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PHARM 346 INFECTIOUS DISEASES > Lecture 6 Penicillins > Flashcards

Lecture 6 Penicillins Flashcards

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1
Q

Peniciillin binding proteins are ____ which act as a catalyst in _____ of the ____ _______ wall

A

Enzymes

Synthesis

Peptidoglycan wall

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2
Q

Why is PBP1 in staph aureus not the same as PBP1 in ecoli

A

Numbered by decreasing size in each different type of bacteria

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3
Q

PBP 1a,1b cause ______

PBP 2 determine _____ ______

PBP 3 involved in _____

A

Cell elongation

Bacterial shape

Cell division

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4
Q

Resistance to Beta lactam s …. How?

A

Production of Beta lactamases

Reduced affinity of PBP

I’m permeability of cell membrane

Efflux

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5
Q

Classes of penicillin antibacterial ( 5 of them)

A

Natural penicillins

Penicillinase-resistant penicillins

Aminopenicillins

Carboxypenicillins

Ureidopenicillins

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6
Q

Spectrum of activity of penicillin G, Penicillin V

A

Most active against non beta lactamase producing gram positive bacteria

Anaerobes ( gram positive)

Selected gram negative cocci

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7
Q

Name some bacteria typically susceptible and resistant to penicillin G

A

Susceptible: streptococci, eneterococci, n.meningitidis, some anaerobes, treponema pallidium(syphillis)

Resistant: staphylococci, PRSP, Neisseria gonorrhoeae

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8
Q

Resistance to penicillin ( staphylococcus aureus)

A

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
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9
Q

Resistance to penicilllin (staphylococcus epidermidis)

A

Most produce beta lactamases

Many have changes in PBPs resulting in resistance to almost all Beta lactams (MRSE)

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10
Q

Resistance to penicillin

Streptococcus pyogenes ( group a strep)
Streptococcus agalactiae ( group B strep)

A

ALL susceptible

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11
Q

Resistance to penicillin ( streptococcus pneumoniae

A

S.africa, Spain (50%)
USA ( 30-50%)
Canada (20%)

  • altered PBPs
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12
Q

Resistance to penicillin

Enterococci
Enterococcus faecalis
Enterococcus faecium

A

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

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13
Q

Resistance to penicillin ( N.gonorrhoeae)

A

Beta lactamases production

Decreased affinity to PBP

Can no longer use penicillin empirically for gonorrhea

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14
Q

Why are enterobacteriales instrincally resistant to penicillin

A

Beta lactamase production

Reduced affinity for PBP

Cell wall impermability

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15
Q

Quick summary on penicillin resistance

A

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)

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16
Q

Penicillinase resistant semi synthetic penicillins

A

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)

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17
Q

Aminopenicillins ( amoxicillin, ampicillin)

A

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

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18
Q

Comparison of ampicillin/amoxicillin spectrum to penicillin G

A

More active against
- S. Pneumoniae
- Enterococcus
- L. Monocytogenes

Greater gram negative effect, but now many resistant

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19
Q

Ampicillin route

A

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

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20
Q

Amoxicillin route, compare to ampicillin

A

Only available as PO, except if with amoxi/clav ( IV available)

Relative to ampicillin
- increase resistance to gastric acid
- increase absorption
- less diarrhea

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21
Q

Clavulanic acid

A

Beta lactamase inhibitor

Irreversibly binds to beta lactamases

Combined with amoxi

Inhibits plasmid-mediated beta lactamases of staphylcocci, h. Influenzae,M. Catarrhalis, some enterobacterales

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22
Q

Clavulanic acid

Absorption
Half life
Side effects

A

Well absorbed orally
Half life is 1 hour
25-40% excreted unchanged in urine

AE: diarrhea/ nausea

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23
Q

Max dose of Clavulanic acid in children

A

10mg/kg/day

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24
Q

Expanded spectrum of amoxi/clav

A

Beta lactamase producing staphycocci

Haemophilia influenzae, Nora Ella catarrhalis

Many enterobacterales

Not AmpC Beta lactamase producing eneterbacterales or pseudomonas

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25
Antipsudomonal penicillins
Ureidopenicillins (Piperacillin)
26
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
27
Piperacilin/ Tazobactam (Does not improve activity against AmpC producing _______ )
SPICE A Serratia, Providencia, Indole-positive proteus, citrobacter, enterobacter, Acinetobacter
28
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
29
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
30
Effect of food on certain penicillins
Penicillins G - yes Penicillin v - no Cloxacillin - Yes Amplicillin - yes Amoxicillin - NO Piperacillin- N/A
31
Effect of food on certain penicillins
Penicillins G - yes Penicillin v - no Cloxacillin - Yes Amplicillin - yes Amoxicillin - NO Piperacillin- N/A
32
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
33
What are the main adverse effects of penicillins
Hypersensitive reactions ranging from rash to anaphylaxis
34
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
35
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
36
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
37
Adverse Effects - Hematologic
Coombs positive hemolytic anemia Rare Type II reaction Penicillin binds to RBC Antibody forms
38
Adverse Effects - Gastrointestinal
Hepatic - increase alkaline phosphates - most often in past oxacillin, carbeincillin - hepatic injury uncommon
39
Drug interaction penicillin
Allopurinol and ampicillin - increased incidence of rash Oral contraceptive Aminoglycosides Probenecid
40
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.
41
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.
42
What happens when PBP1a and PBP1b in E. coli are inhibited?
Inhibition of PBP1a and PBP1b causes cell elongation and rapid cell lysis.
43
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.
44
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.
45
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.
46
What is the function of β-lactamase?
β-lactamase breaks the β-lactam ring of penicillin, rendering the antibiotic ineffective.
47
What are natural penicillins?
Natural penicillins include Penicillin G and Penicillin V.
48
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.
49
What bacteria are typically resistant to Penicillin G?
Staphylococci, PRSP (penicillin-resistant Streptococcus pneumoniae), Neisseria gonorrhoeae, H. influenzae, Enterobacteriaceae, and Pseudomonas.
50
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.
51
What percentage of S. aureus isolates in Edmonton were MRSA in 2019?
25% of S. aureus isolates in Edmonton were MRSA in 2019.
52
What is the resistance mechanism in Streptococcus pneumoniae?
Resistance in Streptococcus pneumoniae is due to altered PBPs.
53
What is the susceptibility of Enterococcus faecalis to ampicillin/amoxicillin in 2019?
100% of Enterococcus faecalis isolates were susceptible to ampicillin/amoxicillin in 2019.
54
Why are Enterobacteriales intrinsically resistant to penicillins?
Enterobacteriales are intrinsically resistant due to β-lactamase production, reduced affinity for PBPs, and cell wall impermeability.
55
What is the mechanism of resistance in Neisseria gonorrhoeae?
Resistance in Neisseria gonorrhoeae is due to β-lactamase production and decreased affinity of PBPs.
56
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.
57
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.
58
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.
59
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.
60
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.
61
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.
62
What are antipseudomonal penicillins?
Antipseudomonal penicillins include carboxypenicillins (e.g., ticarcillin) and ureidopenicillins (e.g., piperacillin).
63
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.
64
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.
65
How are penicillins excreted from the body?
Most penicillins are excreted intact by the kidneys through glomerular filtration and renal tubular secretion.
66
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.
67
What is the most common adverse effect of penicillins?
The most common adverse effect of penicillins is hypersensitivity reactions, ranging from rash to anaphylaxis.
68
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%.
69
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.
70
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.
71
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.
72
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.
73
What are the gastrointestinal adverse effects of penicillins?
Gastrointestinal adverse effects include diarrhea, nausea, and, rarely, hepatic injury with elevated liver enzymes.
74
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.
75
How does probenecid affect penicillin excretion?
Probenecid reduces the renal excretion of penicillins, leading to increased blood levels.
76
What is the absorption rate of Penicillin G?
Penicillin G is 20% absorbed when taken orally.
77
What is the absorption rate of Amoxicillin?
Amoxicillin is 75% absorbed when taken orally.
78
What is the protein binding percentage of cloxacillin?
Cloxacillin is 94% protein-bound.
79
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.
80
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.
81
What is the maximum dose of clavulanic acid for children?
The maximum dose of clavulanic acid for children is 10 mg/kg/day.
82
What is the spectrum of activity of ticarcillin?
Ticarcillin is a carboxypenicillin with activity against Pseudomonas aeruginosa and other Gram-negative bacteria.
83
What is the spectrum of activity of piperacillin?
Piperacillin is a ureidopenicillin with activity against Pseudomonas aeruginosa, Enterobacteriaceae, and Bacteroides fragilis.
84
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.
85
What is the incidence of skin rash with ampicillin?
The incidence of skin rash with ampicillin is increased, especially when combined with allopurinol.
86
What is the effect of food on the absorption of Penicillin V?
Food does not affect the absorption of Penicillin V.
87
What is the effect of food on the absorption of Amoxicillin?
Food does not affect the absorption of Amoxicillin.
88
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.
89
What is the incidence of hepatic injury with penicillins?
Hepatic injury is uncommon (1-4%) and usually reversible upon discontinuation of the drug.

PHARM 346 INFECTIOUS DISEASES (33 decks)

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