by binding to ribosome

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History and Development ofAntimicrobial Drugs

• Development of new generation of drugs
• In 1960s scientists alteration of drug structure
  gave them new properties
• Penicillin G altered to create ampicillin
• Broadened spectrum of antimicrobial killing

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Features of Antimicrobial Drugs

• Most modern antibiotics come from organisms
  living in the soil
• Includes bacterial species Streptomyces and
  Bacillus as well as fungi Penicillium and
  Cephalosporium
• To commercially produce antibiotics
• Strain is grown until maximum antibiotic
  concentration is reached
• Drug is extracted from broth medium
• Extensively purified
• May be chemically altered
• Termed semi-synthetic

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Features of Antimicrobial Drugs

• Selective toxicity
• Antibiotics cause greater harm to microorganisms
  than to human host
• Toxicity of drug is expressed as therapeutic
  index
• Lowest dose toxic to patient divided by dose
  typically used for treatment
• High therapeutic index less toxic to patient
• Narrow therapeutic index more toxic, monitor
  closely

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Features of Antimicrobial Drugs

• Antimicrobial action
• Bacteriostatic drugs
• Inhibit bacterial growth
• rely on host immunity
• Bacteriocidal drugs
• Kill bacteria
• Most useful in situations when host defenses
  cannot control pathogen

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Features of Antimicrobial Drugs

• Spectrum of activity
• Antimicrobials vary with respect to range of
  organisms controlled
• Narrow spectrum
• Work on narrow range of organisms
• Gram-positive only OR Gram-negative only
• Advantage effects pathogen only
• Disadvantage requires identification of pathogen
• Broad spectrum
• Advantage Work on broad range of organisms
• Disadvantage disruption of normal flora

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Features of Antimicrobial Drugs

• Effects of combinations of antimicrobial drugs
• Combination sometimes used to treat infections
• Synergistic whole is gt sum
• Antagonistic whole is lt sum
• Additive whole is the sum

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Features of Antimicrobial Drugs

• Tissue distribution, metabolism and excretion
• Drugs differ in how they are distributed,
  metabolized and excreted
• Half-life Rate of elimination of drug from body
• Time it takes for the body to eliminate one half
  the original dose in serum
• Half-life dictates frequency of dosage
• Patients with liver or kidney damage tend to
  excrete drugs more slowly

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Features of Antimicrobial Drugs

• Adverse effects
• Allergic reactions
• Toxic effects
• Suppression of normal flora
• Antimicrobial resistance

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Mechanisms of Action of Antibacterial Drugs

• Mechanism of action include
• Inhibition of cell wall synthesis
• Penicillins, Cephalosporins, Vancomycin,
  Bacitracin
• Inhibition of protein synthesis
• Aminoglycosides, tetracyclines, macrolides,
  chloramphenicol, lincosamides
• Inhibition of nucleic acid synthesis
• Fluoroquinolones, rifamycins
• Inhibition of metabolic pathways
• Sulfonamides, trimethoprim
• Interference with cell membrane integrity
• Polymyxin

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Mechanisms of Action Cell Wall Synthesis

• Inhibition of cell wall synthesis
• Antimicrobials that interfere with the synthesis
  of peptidoglycan
• These drugs have very high therapeutic index
• Antimicrobials of this class include
• ß lactam drugs (penicillin, cephalosporin)
• Vancomycin
• Bacitracin

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Mechanisms of Action Cell Wall Synthesis

• Drugs vary in spectrum
• Some more active against Gram ()
• Some more active against Gram (-)
• Resistance through production of ß-lactamase
  enzyme
• Penicillins ß lactamase inhibitor
• Augmentin amoxicillin clavulanic acid

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Mechanisms of Action Cell Wall Synthesis

• Vancomycin
• Inhibits formation of glycan chains
• Does not cross lipid membrane of Gram (-)
• Important in treating infections caused by
  penicillin resistant Gram () organisms
• Given intravenously due to poor GI absorption
• Acquired resistance most often due to alterations
  in side chain of NAM molecule
• Prevents binding of vancomycin to NAM component
  of glycan

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Mechanisms of Action Cell Wall Synthesis

• Bacitracin
• Interferes with transport of PTG precursors
  across cytoplasmic membrane
• Toxicity limits use to topical applications
• Common ingredient in non-prescription first-aid
  ointments

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Mechanisms of Action Protein Synthesis

• Inhibition of protein synthesis
• Structure of prokaryotic ribosome acts as target
  for many antimicrobials of this class
• Drugs of this class include
• Aminoglycosides
• Tetracyclins
• Macrolids
• Chloramphenicol
• Lincosamides
• Oxazolidinones
• Streptogramins

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Mechanisms of Action Protein Synthesis

• Aminoglycosides
• Irreversibly binds to 30S ribosomal subunit
• Blocks initiation translation
• Causes misreading of mRNA
• Not effective against anaerobes, enterococci and
  streptococci
• Often used in synergistic combination with
  ß-lactam drugs
• Examples include
• Gentamicin, streptomycin and tobramycin
• Side effects with extended use include
• Nephrotoxicity
• Otto toxicity

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Mechanisms of Action Protein Synthesis

• Tetracyclins
• Reversibly bind 30S ribosomal subunit
• Blocks attachment of tRNA to ribosome
• Prevents continuation of protein synthesis
• Narrow range Effective against certain Gram ()
  and Gram (-)

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Mechanisms of Action Protein Synthesis

• Macrolids
• Reversibly binds to 50S ribosome
• Prevents continuation of protein synthesis
• Effective against variety of Gram () organisms
• Often drug of choice for patients allergic to
  penicillin
• Macrolids include
• Erythromycin, clarithromycin and azithromycin
• Resistance can occur via modification of RNA
  target

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Mechanisms of Action Protein Synthesis

• Chloramphenicol
• Binds to 50S ribosomal subunit
• Prevents peptide bond formation
• Wide spectrum
• Drug of last resort
• Rare but lethal side effect is aplastic anemia

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Mechanisms of Action Protein Synthesis

• Lincosamides clindamycin
• Binds to 50S ribosomal subunit
• Prevents continuation of protein synthesis
• Inhibits variety of Gram () and Gram (-)
  organisms
• Useful in treating infections from intestinal
  perforation
• Especially effective against Bacterioides
  fragilis and Clostridium difficile

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Mechanisms of Action Protein Synthesis

• New class effective against ß-lactams and
  vancomycin resistant Gram () forms
• Oxazolidinones
• Binds 50S ribosomal subunit
• Interferes with initiation
• Streptogramins
• Bonds to two different sites on 50S ribosomal
  subunit

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Mechanisms of Action DNA Replication

• Fluoroquinolones
• Inhibit action of topoisomerase DNA gyrase
• Topoisomerase maintains supercoiling of DNA
• Broad-Spectrum Effective against Gram () and
  Gram (-)
• Examples include
• Ciprofloxacin and ofloxacin
• Resistance due to alteration of DNA gyrase

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Mechanisms of Action RNA Synthesis

• Rifamycins
• Block prokaryotic RNA polymerase
• initiation of transcription
• Rifampin most widely used rifamycins
• Broad-spectrum Effective against many Gram ()
  and some Gram (-) as well as Mycobacterium
• Treatment of
• Tuberculosis
• Hansens disease
• N. meningitidis meningitis
• Resistance develops rapidly

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Mechanisms of Action Inhibition of Metabolic
Pathways

• Folate inhibitors
• Mode of actions to inhibit the production of
  folic acid
• Mimic PABA
• Antimicrobials in this class include
• Sulfonamides
• Trimethoprim
• Human cells lack specific enzyme in folic acid
  pathway
• Resistance due to plasmid

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Mechanisms of Action Cell Wall Integrity

• Polymixn B most common
• Common ingredient in first-aid skin ointments
• Binds membrane of Gram (-) cells
• Alters permeability
• Also binds eukaryotic cells
• Limits use to topical application

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Susceptibility of Bacteria to Antimicrobial Drug

• Susceptibility of organism to specific
  antimicrobials is unpredictable
• Often drug after drug tried until favorable
  response was observed
• Better approach
• Determine susceptibility
• Prescribe drug that acts against offending
  organism
• Best to choose one that affects as few others as
  possible

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Determining Susceptibility of Bacterial to
Antimicrobial Drug

• MIC Minimum Inhibitory Concentration
• Quantitative test to determine lowest
  concentration of specific antimicrobial drug
  needed to prevent growth of specific organism

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Determining Susceptibility of Bacterial to
Antimicrobial Drug

• Kirby-Bauer disc diffusion method
• qualitative determination of susceptibility
• Discs impregnated with specific concentration of
  antibiotic placed on plate and incubated
• Clear zone of inhibition around disc reflects
  susceptibility

• size of clearing zone indicates if susceptible or
  resistant

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Determining Susceptibility of Bacterial to
Antimicrobial Drug

• E-test
• Uses strips impregnated with gradient
  concentration of antibiotic
• Test organism will grow and form zone of
  inhibition
• Zone is tear-drop shaped
• Zone will intersect strip at inhibitory
  concentration

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Resistance to Antimicrobial Drugs

• Mechanisms of resistance
• Drug inactivating enzymes
• Penicillinase breaks ß-lactam ring of penicillin
  antibiotics
• Alteration of target molecule
• Minor structural changes in antibiotic target can
  prevent binding
• Changes in ribosomal RNA prevent macrolids from
  binding to ribosomal subunits

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Determining Susceptibility of Bacterial to
Antimicrobial Drug

• Mechanisms of resistance
• Decreased uptake of the drug
• Alterations in porin proteins decrease
  permeability of cells
• Increased elimination of the drug
• Some organisms produce efflux pumps
• Tetracycline resistance

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Resistance to Antimicrobial Drugs

• Acquisition of resistance
• Can be due to spontaneous mutation
• vertical evolution
• Or acquisition of new genes
• horizontal transfer
• Plasmid mediated

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Resistance to Antimicrobial Drugs

• Spontaneous mutation
• Example of spontaneous mutation
• Resistance to streptomycin is result a change in
  single base pair encoding protein to which
  antibiotic binds
• When antimicrobial has several different targets
  it is more difficult for organism to achieve
  resistance through spontaneous mutation

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Resistance to Antimicrobial Drugs

• Acquisition of new genes through gene transfer
• Most common mechanism of transfer is through
  conjugation
• Transfer of R plasmid
• Plasmid often carries several different
  resistance genes
• Organism acquires resistance to several different
  drugs simultaneously

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Resistance to Antimicrobial Drugs

• Examples of emerging antimicrobial resistance
• Enterococci
• Intrinsically resistant to many common
  antimicrobials
• Some strains resistant to vancomycin
• VRE Vancomycin resistant enterococcus
• Many strains achieve resistance via transfer of
  plasmid

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Resistance to Antimicrobial Drugs

• Staphylococcus aureus
• Common cause of nosocomial infections
• Becoming increasingly resistant
• Most strains acquired resistance to penicillin
• Until recently most infections could be treated
  with methicillin
• MRSA ? methicillin resistant Staphylococcus
  aureus
• many of these strains still susceptible to
  vancomycin
• VISA ?vancomycin intermediate Staphylococcus
  aureus

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Resistance to Antimicrobial Drugs

• Streptococcus pneumoniae
• Has remained sensitive to penicillin
• Some strains have now gained resistance
• Resistance due to modification in genes coding
  for penicillin-binding proteins
• Acquisition via DNA mediated transformation

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Resistance to Antimicrobial Drugs

• Slowing emergence and spread of resistance
• Responsibilities of physicians and healthcare
  workers
• Prescribe antibiotics for specific organisms
• Educate patients on proper use of antibiotics
• Responsibilities of patients
• Follow instructions carefully
• Complete prescribed course of treatment
• Misuse leads to resistance

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Resistance to Antimicrobial Drugs

• Slowing emergence and spread of resistance
• Importance of an educated public
• Greater effort made to educate public about
  appropriateness and limitations of antibiotics
• Antibiotics have no effect on viral infections
• Misuse selects antibiotic resistance in normal
  flora
• Global impacts of the use of antimicrobial drugs
• Organisms which develop resistance in one country
  can be transported globally
• Many antimicrobials are available as
  non-prescription basis
• Use of antimicrobial drugs added to animal feed
• Produce larger more economically productive
  animals
• Also selects for antimicrobial resistant organisms

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Mechanisms of Action of Antiviral Drugs

• Available antiviral drugs effective specific type
  of virus
• None eliminate latent virus
• Targets include
• Viral uncoating
• Nucleoside analogs
• Non-nucleoside polymerase inhibitors
• Non-nucleoside reverse transcriptase inhibitors
• Protease inhibitors
• Neuraminidase inhibitors

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Mechanisms of Action of Antiviral Drugs

• Viral uncoating
• Drugs include amantadine and rimantadine
• Mode of action is blocking uncoating of influenza
  virus after it enters cell
• Prevents severity and duration of disease
• Resistance develops frequently and may limit
  effectiveness of drug

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Mechanisms of Action of Antiviral Drugs

• Nucleoside analogs
• Incorporation of analog results in termination of
  growing nucleotide chain
• Examples of nucleoside analogs
• Zidovudine (AZT)
• Didanosine (ddI)
• Lamivudine (3TC)

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Mechanisms of Action of Antiviral Drugs

• Non-nucleoside polymerase inhibitor
• Inhibit activation of viral polymerases by
  binding to site other than nucleotide binding
  site
• Example foscarnet and acyclovir
• Non-nucleoside reverse transcriptase inhibitor
• Inhibits activity of reverse transcriptase by
  binding to site other than nucleotide binding
  site
• Example nevirapine, delavirdine, efavirenz
• Used in combination to treat HIV

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Mechanisms of Action of Antiviral Drugs

• Protease inhibitor
• Inhibit HIV encoded enzyme protease
• Enzyme essential for production of viral
  particles
• Examples indinavir and ritonavir
• Neuraminidase inhibitor
• Inhibit neuraminidase enzyme of influenza
• Enzyme essential for release of virus
• Examples zanamivir and oseltamivir

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Mechanisms of Action of Antifungal Drugs

• Target for most antifungal medications is plasma
  membrane
• Ergosterol
• Include
• Polyenes
• Azoles
• Allylamines
• Other targets
• Cell wall synthesis
• Cell division
• Nucleic acid synthesis

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Mechanisms of Action of Antifungal Drugs

• Cell wall synthesis
• Echinocandins
• interfere with synthesis of fungal cell wall
• Cell division
• Griseofulvin
• Exact mechanism unknown
• Appears to interfere with action of tubulin
• Selective toxicity may be due to increased uptake
  by fungal cells
• Used to treat skin and nail infections
• Nucleic acid synthesis
• Flucytosine
• Inhibits enzymes required for nucleic acid
  synthesis
• Flucytosine converted to 5-fluorouricil

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Mechanisms of Action of Antiprotozoans and
Antihelminthics

• Many antiparasitic drugs most likely interfere
  with biosynthetic pathways of protozoan parasites
  or neuromuscular function of worms
• Example of parasitic drugs includes
• Malarone
• Synergistic combination of atovaquone and
  proguanil HCl
• Interferes with mitochondrial electron transport
  and disruption of folate synthesis