Antimicrobial Medications
Chapter 21
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
History and Development of
Antimicrobial 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
(1930’s)
• 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
Discovery of Antibiotics
Antimicrobial drugs naturally produced
by microorganisms
Alexander Fleming discovered penicillin 1929
staphylococcus
Penicillium (mold)
History and Development of
Antimicrobial 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
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
History and Development of
Antimicrobial 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
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
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
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
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
Features of Antimicrobial Drugs
• Effects of combinations of antimicrobial
drugs
– enhances each other’s effect--- synergistic
– interferes with each other’s effect --antagonistic
– neither synergistic nor antagonistic effect -additive
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
Mechanism of Antimicrobial Drugs
Action
target
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
Fig. 3.34
Inhibition of cell wall synthesis - lactam drugs
Penicillin G
Target - peptidoglycan synthesis;
Transpeptidases
Side
chain
aka penicillin-binding proteins (PBPs)
•High therapeutic index
(note: allergies)
•Not effective against most Gram-negatives
•Acid-sensitive
•Destroyed by penicillinase (a -lactamase)
Family of penicillins
•Natural penicillins
•Penicillinaseresistant penicillins
•Broad-spectrum
penicillins
•Penicillins + lactamase inhibitor
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
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
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•
•
•
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Aminoglycosides
Tetracyclins
Macrolids
Chloramphenicol
Lincosamides
Oxazolidinones
Streptogramins
Antibiotics protein synthesis
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
Mechanisms of Action of
Antibacterial Drugs
• Inhibition of nucleic acid synthesis
– These include
• Fluoroquinolones
• Rifamycins
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 Hansen’s
disease as well as preventing meningitis after
exposure to N. meningitidis
– Resistance due to mutation coding RNA polymerase
• Resistance develops rapidly
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
Enzymes
Enzyme inhibition
Competitive inhibition - Inhibitor/substrate act at the same site
Ex.:  PABA   folic acid  coenzyme
Sulfa
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 particlesprotease inhibitors
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 strain’s ability to growth
in broth containing different concentrations of test
drug
Determining the susceptibility of a bacterial strain to an
antimicrobial drug - Minimum Inhibitory Concen. (MIC)
Determining the susceptibility of a bacterial strain to an
antimicrobial drug - Minimum Inhibitory Concen. (MIC)
Resistant vs intermediate vs susceptible
Determining the susceptibility of a bacterial strain to an
antimicrobial drug - Disk diffusion (Kirby-Bauer) test
Determining the susceptibility of a bacterial strain to an
antimicrobial drug - Disk diffusion (Kirby-Bauer) test
Resistance to antimicrobial drugs
Mechanisms of resistance
Acquisition of resistance
Spontaneous mutation
Single-step
S R
Multi-step
SS S S R
Gene transfer
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.
Acquisition of resistance
Gene transfer
Resistance plasmids
(R plasmids)
Can encode resistance to multiple medications
Don’t use antimicrobial medications except when necessary!!!!!
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
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
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.
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
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