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346 > Penicillins > Flashcards

Penicillins Flashcards

1
Q

β-lactam Mechanism of Action

A

watch video:

https://www.youtube.com/watch?v=qBdYnRhdWcQ

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2
Q

Penicillin Binding Proteins (PBPs)

A

• Enzymes which act as catalysts in synthesis of the
peptidoglycan cell wall

• Many different types and amounts of PBPs in different
bacteria (related bacteria similar)

• Numbered by decreasing size in each different type of
bacteria.

  • Therefore: PBP1 in S. aureus ≠ PBP1 in E. coli
  • Different PBPs may have different effects on cell
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3
Q

Effects of E. coli PBPs

A

• PBP 1a, 1b cause cell elongation
(inhibition causes rapid cell lysis)

• PBP 2 determine bacterial shape
(inhibition → stable round forms which grow for several
generations then lyse)

• PBP 3 involved in cell division
(inhibition → filamentous forms which grow for 5-6
generations then become deformed and die)

• PBP 4, 5, 6 of little consequence

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4
Q

Resistance to β-Lactams

A
  • Production of β-lactamases
  • Reduced affinity of PBP for β-lactam antibacterials
  • Impermeability of cell membrane
  • Efflux
  • Organisms lacking a cell wall, (e.g., Mycoplasma)
  • Tolerance (↓ activity of autolysins)
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5
Q

Classes of Penicillin

Antibacterials

A

Natural Penicillins
Penicillin G, Penicillin V

Penicillinase-resistant Penicillins
Cloxacillin

Aminopenicillins
Ampicillin, Amoxicillin

Carboxypenicillins
(Ticarcillin → no longer available in Canada)

Ureidopenicillins
Piperacillin

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6
Q

Spectrum of Activity of

Penicillin G, Penicillin V

A

• Most active against non-β-lactamase producing
Gram-positive bacteria, but we have seen increasing
resistance

• Anaerobes (Gram-positive)

  • However, there are β-lactamase producing strains
  • B. fragilis is Gram-negative and not covered

• Selected Gram-negative cocci
- e.g., Neisseria meningitidis

penV more resistant to stomach acid especially with potassium salt

penG more orally
Narrow spetrum
Not for empiric treatment
Known pathogen

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7
Q

Spectrum of Activity of Penicillin G

A

see slide 11

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8
Q

Resistance to Penicillin

Staphylococcus aureus

A

• most now produce β-lactamases

• some have altered PBPs (MRSA)
- PBP2a are produced that can take over role of PBPs
bound by penicillins - results in resistance to almost
all β-lactams
- Incidence MRSA Edmonton
* Dynalife 2008 (19%), 2019 (25%)
* UAH 2008 (28%), 2019 (23%)

• in some areas in US > 50% of S. aureus are MRSA

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9
Q

Resistance to Penicillin

Staphylococcus epidermidis (CoNS)

A

• Most produce β-lactamase

• Many have changes in PBPs resulting in resistance to
almost all β-lactams (MRSE)

• MRSE Edmonton - ~50-70%

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10
Q

Resistance to Penicillin

Streptococcus pyogenes (Group A Streptococci)

A

• All susceptible!

NO REPORTS OF RESISTANCE
Some reports of reduced suscept

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11
Q

Resistance to Penicillin

Viridans Group of Streptococci

A

• resistance due to β-lactamase and transfer of
resistance gene PBP2b from S. pneumoniae
- (penicillin resistant UAH 20% 2012 ; 44% 2019)

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12
Q

Resistance to Penicillin

Streptococcus agalactiae (Group B Streptococci)

A

• Canada - All susceptible

• 4 clones with reduced susceptibility to β-lactams
reported due to point mutation
(AAC Aug 2008, pg 2915-2918)

• (resistant strain reported in cattle - altered PBP)

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13
Q

Resistance to Penicillin

Streptococcus pneumoniae

A

• S. Africa, Spain (50%), U.S.A. (30 - 50%),
Canada (~20%)
- altered PBPs

• Dynalife Community (% non-susceptible)

  • 2006 - 11% non-susceptible
  • 2019 - 9% non-susceptible
  • 2019 - 12% (Meningeal*)
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14
Q

Resistance to Penicillin

Enterococci

A

• β-lactamase production, altered PBPs rare with E.
faecalis, but more common with E. faecium

• Enterococcus faecalis
- 100% Susceptible to ampicillin/amoxicillin (2019
Edmonton community)
- 99% Susceptible to ampicillin/amoxicillin (2019 UAH)

• Enterococcus faecium
- 36% susceptible to amp/amox (2019 Edmonton
Community)
- 8% susceptible to amp/amox (2019 UAH)

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15
Q

Resistance to Penicillin

N. gonorrhoeae

A
  • β-lactamase production
  • decreased affinity of PBPs
  • Can no longer use penicillin empirically for gonorrhea
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16
Q

Resistance to Penicillin

Enterobacterales

A

Enterobacterales are intrinsically resistant to penicillin due to:

  • β-lactamase production
  • reduced affinity for PBP
  • cell wall impermeability
17
Q

Summary Penicillin Resistance

A

see slide 20

18
Q

Penicillinase-Resistant
Semi-synthetic Penicillins

cloxacillin role?

A

• Bulky side chain provides β-lactamase resistance with
staphylococci (protects site on β-lactam ring from
bindingto β-lactamase breaking open the β-lactam
ring)

• ↑ activity against β-lactamase producing
staphylococci, but not methicillin-resistant
staphylococci (MRSA, MRSE)

• Cloxacillin has a limited spectrum
- Penicillin and ampicillin are more active against
Streptococci
- Cloxacillin usually only used to treat skin infections
with S. aureus and S. pyogenes
- inactive against Enterococci, Listeria, and Gram
negatives

19
Q

Aminopenicillins

A
  • Amino group added to side chain
  • ↑ entry into cell, ↑ affinity for PBP

• ↑ spectrum against “easily killed” Gram-negatives
(H. influenzae, E. coli, Proteus mirabilis)

• But resistance developing due to β-lactamase
production
- N. gonorrheae, H. influenzae, E. coli, P. mirabilis

• Some resistance due to changes in PBPs
- e.g., some H. influenzae (~5%) have changed PBPs

20
Q

Comparison of

Ampicillin/Amoxicillin Spectrum to Penicillin G

A

• more active against

  • S. pneumoniae (97% Susceptible – Dynalife Dx 2019)
  • Enterococcus
  • L. monocytogenes
  • ↑ Gram-negative effect, but now many resistant
  • % Susceptible Dynalife (Community) 2019
    • H. influenzae 76%
    • E. coli 56%
    • Proteus mirabilis 69%
21
Q

Ampicillin

A
  • Available IV, IM, PO
  • PO → 30-60% absorbed, acid labile, (diarrhea)

• Well-distributed → CSF*, pleural, joint, and peritoneal
fluids

• ↑ incidence skin rash

22
Q

Amoxicillin

A

• Only available PO (unless combined with
clavulanic acid – IV formulation available)

• Relative to ampicillin

  • ↑ resistance to gastric acid (can take with food)
  • ↑ absorption (2 - 2.5 x blood levels of ampicillin)
  • less diarrhea
23
Q

Clavulanic Acid

Inhibitor?

A
  • β-lactamase Inhibitor
  • irreversibly binds to β-lactamase (suicide inhibitor)
  • combined with amoxicillin (Clavulin®, Augmentin®)

• inhibits plasmid-mediated β-lactamases of
Staphylococci, H. influenzae, M. catarrhalis, some
Enterobacterales (Enterobacteriaceae), B. fragilis

24
Q

Clavulanic Acid

Characteristics

A
  • well absorbed orally
  • t 1/2 1 hour (similar to amoxicillin)
  • 25 - 40% excreted unchanged in urine
  • excretion not inhibited by probenecid
  • few side effects on its own - diarrhea / nausea
    • To prevent this:
      • adult oral dose clavulanic limited to 125 mg/dose
        (i. e., BID-TID)
      • Maximum dose children 10 mg/kg/day
      • does not cross into the CSF well
25
Q

Amoxicillin / Clavulanic Acid

A

Expanded spectrum includes:

• β-lactamase producing Staphylococci (not MRSA,
MRSE),

• Haemophilus influenzae, Moraxella catarrhalis

• Many Enterobacterales (E.coli, Klebsiella
pneumoniae, Proteus mirabilis)

• Not AmpC β-lactamase producing Enterobacterales
or Pseudomonas

• Bacteroides spp., including B. fragilis

26
Q

Antipseudomonal Penicillins

A

• Carboxypenicillins (Ticarcillin) ???
(please check, this is crossed - out in the slide)

• Ureidopenicillins (Piperacillin)

27
Q

Ureidopenicillins

Piperacillin / Tazobactam

A

• Spectrum of activity includes
- β-lactamase producing Staphylococci (not MRSA)
- Streptococci and Enterococci (comparable to
ampicillin/amoxicillin)
- Good activity against Pseudomonas aeruginosa
* UAH – 84% Susceptible (2019)
* Edmonton Community – 94% Susceptible (2019)
- H. influenzae, M. catarrhalis
- Many Enterobacterales, including ESBL* producing
E.coli, Klebsiella
- Bacteroides fragilis

• Does not improve activity against AmpC producing
  “SPICE A” organisms
  - Serratia, 
    Providencia, 
    Indole-positive Proteus (P. vulgaris), 
    Citrobacter, 
    Enterobacter,
    Acinetobacter
28
Q

Distribution of Penicillins

A

• well distributed to most areas

• in presence of inflammation - good levels middle ear,
pleural, peritoneal, and synovial fluids and adequate
CSF levels

• in absence of inflammation
- levels minimal in CSF, eye, brain, prostate
- in CNS – inflammation permits entry and alters anion
pump that removes penicillins from CNS (as in
meningitis)

• Protein binding variable
- 17% ampicillin - 94% cloxacillin

29
Q

Metabolism / Excretion of Penicillins

A

• Most excreted intact by kidneys by glomerular
filtration and renal tubular secretion

• Most have high levels in urine, even with moderate
renal failure
- but once CrCl < 10 mL/min, urine levels not > blood
levels

• minor degree metabolism in all

• some degree of biliary excretion in all, particularly with
  antistaphylococcal penicillins (e.g., cloxacillin)

• t 1/2 vary 30 - 72 min

30
Q

Various Penicillins
comparison of % absorbed, effect of food, protein binding %, % metabolized, t 1/2 h CrCl > 90,
t 1/2 h CrCl < 10

which ones have asborbtion affected by food and should be taken on empty stomach?

A

see slide 37

pen G, Cloxaxillin, ampicillin

Pen V better abs on empty stomach but not as important

31
Q

Dosage Adjustments

A

• ↓ renal function elderly, neonates, and those with
compromised renal function

• CrCl < 10 ml/min
- slight reduction in most
- No change for cloxacillin (hepatic and biliary
compensation)

32
Q

Adverse Effects

A

• Main adverse effects of penicillins are hypersensitivity
reactions ranging from rash to anaphylaxis

• 1-10% of patients receiving penicillin will have an
adverse reaction, including allergy

• Estimated as many as 1/2 of all allergic reactions
occurring in hospital are due to β-lactam antibacterials
( Bugs & Drugs )

• 0.01-0.02% treated with parenteral penicillin have life
threatening anaphylactic reactions, with a fatality rate
of 0.0015-0.02% ( Bugs & Drugs )

33
Q

Adverse Effects – CNS Toxicity

A 
• Myoclonic Seizures (Rare)
  - More likely if penicillin given
  - Large Doses
  - (usual adult dose penicillin ranges from 500,000U
     bid – 2 million units q2h)

• Or penicillin given in patients with renal failure without
dosage adjustment
- (direct application to cortex → seizures)
- (instillation into ventricles at the time of shunt
placement no seizures)

34
Q

Adverse Effects – Renal

A

• Interstitial Nephritis <1% (Type III Reaction)
- Rare - ranges from allergic angiitis to interstitial
nephritis
- fever, rash, eosinophilia, proteinuria, hematuria
- may progress to anuria and renal failure
- Usually only after long term, high dose therapy
- most common with methicillin, but may occur with any
penicillin
- most return to normal after discontinue drug

35
Q

Adverse Effects – Hematologic

A

• 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 sometimes be tolerated
- In patients with previous hemolytic reaction to
pencillin, re-administration of pencillin may result in a
rapid hemolytic response resulting in death

• Coombs positive hemolytic anemia
- Rare
- Type II reaction
* penicillin binds to RBC
* antibody forms
* Complement is fixed and Membrane Attack
Complex (MAC) forms with destruction of RBC

36
Q

Adverse Effects – Gastrointestinal

A

• Hepatic
- ↑ alkaline phosphatase, ↑ AST
- most often in past with oxacillin, carbenicillin (which
we don’t use clinically now)
- hepatic injury uncommon (1- 4%) - enzymes return to
normal when discontinue drug

37
Q

Drug Interactions

A

• Allopurinol and Ampicillin
- increased incidence of rash ( up to 14 - 22.4%)

  • Oral Contraceptives
  • Aminoglycosides (synergy; in vitro inactivation)
Prolong half life of 
Avoid giving together
Separate by hours
Ynergistic
Inactivate each other in vitro

• Probenecid (reduced excretion/increased levels)
Prolonged dosing intervals, purposely given with beta lactams

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