Penicillins Flashcards
Penam
Pharmacophore of all PCNs (just the beta Lactam ring fused to thiazolidine)
Penicillin requirements for activity
Beta-Lactam ring fused with thiazolidine ring (5 membered ring with sulfur)
Carboxylic acid at C3
Substituted amide side chain–>6-APA is inactive( 6- APA is the name of structure without amide side chain)=> R group on amide determines narrow or broad spectrum, oral B.A., and resistance to beta-lactamases
Penicillin structure as a whole is similar to…
D-Ala–D-Ala in peptidoglycan layer. Transpeptidase will bind to PCNs instead of D-Ala–D-Ala b/c of structure similarities
Cross linking enzyme is…
Transpeptidase
Mechanisms at which bacteria develop resistance to Beta Lactam antibiotics
- Alterations in the penicillin binding proteins
- Ineffective penetration to site of action (elfflux pumps or antibiotic is unable to penetrate cell wall)
- Enzymatic alteration of drug (bacteria makes enzymes that deactivate the drug i.e. Beta lactamases)
Intrinsic resistance do to structural differences in PBP
Abx are not able to bind well
Ex: Enterococcus faecium=>PBP5 decreased binding affinity of PBP to PCN
Acquired resistance due to homologous recombination
Alterations involving DNA exchange that lead to increased resistance or decreased binding affinity to Abx
Methicillin Resistant Staph Aureus (MRSA)=> gene MeCa encodes for an additional PBP2
Penicillin Resistant Strep Pneumoniae (PRSR)=> expresses PBP2x
Pseudomonas aeruginosa
Resistance from ineffective penetration of drug to site of action:
1. Reduced permeability
2. MexAB OprF efflux pump system
Resistant to many Beta Lactam drugs because it doesn’t have many highly permeable porins
Extended spectrum beta lactamases (ESBL)
Enterobacteriacea
Can inactivate PCNs, cephalosporins, monobactams and many other Abx.
How do beta lactamases alter structure of PCN?
Opens up B-Lactam ring through hydrolysis reaction, inactivating antibiotic
Beta-Lactamase Inhibitors
Clavulanic Acid
Sulbactum
Tazobactum
They all have structural similarity to penam(beta Lactam + fused ring) structure in PCN
They are used in combination because they have no antibacterial activity by themselves. Beta-lactamase inhibitors bind beta lactamase and covalently modify them. This allows PCN to have activity (binding Transpeptidase and preventing cross linking) without being degraded/inactivated by beta-lactamase
PCN/ Beta-lactamase inhibitor combinations
Amoxicillin/Clavulanate (Augmentin)
Ticarcillin/Clavulanate
Ampicillin/Sulbactum
Piperacillin/Tazobactum (Zosyn)
Alteration of PCN to resist beta lactamase is done by….
Introducing bulky, ortho- substituted R groups to adjacent C=O
This provides steric henderence not allowing the beta lactamase to access beta Lactam ring of PCN
Instability of PCN in acid
Determines oral B.A. More stable can be given PO
Electron withdrawing R groups increase stability by preventing hydrolysis (nucleophhilic attack that results in opening of beta Lactam ring, which Inactivates PCN) in acidic environment
Benzylpenicillin (Penicillin G)
Natural PCN Gram (+) spectrum (narrow) Beta lactamase susceptible Poor B.A., used parenterally Salt with potassium: given IV Salt with organic bases(procaine, benzathine): Given IM depot. Indicated when you want a slow release of PCN
Phenoxymethylpenicillin (Penicillin V)
Natural PCN
Phenoxymethyl side chain is electron withdrawing and more stable in acidic environment then Penicillin G so it can be given orally
Gram (+) bacteria spectrum (narrow)
Susceptible to beta lactamase bc no bulky, ortho substituted R group
Methicillin
Antistaphylococcal PCN
Narrow spectrum used for penicillinase producing staph aureus. Bulky, ortho substituted group inhibits access of beta lactamase (penicillinase). Only useful for MSSA
Altered PBP2a lead to MRSA=> resistance to methicillin
Not used clinically b/c of nephrotoxicity
Naficillin
Antistaphylcoccal PCN
Penicillinase resistance from bulky, ortho substituted R group(steric henderence)
Not acid stable=> given parenterally
Oxacillin
Antistaphylcoccal PCN
Penicillinase resistance from bulky, ortho substituted R group(steric henderence)
Not acid stable=> given parenterally
Cloxacillin
Antistaphylcoccal PCN
Penicillinase resistance from bulky, ortho substituted R group(steric henderence)
Acid stable=> given orally
One chloro substituted group
Dicloxacillin
Antistaphylcoccal PCN Penicillinase resistance from bulky, ortho substituted R group(steric henderence) Acid stable=> given orally Two chloro substituted groups Take 1-2 hours before food
Ampicillin
Aminopenacillin
Given orally or parenterally
Amino group in side chain:
1. Polar (allows entry into gram(-)bacteria)
2. Electron withdrawing and has charge repulsion that contributes to acid stability
3. Not bulky so it is penicillinase susceptible. Give with sulbactum
Broad spectrum activity: gram(-) and gram (+)
ADR: Diarrhea
Amoxicillin
Amoxicillin/Clavulanate (Augmentin)
Aminopenacillin
Given orally or parenterally. More B.A. Than ampicillin and only difference is amoxicillin has OH group
Amino group in side chain:
1. Polar (allows entry into gram(-)bacteria)
2. Electron withdrawing and has charge repulsion that contributes to acid stability
3. Not bulky so it is penicillinase susceptible. Give with Clavulanate
Broad spectrum activity: gram(-) and gram (+)
ADR: Diarrhea
Ticarcillin
Antipseudomonal PCN
Unstable in acid: parental administration only
Broad spectrum: gram (-) and gram (+)
Extended spectrum b/c effective against pseudomonas
Sensitive to beta lactamase: give with clavulanate
Disodium salt: cardiovascular risks
Piperacillin
Piperacillin/Tazobactum (Zosyn)
Antipseudomonal PCN
Unstable in acid: parental administration only
Broad spectrum: gram (-) and gram (+)
Extended spectrum b/c effective against pseudomonas
Sensitive to beta lactamase: give with tazobactum
Side chain provides additional contact with peptidoglycan
