Transcript 10 Antimicrobial Therapy

Antimicrobial Therapy
Chapter 10
History of Antimicrobials
•
•
•
•
1600s
Quinine for malaria
Emetine for amebiasis (Entamoeba histolytica)
1900-1910
Arsphenamines for syphilis
1935
Sulfonamides - broadly active
1940
Penicillin - substantially more active than sulfa drugs
Originally discovered in 1929 by Alexander Fleming (Scottish)
Nobel Prize, 1945
Knighted, 1944
Produced by fungus Penicillium chrysogenum
•
•
•
•
•
•
•
•
•
Mechanisms of Action of Anitmicrobial
Drugs
•
•
Selective toxicity
Antimicrobials must be toxic to the microbe, but not to the host
Unfortunately, no such antibiotic exists
Mechanisms of action
Cell wall synthesis inhibitors
Cell membrane inhibitors
Protein synthesis inhibitors
Nucleic acid synthesis inhibitors
Metabolic Pathways
•
•
•
•
•
•
•
Cell Wall Inhibitors
•
Cell wall
Outer layer of bacterial cell
Barrier to outside
Maintains osmotic pressure
Peptidoglycan (polymer)
Polysaccharide and cross-linked
peptides (transpeptidation)
N-acetylglucosamine (NAG)
N-acetylmuramic acid* (NAM)
*Only found in bacteria
Synthesis of peptidoglycan layer is
performed by several enzymes
Gram+ have substantially thicker
peptidoglycan layer
•
•
•
•
•
•
•
•
•
•
Cell Wall Inhibitors
•
Penicillin and Cephalosporin
Highly insoluble in natural form
Usually converted to a salt to increase solubility
Contains a β-lactam ring that interferes with cell wall
synthesis
Penicillin is first bound by cellular penicillin binding
receptors (PBP)
This binding interferes with transpeptidation reaction
This prevents peptidoglycan synthesis
•
•
•
•
•
•
Cell Wall Inhibitors
Semisynthetic
penicillins
Cell Membrane Function Inhibitors
•
•
•
•
The cell membrane is a biochemically-rich compartment
Polymyxins
Contain detergent-like (amphipathic) cyclic peptides
These damage membranes containing phosphatidylethanolamine
Novobiocin - inhibits teichoic acid synthesis
Ionophores - disrupt ion transport
Discharge membrane potential
Disrupts oxidative phosphorylation
•
•
•
•
Protein Synthesis Inhibitors
Protein Synthesis Inhibitors
• Most interfere with ribosomes
• By preventing ribosome function, polypeptide
synthesis is inhibited
• Compounds
•
•
Aminoglycosides (e.g., streptomycin)
Bind to 30S subunit
Interferes with initiation complex
mRNA localization to P site
fMet tRNA
Incorrect amino acid is incorporated into polypeptide
Tetracyclines
Bind to 30S subunit
Prevents IF3 binding
No tRNA binding
•
•
•
•
•
•
•
•
Protein Synthesis Inhibitors
• Others
•
•
•
•
•
•
•
•
Macrolides - initiation complex, translocation
Azalides - initiation complex, translocation
Ketolides - initiation complex, translocation
Lincomycins - initiation complex, translocation
Glycylcyclines - Tet analogs; bind with higher affinity
Chloramphenicol - Inhibits peptidyl transferase
Streptogramins - Irreversible binding to 50S subunit; unknown
mechanism
Oxazolidinones - Inhibit fMet tRNA binding to P site
Nucleic Acid Synthesis Inhibitors
•
•
•
•
Types
DNA/RNA polymerase inhibitors
Base analogs
Rifampin
Binds with high affinity to β subunit of DNA-dependent RNA
polymerase
Prevents RNA synthesis
Quinolones - inhibit bacterial DNA gyrase
Sulfonamides
Structural homologs of p-aminobenzoic acid (PABA)
PABA is required for folic acid synthesis by dihydropteroate
synthetase (DHPS)
Folic acid is a nucleotide precursor
Sulfa compounds compete with PABA for the active site of DHPS
•
•
•
•
•
•
•
•
Nucleic Acid Synthesis Inhibitors
DHPS
Resistance to Antimicrobial Drugs
•
Mechanisms of resistance
Enzymes that cleave or otherwise inactivate antibiotics
β-lactamases
Changes in bacterial permeabilities
Prevents entry of antibiotic into cell
Mutation in target molecule
Alter binding characteristics of the antibiotics
Alteration of metabolic pathways
Some resistant bacteria can acquire PABA from the
environment
Molecular pumps (efflux systems)
Secretion systems that export antibiotics faster than the rate of
import
•
•
•
•
•
•
•
•
•
•
Nongenetic Origins of Drug Resistance
•
•
•
Low replication rates
Antibiotic is metabolized or neutralized before it act
Mycobacteria spp.
Alteration of cellular physiology
Bacterial L forms are cell wall-free
Streptococcus spp., Treponema spp., Bacillius spp., others
Colonization of sites where antibiotics cannot reach
Gentamicin cannot enter cells
Salmonella are thus resistant to gentamicin
•
•
•
•
•
•
Genetic Origins of Drug Resistance
•
Chromosomal Resistance
Genes that regulate susceptibility
Often found in enzymes, rRNA and secretion system genes
Mutations in RNApol render it resistant to the effects of rifampin
Efflux pumps with specificity for antibiotics
Found in all bacteria
All possess large hydrophobic cavity for binding antibiotics
•
•
•
•
•
•
Five efflux pumps (“antiporters”) that
regulate antibiotic resistance (Paulsen,
2003)
Genetic Origins of Drug Resistance
•
Extrachromosomal Resistance
Often account for interspecies acquisition of resistance
Contribute to multi-drug resistance (MDR)
Genetic elements are:
Plasmids
Transposons
Conjugation
Transduction
Transformation
•
•
•
•
•
•
•
•
Drug Resistance
Antimicrobial Activity In Vivo
•
Drug-Pathogen Relationships
Environment
State of metabolic activity: slow-growing or dormant bacteria
less susceptible
Distribution of drug: CNS is often exclusionary
Location of organisms: Some drugs do not enter host cells
Interfering substances: pH, damaged tissues, etc.
Concentration
Absorption: some cannot be taken orally
Distribution: some accumulate in certain tissues
Variability of concentration: peaks and troughs
Postantibiotic effect: delayed regrowth of bacteria
•
•
•
•
•
•
•
•
•
•
Antimicrobial Activity In Vivo
• Host-Pathogen Relationships
• Alteration of tissue response
• Suppression of microbe can reduce
inflammatory responses
• Alteration of immune response
• Prevention of autoimmune antibodies (e.g.,
rheumatic fever)
• Alteration of microbial flora
• Expansion of harmful flora (e.g., C. difficile)
Clinical Use of Antibiotics
•
Selection of appropriate antibiotic
Accurate diagnosis is critical
Susceptibility testing should be
performed if:
Isolated microbe is often antibiotic
resistant
Infection would likely be fatal if
incorrect drug is selected
Need rapidly bactericidal activity (e.g.,
endocarditis)
Susceptibility testing is often performed
with antibiotic discs
A large zone of clearance suggest
sensitivity
•
•
•
•
•
•
•
•
necessary to kill or retard bacteria
• It is usually done as a tube test (i.e., liquid
phase)
• Serial dilutions of an antibiotic is made, then a
Minimal
Inhibitory
Concentration
The MIC determines the dose of antibiotic
•
defined number of bacteria are added to the
tubes
Tubes are read the following day (or days) for
the endpoint
Minimal Inhibitory Concentration
Dangers of Indiscriminate Use
• In some countries antibiotics are available OTC
• This has led to the emergence of antibiotic
resistance
• Often the wrong antibiotic is used
• The full regimen is not completed
• Hypersensitivities (e.g., penicillin anaphylaxis)
• Hepatotoxicity
• Changes in normal flora
Antimicrobial Chemoprophylaxis
• Exposure to specific pathogens (e.g., N.
meningitidis)
• Health-related susceptibilities
• Heart disease/valve replacement
• Respiratory disease (e.g., influenza, measles)
• Recurrent urinary tract infections
• Opportunistic infections
• Post surgery
• Disinfectants
• Medical devices (e.g., catheters)
Antifungal Drugs
Antiprotozoal and Antihelminth Drugs
Antiprotozoal and Antihelminth Drugs
Toxic Side Effects
•
•
•
•
•
•
•
Penicillins: Hypersensitivity
Cephalosporins: Hypersensitivity, nephritis, hemolytic anemia
Tetracyclines: Discoloring of teeth
Chloramphenicol: Disruption of RBC production
Erythromycins: Hepatitis
Vancomycin: Deafness, leukopenia, renal damage
Sulfonamides: Hemolytic anemia, bone marrow depression