Pharmacology of Antibiotics Flashcards
What are the different layers of a gram positive and gram negative bacteria?
Gram positive: peptidoglycan, periplasmic space, and plasma membrane
Gram negative: peptidoglycan, periplasmic space, plasma membrane, AND outer membrane
What is an ideal antibiotic?
Substance that kills/inhibits growth of all harmful bacteria in a host, regardless of site of infection, without causing beneficial gut flora or toxicity
What are the target sites of a bacteria for an antibiotic, and what are some examples of each?
- Protein synthesis - macrolides, aminoglycosides (gentamicin), clindamycin
- Cell wall synthesis - B lactams (penicillin, cephalosporins, carbapenems), vancomycin
- Nucleic acid synthesis - quinolones, rifampin
What part of a b-lactam is the most important part for its mechanism?
Its bicyclic fused ring with a b-lactam ring
What is the mechanism of action of b-lactams?
They covalently bind to PBPs (penicillin binding proteins) in the bacterias cytoplasmic membrane.
These PBPs are responsible for the synthesis of the cross linking peptidoglycan cell wall.
The inhibition of this leads to inactivation of inhibitor autolytic enzymes, inducing cell lysis & death.
What can cause b-lactam antibiotic resistance?
The b-lactam antibiotic can be inactivated by beta lactamases produced by the bacteria.
The b-lactam ring in the antibiotic is hydrolysed and gives resistance.
What is given with penicillin to stop resistance, and how do they work?
They are given with b-lactamase inhibitors, e.g. tazobactam, clavulanic acid
They are lipid soluble (hydrophilic) so cannot cross cells.
Where are penicillins eliminated?
In the kidneys.
What is an example of a penicillin G antibiotic, and how is it given?
Benzylpenicillin.
It is acid-labile, so cannot be given orally as stomach acid will destroy it.
It is given IV.
What is an example of a penicillin V antibiotic, and when is it used?
Phenoxymethylpenicillin (oral)
It is used for prophylaxis of pneumococcal and streptococcal infections.
What are some examples of penicillinase-resistant penicillins, and which enzyme are they resistant to?
Flucloxacillin, temocillin.
They are resistant to the bacterial enzyme b-lactamase.
What do staphylococci bacteria produce which makes them resistant to pen G antibiotics (e.g. benzylpenicillin)?
They produce penicillinases, which degrades the penicillin by hydrolysing the b-lactam ring.
Why is flucloxacillin effective to treat penicillin resistant staphylococci?
Because it does not activated by penicillinase.
What are some examples of broad spectrum penicillins?
- Ampicillin
- Amoxicillin
- Doxycycline
- Azithromycin
- Co-amoxiclav
How is ampicillin administered and how much gets absorbed?
Administered orally, and <50% is absorbed.
What can further reduce the absorption of ampicillin?
If taken with food.
You should take it on an empty stomach.
Which broad spec. penicillin is commonly used and why?
Amoxicillin, because it has better absorption.
What does co-amoxiclav consist of?
Amoxicillin + clavulanic acid (a b-lactamase inhibitor)
What are anti-pseudomonal penicillins?
They are combined with b-lactamase inhibitors, used for pseudomonas and other gram -VE bacteria.
What does tazocin and timentin consist of?
Tazocin: piperacillin + tazobactam
Timentin: ticarcillin + clavulanic acid
What type of infections do anti-pseudomonal pencillins treat?
Septicaemia, complicated UTI’s, skin/soft tissue infections, pneumonia
What is mecillinams the active drug of, and which type of bacteria is it used against?
It is the active substance of pivmecillinam (prodrug), which is hydrolysed into mecillinam.
It is used against gram -VE bacteria.
What type of antibiotics are cephalosporins and where are they isolated from?
They are b-lactams, and are isolated from fungi.
What are you at risk of if you take cephalosporins?
Clostridium difficile (c. difficile)
Which types of cephalosporin antibiotics are used for CNS infections?
Cefotaxime and ceftriaxone
Would patients with a penicillin allergy also be allergic to cephalosporins?
Yes.
Which type of cephalosporin is most commonly used?
Cefalexin.
What is an example of a carbapenem?
Imipenem (used with cilastatin to block its renal absorption)
They all end in -penem
How are carbapenems given, and why?
They are orally inactive, so are given IV.
What can high levels of cabapenems cause?
Neurotoxicity.
What is meropenem, and imipenem (+cilastatin) used for?
They are used for pseudomonas bacteria.
Also used for severe hospital infections and polymicrobial infections e.g. septicaemia, hospital pneumonia, complicated UTIs, etc
What is ertapenem used for?
Abdominal/gynaecological infections, as well as foot infections in diabetics.
What is an example of a monobactam and what is their activity limited to?
Aztreonam.
They only bind to gram -VE aerobic bacteria
Why aren’t monobactams used in gram +VE bacteria?
Because monobactams don’t bind to penicillin binding proteins on gram +VE bacteria, making them ineffective.
What are some examples of glycopeptides?
Vancomycin, telavancin, dalbavancin, teicoplanin
What do glycopeptides treat?
MRSA, and severe staphylococcal infections with penicillin allergy
How are glycopeptides given?
Orally for c. difficile, otherwise IV.
Why is teicoplanin’s duration of action & drug conc. longer than most glycopeptides?
Because it is highly protein bound, so once daily dosing is needed to achieve rapid steady plasma concentration.
What are some side effects of glycopeptides?
- Ototoxicity
- Nephrotoxicity
- Red mans syndrome
What is the mechanism of action of vancomycin?
It binds to terminal peptides of the peptidoglycan precursors.
This prevents transpeptidation and transglycosylation - preventing cell wall synthesis.
Why does vancomycin not work for gram -VE bacteria?
Because gram -VE bacteria have a lipopolysaccharide outer membrane, so it doesn’t allow vancomycin to enter.
What is an example of a lipopeptide?
Daptomycin
What is the mechanism of action of lipopeptides?
It inserts itself into the membrane and forms pores which leads to loss of intracellular K+ & disrupts membrane potential.
Essential pathways are also inhibited.
What should be measured when taking lipopeptides?
Creatine kinase levels.
What is an examples of a tetracycline?
Doxycycline
What is the mechanism of action of tetracyclines?
They inhibit bacterial protein synthesis by inhibiting the binding of t-RNA to the mRNA ribosome complex.
They passively diffuse through the membrane porins of the gram -VE bacteria where they accumulate and uptake into the cytoplasm.
How is absorption of tetracyclines improved?
Orally without food.
Avoid milk, iron preparations, and antacids.
Which groups of people should avoid taking tetracyclines, and why?
Avoid in children <12 years old, and pregnant & breast feeding woman as it can affect skeletal development in growing bones and teeth (by binding to calcium)
What are some examples of aminoglycosides?
- Amikacin
- Gentamicin
- Neomycin
- Tobramycin
What are aminoglycosides dose dependent on?
Weight and renal function
What are some some effects of aminoglycosides?
- Nephrotoxicity
2. Ototoxicity
What is the mechanism of action of aminoglycosides?
They enter the bacterial cell via ion binding and inhibit protein synthesis by binding to a-site of 30S ribosomes.
A misfolded protein is formed, so protein synthesis is not entirely inhibited.
What is the mechanism of action of macrolides?
They inhibit protein synthesis by targeting 50S ribosomes.
They bind at growing peptide exit tunnels and inhibit translocation, stopping the synthesis of proteins.
They can also inhibit modulators of translation
Are macrolides inhibitors of CYP450?
Yes.
Which type of bacteria is erythromycin used for?
Gram -VE bacteria.
What happens to clarithromycin in the liver?
It gets converted into its active metabolite.
What are some examples of quinolones?
- Ciprofloxacin
- Levofloxacin
- Ofloxacin
- Moxifloxacin
All ending in -FLOXACIN
What is the mechanism of action of quinolones?
They bind/stabilise topoisomerase II or IV DNA complexes, which leads to the breakage of double stranded DNA,
Why aren’t quinolones the first choice drug to be used in the UK?
Because of their adverse effects, e.g. tendon damage, convulsions, musculoskeletal effects in children
Which types of bacteria does quinolones fight against?
Both gram +VE and -VE bacteria.
What can ciprofloxacin treat?
- Bone/joint infections
- Gonorrhoea
- Chlamydia
- Other gram -VE bacteria
What is concentration-dependent killing (on a graph), and how do you maximise the concentration?
Line must reach CMax and stay above the MIC.
The higher the conc. of drug above the MIC, the greater the antimicrobial activity.
This can be achieved by increasing the dose of the drug.
What is time-dependent killing (on a graph) and how can you maximise the duration of exposure?
T>MIC
Duration of time over MIC must be prolonged.
Maximise the duration of exposure of drug by increasing the duration of infusion/frequency of administration.
Which type of infusion can be used to maximise time-dependent antibiotics?
Extended or continuous infusions.
A continuous infusion line can increase the duration of exposure of drug (T>MIC).
What are the 3 methods of genetic transfer in bacteria?
- Transformation - bacteria takes a piece of DNA from its environment
- Conjugation - DNA transferred between bacteria through a tube between cells
- Transduction - DNA accidentally moved from one bacterium to another via a virus.
What biochemical mechanisms can induce antibiotic resistance?
- Immunity of the cell
- Inactivation/chemical modification of antibiotic
- Modification/replacement of target site
- Reduced uptake of antibiotic into the cell
