Penicillins Flashcards
Pure penicillin is ____ to degradation by acids.
highly susceptible; pH was 5-7
Serial passages of penicillin over ____and ____ results in resistant organisms.
staphylococcus; streptococcus species
Organisms that are inherently resistant to penicillins
Gram - bacilli
Peniciilins have a ___ safety margin compared to other available compounds.
WIDE
Structure of Penicillin: nucleus
beta-lactam and thiazolidine rings
Nucleus is important because:
required for biological activity
Breakdown of beta-lactam by beta-lactamase results in
loss of activity
Acyl side chain modifications
change spectrum of activity, stability to enzymes, and pharmacokinetic properties
MOA for Penicillin
PEN inhibits transpeptidase responsible for cross-linking peptide chains resulting in a dysfunctional wall
Normal function of PBP:
synthesize peptidoglycan, maintain cell shape, and septum formation
Disruption of cell wall stimulates
autolysis and cell death
Penicillin G could be given:
orally, IV, IM
Penicillin G benefits over other agents:
readily distributed into multiple tissues and wide therapeutic index (safe)
Penicillin G challenges:
rapid acid degradation, susceptibility to beta-lactamases, narrow spectrum of activity
Natural Penicillins oral absorption:
PCN VK (60%) >PCN G (30%)
Natural Penicillins 1/2 life
short
Natural Penicillins route of elimination
renal
Natural Penicillins CSF distribution
better into inflamed than non-inflamed but still poor
Natural Penicillins protein binding
50
PCN VK is more/less stable than PCN G
more, produces 2-5x greater serum concentration
Natural Penicillins can/cannot be removed by hemodialysis
can
Bacterialcidal activity for beta-lactams is measured by
T>MIC; duration of time that free drug levels exceed MIC
for stasis:
for cidal:
30%
50%
Spectrum coverage for Natural PCNs
dark purple: streptococcus spp, S. pneumoniae, E. faecalis
light purple: viridans strep
dark red: Neisseria spp
anaerobes: +/- (oral +)
Misc: T. pallidum (syphillis), B. burgdorferi (Lyme)
Common indications for Natural PCNs
syphilis (dosing depends on stage of syphilis) neurosyphilis endocarditis meningitis streptococcal pharyngitis streptococcal toxic shock
Long acting parenteral agents:
Penicillin G procaine, penicillin G benzathine (Bicillin LA), penicillin G benzathine/procaine (Bicillin CR)
Long acting parenteral agents administration
IM; avoid IV due to increased risk of cardiac arrest
Purpose for developing PCN long acting parenteral agents
developed in response to short half-life and poor oral absorption of PCN
Penicillinase resistant penicillins active against penicillinase producing staph aureus:
Oxacillin and Nafcillin
Spectrum coverage for oxacillin and nafcillin:
GRAM + ONLY
dark purple: streptococcus, s.pneumoniae, MSSA/MSSE
light purple: viridans
Nafcillin/Oxacillin oral absorption:
poor oral, IV only
Nafcillin/Oxacillin 1/2 life:
short
Nafcillin/Oxacillin Route of elimination:
hepatic, biliary
Nafcillin/Oxacliin distribution
skin joint lung urine CSF with inflammation bile peritoneal
Nafcillin/Oxacliin dosing
the same for both and varies with infection; can be administered as continuous infusion
Nafcillin/Oxacliin challenges
poor oral absorption due to gastric acid breakdown
Dicloxacillin oral bioavailability
increased 50% from Nafcillin/Oxacliin
Dicloxacillin protein binding
high
Dicloxacillin 1/2 life
short
Purpose of isoxazoyl group in dicloxacillin
mitigates penicillinase and gastric acid breakdown
Dicloxacillin used for
treatment of mild bacterial skin/skin structure infections
Resistance mechanisms for penicillins
alterations in PBPs (s. pneumo/neisseria, enterococcus)
PCN penicillinase (s.aureus) Oxacillin/methicillin resistance by altering PBP2 (s.aureus)
Adverse effects for Pencillins
well tolerated neurologic GI hepatic renal allergy electrolyte abnormalities hematologic thrombophlebitis
Penicillins have a ____ spectrum of activity
narrow
Penicillins are primarily used as ___ therapy
definitive
Penicillins are bactericidal/bacteriostatic
bactericidal
Extended spectrum penicillins include
aminopenicillins and ureidopenicillins
Clinical needs for extended spectrum penicillins
safe antimicrobials
improved gram - activity by enhancing penetration through outer membrane and having higher affinity for PBP
Ampicillin has enhanced cell wall penetration because it is a
zwitterion at neutral pH
Zwitterions penetrate through ____ within the cell membrane
porins
Ampicillin oral absorption:
50% (fair)
Ampicillin elimination:
RENAL
Ampicillin 1/2 life:
short
Ampicillin is associated with which side effect:
diarrhea
Ampicillin has saturable
absoprtion
Ampicillin tissue penetration
lung, bone, CNS with inflammation
Amoxicillin is administered
orally only in the US
Amoxicillin oral absorption
75% so higher than ampicillin
Amoxicillin has ____ frequency of diarrhea
reduced
Amoxicillin is primarily used for
URI
Amoxicillin has activity against ____ so it can be used for URI
s. pneuomoniae
Amoxicillin dosing depends on
indication
Ampicillin/Amoxicillin spectrum coverage:
dark purple: streptococcus, S. pneumoniae, E. faecalis
light purple: viridans, E. faceium
dark red: Neisseria
light red: H. influenzae, E. coli, P. mirabilis
anaerobes: +/- (oral +)
Misc: L. monocytogenes, H. pylori, Salmonella, Shigella
** not stable against penicillinase **
Common indications for Ampicillin/Amoxicillin
Empiric therapy: Group A strep s.pneumoniae (high dose amoxicillin) H.pylori Listeria (especially CNS) use ampicillin
Definitive therapy:
Enterococcus
S. pneumoniae
H. influenzae (beta-lactamase negative)
Sulbactam is added to ampicillin to
minimize impact of beta lactamases
Sulbactam is a _____ inhibitor
suicide
Suicide inhibitor
permanently inactivates beta-lactamases and cannot be recycled
also has minor PBP inhibitory properties
Spectrum of inhibition for ampicillin/sulbactam
penicillinases (MSSA)
cephalosporinases (klebsiella)
broad spectrum beta lactamases (E. coli)
Sulbactam has weak intrinsic activity against
Neisseria and acinetobacter
Ampicillin/sulbactam oral absorption
50/20
Ampicillin/sulbactam 1/2 life
short
Ampicillin/sulbactam elimination
RENAL
Ampicillin/sulbactam is administered
IV only as combo in 2:1 ratio
Sulbactam tissue penetration
CSF- similar to ampicillin in inflamed cases
lung- similar to ampicillin
bone- 15% so less than ampicillin
Clavulanate is a ____ inhibitor
suicide
Clavulanate extends amoxicillin’s spectrum of activity through
inhibition of beta-lactamases
Clavulanate does not have activity against
acinetobacter
Clavulanate has activity against
s. aureus, h. influenzae, E. coli, klebsiella, p. mirabilis, salmonella, shigella, norcardia, and some mycobacterium
Amoxicillin/clavulanate oral absorption
high 75/75
Amoxicillin/clavulanate 1/2 life
short
Amoxicillin/clavulanate elimination
renal/ hepatic-renal
Amoxicillin/clavulanate adverse effects
diarrhea! from clav component and less diarrhea is seen with newer formulations
Amoxicillin/clavulanate dosage forms
tablet, ER tablets, liquid
Aminopenicillin + inhibitor spectrum coverage:
dark purple: streptococcus, s. pneumoniae, MSSA/MSSE, e. faecalis
light purple: viridans, e. faecium
dark red: Neisseria, h. influenzae, m. catarrhalis, E. coli, klebsiella, p. mirabilis
light red: morganella
anaerobes: ++ (oral and gut b. fragilis)
Misc: similar to ampicillin for acinetobacter
Ampicillin/sulbactam indications
empiric use:
surgical prophylaxis for intra-ab surgery
head and neck infections
sinus infections
XDR acinetobacter infections (due to sulbactam activity)
definitive:
- intra-ab infections
- gynecologic infections
- head and neck infections
Amoxicillin/clavulanate indications
URI like sinusitis, outpatient community acquired pneumonia, otitis media, strep throat
Ureidopenicillins have a ___ spectrum of activity
broader
Ureidopenicillins have
enhanced cell wall penetration and improved binding affinity to multiple PBP
Ureidopenicillin drug
pipercillin/tazobactam
Pipercillin/tazobactam oral absorption
poor
Pipercillin/tazobactam administration
IV only
Pipercillin/tazobactam 1/2 life
short
Pipercillin/tazobactam elimination
renal: 68/80 mostly renal
biliary: 20/20
Pipercillin/tazobactam penetration into CNS
not good
Pipercillin/tazobactam penetration into tissues
bile, lung, skin, urine, bone, peritoneum
Pipercillin/tazobactam spectrum coverage:
dark purple: streptococcus, s. pneumoniae, MSSA/MSSE, E. faecalis
light purple: viridans, E. faecium
dark red: Neisseria, h. influenzae, m. catarrhalis, E. coli, klebsiella, p. mirabilis, morganella, enterobacter, citrobacter, serratia, p. aeruginosa
light red: acinetobacter
anaerobes: ++ oral and gut
Misc: variable activity against ESBL and AmpC
Pipercillin/tazobactam indications
healthcare associated infections (suspicion for multi drug resistant organisms)
intra-ab infections
pneumonia
complicated skin/skin structure infections
fever and neutropenia
NOT GOOD FOR CNS/MENINGITIS
Pipercillin/tazobactam adverse effects
well tolerated neurologic GI hepatic (kcholestatis jaundice is higher than other PCNs) renal allergy electrolyte imbalance (sodium overload) hypokalemia hematologic thrombophlebitis
Which organism do all PCN drugs not cover?
MRSA/MRSE
Which PCN drug/derivative covers p. aeurginosa and acinetobacter?
pipercillin/tazobactam
Which PCN drug/derivative covers B. fragilis (gut anaerobes)?
pipercillin/tazobactam and aminopenicillins+inhibitor
In the hospital setting _____ is the most used PCN agent due to its broad spectrum of activity
pipercillin/tazobactam
