Penicillins- Cell wall synthesis inhibitors Flashcards
What is the overall mechanism of action of penicillins?
Inhibit synthesis of bacterial cell walls
What is a beta lactam?
1) Four-membered ring
2) Ketone group next to amino group; the hydrogen next to the ketone group is below the plane
- In the Carbapenems, this H (coming above the plane) seems to stabilize the molecule, and make it more resistant to beta-lactamases
What is the basic chemistry of ALL penicillins?
1) All contain Ring A (thiazolidine ring) attached to Ring B (beta-lactam ring)
2) The beta-lactam ring always has a secondary amine at the corner, with an –R group attached
3) The beta-lactam ring is essential for activity
4) Ordered/measured in units (or million units) for Pen G only => mg for all others
What are the basic properties of EARLY penicillins (Pen G and Pen V)?
1) Greatest activity against gram positive cocci, gram negative cocci, some (mouth) anaerobes
2) Little activity against gram negative rods, bowel anaerobes
3) Very susceptible to beta-lactamases
4) NOW virtually useless against Staph species
What are the basic properties of aminopenicillins (ampicillin and amoxicillin)?
1) Improved activity against gram negative rods (e.g E. coli, H. flu)
2) Still vulnerable to beta-lactamases
What are the basic properties of anti-staphylococcal semisynthetic penicillins (nafcillin, dicloxacillin)?
1) More resistant to staphylococcal variety of beta-lactamases
(i. e. can be used more for staph)
2) Only useful for staph species and (some) streptococci
3) Not useful for anaerobes, GNR, or even enterococcus
What are the basic properties of extended spectrum anti-pseudomonal penicillins (piperacillin)?
1) Much more activity against pseudomonas, other GNR
2) Some activity against GPC, anaerobes
3) Can be destroyed by beta-lactamases
How do penicillins interfere with bacterial cell wall synthesis?
1) Cell wall composed of complex cross-linked polymer called peptidoglycan
2) Penicillin-binding proteins (PBP’s) catalyze the transpeptidase reaction that removes the terminal D-alanine as it forms a crosslink with a nearby peptide
3*) Beta-lactams are analogs of the natural D-Ala-D-Ala substrate, and bind covalently to the PBP’s at the active site, thereby blocking the enzyme!
4) Failure to produce a competent (crosslinked) cell wall leads (somehow!) to bacterial cell death
What are 4 ways bacteria can become resistant to penicillins?
1) Inactivation of drug by beta-lactamase
2) Modification of target PBP’s
3) Impaired penetration of drug to reach target PBP’s
4) Presence of a new efflux pump
Modification of target PBPs is responsible for which specific resistant bacterial strains?
1) Responsible for MRSA
2) Responsible for Pen-resistant pneumococci and enterococci
In what type of bacteria would impaired penetration of the drug to reach the target PBP cause resistance?
1) Seen only in GN species
- Due to impermeability of an outer cell wall membrane seen only in GNR (change in porin channel, for example)
2) Usually not sufficient by itself to cause resistance; may be paired with a beta-lactamase
In what bacterial type are efflux pumps present, leading to penicillin resistance?
Seen in some gram negatives
What is the mechanism of action of Penicillin G Potassium Salt?
- Binds to PBP’s, and thereby inhibits the assembly of the bacterial cell wall, leading to bactericidal action
What bacteria are sensitive to Penicillin G?
Sensitive: streptococci, enterococcus, oral anaerobes, meningococcus, syphilis
What bacteria are resistant to Penicillin G?
Resistant: most staph (>85%), some pneumococcus (10-30%), bowel anaerobes, most GNR’s
How is Penicillin G usually administered?
IV (poor oral bioavailability)
What toxicity is associated with PenicillinG?
- Contraindicated in Pen-allergic patients
- Anemia, drug allergy especially rash, anaphylaxis, seizures following high doses
What drug interactions should be considered with Penicillin G?
- Synergy with gentamicin against staph and enterococcus
- Probenecid inhibits renal active tubular secretion
