Antimicrobial Medications

1
Antimicrobial Medications

• Chapter 21

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Preview

• History of antimicrobials
• Wars between human and pathogens
• How antimicrobials kill--features and mechanism
  of antimicrobials
• Fighting back of pathogens-mechanism of
  resistance to antimicrobial drugs
• Human returns

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History and Development ofAntimicrobial Drugs

• Discovery of antimicrobial drugs
• Salvarsan
• Discovered by Paul Erlich for treatment of
  syphilis (1910)
• Basis for modern pharmaceutical research
• Prontosil dye
• effective against streptococcal infections by Dr.
  Domagk (1930s)
• No effect on Streptococcus growing in vitro
• Enzymes in blood split prontosil into small
  sulfonamide molecules
• Sulfonamide was the first sulfa drug
• Acts as a competitive inhibitor to
  para-aminobenzoic acid

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Discovery of Antibiotics
Antimicrobial drugs naturally produced by
microorganisms
Alexander Fleming - discovered penicillin 1929
staphylococcus
5
History and Development ofAntimicrobial Drugs

• Discovery of antibiotics
• Ernst Chain and Howard Florey successfully
  purified penicillin
• Successfully treated patients with infection
• Mass production of penicillin during WWII
• Treatment of wounded soldiers and war workers
• Selman Waksman isolated streptomycin from soil
  bacterium Streptomyces griseus

6
Features of Antimicrobial Drugs

• Most modern antibiotics come from organisms
  living in the soil
• bacterial species Streptomyces and Bacillus
• Fungus sepcies Penicillium and Cephalosporium
• To commercially produce antibiotics
• Antibiotic extensively purified from culture
  medium
• In some cases drugs are chemically altered to
  impart new characteristics
• Termed semi-synthetic

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History and Development ofAntimicrobial Drugs

• Development of new generation of drugs
• alteration of drug structure gave them new
  properties
• Penicillin G altered to created ampicillin
• Broadened spectrum of antimicrobial killing

8
Features of Antimicrobial Drugs

• Selective toxicity
• Antibiotics cause greater harm to microorganisms
  than to human host
• Generally by interfering with biological
  structures or biochemical processes common to
  bacteria but not to humans
• Toxicity of drug is expressed as therapeutic
  index
• Lowest dose toxic to patient divided by dose
  typically used for treatment

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Features of Antimicrobial Drugs

• Antimicrobial action
• Drugs may kill or inhibit bacterial growth
• Inhibit bacteriostatic
• Kill bacteriocidal
• Bacteriostatic drugs rely on host immunity to
  eliminate pathogen
• UTI drugs
• Bacteriocidal drugs are useful in situations when
  host defenses cannot be relies upon to 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
• Broad spectrum
• Work on broad range of organisms
• Gram-positive AND Gram-negative
• Disadvantage of broad spectrum is disruption of
  normal flora

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Features of Antimicrobial Drugs

• Tissue distribution, metabolism and excretion
• Drugs differ in how they are distributed,
  metabolized and excreted
• Important factor for consideration when
  prescribing
• Rate of elimination of drug from body expressed
  in half-life
• 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

• Effects of combinations of antimicrobial drugs
• enhances each others effect--- synergistic
• interferes with each others effect
  ---antagonistic
• neither synergistic nor antagonistic effect --
  additive

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Features of Antimicrobial Drugs

• Adverse effects
• Allergic reactions
• Allergies to penicillin
• Allergies often life threatening
• Toxic effects
• Aplastic anemia
• Body cannot make RBC or WBC
• Suppression of normal flora
• Antibiotic associated colitis
• Clostridium difficile given opportunity to
  establish themselves
• Antimicrobial resistance
• Microorganisms have innate or adaptive resistance
  to antibiotics

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Mechanism of Antimicrobial Drugs Action
target
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Inhibition of cell wall synthesis - ?-lactam drugs
Penicillin G
Target - peptidoglycan synthesis
Transpeptidases aka penicillin-binding proteins
(PBPs)

• High therapeutic index
• (note allergies)

• Not effective against most Gram-negatives
• Cell wall
• PBP

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Fig. 3.34
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Inhibition of cell wall synthesis - ?-lactam drugs
Penicillin G
Target - peptidoglycan synthesis
Transpeptidases aka penicillin-binding proteins
(PBPs)

• High therapeutic index
• (note allergies)

• Not effective against most Gram-negatives

• Acid-sensitive

• Destroyed by penicillinase (a ?-lactamase)

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Family of penicillins

• Natural penicillins

• Penicillinase-resistant penicillins

• Broad-spectrum penicillins

• Penicillins ?-lactamase inhibitor

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Mechanisms of Action of Antibacterial Drugs

• Vancomycin
• Inhibits formation of glycan chains
• Does not cross lipid membrane of Gram -
• Gram - organisms innately resistant
• Important in treating infections caused by
  penicillin resistant Gram organisms
• Must be given intravenously due to poor
  absorption from intestinal tract
• Acquired resistant 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 of Antibacterial Drugs

• Inhibition of protein synthesis
• Structure of prokaryotic ribosome acts as target
  for many antimicrobials of this class
• Differences in prokaryotic and eukaryotic
  ribosomes responsible for selective toxicity
• Drugs of this class include
• Aminoglycosides
• Tetracyclins
• Macrolids
• Chloramphenicol
• Lincosamides
• Oxazolidinones
• Streptogramins

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Antibiotics protein synthesis
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Mechanisms of Action of Antibacterial Drugs

• Tetracyclins
• Reversibly bind 30S ribosomal subunit
• Blocks attachment of tRNA to ribosome
• Effective against certain Gram and Gram -
• Newer tetracyclines such as doxycycline have
  longer half-life
• Allows for less frequent dosing
• Resistance due to decreased accumulation by
  bacterial cells
• Can cause discoloration of teeth if taken as
  young child

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Mechanisms of Action of Antibacterial Drugs

• Inhibition of nucleic acid synthesis
• These include
• Fluoroquinolones
• Rifamycins

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Mechanisms of Action of Antibacterial Drugs

• Rifamycins
• Block prokaryotic RNA polymerase
• Block initiation of transcription
• Rifampin most widely used rifamycins
• Effective against many Gram and some Gram - as
  well as members of genus Mycobacterium
• Primarily used to treat tuberculosis and Hansens
  disease as well as preventing meningitis after
  exposure to N. meningitidis
• Resistance due to mutation coding RNA polymerase
• Resistance develops rapidly

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Mechanisms of Action of Antibacterial Drugs

• Inhibition of metabolic pathways
• Relatively few
• Most useful are folate inhibitors
• Mode of actions to inhibit the production of
  folic acid
• Antimicrobials in this class include
• Sulfonamides
• Trimethoprim

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Enzymes
Enzyme inhibition
Competitive inhibition
- Inhibitor/substrate act at the same site
Ex. ? PABA ? ? folic acid ? coenzyme
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Antiviral Drugs

• Nucleic Acid synthesis
• Virally-encoded enzymes as target for antiviral
  drugs
• Reverse transcriptase, Error-prone (?
  mutations) ex. AZT - nucleotide analog.
• Herpes simplex virus (HSV) has an enzyme convert
  acyclovir to a nucleotide analog.
• Viral uncoating--block influenza A viruses.
• Assembly and Release of viral particles-
• protease inhibitors

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Determining Susceptibility of Bacteria to
Antimicrobial Drug

• Determining MIC
• MIC Minimum Inhibitory Concentration
• Quantitative test to determine lowest
  concentration of specific antimicrobial drug
  needed to prevent growth of specific organism
• Determined by examining strains ability to
  growth in broth containing different
  concentrations of test drug

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Determining the susceptibility of a bacterial
strain to an antimicrobial drug - Minimum
Inhibitory Concen. (MIC)
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Determining the susceptibility of a bacterial
strain to an antimicrobial drug - Minimum
Inhibitory Concen. (MIC)
Resistant vs intermediate vs susceptible
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Determining the susceptibility of a bacterial
strain to an antimicrobial drug - Disk diffusion
(Kirby-Bauer) test
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Determining the susceptibility of a bacterial
strain to an antimicrobial drug - Disk diffusion
(Kirby-Bauer) test
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Resistance to antimicrobial drugs
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Mechanisms of resistance
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Acquisition of resistance
Spontaneous mutation Gene transfer
Single-step
S ? R
Multi-step
S?S ?S ?S ?R
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Acquisition of Resistance

• Spontaneous mutation
• Occurs at low rate
• have profound effect of resistance of bacterial
  population
• Example of spontaneous mutation
• Resistance to streptomycin is result a change in
  single base pair encoding protein to which
  antibiotic binds
• Better drug development target multiple proteins.

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Acquisition of resistance
Gene transfer
Resistance plasmids (R plasmids)
Can encode resistance to multiple
medications Dont use antimicrobial medications
except when necessary!!!!!
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Examples of drug resistant bugs

• Staphylococcus aureus (Superbug)
• Common cause of nosocomial infections
• Becoming increasingly resistant
• most strains acquired resistance to penicillin in
  past 50yrs.
• Due to acquisition of penicillinase genes
• treated with methicillin (penicillinase resistant
  penicillin)
• MRSA ? methicillin resistant Staphylococcus
  aureus
• MRSA many of these strains still susceptible to
  vancomycin
• Some hospitals identified VISA
• VISA ?vancomycin intermediate Staphylococcus
  aureus

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Examples of drug resistant bugs

• Streptococcus pneumoniae
• Has remained sensitive to penicillin
• Some strains have now gained resistance
• Gain of gene coding for penicillin-binding
  proteins
• Generally via DNA mediated transformation

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Examples of drug resistant bugs

• Mycobacterium tuberculosis
• First-line drugs incur spontaneous mutations
  readily
• often develop resistant to one of the multiple
  drugs used to treat
• Reason for multiple drug therapy required
• multi-drug-resistant resistant to rifampin and
  isoniazid.

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Solutions

• Slowing emergence and spread of resistance
• Responsibilities of physicians and healthcare
  workers
• Increase efforts to 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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Solutions

• Slowing emergence and spread of resistance
• Importance of an educated public
• 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 develop resistance in one country can
  be transported globally
• Many antimicrobials are available as
  non-prescription basis
• Use of antimicrobials drugs added to animal feed
• Produce larger more economically productive
  animals
• Also selects for antimicrobial resistant organisms