Carbapenems, Monobactams, Beta Lactamase Inhibitors

Question 1

Background Information

Answer 1

Are inhibitors of cell wall therefore bactericidal

Are beta lactam ABs

Question 2

Beta Lactam ABs

Drug Groups

Answer 2

Penicillins
Cefalosporins
Carbapenems
Monobactams
Beta Lactamase Inhibitors

Question 3

Chemistry of beta lactam ABs

Answer 3

A ring
   in penicillin: thiazoline ring
   cefalosporins: dihydrothiazine ring
   carboxylic group attached to it: to form water sol/insol 
      complexes 

B ring
respo for antobacterial effect
AA bound to it; variations here resp for pharmacolo diff

Question 4

Bacterial Cell Wall Structure

Answer 4

G+
Plasma membrane surrounded by thick peptidoglycan
–> lipophilic drugs better

G-
Plasma membrane surrounded periplasmatic place and
thin peptidoglycan layer
Porin proteins ‘bind’ peptidoglycan with outer
membrane–> hydrophilic drugs better

Peptidogycan
Polysaccharide rich chain with cont 2 alternating sugars
N Acetylglucosamine and N Acetylmuramic Acid

Question 5

Mode of Action

Answer 5

Beta Lactam ABs inhibit proteins: Penicillin Binding protein = transpeptidase
–> inhibit cross linkage step of cell wall synthesis

Conformation of beta lactam AB is similar to that of
D-Ananyl-D-Alanine
–> beta lactams bind to active site of transpeptidase:
enzyme opens lactam ring and acetylates itself–>
modification–> irreversible inhibition

Question 6

Synthesis of Bacterial Cell Wall

Answer 6

Stage 1
Synth of precursor molecules; incl conversion L-Alanine
into D-Alanine
Good: selective toxicity. L Alanine is encoded in
humans

Stage 2
Polymerisation of precursor molecules

Stage 3
Cross Linkage of Peptidoglycan fibers
Done by PBP

Constant Remodelling
–> point of attack for ABs

Question 7

Mechanisms of Resistance

Answer 7

Presence of beta lactamases
PBP Mutation (ex MRSA)
G-: can’t cross outer membrane-> needs porins
Mutation in porin or efflux mechanism (pumps)

Atypical bacteria that don’t have peptidoglycan layer
Slowly growing bacteria that don’t constantly remodel
IC bacteria–> protected

Question 8

Carbapenems

Spectrum
Indications
SE

Answer 8

Broadest spectrum amongst beta lactams
Less resistance as newer; but carbapenemases +

Many G+s, G-s, anaerobics

Uses
   Hospital acquired infections
   Resp and UITs
   Soft tissue/joint/bone infections
   Gyn

SE
HSR
Irritation at site of infusion
Seizures in patients with renal insufficiencies

Question 9

Carbapenems

Drug Names and Characteristics

Answer 9

Imipenem: parenteral
combo with cilastatin (dipeptidase inhibitor)
prevents imipenem from beind hydrolised -> ineff

Tebipenem: oral
not yet approved in EU

Panipenem: parenteral

Meropenem
Ertapenem
Doripenem

Question 10

Monobactams

Answer 10

No cross resistance as structure differs to other beta lactams; is ‘missing’ a ring

G+ and anaerobes are resistant
Good for many G-s incl pseudomonas

Uses
UTIs RTIs

IV
Renal elimination
!!Cross BBB!!

Only minor SEs, HSR uncommon

Aztreonam
Nocardicin A

Question 11

Beta Lactamase Inhibitors

Answer 11

Irreversibly covalently bind to active site on lactamase
Way higher affinity to beta lactamase than other ABs

Are beta lactam ABs but have low to no antibacterial action

Plasma beta lactamases are usually sensitive (staph; E. Coli)
Inducible chromosomal beta lactamases are not sensitive

Used in combo with beta lactam ABs
Augmentin: amoxicillin + clavulanic acid
Sultamicin: ampicillin + sulbactam
Sulbactam can also be bought as a monoprep.

Tazabactam: combo with piperacillin