Ian B Lec 1 Penicillins & Ceph Flashcards
How is penicillin G administered?
Why is this?
Injection only
Degraded in gastric acid due to low stability
What is the structural difference between penicillin G and V?
What does this mean?
Penicillin G has no polar O group on R group but V does!
Penicillin V is orally active (However not all of it is absorbed)
__% of patients who are allergic to penicillins are allergic to _____ too.
10%
Cephalosporins
Penicillins are peptide derived (cysteine & valine) so they can trigger an _____ response = anaphylaxis
Immune
Why was an acyl group aded to 6-acyl penicillins (derivatives of 6-APA (6-amino-penicillanic acid))?
To improve PK properties
Meant a lower dose was needed
Improved affinity for target
By finishing a course of penicillin you won’t kill 100% of the bacteria but kill the vast majority to reduce the ______.
Now _ and _ cells can kill the rest.
Bioburden
T & B cells
Methicillin is structurally ____.
This means that enzymes find it difficult to _____ it as it doesn’t fit their active site.
This makes it a powerful antibiotic.
Bulky
Metabolise
TRUE/FALSE?
1) Ampicillin can be taken orally
2) Ampicillin is active against both g+ve and -ves
3) Ampicillin can be used to treat Ps. aeruginosa infection
How many times is it give a day? OD, BD, TDS, QDS
1) TRUE
2) TRUE
3) FALSE
QDS
All penicillins show some degree of activity against Gram - ____.
Cocci
Ticarcillin can be used to treat Ps. Aeruginosa.
TRUE/FALSE
TRUE
Gram+ve, -ve and Ps. Aeruginosa
TDS-QDS
What is Flucloxicillin active against?
+ve, -ve, Ps. A?
ONLY G+ve
(some gram -ve cocci)
QDS
Flucloxicilin is stable towards B-lactamases from S.aureaus and gram-ves.
WHY?
Because it is bulky and doesn’t fit in the enzymes active site easily.
Bacteria can’t then cleave the B-lactam ring
Cefalosporin C is NOT used clinically.
It becomes clinical when you add ____ ____.
Side chains
Cefepime and Cefpirome are ___ generation cefalosporin.
4th
Cefamandole is a ____ generation cefalosporin.
How is it administered?
2nd
Orally
Ceftriaxone is a ____ generation cefalosporin
How is is administered?
3rd
Injection only
As the cefalosporin generations progress, the trend is that they become more active against g_ve bacteria
They also become ____ resistant to beta lactamases
G-ve
More
Activity of cefalosporins against g_ve bacteria depends on affinity for _ _ _s
Activity of cefalosporins against g_ve bacteria depends on penetration through the ___ ______.
G+ve bacteria
Penicillin binding proteins
G-ve bacteria
Outer membrane
What are the 4 groups of drugs that contain a beta lactam ring?
- Penicillins
- Cefalosporins
- Carbapenems
- Monobactams
What are the 4 ways resistance can occur?
- Efflux pumps
- Metabolise the drug
- Decrease entry
- Alter active site (e.g change Dala Dala to Dala Dlactate) This leads to VRE in Enterococci
What might piperacillin be a better substrate mimic or PBPs?
- Forms more H bonds
- More peptide bonds
- Higher affinity
- Better binding
Carbapenem is a synthetic antimicrobial
- The _____ is replaced with a _____
Sulphur
Carbon
Imipenem is ____ spectrum
- Relatively _____ to beta lactamases
- Poor in vivo ____
Broad
Resistant
Stability
Aztreonam is a _____
It is highly active against most g_ve bacteria
Stable to most types of B lactamase
IV admin
Monobactam
G-ve
Carbapenems, 3rd generation cefalosporins and Aztreonam synergise with _______.
E.g G_____ and T______
treat Pseudomonas lung infections in CF
Aminoglycosides
Gentamicin
Tobramycin
Sulbactam, Brobactam, Tazobactam and _____ ___ are all what?
Clavulonic acid
Inhibitors of B lactamases
They remain bound once the B lactam ring is hydrolysed
How do B-lactams work?
- Final stage of PG assembly is the ____-____ of the linear glycan strands assembled by trans_____ to the existing PG in the ___ ___.
- Reaction catalysed by t______ enzymes, located on outer face of cell membrane.
- They remove the terminal D-_____ residue from each stem peptide on the newly synthed glycan chain.
- Energy released from breaking the peptide bond used in formation of new peptide bond between the remaining d-alanine on the stem peptide and free ____ group on the 3rd AA of the stem peptides in the existing cross linked PG.
- Acceptor amino group supplied by amino acid L-lysine.
B LACTAM ANTIBIOTICS INHIBIT ______ (PBPs) by acting as alternative substrates (covalently bonding by mimicking D-alanyl-D-alanine)
THUS blocking _____-_____ of the PG.
Cross linking
Transglycosylation
Cell Wall
Transpeptidase
D-alanine
Amino group
TRANSPEPTIDASES
Blocks cross linking
Porins are tr____ protein channels that B lactam drugs pass through.
Bacteria that have fewer channels are more _____
Trimeric
Resistant
Bacteria that make more/less B lactamases are more resistant.
LESS - they are released into the inner and outer layer gaps
If more were made then they would be released and diffuse away quickly into the medium
If a B lactam drug gains access to the bacteria then a pump can push it back outside the cell.
This is a mechanism of _______.
The efflux pump is a _ _ _ (_ ______) efflux pump
It works by binding the xenobiotic, inverting the protein in membrane which causes a change in _____ and the drug is released on the ex_______ side.
Resistance
PGP (P glycoprotein efflux pump)
Affinity
Extracellular
Efflux pumps e.g…
PGP1 (MDR1)
ABCB1 (CD243)
Are all transporters that can cause the efflux of _-_____.
B-lactams
Metabolism of drugs can cause resistance:
- B-lactamases
- Hydrolysis e.g to deactivate anti-____ in ___ acid mimetic antibiotics.
- Oxidative demethylation catalysed CYP450
- Anti-folate
- Folic acid mimetics
VRE - _____ _____ _____
Become resistant by obtaining new _ _ _ in the form of ____ or _____ which encode genes that confer Vancomycin resistance.
High level Vanc resistant E.faecalis and E.faecium associated with outbreaks of hospital-acquired (______) infections
Vancomycin Resistant Enterococci
DNA
Plasmids/transposons
Nosocomial
_ different types of Vancomycin resistance shown by Enterococcus.
Van-A VRE resistant to Vanc and T_____
Van-B VRE resistant to Vanc but sensitive to T____
Van-C VRE partially resistant to Vanc and sensitive to T___
6
Teicoplanin
Teicoplanin
Teicoplanin
Mechanism of resistance to Vancomycin in Enterococcus:
Alteration of terminal AA residues of NAM/NA_ peptide subunits.
Normally Vanc binds D-Alanyl-D-alanine but D-Alanyl-D-____ mutation of O for NH results in loss of 1 _-_____ interaction.
NAM/NAG
D-Alanyl-D-Lactate
H-Bonding interaction
(1000-fold decrease in affinity)
