Cell wall inhibitors week 4 Flashcards
What is the typical structure of penicillins?
What do penicillinases/β-lactamases do to penicillins?
How were the various derivatives of penicillin initially characterized?
What is the prototype/standard penicillin? What are the ways in which it is administered? How do the various ways of adminstration differ?
Which form of penicillin is typically administered orally?
- The various derivative of penicillin was initially characterized on the basis of their activity and were termed penicillin A, B, C, etc. Benzylpenicillin (G) has become the standard. Because initially the doses were defined in terms of units of biologic activity, penicillin G is prescribed in terms of units. Other penicillins are prescribed in terms of mg. One unit of penicillin G is equivalent to 0.6 mcg.
- Penicillin G has been formulated into various preparations. The intravenous formulation is potassium penicillin G, which contains 1.7 mEq of potassium per 1 million units. Repository formulations of penicillin for intramuscular use are designed to be slowly absorbed over a prolonged time period. Procaine penicillin G allows the slow release of penicillin G over 12 hours. Benzathine penicillin G allows the slow release of penicillin G over days.
- First Aid ‘15: Penicillin V is orally administered.
What is the mechanism of action of B-lactam agents (penicillin)?
Where is the target of B-lactam agents located? What are the various types (of B-lactam targets)?
How do the outcomes differ when penicillin acts on one type of target vs another?
What are autolysins?
Mechanism of Action of Beta-Lactam Agents:
Bacterial cell walls are required for growth and stability. Stability is provided by the rigid peptidoglycan component of the cell wall. Transpeptidase is the enzyme responsible for the terminal cross-linking of the glycopeptide polymer. The terminal glycine residue of the pentaglycine is linked to the fourth residue of the pentapeptide (D-alanine). Penicillin acylates transpeptidase with cleavage of the beta-lactam ring. Penicillin-Binding Proteins (PBPs) are found in the plasma membrane and are targets for beta-lactams. Transpeptidase is one of the PBPs, but others are involved in structure integrity of the cell wall at cell division. Inhibition of PBP1 causes lysis; inhibition of PBP3 causes production of long filamentous forms. Beta-lactam antibiotics vary in their affinity for PBP. Autolysins are cell wall enzymes responsible for the normal breakdown of the cell wall in processes such as cell division. Interference with peptidoglycan assembly in the presence of autolysis can lead to cell lysis.
List 3 mechanisms by which bacteria can gain resistance to penicillin?
- Altered target site
- Decreased penetration (permeability of penicillin)
- Enzymatic inactivation
Explain how bacteria gain resistance via altering the target of penicillin.
Give examples of bacteria that have this mechanism of resistance to penicillin.
Altered target site: Certain bacteria may produce PBP which have decreased affinity for beta-lactams. They may be reflected as intrinsic resistance or developed resistance. The production of altered PBP is chromosomally mediated. Examples:
a. Methicillin-resistant staphylococci.
b. Penicillin-resistant pneumococci.
c. Relative resistance of Enterococcus to penicillin.
Explain how bacteria gain resistance via decreasing permeability to penicillin.
Give examples of bacteria that have this mechanism of resistance to penicillin.
Decreased penetration: Gram-positive bacteria have their peptidoglycan located near the surface and beta-lactams have easy access to target sites. In gram-negative bacteria, the outer membrane is more complex. The outer membrane is relatively impenetrable. Beta-lactams diffuse through aqueous channels in the outer membrane called porins. The size and number of the porins differ among various bacteria. Porins are formed by proteins in the outer membrane. Beta-lactams differ in the speed with which they can cross the porins. Absence of porins for a particular betalactam may cause intrinsic resistance. Alteration in porin proteins may also cause induced resistance.
Explain how bacteria gain resistance via enzymatic inactivation.
Give examples of bacteria that have this mechanism of resistance to penicillin.
Enzymatic inactivation. Bacteria may produce enzymes, beta-lactamases, which hydrolyze the beta-lactam bond and render the antibiotic inactive. Different organisms produce different types and amounts of betalactamases. Beta-lactamases may be substrate specific, such as a penicillinase or cephalosporinase, or they may be broader spectrum.
a. Staphylococcus aureus produces large amounts of an extracellular penicillinase encoded by a plasmid.
b. In gram-negative bacteria, beta-lactamases are found in the periplasmic space and are relatively broad spectrum. Their synthesis can be encoded by plasmids or chromosomes and they may cause intrinsic or acquired resistance.
State the following facts about Penicillin G and V:
Mechanism of action
Clinical use
Toxicities
Mechanism of resistance
Penicillin G, V Penicillin G (IV and IM form), penicillin V (oral). Prototype β-lactam antibiotics.
Mechanism: Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall. Activate autolytic enzymes.
Clinical Use: Mostly used for gram-positive organisms (S. pneumoniae, S. pyogenes, Actinomyces). Also used for gram-negative cocci (mainly N. meningitidis) and spirochetes (namely T. pallidum). Bactericidal for gram-positive cocci, gram-positive rods, gram-negative cocci, and spirochetes. Penicillinase sensitive.
Toxicity: Hypersensitivity reactions, hemolytic anemia.
Mechanis of resistance: Penicillinase in bacteria (a type of β-lactamase) cleaves β-lactam ring.
Name the penicillinase resistant penicillins.
Oxacillin, methicillin, naficillin, dicloxacillin
State the following facts about the penicillinase resistant penicillins:
Mechanism of action
Clinical use
Toxicity
Dicloxacillin, nafcillin, oxacillin (penicillinase-resistant penicillins)
Mechanism: Same as penicillin. Narrow spectrum; penicillinase resistant because bulky R group blocks access of β-lactamase to β-lactam ring.
Clinical Use: S. aureus (except MRSA; resistant because of altered penicillin-binding protein target site).
“Use naf (nafcillin) for staph.”
Toxicity: Hypersensitivity reactions, interstitial nephritis
Name the penicillinase sensitive penicillins.
State the following facts about the penicillinase sensitive penicillins:
Mechanism of action
Clinical use
Toxicity
Mechanism of resistance
What is given with these penicillins to increase efficacy?
Amoxicillin, ampicillin (aminopenicillins, penicillinase-sensitive penicillins)
Mechanism: Same as penicillin. Wider spectrum; penicillinase sensitive. Also combine with clavulanic acid to protect against destruction by β-lactamase.
AMinoPenicillins are AMPed-up penicillin. AmOxicillin has greater Oral bioavailability than ampicillin.
Clinical Use: Extended-spectrum penicillin—H. influenzae, H. pylori, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, enterococci. Coverage: ampicillin/amoxicillin HHELPSS kill enterococci
Toxicity: Hypersensitivity reactions, rash, pseudomembranous colitis
Mechanism of resistance: Penicillinase in bacteria (a type of β-lactamase) cleaves β-lactam ring.
State the following facts about Piperacillin, ticarcillin, carbenicillin:
Mechanism of action
Clinical use
Toxicity
What is given with these penicillins to increase efficacy?
Piperacillin, ticarcillin (antipseudomonals)
Mechanism: Same as penicillin. Extended spectrum.
Clinical Use: Pseudomonas spp. (such as P. aeruginosa) and gram-negative rods; susceptible to penicillinase; use with β-lactamase inhibitors
Toxicity: hypersensitivity reactions
Following oral administration of penicillins, where do they go? What are areas of poor penetration?
Most penicillins are eliminated via what route? Which penicillin is an exception to his?
What is the relative half life? What does this mean for frequency of dosing?
- Following oral administration, all penicillins are protein bound. The free drug may readily diffuse into tissues and certain body fluids. Areas of poor penetration include:
a. CSF
b. Brain
c. Ocular fluid
d. Prostate
e. Phagocytic cells - Most penicillins are not metabolized significantly by the liver. An exception is oxacillin.
- Penicillins are excreted in the urine. The process involves glomerular filtration and tubular secretion. This results in urine levels, which are markedly higher than serum levels.
- Serum half-life is relatively short (30-60 minutes) and thus penicillins must be administered frequently (i.e., every 2-4 hours).
The major side effects of penicillins are hypersensitivity reactions. What are the types of hypersensitivity reactions that can occur? Which is the most frequent?
What is the mechanism by which penicillins cause hypersensitivity reactsions?
What are other adverse reactions that may occur with penicillins?
Generally, penicillins are considered among the safest antimicrobial agents. The major sideeffects are hypersensitivity reactions. When a specific penicillin is administered to a large group of patients, about 5% will develop some type of hypersensitivity reaction.
- Types of hypersensitivity reactions:
a. Skin rashes are the most frequent and can vary from mild to quite severe.
b. Anaphylaxis is an IgE-mediated reaction, which may be associated with angioedema. This is a serious reaction, which can be fatal. It is estimated that 1 in 100,000 patients who are treated die from anaphylaxis.
c. Serum sickness is an immune complex-mediated reaction to a penicillin.
d. Allergic vasculitis.
e. Fever: may cause one to think there is another source of infection
f. Eosinophilia. - Mechanism: Penicillins and their breakdown products act as haptens.
- An allergic reaction to penicillin markedly increases the possibility that re-administration of any penicillin derivative will case an untoward reaction. Patients with an IgE-mediated hypersensitivity reaction should not receive any penicillin.
- Other adverse reactions:
a. Bone marrow suppression.
b. Thrombophlebitis.
c. Seizures -inhibition of GABA receptors.
d. Hyperkalemia -1.7 mEq of K+ per 1 million units of penicillin G
Name the β-lactamase inhibitors and what penicilins they are administered with.
β-lactamase inhibitors are CAST: Cluvalanic Acid, Sulbactam, & Tazobactam
Cluvalanic Acid + Amoxicillin
Sulbactam + Ampicillin
Tazobactam + Piperacillin (ticarcillin, carbenicillin)
