Antibiotics Flashcards
Where are antibiotics founds?
What do they do?
What do we do to modify them?
• Natural products of fungi and bacteria - soil dwellers
• Natural antagonism and selective advantage (have to survive against each other)
• Kill or inhibit the growth of other microorganisms
• Most derived from natural products by fermentation, then modified chemically
pharmacological properties
antimicrobial effect
• Some totally synthetic e.g. sulphonamides
• They can also become resistant
• They have to survive and compete with each other and so they have natural antagonism leading to advantages in the soil
What is MIC?
MIC = minimum inhibitory concentration, minimum dose for a drug to be effective biologically. needs to be achieved to make sure the drug is effective. You need to reach and maintain the MIC
We need to keep a balance between toxic effect and therapeutic effect
What does competition of flora do?
Limits growth of competitors and pathogens.
What happens if we lose flora?
What does antibiotics and immunity lead to?
Loss of flora leads to bacterial or pathogen overgrowth.
Antibiotic associated colitis- pseudomembranous colitis. Clostridium difficile (3% of normal flora). Leads to ulcerations, inflammation, severe diarrhoea and serious hospital cross-infection risks.
Antibiotic + immunity = bacterial clearance.
How can antibiotics be classified?
Type of activity.
Structure.
Target site for activity.
Compare and contrast Bactericidal vs bacteriostatic
Bactericidal
Requires a certain dose
Kill bacteria
Used when the host defense mechanisms are impaired
Required in endocarditis, kidney infection
Bacteriostatic Tetracyclin Inhibit bacteria Used when the host defense mechanisms are intact. Allows the immunity to clear out Used in many infectious diseases
Describe the spectrum of antibiotics
• Broad Spectrum Antibiotics: o Effective against many types o Example: Cefotaxime • Narrow Spectrum Antibiotics: o Effective against very few types o Example: Penicillin G
Define Cephalosporins
Describe the refinement of antibiotic activity
- Cephalosporins are like penicillin but clinically modified.
- 1st generation not good at killing gram-negative bacteria, but good for streptococcus pneumoniae and staphylococcus aureus.
- 2nd generation got better at killing gram-negative but worse at the others.
- 3rd generation is best at killing gram-negatives and streptococcus pneumoniae but poor at staphylococcus aureus.
- Modification to get different spectrum of activity.
Describe the molecular structure of antibiotics
Families of antibiotics behave similarly.
Structural mimics of natural substrates for enzymes – e.g. B-lactams.
B-lactam ring in penicillin and cephalosporins and natural competitors for enzymes building bacterial cell wall.
Describe the targets of activity for antibiotics
- Many targets in bacterial structure- e.g. cell wall synthesis, folic acid metabolism, cell membrane, DNA/RNA processing, protein synthesis and protein synthesis.
- Cell wall inhibitors- penicillin, vancomycin, cephalosporins and B-lactams.
- Protein synthesis inhibitors (50s and 30s inhibitors). 50s- erythromycin, linezolid, chloramphenicol (aminoglycosides and highly toxic so I.V.). 30s- tetracycline, gentamycin (aminoglycosides and highly toxic). Can inhibit bacterial ribosomes and not eukaryotic ribosomes due to different subunits and very selective toxicity/safe.
- DNA/RNA processing- very different in prokaryotes so good selective toxicity. DNA gyrase (topoisomerase)- quinolones. DNA-dependant RNA polymerases- rifampin- key for tuberculosis. No messenger RNA or proteins.
- Folic acid metabolism- humans cannot synthesis vit B9/12, but bacteria can. If inhibited, loses cofactor for many metabolic enzymes. Very selective toxicity- trimethoprim and sulphonamides.
- Cell membrane- colistin (e. coli and other gram-negatives resistant to most drugs except this one but very toxic so avoid use. Also gaining resistance).
- Free radical generating antibiotics damage multiple targets- metronidazole. Anaerobic bacteria treated with this because metabolism better in anaerobic environment. Nitrofurantoin also good in urinary tract- 99% metabolised goes straight to kidneys, bladder and urethra. Very little resistance.
Describe the structure of gram positive and gram negative cell wall and membrane
Describe the structure of peptidoglycan
How is it made?
How does vancomycin and penilcins work?
- Target enzymes that make peptidoglycan, which are on outer side of inner membrane- very porous and antibiotics can penetrate to reach and inhibit those enzymes.
- Gram-negatives have outer membrane that mean only through porins can antibiotics to enter- not porous.
- Peptidoglycan made of pentapeptides crosslinked and hold matrix together with chains of polysaccharide. Different in structure in different bacteria so B-lactam that works in E.coli might not in S. aureus.
- Precursor monomer of disaccharide with 5 peptides. Last 2 are isomers of alanine. D-ala and D-ala.
- Some antibiotics block production of D-ala, preventing production of peptidoglycan.
- Transport (linked to transport proteins) of precursor across membrane to assemble (some antibiotics inhibit).
- Enzyme recognises D-ala-D-ala and cleaves off terminal D-ala and links to pentapeptide. Cross-linking completed by trans carboxypeptidases (simple but only in prokaryotes). B-lactams inhibit these enzymes. Vancomycin binds to end terminal, preventing binding to cleavage molecule. Penicillins and cephalosporins prevent crosslinking by competitively inhibiting the enzymes- known as penicillin binding proteins (PBPs).
- Degrading B-lactam ring will change shape so no longer competitive inhibitor.
When do we use antibiotics?
- Treatment of bacterial infections.
- Prophylaxis- close contacts of transmissible infections to lower carriage rates and increases 80% in outbreaks.
- Prevention of infection.
- Peri-operative cover for gut surgery.
- People with increased susceptibility to infection.
- Inappropriate use- viral sore throats- patient pressure.
What are the routes of administration?
- Community infections often treated orally by GP.
- Serious infections- hospitalisation- systemic treatment via I.V. Rapid delivery for high concentration in blood. For people unable to take oral- vomiting, unconscious, poor gut absorption due to trauma. I.V. for perivascular collapse (septicaemia).
- Intramuscular for meningitis.
- Topical- conjunctivitis, superficial skin infections, burns, antiseptic creams, heavy metal ointments.
What does the dose of antibiotic MIC depend on?
- This will depend upon the age, weight, renal and liver function of the patient and the severity of infection
- Depend on the susceptibility of the organism
- Will also depend upon properties of the antibiotic i.e. enough to give a concentration higher than the MIC (minimum inhibitory concentration) ! at the site of infection
Describe the combinations of antibiotics
- BEFORE an organism identified in life-threatening infections e.g. endocarditis, septicaemia
- Polymicrobial infections e.g. abscess, G.I. perforation, anaerobes and aerobes
- Less toxic doses of an individual drug possible
- Synergy e.g. penicillin and gentamicin, Co-trimoxazole (sulphonamides + trimethoprim)
- Reduce antibiotic resistance e.g. Tuberculosis
