47 - Antibiotics I Flashcards
What size are bacteria?
Bacteria are small
0.2-5 micrometers
Describe bacilli
Rods
Describe cocci
Round
diplococci = pairs streptococci = chains staphylococci = grapelike clusters
Describe spirochetes
Spiral shaped
Describe pleomorphic
Many-shaped bacteria
What does gram positive and negative mean?
Gram positive - positive staining pattern when performing a Gram stain
Gram negative - negative staining pattern when performing a Gram stain
How do we name bacteria?
By common characteristics
- Gram-positive cocci
By genus and species
- Escherichia coli
- Escherichia = determined by common genetic or morphological biochemical characteristics
- Coli = named by physical or pathogenic characteristics
What are the key structural features of bacteria that are of pharmacological interest?
- Cell wall
- Peptidoglycan
- Lipopolysaccharide (LPS)
- Cytoplasmic membrane
- Cytoplasm
Describe the cell wall
Cell wall: all bacteria have a cell wall that consists of peptidoglycan.
Describe the peptidoglycan
Peptidoglycan: a macromolecule composed of peptides and sugars that provide a rigid support structure that is found only in bacteria.
- Thick wall of peptidoglycan = gram (+)
- Thin wall of peptidoglycan = gram (-)
Describe lipopolysaccharide
Lipopolysaccharide (LPS): makes up the outer membrane structure of gram (-) bacteria cell wall and consists of phospholipid and polysaccharides.
Describe the cytoplasmic membrane
Cytoplasmic membrane: similar in structure to the eukaryotic cell membrane (except for sterols).
Describe the cytoplasm
Cytoplasm: contains the ribosomes, nutrients, metabolites, plasmids, nucleoid DNA
Quiz: This gram + coccus is a catalase-positive, coagulase-positive and cause disease ranging from pneumonia to pyogenic skin infections
Staphylococcus aureus
Don’t need to know
Quiz: This gram (-) rod is oxidase negative, common in UTIs
E coli
Don’t need to know
Quiz: Gram positive rod, spore forming, anaerobic, normal flora microbe, found in hospital, causes diarrhea
Clostridium difficile
Don’t need to know
Quiz: Gram negative involved in sexually transmitted diseases
Neisseria gonorrhoeae
Don’t need to know
What bacteria cell factors influence antibiotic action in GRAM NEGATIVE bacteria?
- LPS (lipopoly-saccharide) - Lipid bilayer of cytoplasmic membrane - Hydrophilic pores - Nutrient receptor proteins on outer membrane
Describe how the LPS (lipopolysaccharide) of gram negative bacteria affects antibiotics
Retards or prevents penetration of bulky, high molecular weight antibiotics, such as erythromycin.
Describe how the lipid bilayer of the cytoplasmic membrane of gram negative bacteria affects antibiotics
Penetration of water-soluble drugs is severely hindered.
Describe how the hydrophilic pores of gram negative bacteria effect antibiotics
Allow penetration of water-soluble molecules up to 650 Daltons (size***), such as sulfonamides.
Describe how the nutrient receptor proteins on the outer membrane of gram negative bacteria affects antibiotics
Agents structurally related to nutrients (sideromycins) utilize these natural receptors.
What bacteria cell factors influence antibiotic action in GRAM POSITIVE bacteria?
- Teichoic & teichuronic acid
- Lipid bilayer of cytoplasmic membrane
- Nutrient transport proteins of cytoplasmic membrane
Describe how the teichoic & teichuronic acid of gram positive bacteria effect antibiotics
Strong anionic character of these polymers may affect rate of penetration.
Describe how the lipid bilayer of the cytoplasmic membrane of gram positive bacteria effect antibiotics
Rate of penetration depends on lipophillicity (water-soluble drugs are hindered).
Describe the nutrient transport proteins of the cytoplasmic membrane of gram positive bacteria effect antibiotics
Facilitate rapid penetration of agents similar in structure (D-cycloserine, phosphomycin, tetracycline).
What is chemotherapy?
Chemotherapy : treatment of a disease with the use chemicals to kill or impair the growth of microorganisms or cancerous cells.
What is the basis of antimicrobial chemotherapy?
Grounded in the principles of the germ theory of disease (microorganisms cause certain diseases) based on the discoveries of Louis Pasteur and Robert Koch.
What are antimicrobial chemotherapy agents aimed at doing?
Agents aimed at eradicating microorganisms (bacteria, fungi, viruses, parasites) that are causing disease in the body.
How are antimicrobial chemotherapy agents classified?
Agents are classified or grouped based on the spectrum of microorganisms killed by the agent, the biochemical pathway targeted by the agent, and the chemical structure of the agent.
What is selective toxicity?
Selective toxicity : aimed at killing or impairing growth of the specific target organism without harming the host.
What are drug targets of antimicrobial chemotherapy?
Drug targets: aim to achieve selective toxicity by using drugs targeted to structures unique to the microorganism.
What are the common strategies for killing or inhibiting microorganism growth?
1 - Disrupt coding/genetic machinery (target folate synthesis needed to make DNA, disrupting mRNA synthesis),
2 - Blocking protein synthesis
3 - Disrupting cell wall or membrane synthesis.
What do MOST drugs target?
MORE drugs target the wall, LESS drugs target the membrane
What does a bactericidal agent do?
Bactericidal: an agent that will kill the bacteria. Once the organism is exposed to the drug, it is no longer viable
What does a bacteriostatic agent do?
Bacteriostatic: an agent that will inhibit growth of the bacteria but will not kill the bacteria
- Therapeutic success is dependent upon the host defense mechanisms to clear the infection.
- If the drug is removed, the bacteria will once again begin to grow.
What is the minimum inhibitory concentration (MIC)?
Will not be tested on this, but should be familiar with it
MIC - the lowest concentration of an antimicrobial agent that will inhibit the visible growth of bacteria in liquid culture (turbidity)
What is the minimum bactericidal concentration (MBC)?
Will not be tested on this, but should be familiar with it
- Once the lab has MIC results, it is a simple matter to obtain the MBC.
- Minimum Bactericidal Concentration (MBC) starts with the liquid culture wells, using each one to plate a subculture on agar.
- MBC is the concentration of antibiotic from the original MIC plate that shows NO GROWTH after subculture.
What is the Kirby-Bauer Disc method?
Will not be tested on this, but should be familiar with it
- The “Classic” Disc Method – antibacterial agents in single concentration discs are added to agar plates streaked for a lawn of bacterial growth. Growth is inhibited in a zone where the drug has diffused into the surrounding agar.
Zone diameter is read from an interpretation chart to determine dose. - An agar-based version of the MIC test. This uses a stable gradient of antibiotic concentrations present on a dry plastic strip. The zone of inhibition widens as concentration increases.
What is a narrow spectrum antibiotic?
- a drug that has an effect on one type or species of organisms.
- If a particular pathogen is known to be the causative agent for a given disease/infection, using a narrow spectrum antibiotic is a logical therapeutic choice.
What is a narrow spectrum antibiotic?
- a drug that has an effect on a wide variety of organisms.
- If the causative infectious agent is not known, an approach may be to treat with a board spectrum antibiotic.
What is prophylactic therapy?
Prophylactic therapy: treatment in the absence of infection in order to prevent disease.
What is pre-empitive therapy?
Pre-emptive therapy: treatment of high-risk patients that have become infected but are asymptomatic.
What is empirical therapy?
Empirical therapy: treatment of a symptomatic patient without further testing or confirmation of the organism.
What is definitive therapy?
Definitive therapy: treatment once the pathogenic organism has been identified and appropriate drug identified.
What is suppressive therapy?
Suppressive therapy: generally a low dose therapy used as a secondary prophylaxis. Problem that caused initial infection is likely still present.
What is resistance?
Resistance: An organism is said to develop resistance to a chemotherapeutic agent when the agent is no longer or less effective toward an organism. Resistance will develop as a result of organismal changes (evolution) and/or clinical practices.
Why does resistance develop?
Resistance develops due to…
- reduced drug entry in to the organism
- increased drug export from the organism
- expression of enzymes by the organism that destroy the drug
- changes in expression enzymes that activate the drug (pro-drug)
- impaired drug binding to the original target
- development of new or different pathways that are not inhibited by the drug
Describe the basics of resistance
** Bacteria will develop resistance through the acquisition of new genetic material or a mutation in the existing genome that is selected under clinical/antibiotic pressure**
What are the five antibiotics that exhibit drug resistance?
NEED TO KNOW
E - Enterococcus faecium S - Staphylococcus aureus K - Klebsiella pneumoniae A - Acinetobacter baumanni P - Pseudomonas aeruginosa E - Enterobacter species
Think “ESCAPE” = “ESKAPE”
How do bacteria become resistant to daptomycin?
Reduced drug entry into the organism
- Specific gene mutation (mprF) that results in a change in membrane charge
- There is an overall increase in the net positive charge which will repel the antibiotics with cationic properties
- Example: Increased positive charge due to
the addition of L-lysine to
phosphatidylglycerol of the membrane
How do bacteria become resistant to tetracycline?
Increased drug export from the organism
- Expression of an efflux pump.
- Common resistant organisms include Neisseria gonorrhoeae, Escherichia coli, Streptococcus pneumoniae, and Pseudomonas aeruginosa.
- Efflux pump is expressed on the cytoplasmic membrane and actively pumps drug out of the cell.
How do bacteria become resistant to metronidazole?
Changes in the expression of enzymes that activate the pro-drug
- Metronidazole needs to be reduced to generate reactive oxidative species
- Mutation in rdxA gene (oxygen-insensitive nitroreductase) alters or decreases activation of the drug
- The chemical reduction of metronidazole “activates” the drug. Mutation in reducing enzymes will result in impaired drug activation.
How do bacteria become resistant to streptomycin?
Expression of enzymes by the organism that destroys the drug
- Aminoglycoside-modifying enzymes chemically modify the antibiotic and alter binding of the drug to its target
- Phosphorylation, adenylation, and acetylation of streptomycin can alter target (bacterial ribosome) binding
How do bacteria become resistant to amoxicillin?
Expression of enzymes by the organism that destroys the drug
- Expression of the enzyme b-lactamase which can hydrolyze the lactam ring of amoxicillin (as well as other penicillins and cephalosporins) and render the compound ineffective
How do bacteria become resistant to trimethoprim and sulfonamides?
Impaired drug binding to the original target
- Expression of the drug-insensitive enzymes dihydropteroate synthase and dihydrofolate reductase.
How do bacteria become resistant to vancomycin?
Development of new or different pathways that are not inhibited by the drug
- Substitution on the peptidoglycan stem so that agent can no longer bind to target.
- In the absence of vancomycin binding to target, vancomycin can no longer inhibit polymerization of the peptidoglycan.
