topic 9 Flashcards
What are the categories of penicillin?
- The penicillins
- Penicillin G, Penicillin V
- Anti-staphylococcus, aka Beta-lactamase resistant
- Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin
- Aminopenicillins (2nd generation)
- Ampicillin, Amoxicillin
- Antipseudomonal (3 rd and 4 th generation)
- Carbenecillin
- Ticarcillin
- Piperacillin
What are the important parts of the structure of penicillins?
There is a beta lactam ring. The different penicillins are made by adding different groups to the central structure. Destroying the b-lactam ring will make any b-lactam ineffective.
What should be considered when thinking of the administration and absorption of penicillin?
Most penicillins are available in oral and IV forms, choice depends severity of infection (IV for more severe), convenience (oral is usually more convenient), bioavailability e.g. stability to gastric acid. IM for longer lasting depot (e.g. Procaine Pen G)
Pen G, Pen K, and the beta-lactamase resistant penicillins are less stable in an acid environment. Food increases gastric acid secretion, and these penicillins should be taken away from meals.
How are penicillins eliminated?
- The beta-lactamase resistant penicillins are excreted through a hepatic route.
- The rest of penicillins are excreted by the kidneys by filtration and tubular secretion in an unchanged form. Need to adjust dose in renal failure
In general, penicillins have relatively short half-life and are given at short dosing intervals
How are penicillins distributed?
Generally well distributed throughout body
Poor penetration across meninges into CSF, but
increased permeability when meninges inflamed
Crosses placenta, class B pregnancy risk
What is the general mechanism of action of penicillins?
- Penicillins bind to and inhibit Penicillin Binding Proteins (PBPs)
- PBPs are needed for cell wall (peptidoglycan) synthesis in bacteria
- Cell wall becomes less stable
- Bacteria die from lysis from fragile cell wall (osmotic stress)
- Penicillins work only on organisms with a cell wall
•Penicillins work only when the organisms are
modifying or synthesizing new cell walls, which
occurs during growth
How do penicillins react with gram + and gram- strains? Are they bactericidal or bacteristatic?
Penicillins are bactericidal.
since both gram + and gram - strains have a peptidoglycan layer (even though gram - strains have an outer membrane around it), penicillins work on both.
What is the molecular mechanism of penicillin on peptidoglycans? What is the peptidoglycan monomer made up of? What does PBP do?
The peptidoglycan monomer consists of two monosaccharides (NAM/NAG) that are bound to each other. NAM is also bound to a tetra peptide made of specific amino acids.
PBP functions to cross link the different monomers.
Penicillin resembles the tetrapeptide chain and thus covalently binds to PBP making it ineffective.
What are beta lactamases? How do they work?
Beta lactamases are enzymes that cleave the beta lactam ring. By doing so, they convert penicillin to penicilloic acid which lacks antibacterial properties.
They are widespread.
How do beta lactamases work in both gram + and gram - bacteria?
In gram + bacteria, beta-lactases are secreted extracellularly and are produce in large quantities. They work mainly against penicillins. Staphylococcus is the main strain that develops beta-lactamase and it usually does so quickly.
In gram - bacteria, they secrete beta-lactamase in periplasmic space in lower quantities. They work against both penicillins and cephalosporins.
What are 3 other ways in which bacteria can gain resistance to penicillins and how do they work?
Mutations in the PBP-make it so it doesn’t bind penicillin as well.
Efflux pumps-gram- strains have pumps that transport penicillin from periplasm across outer membrane.
Mutated porins-Gram negative bacteria have porins in their outer membrane that allow things to enter periplasm. Mutations in them can make it so penicillin can’t enter.
What is the most common untoward effect of penicillin?
Hypersensitivity reactions are the most common adverse effect
• About 5% of patients will have an adverse reaction
• Symptoms range from a maculopapular rash
(most common with ampicillin), fever, to severe
including serum sickness, angioedema and
anaphylaxis
• Rash is seen in nearly 100% of patients with
mononucleosis treated with ampicillin
• Penicillins are generally cross-sensitizing and
cross-reactive
• Adverse effects can occur without prior known
exposure
• Previous hypersensitivity is generally a contraindication for use.
What are major/minor antigenic determinants?
They are the macromolecule that causes the allergic reaction.
Major/minor refers to the frequency with which they cause Ab production, not the severity of the reaction.
The major determinant is penicilloic acid, but only when it is bound to other proteins which makes it a hapten.
The minor determinant is intant penicillin and penicillanic acid derivatives.
What are two other untoward effects of penicillin?
GI:
•Nausea, abdominal discomfort, diarrhea as is
common with all antibiotics, in part due to disruption of normal gut flora
•C. Difficile colitis , which may occur with any
antibiotic (when normal gut flora die, it takes advantage and grows).
Renal:
- Interstitial nephritis
- All penicillins have been associated with interstitial nephritis, but methicillin historically had a much higher rate and is not available clinically any more (allergic RXN in kidneys).
What are the two penicillins in the category “the penicillins”? What is their spectrum? What is the difference between the two?
Penicillin G and V.
- Spectrum against:
- gram positives, anaerobes, gram neg. cocci, spirochetes, but Not effective against gram-negative bacilli
Resistance has now developed in many organisms.
They are adminstered differently. Penicillin V is more stable in an acidic environment and thus can be given orally. Penicillin G is usually given IM/IV
