Ian B Lec 1 Penicillins & Ceph

Question 1

How is penicillin G administered?

Why is this?

Answer 1

Injection only

Degraded in gastric acid due to low stability

Question 2

What is the structural difference between penicillin G and V?

What does this mean?

Answer 2

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)

Question 3

__% of patients who are allergic to penicillins are allergic to _____ too.

Answer 3

10%

Cephalosporins

Question 4

Penicillins are peptide derived (cysteine & valine) so they can trigger an _____ response = anaphylaxis

Answer 4

Immune

Question 5

Why was an acyl group aded to 6-acyl penicillins (derivatives of 6-APA (6-amino-penicillanic acid))?

Answer 5

To improve PK properties
Meant a lower dose was needed
Improved affinity for target

Question 6

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.

Answer 6

Bioburden

T & B cells

Question 7

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.

Answer 7

Bulky

Metabolise

Question 8

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

Answer 8

1) TRUE
2) TRUE
3) FALSE

QDS

Question 9

All penicillins show some degree of activity against Gram - ____.

Answer 9

Cocci

Question 10

Ticarcillin can be used to treat Ps. Aeruginosa.

TRUE/FALSE

Answer 10

TRUE
Gram+ve, -ve and Ps. Aeruginosa

TDS-QDS

Question 11

What is Flucloxicillin active against?

+ve, -ve, Ps. A?

Answer 11

ONLY G+ve

(some gram -ve cocci)

QDS

Question 12

Flucloxicilin is stable towards B-lactamases from S.aureaus and gram-ves.

WHY?

Answer 12

Because it is bulky and doesn’t fit in the enzymes active site easily.

Bacteria can’t then cleave the B-lactam ring

Question 13

Cefalosporin C is NOT used clinically.

It becomes clinical when you add ____ ____.

Answer 13

Side chains

Question 14

Cefepime and Cefpirome are ___ generation cefalosporin.

Answer 14

4th

Question 15

Cefamandole is a ____ generation cefalosporin.

How is it administered?

Answer 15

2nd

Orally

Question 16

Ceftriaxone is a ____ generation cefalosporin

How is is administered?

Answer 16

3rd

Injection only

Question 17

As the cefalosporin generations progress, the trend is that they become more active against g_ve bacteria

They also become ____ resistant to beta lactamases

Answer 17

G-ve

More

Question 18

Activity of cefalosporins against g_ve bacteria depends on affinity for _ _ _s

Activity of cefalosporins against g_ve bacteria depends on penetration through the ___ ______.

Answer 18

G+ve bacteria
Penicillin binding proteins

G-ve bacteria
Outer membrane

Question 19

What are the 4 groups of drugs that contain a beta lactam ring?

Answer 19

• Penicillins
• Cefalosporins
• Carbapenems
• Monobactams

Question 20

What are the 4 ways resistance can occur?

Answer 20

• Efflux pumps
• Metabolise the drug
• Decrease entry
• Alter active site (e.g change Dala Dala to Dala Dlactate) This leads to VRE in Enterococci

Question 21

What might piperacillin be a better substrate mimic or PBPs?

Answer 21

• Forms more H bonds
• More peptide bonds
• Higher affinity
• Better binding

Question 22

Carbapenem is a synthetic antimicrobial

- The _____ is replaced with a _____

Answer 22

Sulphur

Carbon

Question 23

Imipenem is ____ spectrum

• Relatively _____ to beta lactamases
• Poor in vivo ____

Answer 23

Broad
Resistant
Stability

Question 24

Aztreonam is a _____
It is highly active against most g_ve bacteria
Stable to most types of B lactamase

IV admin

Answer 24

Monobactam

G-ve

Question 25

Carbapenems, 3rd generation cefalosporins and Aztreonam synergise with _______. E.g G_____ and T______ treat Pseudomonas lung infections in CF

Answer 25

Aminoglycosides Gentamicin Tobramycin

Question 26

Sulbactam, Brobactam, Tazobactam and _____ ___ are all what?

Answer 26

Clavulonic acid Inhibitors of B lactamases They remain bound once the B lactam ring is hydrolysed

Question 27

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.

Answer 27

Cross linking Transglycosylation Cell Wall Transpeptidase D-alanine Amino group TRANSPEPTIDASES Blocks cross linking

Question 28

Porins are tr____ protein channels that B lactam drugs pass through. Bacteria that have fewer channels are more _____

Answer 28

Trimeric Resistant

Question 29

Bacteria that make more/less B lactamases are more resistant.

Answer 29

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

Question 30

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.

Answer 30

Resistance PGP (P glycoprotein efflux pump) Affinity Extracellular

Question 31

Efflux pumps e.g... PGP1 (MDR1) ABCB1 (CD243) Are all transporters that can cause the efflux of _-_____.

Answer 31

B-lactams

Question 32

Metabolism of drugs can cause resistance: - B-lactamases - Hydrolysis e.g to deactivate anti-____ in ___ acid mimetic antibiotics. - Oxidative demethylation catalysed CYP450

Answer 32

- Anti-folate | - Folic acid mimetics

Question 33

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

Answer 33

Vancomycin Resistant Enterococci DNA Plasmids/transposons Nosocomial

Question 34

_ 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___

Answer 34

6 Teicoplanin Teicoplanin Teicoplanin

Question 35

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.

Answer 35

NAM/NAG D-Alanyl-D-Lactate H-Bonding interaction (1000-fold decrease in affinity)