Antimicrobial Medications

Kathy Huschle
Northland Community and Technical College
History
Paul Ehrlich 1910
Upon making the observation that some dyes stained
bacterial cells, but not animal cells, Ehrlich determined
that there was a fundamental difference between the 2
types of cells. He began the search for the magic bullet-
a drug that would kill a microbial pathogen without
harming the human host.

History
After 605 tests to find a cure for syphilis, Ehrlich was
successful in 1910. He proved that arsphenamine, a
compound of arsenic, was effective in treating lab
animals. The ability of the new drug, named
Salvarson, to cure syphilis, proved that chemicals
could be used to selectively kill microorganisms without
harming the human host permanently.
Paul Ehrlich
History
Gerhard Domagk 1932
accidentally discovered the first sulfa drug,
sulfanilamide, while testing a red dye called Prontosil
on streptococci
Gerhard
Domagk
History
Fleming 1928
noticed that colonies of Staphylococcus were
inhibited by mold
Fleming identified the mold as a species of
Penicillium
with further testing, it was shown that Penicillium
was a bacteria-killing substance

Alexander
Fleming

History
Ernst Chain & Howard Florey
successfully purified penicillin
1941 - 1st test on an ill human
the patient improved dramatically,
but died when the penicillin ran out
mass development of penicillin was
spurred on by WW2
first antibiotic developed for the
general public

Sir Howard Florey
Dr. Ernst Chain
Terms
chemotherapeutic agent
any drug used for any medical condition
antimicrobial drug
a chemical that destroys pathogens, includes
antibiotics and chemically synthesized drugs
antibiotic
an antimicrobial agent produced naturally by a
bacterium or fungus
bactericidal
capable of killing a microorganism
bacteriostatic
inhibits the growth of microorganisms



Features of Antimicrobial Drugs
the pharmacological properties of a potential
antimicrobial agent needs to be considered to
determine if the agent is the best for the particular
infection
properties that are considered include
selective toxicity
spectrum of activity
distribution, metabolism, excretion
interaction between drugs
adverse effect
resistance
Selective Toxicity
antimicrobials
cause greater harm to microorganism than to human
host
are able to attack biological structures or functions
unique to the microorganism
non-toxic to humans is ideal, but realistically all
antimicrobial drugs can be harmful in high
concentrations

Selective Toxicity
measurement of the toxicity of a drug is called the
therapeutic index
the therapeutic index of a medication is a
comparison of the amount that causes the therapeutic
effect to the amount that causes toxic effects
a high therapeutic index is LESS toxic to the patient
Penicillin G: high index
a low therapeutic index requires monitoring of the
patient to be certain that it does not reach a toxic level
if a drug is too toxic for the systemic (internal) system,
it may be used as a topical application
Spectrum of Activity
refers to the range of microorganisms that a
antimicrobial agent can kill or inhibit
broad spectrum
affect a wide range
can disrupt the normal flora of the body
used particularly in the cases of rapid onset life-
threatening infections, when there is no time to
culture the causative agent
narrow spectrum
limited range
requires the identification of the pathogen
Distribution, Metabolism, Excretion
antimicrobials have to get where they are needed
a drug that is destroyed by acid cannot be taken
orally
the rate of elimination is expressed as the half-life
of the drug
the half-life is the time it takes the body to
eliminate 1/2 of original dose
knowing the half-life of a drug will determine
how frequently the doses have to be
administered
this is why some medications are prescribed
every four hours, others 2X per day

Interaction Between Drugs
combined drug therapy
sometimes necessary to use two antimicrobial
agents for successful treatment of an infection
it is possible that one antimicrobial agent could
influence the action of the other
synergism
action of one antimicrobial agent enhancing the
others activity
antagonistic action
action of one interferes with the other
additive
neither synergistic or antagonistic


Adverse Effects
most all antimicrobial agents have concerns and dangers
allergic reactions
toxic effects to the body such as kidney damage
suppression of normal flora
normal flora is an important key to our immune
system
if it is altered too greatly, it can create an
imbalance of those friendly microorganisms

Resistance
resistance to antimicrobial agents is of mounting concern
in the medical field
innate or intrinsic resistance can be found in
antimicrobial agents naturally
this natural resistance, leads to survival of the fittest,
or survival of those antimicrobial agents that are
resistant
this resistance is then inherited by the offspring
Resistance
Resistance
3 major mechanisms that lead to antimicrobial agents
resistance
inactivation of the antimicrobial agent by an enzyme
prevention of the antimicrobial agent from reaching its
target cell structure
alteration of the target cell structure so that it is no
longer affected by the antimicrobial agent
Mechanisms of Action of
Antimicrobials
different cell structures or microbial processes are
the targets of antimicrobial agents
structures that are different or absent from
eukaryotic cells
cell wall synthesis
protein synthesis
nucleic acid synthesis
metabolic pathways
plasma membrane integrity
Cell Wall Inhibitors
target peptidoglycan
peptidoglycan only occurs in bacteria, which makes it
an excellent target
penicillin, cephalosporin, vancomycin, bacitracin
(topical)

Protein Synthesis Inhibitors
all living organisms depend on protein synthesis
inhibitors act at different stages of protein
synthesis
there is enough difference in the ribosomal
structure (where proteins are synthesized)
between prokaryotic and eukaryotic cells
aminoglycosides
streptomycin, gentamicin, neomycin
Protein Synthesis Inhibitors
chloramphenicol
last resort because of its rare, but life-
threatening side effects
the inability to form red or white blood cells

Proteins being tested with chloramphicol
DNA Replication Inhibitors
target is the enzymes necessary for DNA replication
block bacterial DNA replication
fluoroquinolones
one of the enzymes inhibited is gyrase, which
prevents the unwinding of the DNA double helix
ciprofloxacin
rifamycins
blocks the initiation of transcription
rifampin


Metabolic Pathway Inhibitors
very few of these agents are available
sulfonamides (sulfa drugs)
Trimethoprim
the above 2 drugs inhibit the metabolism of folic acid at
different steps in the process
animal cells lack these enzymes
makes folic acid a dietary requirement

Membrane Transport Inhibitors
damage to the plasma membrane leads to leakage of
the cell contents and ultimately death of the cell
polymyxins
cause changes in structure of membrane
can bind to eukaryotic cells
limits the use of polymyxins to topical use

Antimicrobial Susceptibility Testing
determines effectiveness of an antimicrobial agent to a
specific microorganism
Minimum Inhibitory Concentration (MIC)
determines the lowest concentration of an
antimicrobial agent needed to prevent growth of
the microorganism in the lab
Tests for finding Minimum inhibitory concentration
Antimicrobial Susceptibility Testing
Kirby-Bauer
qualitative determination of effectiveness
automated liquid diffusion
commercial modification that speeds up the
process of determining the effectiveness of a drug
able to know in 4 hours


Kirby-Bauer
Resistance to Antimicrobial Drugs
overuse and misuse of antimicrobial drugs
resistance is generally a result of
inactivation by microbial enzyme
prevention of reaching target
alteration of target
Mechanisms of Resistance
some resistance is innate, some is acquired
most common methods of acquiring drug resistance
include
1. drug-inactivating enzymes (produced by the
organism)
the organism chemically modifies an
antimicrobial drug to render it ineffective
Mechanisms of Resistance
2, alteration in target molecule
structural changes from mutation of the organism
prevents the drug from recognizing and binding to
the target
3. decreased uptake of drug
alterations in porin proteins found in the plasma
membrane can alter permeability of the membrane
may prevent some drugs from crossing the
barrier and entering the cell

Multi-resistant S. aureus
Mechanisms of Resistance
4. increased elimination
efflux pumps are the mechanisms that
bacterial cells use to eliminate harmful
compounds from the cell
an alteration that increases the
expression of the efflux pumps , can
increase the ability of a cell to eliminate
an antimicrobial drug
Emerging Antimicrobial Resistance
some examples of increasing
resistance include
vancomyvin- resistant
enterococci
vancomycin is a last resort
drug for enterococci
infections
the resistance to
vancomycin is coded in the
plasmid, so the potential for
spreading to other
organisms is possible
methicillin-resistant
Staphylococcus arueus
(MRSA)
concern in hospitals

Slowing Antimicrobial Resistance
can be minimized by
discriminating use of drugs in appropriate
concentrations and dosages
compliance of patients to follow the instructions
completely
Antiviral Drugs

not much progress in the development of antiviral
drugs
targets for selective toxicity are difficult to find
viruses are only nucleic acid and protein
lack the structures that are successful targets
for bacteria cells such as cell wall, plasma
membrane
role of mammalian host cell gets in the way
virus is only active while inside a host cell

Antiviral Drugs
no broad spectrum drugs are available
best treatment for viral diseases is vaccination
recovery from a viral infection is almost totally
dependent on your immune system


Antiviral Drugs
several antiviral drugs that are being used include
amantadine and rimantadine
block uncoating of the protein coat from the nucleic
acid
acyclovir
antiherpes drug
nucleioside analog
terminates growing nucleotide chain

Antiviral Drugs
azidothymidine (AZT)
AIDS treatment
blocks ability of reverse transcriptase to synthesize
DNA from the RNA template
mutational resistance is rapidly developed
Antifungal Drugs
pathogens such as fungi, more closely resemble their
eukaryotic cousin, the human cell
very few drugs have been developed that can be
used systemically (orally) for fungal infections
polyene antibiotics
alter permeability of plasma membrane of the
fungus
most antifungal drugs are administered topically,
because of their low therapeutic index
Antiprotozoan Agents
protozoa and helminths have complex life cycles
often interact with mammalian cells
antiprotozoan agents attack at certain stages of their
life cycle