(F) Chapter 11 - Principles of Antimicrobial Action and Resistance
(F) Chapter 11 - Principles of Antimicrobial Action and Resistance
(F) Chapter 11 - Principles of Antimicrobial Action and Resistance
Antibiotics maybe:
1. Obtained and purified from other microorganisms
2. Chemically synthesized
Antimicrobial agents
natural and synthesized substances
play a central role in the control and management
of infectious diseases
1. Antibacterial
2. Antifungal
3. Antiparasitic
4. Antiviral
ANTIMICROBIAL ACTION
Principles
1.
2.
3.
4.
categorized
Aminoglycosides
Tetracyclines
Glycylcyclines
o Binds to 50S
Macrolide-LincosamideStreptogramin
Oxazolidinone
Chloramphenicol
Inhibitors of DNA & RNA Synthesis
o Fluoroquinolone
o Ciprofloxacin
o Metronidazole
o Rifampin
Inhibitors of Folic Acid Synthesis
o Sulfonamides
o Trimethoprim
A.
1.
Beta-Lactams
Core - four-member, N containing, Beta-lactam
ring
Largest group of antibacterial agents
Lacks toxicity to humans
Beta-lactam ring
key to the mode of action of Betalactams
similar to acyl-D-alanyl-D-alanine
Beta-lactam binds enzyme, inhibiting
transpeptidation and cell wall synthesis
Penicillin-binding proteins (PBPs)
Types:
1. Penicillin
a. Penicillin
b. Ampicillin
c. Meziocillin
d. Piperacillin
2.
Cephalosporins
a. Cefazolin
b. Cefuroxime
c. Cefotetan
d. Cefotaxime
e. Ceftriaxone
f. Ceftazidime
g. Cefepime
3. Carbapenems
a. Meropenem
b. Imipenem
c. Doripenem
4. Monobactams
a. Aztreonam
Penicillin-binding Proteins (PBP)
Enzymes essential to produce and maintain their
peptidoglycan layer
B-lactam + PBP = cell wall synthesis is halted due to
osmotic instability
Spectrum of Activity type of bacteria against which a
particular antimicrobial agent does and does not have
activity.
Integron
large cassette region that contains antibiotic
resistance genes
Integrase
required for movement of integrin from one
genetic element to another\
Resistance Mechanisms
1. Genetic mutations in PBP coding sequence
2. Genetic Recombination
3. Overproduction of PBP
4. Acquiring new genetic coding sequence
Glycopeptides
Inhibit bacterial cell wall synthesis by binding to
end of peptidoglycan
Interferes with transpeptidation
Interferes with PBP enzymes that incorporate
precursors into growing cell wall
a.
b.
3.
Vancomycin
Levels should be monitored
Potential for toxicity
Teicoplanin
Approved
Not available in the US
Lipoglycopeptides
Semi-synthetic molecules
Glycopeptides that contain hydrophobic chemical
groups
Increase cell permeability
Cause depolarization of cell membrane potential
Inhibits transglycosylation
a. Oritavancin
b. Telavancin
Transglycosylation
-
B.
1.
Lipopeptides
a. Daptomycin
Recently developed
Bind and disrupts cell membrane of Gram +
bacteria
Has potent activity against Gram + cocci,
MRSA,VRSA
b. Bacitracin
Inhibits recycling of certain metabolites required
for maintaining peptidoglycan synthesis
Only used as tropical antibacterial agent
Internal consumption is avoided
2.
Polymyxins
Cyclic polypeptide agents that disrupt cell
membranes
Acts as detergents (interacts with phospholipids
and increased permeability)
Disruption results to leakage of macromolecules
and ions
Not equally effective agains all bacteria and more
effective against Gram - and poor activity to
Gram +
Pose a risk for toxicity for humans have
membranes
Last resort microbial agents
Spectrum of
Acinetobacter
C.
1.
Activity:
Gram
-,
P. aeruginosa,
Aminoglycosides
Inhibit protein synthesis
Irreversible binding to protein receptors on 30S
ribosomal unit
Major toxicity:
1. Nephrotixicity
2. Auditory/Vestibular Toxicity
Interrupts the following:
o Initial formation of protein synthesis
complex
o Reading of mRNA code
o Formation of rRNA complex
Gentamycin
Commonly used aminoglycoside
1. Tobramycin
2. Amikacin
3. Streptomycin
2.
Macrolide-Lincosdamide-Sreptogramin
Inhibits protein synthesis by binding to 23s rRNA
on bacteria 50S ribosomal subunit
Disrupts pepide chain (blocks translocation
reaction
Bacteriostatic
Can be bactericidal if organism is low and if used
in high concentrations
Quinupristin- dalfopristin
Dual streptogramin
Targets 2 sites of 50S ribosomal subunit
Toxicity is generally low
Lincosamides, Clindamycin, Lincomycin
Bind to 50S ribosomal subunit
Prevent elongation
Interfere with peptidyl transfer
Spectrogramins
Naturally occurring cyclic peptides
a. Quinupristin-daltopristin
Enter cell through massive diffusion
Bind irreversibly to 50s subunit that induces
conformational change in the ribosomal structure
Alteration of ribosome
Interferes with peptide bond formation that
disrupts elongation
Toxicity:
1. Low toxicity
2. Localized phlebitis major complication of IV
infusion
3.
Ketolides
Consist of:
1. Chemical derivatives of erithromycn A
2. Other macrolides
Bind to 23s rRNA of 50S ribosomal subunit
Inhibits protein synthesis
4.
Telithromycin
Maintain activity agains most macroled-resistant
gram +
Does not induce common macrolide resistance
mechanism
Effective against respiratory pathogens &
intracellular organisms
Low toxicity
Major side effects:
1. Gastrointestinal symptoms
5.
Oxazolidinones
Represented by linezolid
Linezolid
o Synthetic agent
o Inhibits protein synthesis by interactive
with 23s rRNA in 50S ribosomal subunit
o Interfere with binding of tRNA for
formylated-methionine
Low toxicity
Gastrointestinal symptoms
6.
Chloramphenicol
Inhibits addition of amino acid to growing peptide
chain
Reversibly bind to 50S ribosomal subunit
Inhibits transpeptidation
Highly active
Uses has dwindled because of drug toxicity and
development of new effective and safer drugs
Bone marrow toxicity
Major side effect: Aplasia
7.
Tetracyclines
Broad spectrum bacteriostatic
Inhibit protein synthesis by binding reversibly to
30S ribosomal subunit
-
Toxicity:
o Upper gastrointestinal effects
o Cutaneous phototoxicity
o Photoallergic immune reaction
Glycylglycines
Semi-synthetic tetracycline derivatives
Tigecycline
o 12st agent of glycylglycines approved
for clinical use
o Inhibits protein synthesis by binding
reversibly to 30S ribosomal subunit
o Has advantage of being refractory to
most common tetracycline resistance
o Most common effects are:
Nausea
Vomiting
Diarrhea
D.
1.
Fluoroquinolones
Simply quinolones
Derivatives of Nalidixic acid
o Ciprofloxacin
o Ofloxacin
Bind and interfere with DNA gyrase enzymes
regulating DNA supercoiling
Also inhibit topoisomerase IV
Topoisomerase IV
o Unlinks DNA after replication
Potent bactericidal agents
Toxicity:
o Tendinitis
o Rupture of Achilles tendon
2.
3.
Autotoxic compounds
Free radicals
Activation requirements
o Reduction under low redox potentials
(anaerobic)
Low toxicity
Side effects: Mild gastrointestinal symptoms
Spectrum of Activity: Effective against Anaerobic,
Microaerophilic
gram
and
Protozoans
(Trichomonas, Giardia, Entamoeba histolytica)
Rifamycin
Include Rifampin (Rifampicin)
Semisynthetic
Bind to the enzyme
o DNA dependent
o RNa polymerase
Inhibits RNA synthesis
Does not effectively penetrate oputer membrane
of gram (-)
Spontaneous mutation
Rifampin are usually used in combination with
other agents
Side effects:
o Gastrointestinal symptoms
o Hypersensitivity reactions
E.
1.
Sulfonamides
Disrupts folic acid pathway
Bind to dihydropteroate synthase
Moderate toxicity
Side effects:
o Vomiting
o Nausea
o Hypersensitivity reactions
Antagonistic for other medications
2.
Trimethoprim
Targets folic acid pathway
Inhibits dihydrofolate reductase
Usually
combined
with
sulfonamide
(sulfamethoxazole) to simultaneously attack 2
targets
Mild toxicity
Adverse side effects:
o Person with AIDS develop side effects
more often
3.
Nitrofurantoin
Consists of nitrogroup on heterocyclic ring
Mechanism is diverse and multifaceted
Used to treat uncomplicated UTI
Side effects:
o Gastrointestinal infections or symptoms
Diarrhea
Nausea
Vomiting
o Chronic pulmonary condition
o Irreversible pulmonary fibrosis
Aspects
1.
2.
3.
Biologic resistance
Changes that result in observed
susceptibility to a particular agent
Clinical resistance
Most laboratory
resistance
methods
S. pneumoniae
Inhibited by penicillin
B.
Environmentally
Mediated
Resistance
Antimicrobial Resistance
1. Drug
2. Microorganisms
3. Environment
used
to
Intrinsic Resistance
Results from the normal genetic, structural or
physiologic state of microorganism
Considered as natural inherited characteristic
Resistance pattern may be predictable
Intrinsic resistance profiles are also useful
markers to aid identification of certain bacteria
reduced
detect
Antimicrobial
Intrinsic Resistance
Anaerobic bact vs.
aminoglycosides
Enterococci vs.
aminoglycosides
Gram + vs. Aztreonam
Enterococci vs.
cephalosporin
Gram vs. Vancomycin
P. aeruginosa vs.
Sulfonamides
Klebsiella spp vs.
ampicillin
Stenotrophomonas
maltophilia vs. imipenem
Aerobic bact vs.
metronidazole
Lactobacilli and
Leuconostoc sp. vs.
vancomycin
Environmental factors
1. pH
2. anaerobic atmosphere
3. cation concentration
4. thymidine content
pH
Erythromycin & Aminoglycosides
o Low pH; Low effect of agent
Tetracycline
o High pH; Low effect of agent
C.
Presence of Metabolites
Enterococci
o Uses thymine and exogenous folic acid
to circumvent activities of sulfonamides
and trimethoprim
o Absence
of
metabolites,
full
susceptibility to antibiotics
Microorganism Mediated Resistance
Lack of PBP
Lack of uptake
Production of enzymes
Inability to anaerobically
reduce to active form
Lack of appropriate cell
wall precursor target
Acquired Resistance
Results from altered cellular physiology and
structure caused by changes in microorganism
genetic makeup
Trait associated with specific strains of particular
organism
Unpredictable
May be acquired by:
o Genetic mutation
o Acquisition of genes
o Combination of mutational and gene
transfer events
COMMON PATHWAYS FOR ANTIMICROBIAL
RESISTANCE
1.
2.
Mechanism
Lack
of
ocidative
metabolism
3.
4.
5.
6.
4.
5.
Quinolones
a. Decreased uptake
- Alterations in the outer membrane
b. Altered target
- Changes in DNA gyrase subunits
Macrolides
a. Efflux
- Pumps drugs out of cell
b. Altered target
- Enzymatic alteration