Penicillins Flashcards
β-lactam Mechanism of Action
watch video:
https://www.youtube.com/watch?v=qBdYnRhdWcQ
Penicillin Binding Proteins (PBPs)
• 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
Effects of E. coli PBPs
• 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
Resistance to β-Lactams
- 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)
Classes of Penicillin
Antibacterials
Natural Penicillins
Penicillin G, Penicillin V
Penicillinase-resistant Penicillins
Cloxacillin
Aminopenicillins
Ampicillin, Amoxicillin
Carboxypenicillins
(Ticarcillin → no longer available in Canada)
Ureidopenicillins
Piperacillin
Spectrum of Activity of
Penicillin G, Penicillin V
• 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
Spectrum of Activity of Penicillin G
see slide 11
Resistance to Penicillin
Staphylococcus aureus
• 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
Resistance to Penicillin
Staphylococcus epidermidis (CoNS)
• Most produce β-lactamase
• Many have changes in PBPs resulting in resistance to
almost all β-lactams (MRSE)
• MRSE Edmonton - ~50-70%
Resistance to Penicillin
Streptococcus pyogenes (Group A Streptococci)
• All susceptible!
NO REPORTS OF RESISTANCE
Some reports of reduced suscept
Resistance to Penicillin
Viridans Group of Streptococci
• resistance due to β-lactamase and transfer of
resistance gene PBP2b from S. pneumoniae
- (penicillin resistant UAH 20% 2012 ; 44% 2019)
Resistance to Penicillin
Streptococcus agalactiae (Group B Streptococci)
• 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)
Resistance to Penicillin
Streptococcus pneumoniae
• 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*)
Resistance to Penicillin
Enterococci
• 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)
Resistance to Penicillin
N. gonorrhoeae
- β-lactamase production
- decreased affinity of PBPs
- Can no longer use penicillin empirically for gonorrhea
Resistance to Penicillin
Enterobacterales
Enterobacterales are intrinsically resistant to penicillin due to:
- β-lactamase production
- reduced affinity for PBP
- cell wall impermeability
Summary Penicillin Resistance
see slide 20
Penicillinase-Resistant
Semi-synthetic Penicillins
cloxacillin role?
• 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
Aminopenicillins
- 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
Comparison of
Ampicillin/Amoxicillin Spectrum to Penicillin G
• 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%
Ampicillin
- Available IV, IM, PO
- PO → 30-60% absorbed, acid labile, (diarrhea)
• Well-distributed → CSF*, pleural, joint, and peritoneal
fluids
• ↑ incidence skin rash
Amoxicillin
• 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
Clavulanic Acid
Inhibitor?
- 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
Clavulanic Acid
Characteristics
- 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
- adult oral dose clavulanic limited to 125 mg/dose
- To prevent this:
Amoxicillin / Clavulanic Acid
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
Antipseudomonal Penicillins
• Carboxypenicillins (Ticarcillin) ???
(please check, this is crossed - out in the slide)
• Ureidopenicillins (Piperacillin)
Ureidopenicillins
Piperacillin / Tazobactam
• 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
Distribution of Penicillins
• 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
Metabolism / Excretion of Penicillins
• 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
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?
see slide 37
pen G, Cloxaxillin, ampicillin
Pen V better abs on empty stomach but not as important
Dosage Adjustments
• ↓ 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)
Adverse Effects
• 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 )
Adverse Effects – CNS Toxicity
• 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)
Adverse Effects – Renal
• 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
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 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
Adverse Effects – Gastrointestinal
• 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
Drug Interactions
• 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
