Antibiotics Flashcards
Antibiotics are widely used and misused
Widely used and misused drugs – 20-50% questionable use
In hospitals - >10% of drug budget
25% of patients have received antibiotics within previous 24h
In ICU 50% of patients are on antibiotics
50 million prescriptions per year
80% of human use is in the community as a result of prescription of antibiotics
50% - respiratory infections
15% urinary tract infections
What are antibiotics natural products of?
What does chemical modification allow?
Natural products of fungi and bacteria - soil dwellers
- Have natural antagonism and selective advantage over other organisms in the soil
- Kills or inhibit the growth of other microorganisms
Most derived from natural products by fermentation, then modified chemically :
- Increased pharmacological properties
- Increased antimicrobial effect
so can be absorbed and survive inside bloodstream
some antibiotics synthetic e.g sulphonamides
Antibiotics have selective toxicity, what does this mean?
Due to differences in structure and metabolic pathways between host and pathogen
Harm microorganisms, not the host
Target in microbe, not host (if possible)
Difficult for viruses (intracellular), fungi and parasites
Variation between microbes
Effect on commensals – can be severe, needs to be considered when using antibiotics
Antibiotics must have therapeutic margin, what is this?
Difference between active dose that needs to be given to kill the organism, compared to the toxic dose that will cause a toxic effect in the host.
Antibiotics must have an active dose (MIC)
Active dose (MIC) vs toxic effect
Narrow for toxic drugs – e.g aminoglycosides, vancomycin, ototoxic, nephrotoxic
If you don’t get dose right it can have toxic effects
There is no safe drug, need to balance therapeutic imperative and host damage..
What antibiotics are involved in loss of flora?
Bacterial/pathogen overgrowth
E.g in colitis
Clindamycin, broad spectrum lactams, fluoroquinolones
Pseudomembranous colitis – caused if C. difficile overgrows
Overgrowth of clostridium difficile
What does overgrowth cause?
But can be part of normal flora of 3% of population
a spore forming condition which can contaminate environment, can get outbreaks
Causes:
Ulcerations – inflammation
Severe diarrhoea
Serious hospital cross infection risks
A combo of antibiotics and immunity causes bacterial clearance
What do immunosuppression patients need?
Immunosuppression patients e.g due to cancer chemotherapy, myeloma, HIV with low CD4, elderly, babies, diabetes, alcoholics
Treating these people requires different antibiotics, e.g different dosage, to ensure bacteria is cleared
Classified by:
Type of activity
Structure
Target site for activity
Antibiotics activity can be bactericidal or bacteriostatic
What is bactericidal antibiotics?
Kill bacteria
Used when the host defence mechanisms are impaired
Required in endocarditis, kidney infection
What are bacteriostatic antibiotics?
Inhibit bacteria
Used when the host defence mechanisms are intact
Used in many infectious diseases
Varies for drug, species and concentration of drug e.g normal concentration might be bactericidal but increasing its concentration might make it bacteriostatic.
Both work clinically very well.
What two spectrums can antibiotics be?
Broad spectrum antibiotics
- Effective against many types e.g cefotaxime
Narrow spectrum antibiotics
- Effective against very few types e.g Penicillin G
How has the activity of cephalosporins been refined?
First generation cephalosporins not very good at killing gram negatives but good at gram positives
Second generation even distribution
Third generation good for gram negatives but lost activity against some gram positives
What antibiotics are beta-lactams?
Penicillin’s
Basic penicillin’s e.g benzylpenicillin (PenG, penicillin V)
- Active against streptococci, pneumococci, meningococci
- Most strains of Staphylococcus aureus are resistant
- Need a different type to kill off Staph Aureus
Anti-staphylococcal penicillin’s e.g flucloxacillin
- Narrow spectrum, G+ves beta-lactamase resistant, less potent that PenG for some other organisms
- Not MRSA
What are the other types of penicillin besides basic and anti-staphlococcal penicillin?
Broader spectrum penicillin’s e.g ampicillin
- Spectrum of activity is similar to basic penicillin’s but also includes some gram negative organisms and also enterococci
Anti-pseudomonal penicillin’s e.g piperacillin
- Extended spectrum beta-lactam antibiotic
- Also G+ve, G-ve, anaerobes
Beta-lactam/beta-lactamase inhibitor combinations e.g co-amoxiclav (Augmentin)
- Spectrum like amoxicillin plus activity against some gram-negatives and S.aureus
Many antibiotics target enzymes that make cell walls
If bacteria can’t make cell wall it dies
What antibiotics target cell wall synthesis?
Cyclocserine
Vancomycin
Penicillin’s
Monobactams
Carbapenems
Beta lactam antibiotics
Cephalosporins
What antibiotics inhibit protein synthesis?
50S inhibitor:
- Erythromycin (Macrolides)
- Clindamycin
- Chloramphenicol – toxic, used topically e.g eyedrops
- linezolid
30S inhibitors:
- Tetracycline
- Spectinomycin
- streptomycin
- Gentamicin, tobramycin (aminoglycosides)
- Amikacin
- Tigecyclin
- Doxycycline
have little effect on protein synthesis of eukaryotes
What antibiotics affect DNA and RNA processing?
Quinolones inhibit DNA gyrase, unique to bacteria when they wind and unwind their DNA in replication.
Humans use topoisomerase 4 instead of DNA gyrase, so selective toxicity against bacterial GYRASE and not against human Topoisomerase enzyme
Rifampicin key in TB medication, blocks bacteria’s ability to produce mRNA.
Inhibits bacterial RNA polymerase, bacteria dies
Gram-positive bacteria, antibiotics can diffuse through cell wall and inhibit enzymes that make cell wall
Why can’t antibiotics get through the membrane of gram negative bacteria?
Outer membranes full of lipopolysaccharides – impermeability barrier
Antibiotics have to get through the membrane, can only do this by going through certain pores. Not many can get through these pores – PenG wouldn’t work well here
Peptidoglycan in the periplasmic space, drug needs to get here before it can inhibit enzymes making peptidoglycan - so many antibiotics you can’t use here
Many antibiotics you can’t use on gram –ve bacteria, this is why you can’t use the same antibiotics as in gram positive bacteria, and the targets are different
Site of action of inhibitors of bacterial cell wall synthesis
Monomers have 5 amino chains and ends in terminal with two D-ala-D-ala
These are attached to lipid molecules and transported across lipid membrane, dimerised and cross linked, during this process
Add on poly-pentaglycine chains
Polymerised by enzymes, cleaves off terminal D-ala and cross link it, in red circle
Enzymes that make crosslink and make peptidoglycan structure called trans peptidases and carboxy-peptidases or known as penicillin binding proteins because they enzymes are inhibited by beta-lactam type antibiotics
- Enzymes can’t work if they’re bound by penicillin and beta lactam antibiotics, therefore bacteria can’t cross link its peptidoglycans and dies
Vancomycin, treats MRSA, binds to the terminal D-ala-D-ala
Blocks availability of the active site for the enzyme that normally polymerases the polysaccharides, acts as antibiotic, preventing cell wall synthesis in a different way than beta lactam antibiotics does
Blocks access of antibiotics
How do beta lactams work on pencillin binding proteins in gram negative bacteria?
normally bacteria builds up subunits using PBP enzyme for cross linking, peptidoglycan exists in periplasmic space.
Beta-lactam antibiotic comes , gets through porin of a gram negative bacteria
binds to PBP (enzymes that cross link peptidoglycan) blocks enzymes from working. Bacteria induces autolytic enzyme response
causes bacterial cell to die because it can’t make peptidoglycan structures.
What do the enzymes dihydrofolic acid and dihydrofolate reductase do?
What drugs work to inhibt enzymes involved in folic acid metabolism pathway?
Humans need to get vitamin B9 from our diet, dihydrofolic acid, take it in and reduce it with dihydrofolate reductase to tetrahydrofolic acid
Trimethoprim works better against bacterial dihydrofolate reductase than human dihydrofolate reductase – potent selective toxicity
Using two drugs together, sulfonamides and trimethoprim, gives better antibacterial effects than either given on their own
Dapsone, another drug used to treat leprosy, inhibits dihydropteroate synthetase
How do protein synthesis inhibitors work?
Examples of them
Antibiotics bind to ribosomes involved in protein synthesis
Blocks it from undergoing protein synthesis
antibiotics work at different stages of protein synthesis
30S ribosome:
- Streptomycin
- gentamicin
- tetracyline
50S ribosome:
- chlorampheicol
- erhtyromycin
- fusidic acid
What is minimum inhibiton concentration?
The conc. you need to achieve in body to get clearance of infection / for the antibiotic to have an effect
Depend on age, weight, renal and liver function of the patient and the severity of infection
On the susceptibility of the organism to the antibiotic you’ve chosen, MIC level varies for different antibiotics
And upon properties of the antibiotic ie enough to give a concentration higher than the MIC
Have to achieve MIC at the site of infection, MIC must be good enough to treat infection– depends on the dose we give
second dose need to be given near first dose so conc. doesn’t drop below MIC
