Lecture 6 Penicillins Flashcards
Peniciillin binding proteins are ____ which act as a catalyst in _____ of the ____ _______ wall
Enzymes
Synthesis
Peptidoglycan wall
Why is PBP1 in staph aureus not the same as PBP1 in ecoli
Numbered by decreasing size in each different type of bacteria
PBP 1a,1b cause ______
PBP 2 determine _____ ______
PBP 3 involved in _____
Cell elongation
Bacterial shape
Cell division
Resistance to Beta lactam s …. How?
Production of Beta lactamases
Reduced affinity of PBP
I’m permeability of cell membrane
Efflux
Classes of penicillin antibacterial ( 5 of them)
Natural penicillins
Penicillinase-resistant penicillins
Aminopenicillins
Carboxypenicillins
Ureidopenicillins
Spectrum of activity of penicillin G, Penicillin V
Most active against non beta lactamase producing gram positive bacteria
Anaerobes ( gram positive)
Selected gram negative cocci
Name some bacteria typically susceptible and resistant to penicillin G
Susceptible: streptococci, eneterococci, n.meningitidis, some anaerobes, treponema pallidium(syphillis)
Resistant: staphylococci, PRSP, Neisseria gonorrhoeae
Resistance to penicillin ( staphylococcus aureus)
Most now produce beta lactamases
Some hav altered PBPs (MRSA)
- PBP2a are produced that can take over role of PBP bound by penicillin- results in resistance to almost all beta lactams
Resistance to penicilllin (staphylococcus epidermidis)
Most produce beta lactamases
Many have changes in PBPs resulting in resistance to almost all Beta lactams (MRSE)
Resistance to penicillin
Streptococcus pyogenes ( group a strep)
Streptococcus agalactiae ( group B strep)
ALL susceptible
Resistance to penicillin ( streptococcus pneumoniae
S.africa, Spain (50%)
USA ( 30-50%)
Canada (20%)
- altered PBPs
Resistance to penicillin
Enterococci
Enterococcus faecalis
Enterococcus faecium
Eneterococci :
- Beta lactamases Many production, altered PBPs rare with E. faecalis, but more common with E. faecium
Enterococcus faecalis:
- 100% susceptible to ampicillin/amoxicillin
Enterococcus faecium
- 36 % susceptible to amp/amox (EDM)
- 8% susceptible to amp/amox
Resistance to penicillin ( N.gonorrhoeae)
Beta lactamases production
Decreased affinity to PBP
Can no longer use penicillin empirically for gonorrhea
Why are enterobacteriales instrincally resistant to penicillin
Beta lactamase production
Reduced affinity for PBP
Cell wall impermability
Quick summary on penicillin resistance
S.aureus, S.epidermidis = Beta lactamases Many production, PBP (MRSA) (MRSE)
S. Pyogenes ( NONE)
S.pneumoniae ( PBP)
N.gonorrhoeae ( Beta lactamase, PBP)
H. Influenzae ( Beta lactamase, PBP)
Enterobacterales ( Instrinsic resistance)
T. Palladium (NONE)
Penicillinase resistant semi synthetic penicillins
Bulky side chain provides beta lactamases resistance with staphylococci
Increase activity again beta lactamases producing staphylococci, but not methicillin resistant staphylococci (MRSA, MRSE)
Cloxacillin has a limited spectrum and used only empirically (only used to treat skin infections with s. Aureus and s.pyogenes)
Aminopenicillins ( amoxicillin, ampicillin)
Amino group added to side chain
Increase entry into cell, increase affinity PBP
Larger spectrum against easily killed gram negatives
Resistance developing due to beta lactamase production
Some resistance due to changes in PBPs
Comparison of ampicillin/amoxicillin spectrum to penicillin G
More active against
- S. Pneumoniae
- Enterococcus
- L. Monocytogenes
Greater gram negative effect, but now many resistant
Ampicillin route
IV, IM, PO
When used orally 30-60% absorbed, acid labile (diarrhea)
Well distributed -> CSF, pleural, joint, and peritoneal fluids
Increase incidence in skin rash
DO not use ampicillin orally anymore, amoxi way better
Amoxicillin route, compare to ampicillin
Only available as PO, except if with amoxi/clav ( IV available)
Relative to ampicillin
- increase resistance to gastric acid
- increase absorption
- less diarrhea
Clavulanic acid
Beta lactamase inhibitor
Irreversibly binds to beta lactamases
Combined with amoxi
Inhibits plasmid-mediated beta lactamases of staphylcocci, h. Influenzae,M. Catarrhalis, some enterobacterales
Clavulanic acid
Absorption
Half life
Side effects
Well absorbed orally
Half life is 1 hour
25-40% excreted unchanged in urine
AE: diarrhea/ nausea
Max dose of Clavulanic acid in children
10mg/kg/day
Expanded spectrum of amoxi/clav
Beta lactamase producing staphycocci
Haemophilia influenzae, Nora Ella catarrhalis
Many enterobacterales
Not AmpC Beta lactamase producing eneterbacterales or pseudomonas
Antipsudomonal penicillins
Ureidopenicillins (Piperacillin)
Piperacillin/ Tazobactam spectrum of activity
Beta lactamase producing staphylcocci ( not MRSA)
Streptococci and enterococci
Good activity against pseudomonas aeruginosa
H. Influenzae, M.catarrhalis
Many enterocbacterales, Including ESBL
Bacteroides fragilis
Piperacilin/ Tazobactam (Does not improve activity against AmpC producing _______ )
SPICE A
Serratia, Providencia, Indole-positive proteus, citrobacter, enterobacter, Acinetobacter
Distribution of penicillins
In prescence of inflammation
In absence of inflammation
In prescence of inflammation - good levels middle ear, pleural, peritoneal, and synovial fluids and adequate CSF levels
In abscence of inflammation
- levels minimal in CSF, eye, brain, prostate
- in CNS- inflammation permits entry and alters anion pump that removes penicillin from CNS
Metabolism/ Excretion of penicillin
Most excreted intact by kidneys by glomerulus filitration and renal tubular secretion
Most have high levels in urine, even with moderate renal failure
Minor degree metabolism in all
Half life vary 30-72 min
Effect of food on certain penicillins
Penicillins G - yes
Penicillin v - no
Cloxacillin - Yes
Amplicillin - yes
Amoxicillin - NO
Piperacillin- N/A
Effect of food on certain penicillins
Penicillins G - yes
Penicillin v - no
Cloxacillin - Yes
Amplicillin - yes
Amoxicillin - NO
Piperacillin- N/A
Dosage Adjustments in penicillin
Lower renal function in elderym neonates, and those with compromised renal function
CrCl < 10ml/min
Slight reduction in most
No change for Cloxacillin
What are the main adverse effects of penicillins
Hypersensitive reactions ranging from rash to anaphylaxis
Adverse effects - CNS toxicity, penicillins
Myoclonic sizures ( rare)
- more likely if penicillin given
- large doses
Or penicillin given in patents with renal failure without dosage adjustment
Adverse Effects - Renal
Interstitial Nephritis < 1 ( Type III reaction)
- rare
- fever, rash, eosinophilia, proteinuria
- may progress to Anuria
- usually after long term
- Most common with methicillin
- most return to normal after discontinue drug
Adverse effects - Hematologic
Neutropenia ( 1-4%) ( type II reaction)
May occur with all penicillins
More often with large doses
WBC count returns to normal after discontinue drug
Lower dose may be tolerated
Adverse Effects - Hematologic
Coombs positive hemolytic anemia
Rare
Type II reaction
Penicillin binds to RBC
Antibody forms
Adverse Effects - Gastrointestinal
Hepatic
- increase alkaline phosphates
- most often in past oxacillin, carbeincillin
- hepatic injury uncommon
Drug interaction penicillin
Allopurinol and ampicillin
- increased incidence of rash
Oral contraceptive
Aminoglycosides
Probenecid
What is the mechanism of action of penicillins?
Penicillins inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), which are enzymes involved in peptidoglycan synthesis.
What is the role of penicillin-binding proteins (PBPs)?
PBPs are enzymes that act as catalysts in the synthesis of the peptidoglycan cell wall in bacteria.
What happens when PBP1a and PBP1b in E. coli are inhibited?
Inhibition of PBP1a and PBP1b causes cell elongation and rapid cell lysis.
What is the effect of inhibiting PBP2 in E. coli?
Inhibition of PBP2 results in stable round forms that grow for several generations before lysing.
What is the effect of inhibiting PBP3 in E. coli?
Inhibition of PBP3 leads to filamentous forms that grow for 5-6 generations before becoming deformed and dying.
What are the four main mechanisms of bacterial resistance to β-lactams?
1) Production of β-lactamases, 2) Reduced affinity of PBPs for β-lactams, 3) Impermeability of the cell membrane, 4) Efflux pumps.
What is the function of β-lactamase?
β-lactamase breaks the β-lactam ring of penicillin, rendering the antibiotic ineffective.
What are natural penicillins?
Natural penicillins include Penicillin G and Penicillin V.
What is the spectrum of activity of Penicillin G?
Penicillin G is most active against non-β-lactamase producing Gram-positive bacteria, some anaerobes, and selected Gram-negative cocci like Neisseria meningitidis.
What bacteria are typically resistant to Penicillin G?
Staphylococci, PRSP (penicillin-resistant Streptococcus pneumoniae), Neisseria gonorrhoeae, H. influenzae, Enterobacteriaceae, and Pseudomonas.
What is MRSA, and how does it resist penicillins?
MRSA (Methicillin-resistant Staphylococcus aureus) produces altered PBPs (PBP2a) that have reduced affinity for β-lactams, making them resistant to most penicillins.
What percentage of S. aureus isolates in Edmonton were MRSA in 2019?
25% of S. aureus isolates in Edmonton were MRSA in 2019.
What is the resistance mechanism in Streptococcus pneumoniae?
Resistance in Streptococcus pneumoniae is due to altered PBPs.
What is the susceptibility of Enterococcus faecalis to ampicillin/amoxicillin in 2019?
100% of Enterococcus faecalis isolates were susceptible to ampicillin/amoxicillin in 2019.
Why are Enterobacteriales intrinsically resistant to penicillins?
Enterobacteriales are intrinsically resistant due to β-lactamase production, reduced affinity for PBPs, and cell wall impermeability.
What is the mechanism of resistance in Neisseria gonorrhoeae?
Resistance in Neisseria gonorrhoeae is due to β-lactamase production and decreased affinity of PBPs.
What are penicillinase-resistant penicillins?
Penicillinase-resistant penicillins, such as cloxacillin, have bulky side chains that protect the β-lactam ring from being broken by β-lactamases.
What is the spectrum of activity of cloxacillin?
Cloxacillin is active against β-lactamase-producing staphylococci but not MRSA or MRSE. It is usually used for skin infections caused by S. aureus and S. pyogenes.
What are aminopenicillins?
Aminopenicillins, such as ampicillin and amoxicillin, have an amino group added to the side chain, which increases their spectrum of activity against Gram-negative bacteria.
What is the spectrum of activity of ampicillin and amoxicillin compared to Penicillin G?
Ampicillin and amoxicillin are more active against S. pneumoniae, Enterococcus, Listeria monocytogenes, and some Gram-negative bacteria like H. influenzae and E. coli.
What is the role of clavulanic acid?
Clavulanic acid is a β-lactamase inhibitor that irreversibly binds to β-lactamase, protecting the β-lactam ring of penicillins from being broken.
What is the spectrum of activity of amoxicillin/clavulanic acid?
Amoxicillin/clavulanic acid has an expanded spectrum that includes Enterococci, H. influenzae, Moraxella catarrhalis, many Enterobacteriaceae, and Bacteroides spp.
What are antipseudomonal penicillins?
Antipseudomonal penicillins include carboxypenicillins (e.g., ticarcillin) and ureidopenicillins (e.g., piperacillin).
What is the spectrum of activity of piperacillin/tazobactam?
Piperacillin/tazobactam is active against β-lactamase-producing Staphylococci, Streptococci, Enterococci, Pseudomonas aeruginosa, H. influenzae, M. catarrhalis, many Enterobacteriaceae, and Bacteroides fragilis.
How are penicillins distributed in the body?
Penicillins are well-distributed to most areas, with good levels in middle ear, pleural, peritoneal, and synovial fluids. In the absence of inflammation, levels in CSF, eye, brain, and prostate are minimal.
How are penicillins excreted from the body?
Most penicillins are excreted intact by the kidneys through glomerular filtration and renal tubular secretion.
What is the half-life of Penicillin G in patients with normal renal function?
The half-life of Penicillin G is 0.5 hours in patients with normal renal function.
What is the most common adverse effect of penicillins?
The most common adverse effect of penicillins is hypersensitivity reactions, ranging from rash to anaphylaxis.
What is the incidence of anaphylactic reactions to parenteral penicillin?
The incidence of life-threatening anaphylactic reactions to parenteral penicillin is 0.01-0.02%, with a fatality rate of 0.0015-0.02%.
What is the risk of CNS toxicity with penicillins?
CNS toxicity, such as myoclonic seizures, can occur with large doses of penicillin or in patients with renal failure without dosage adjustment.
What is interstitial nephritis, and how is it related to penicillins?
Interstitial nephritis is a rare adverse effect of penicillins, characterized by fever, rash, eosinophilia, proteinuria, and hematuria. It is most common with methicillin but can occur with any penicillin.
What is the risk of neutropenia with penicillins?
Neutropenia occurs in 1-4% of patients receiving penicillins, especially with large doses. WBC counts usually return to normal after discontinuing the drug.
What is Coombs-positive hemolytic anemia?
Coombs-positive hemolytic anemia is a type II reaction where penicillin binds to red blood cells, leading to antibody formation and complement-mediated destruction of RBCs.
What are the gastrointestinal adverse effects of penicillins?
Gastrointestinal adverse effects include diarrhea, nausea, and, rarely, hepatic injury with elevated liver enzymes.
What is the interaction between allopurinol and ampicillin?
The combination of allopurinol and ampicillin increases the incidence of rash, occurring in up to 14-22.4% of patients.
How does probenecid affect penicillin excretion?
Probenecid reduces the renal excretion of penicillins, leading to increased blood levels.
What is the absorption rate of Penicillin G?
Penicillin G is 20% absorbed when taken orally.
What is the absorption rate of Amoxicillin?
Amoxicillin is 75% absorbed when taken orally.
What is the protein binding percentage of cloxacillin?
Cloxacillin is 94% protein-bound.
What is the half-life of amoxicillin in patients with normal renal function?
The half-life of amoxicillin is 1 hour in patients with normal renal function.
What is the half-life of piperacillin in patients with normal renal function?
The half-life of piperacillin is 1.3 hours in patients with normal renal function.
What is the maximum dose of clavulanic acid for children?
The maximum dose of clavulanic acid for children is 10 mg/kg/day.
What is the spectrum of activity of ticarcillin?
Ticarcillin is a carboxypenicillin with activity against Pseudomonas aeruginosa and other Gram-negative bacteria.
What is the spectrum of activity of piperacillin?
Piperacillin is a ureidopenicillin with activity against Pseudomonas aeruginosa, Enterobacteriaceae, and Bacteroides fragilis.
What is the role of tazobactam in piperacillin/tazobactam?
Tazobactam is a β-lactamase inhibitor that protects piperacillin from being broken down by β-lactamases.
What is the incidence of skin rash with ampicillin?
The incidence of skin rash with ampicillin is increased, especially when combined with allopurinol.
What is the effect of food on the absorption of Penicillin V?
Food does not affect the absorption of Penicillin V.
What is the effect of food on the absorption of Amoxicillin?
Food does not affect the absorption of Amoxicillin.
What is the effect of renal failure on penicillin excretion?
In renal failure, penicillin excretion is reduced, leading to increased blood levels and potential toxicity.
What is the incidence of hepatic injury with penicillins?
Hepatic injury is uncommon (1-4%) and usually reversible upon discontinuation of the drug.
