Transcript Document 7118352

Antimicrobial
Agents
Use when balance tips in
favor of invading MO
Antimicrobial Therapy
 When balance between MO and host
tilts in direction of MO, body’s
normal defense cannot prevent or
overcome disease
 Turn to Chemotherapy - treatment of
disease with chemical drugs into body
Chemotherapeutic
Agents
 Antimicrobial - to treat infectious
disease, act within host
 Antibiotic - produced naturally by MO
(bacteria, fungi)
 Synthetic drug – synthesized, made in
laboratory
Successful Antimicrobial
 Selective toxicity - harm MO not host
(all drugs have some side-effects)
 No hypersensitivity reaction – does not
elicit harmful host immune reaction
 Penetrate - gets to site of tissue
infection rapidly, retain for adequate
time
 No resistance - MO not readily able to
counteract it
Activity of Antimicrobial
 Easier to find against prokaryote as
different from eukaryotic cell
 Fungi, protozoan, helminth are
eukaryotes; make finding drug with
selective toxicity more difficult
 Especially difficult to find drug
against virus, require host cell to
replicate
Spectrum of Antibiotics
 Narrow spectrum - affects relatively few
kinds of bacteria
 Broad spectrum - effective against large
number Gram(+) & Gram(-) bacteria
 Problem of broad spectrum antibiotic use
is NF destroyed, allow certain NF to
flourish and cause opportunistic infection
 Superinfection - overgrowth of NF due to
antibiotic treatment for an initial
infection
Action of Antimicrobial
 Bacteriocidal - kill bacteria
 Bacteriostatic - prevent growth of
bacteria; host’s defense of phagocytosis
and antibody eliminate bacteria
 Different areas in bacteria serve as
target for action of antimicrobial:
 Cell wall
 Ribosome
 Plasma membrane
 DNA, RNA
 Metabolite
Bacterial Cell Wall Cross Linking
 Interference with synthesis of bacterial cell
wall should not harm host
 Bacterial cell wall contain peptidoglycan not
found in eukaryotic cell
 Many antibiotics prevent synthesis of
peptidoglycan by interfering with linkage by
peptide cross-bridge
Inhibition of Bacteria Cell
Wall Biosynthesis: Lactam Ring
 These antibiotics contain beta lactam
ring that bind to group of bacterial
enzymes called penicillin binding
proteins (PBP)
 PBP involved in peptidoglycan cell wall
synthesis
 Binding of PBP prevents peptide cross
linking, cell wall weakened, bacteria
undergoes lysis
Beta Lactam Ring Antibiotics
 Affect cell wall synthesis, only
effective on actively growing MO
 These antibiotics include:
 Penicillin and derivatives (ampicillin,
methacillin, oxacillin, amoxacillin, augmentin)
 Cephalosporin (cephalothin, cefuroxime,
ceftazidime, cefoxitin)
 Carbapenem (imipenem)
 Monobactam (aztrenam)
Inhibition of Bacterial Cell
Wall Biosynthesis: Others
 Bacitracin - interferes with synthesis of
peptidoglycan by inhibiting recycling of
metabolites
 Vancomycin - binds to precursors used in
cell wall synthesis; interfere with
enzymes that incorporate these
precursors into growing cell wall
Inhibition of mRNA
Translation
 Protein synthesis common feature of all
cells
 Ribosome structure of eukaryote and
prokaryote cell differ (80S vs 70S)
 Many antimicrobials specifically
interfere with mRNA protein synthesis
on prokaryotic 70S ribosomes
 Some antimicrobials act on 50S subunit
of the ribosome, while others act on
30S subunit of ribosome
Inhibition of Bacteria Translation
 Chloramphenicol - acts
at 50S, inhibit
formation of peptide
bond
 Erythromycin - acts at
50S, prevent
translocation
movement of ribosome
 Tetracycline - acts at
30S, interfere with
tRNA attachment
 Aminoglycosides
(gentamycin,
streptomycin) - act at
30S, cause misreading
of mRNA
Injury to Bacteria Plasma
Membrane
 Polypeptide antimicrobials




Polymyxin B
Colistin
Affect permeability of cells
Result in leakage of macromolecules and
ions essential for cell survival
Inhibition of Bacteria
DNA/RNA Synthesis
 Ciprofloxacin (fluoroquinolone) - bind
and interfere with DNA gyrase involved
in DNA supercoiling
 Metronidazole - breaks DNA strand
 Rifampin - binds to DNA dependentRNA polymerase to inhibit mRNA
synthesis
Inhibition Bacteria Folate Synthesis
 Antimetabolite closely resemble
normal substrate
(analogue), competes
for enzyme
 Both sulfonamide and
trimethoprim
interfere with folic
acid pathway
 Often in single pill
used in combination
drug therapy:
TrimethoprimSulfamethoxazole
(TMP-SMX, Bactrim)
 Broad spectrum
antimicrobial
Inhibition of Bacteria
Enzymatic Activity
 Nitrofurantoin - targets synthesis of
several bacterial enzymes and proteins;
may also directly damage DNA
 Isoniazid - structural analogue of
vitamin B6; inhibits synthesis of mycolic
acid of Mycobacteria cell wall
 Ethambutol - inhibits incorporation of
mycolic acid into Mycobacteria cell wall
Summary: Bacteria Antimicrobial
Antifungal Drugs
 Nystatin and amphotericin B combine with sterols
to disrupt fungal plasma membrane
 Effective because animal sterols are mostly
cholesterol while fungal membranes contain mainly
ergosterol against which the drugs target
 Ketoconazole (imadazole) - interfere with sterol
synthesis
 Griseofulvin - binds to keratin on skin, hair, and
nails; interferes with mitosis and fungal
reproduction
Antiviral Drugs: Nucleoside
Analogue
 In viral nucleic
acid, analogue
insert in place of
normal nucleoside
 Nucleic acid
synthesis stops
 Nucleoside
analogue binds
more strongly
with viral enzyme
than host cell
enzyme
 Example:
acyclovir for
herpes virus; also
several
nucleoside
analogues for
HIV infection
Other Antiviral Drugs
 Interferon – protein made by host cell for
first line of antiviral defense; cloned by
recombinant DNA technology, treatment for
severe and chronic virus infections
 Tamiflu, Relenza – interfere with release of
influenza virus from host cell
 Protease inhibitors – interfere with proteolytic
cleavage of HIV polyproteins into individual
proteins, stops replication process
 Anti-sense or siRNA (small, interfering RNA) –
experimental antiviral drugs, inhibits mRNA
translation
Antimicrobial Susceptibility Testing
 Important as different MO species and
strains have different degree of
susceptibility to different antimicrobials
 Susceptibility of MO to antimicrobial may
change with time, even during course of
antimicrobial therapy
Drug Sensitivity Test:
Diffusion Test
• Kirby-Bauer Test –
standardized lab test with
antibiotic impregnated disk,
diffuses out in a concentration
gradient, measure zone of
inhibited bacterial growth
• E Test – utilizes plastic coated
strip containing gradient of
antibiotic that diffuses out,
allows estimate Minimal
Inhibitory concentration (MIC)
that prevents visible bacterial
growth
Drug Sensitivity Test:
Test Tube Dilution
• Broth Dilution Test – measures more
accurately serial antibiotic dilutions in
broth test tube for MIC, followed by
plating for Minimal Bacteriocidal
Concentration (MBC)
Antibiotic Resistance
 Presently a common occurrence
 Bacterial drug resistance requires
interruption or disturbance of the steps
for antimicrobial action
Antibiotic Resistance
 Intrinsic resistance - normal genetic,
structural, or physiologic state of MO;
considered natural and inherited
characteristic associated with majority of
strains of bacterial group
 Acquired resistance - altered cellular
physiology and structure caused by
changes in a MO genetic makeup; may be a
trait associated with only some strains of
bacterial group
Acquired Antibiotic
Resistance
 Acquisition of genes from other MOs via
gene transfer mechanisms (i.e.,
resistance plasmids)
 A combination of mutational and gene
transfer events
Pathways of Antibiotic
Resistance
Enzymatic Degradation:
Penicillinase
 Resistance to penicillin and other
beta-lactam antibiotics
 Production of an enzyme that breaks
beta-lactam ring
Gram(+) MO Resistance to Betalactam Antibiotics
 Enzymatic
degradation – MO
produces betalactamase, cleaves
ring structure of
antibiotic
 Altered
antimicrobial target
– MO mutation of
penicllin binding
proteins (PBP) so
antibiotic no longer
binds to it
Gram(-) Resistance to Beta-lactam
Antibiotics
 Decrease uptake - of antibiotic
 Enzymatic degradation – of antibiotic
 Altered antimicrobial target - PBP
Dissemination of
Antimicrobial Resistance
Prevention of Bacterial
Antimicrobial Resistance
 Use antimicrobial drugs only when
necessary
 Finish prescribed course of antimicrobial
 Use drugs in combination; microbe less
likely to develop resistance to two drugs
at the same time:
 Consider synergistic effects
 Consider antagonistic effects