Cell Wall Agents (Bactericidal) Flashcards
what does the cell wall of gram negative bacteria look like
lipopolysaccharide and porins
what does cell wall of gram positive bacteria look like
murein (peptidoglycan outside)
how to build peptidoglycan
synthesis of murein monomers that are polymerized and crosslinked by transpeptidase
what are penicillin binding proteins
transpeptidases
what do PBP do
crosslink murein chains (to make peptidoglycan)
when do cell wall agents actually kill?
when cell walls are synthesizing
which drugs are inhibitors of murein monomer synthesis
- fosfomycin
- cycloserine
- bacitracin
MOA of fosfomycin
inhibits synthesis of UDP-NAM from UDP-NAG by inhibiting MurA
how does fosfomycin enter cell
via transporters for glycerophosphate or glucose 6 phosphate
what is fosfomycin used for
gram negative bacteria in urinary tract - single dose for uncomplicated lower UTI in women
what causes resistance to fosfomycin
mutations in transporters
what species does fosfomycin act against
e coli, klebsiella, serratia
MOA of bacitracin
interferes with dephosphorylation of bactoprenyl diphosphate, which is a bactoprenol lipid carrier necessary for murein monomer synthesis and export)
adverse effects of bacitracin
significant kidney, neuro and bone marrow toxicity so is not used systemically - only topically or GI tract
how is bacitracin used?
used to treat c diff or VRE in GI tract bc is not orally absorbed (stays in lumen)
which drugs are inhibitors of murein polymerization?
- vancomycin
- telavancin
- daptomycin
what kind of antibiotic is vancomycin
glycopeptide antibiotic
MOA of vancomycin
bind to D-Ala-D-Ala terminus of murein monomer unit, inhibiting peptidogylcan polymerization (blocks addition of murein units to growing polymer chain)
what is vancomycin effective against
gram positive ONLY rods and cocci including MRSA
orally for c diff
how is resistance against vancomycin occur
acquisition of DNA encoding enzymes that catalyze formation of D-Ala-D-lactate which is not bound by vancomycin, alter permeability
when is vancomycin used orally?
only for c diff (because not absorbed orally)
what is red man syndrome
flushing and itching that is due to vancomycin causing mast cell degranulation –> release of histamine
due to amount and rate of IV vancomycin infusion NOT IgE release or allergic reaction
ADE of vancomycin
nephrotoxic and ototoxic when given IV
which drugs bind to mast cells and cause degranulation?
vancomycin and morphine
when does red man syndrome occur
4-10min after start of vancomycin (or morphine) infusion or shortly after completion
how to monitor vancomycin levels
need to monitor the trough (level right before the next dose is due)
how is vancomycin cleared
renally
how does vancomycin have bactericidal activity
time dependent killing, bactericidal activity continues as long as plasma concentration is greater than minimum bactericidal concentration
what is daptomycin effective against
gram positive only
moa of daptomycin
bind to bacterial cell membrane, cause depolarization, disruption of functions and death
what is daptomycin used for
- MSSA/MRSA skin infections or bacteremia
2. right sided endocarditis
why can’t daptomycin be used for pneumonia?
is inactivated by pulmonary surfactant
ADE of daptomycin
myopathy (monitor CK) and nerve conduction deficits
how is daptomycin cleared
renally
what are the beta lactams?
- penicillins
- cephalosporins
- carbapenams
what is the general MOA of all beta lactams?
inhibit transpeptidases that mediate crosslinking because beta lactam ring is the structural analogue of terminal D-Ala-D-Ala
is bactericidal as long as cells are growing
what is D-Ala-D-ala
a substrate for one or more bacterial transpeptidases (penicillin binding protein)
beta lactam rings irreversibly bind to PCP
what are penicillin binding proteins?
transpeptidases that are responsible for synthesis of peptidoglycan wall (crosslink murein chains), and are the target of penicillin and cephalosporins
what determines beta lactam’s spectrum of activity?
- ability to enter periplasmic space
2. affinity for specific transpeptidases
what organisms are resistant to beta lactam drugs?
organisms that lack peptidoglycan cell walls – mycobacteria and protozoa
how do bacteria become resistant to beta lactam drugs?
produce beta lactamases that clip the beta lactam ring so it cannot bind to transpeptidase
how is beta lactam resistance transferred
encoded on DNA plasmids from 1 bacteria to the other
how are antistaphylococcal penicillins helpful against resistance?
have steric hinderence to beta lactamases that are produced by staph
what is added to beta lactams to help with resistance?
beta lactamase inhibitors added to prevent beta lactamase catalyzed degradation of penicillin
what drugs prevent beta lactamase from degrading the drugs?
cephalosporins and carbapenams because of steric hinderance – but extended spectrum beta lactamase and carbapenemases have emerged to resist
how are bacteria beta lactam resistant
have alterations in or acquisition of PBP, but most drugs are active against multiple transpeptidases so the bacteria would have to mutate ALL PBP to be fully resistant
what are gram positive bacteria inherently resistant to?
aztreonam
what are enterococci inherently resistant to
cephalosporins
how is MRSA so resistant to everything
has altered ALL of its PBP so it has inherent resistance to beta lactams
what is MRSA NOT resistant to
ceftaroline
how to gram negative bacteria become beta lactam resistant
they alter their porins
how do intracellular bacteria have resistance
mammalian cells lack beta lactam uptake mechanism
which are the beta lactamase inhibitors
- clavulanic acid
- sulbactam
- tazobactam
MOA beta lactamase inhibitors
resemble beta lactam molecules so the bacteria recognize them and cleave them instead of the “real drug”
what is amoxicillin/clavulanate
beta lactamase inhibitor - augmentin
what is augmentin used for
- acute otitis media where beta lactamase positive strains are likely
- URI
- UTI
- soft tissue when caused by beta lactamase + strain (MSSA)
why is it hard to kill bacteria attached to implanted devices (biofilms)?
because beta lactams are most active in the logarithmic phase (takes out walls as they are produced)
what if a pt has an IgE mediated reaction
do not use other beta lactams because there could be cross reactivity
what if a pt has type IV hypersensitivity
can use other beta lactams
beta lactam ADE
- type I or IV hypersensitivity
- interstitial nephritis
- rash
- eosinophilia
- serum sickness (drug fever)
- hemolysis (lupus)
what ADE occurs at high doses or in renal impaired pt?
seizures because beta lactams are GABA antagonists
how is ceftriaxone cleared
lipophilic so ceftriaxone is highly bound to albumin. it can displace bilirubin from albumin binding to sites in neonates (causing hyperbilirubinemia)
why is ceftriaxone contraindicated in neonates
can displace bilirubin from albumin binding to sites in neonates – hyperbilirubinemia
why is impienem dangerous
high high risk of seizures bc GABA antagonist
how are most beta lactams cleared?
renally cleared except ceftriaxone
what does penicillin have greatest activity
gram + and gram - cocci, non beta lactamase producing anaerobes
what are antistaphylococcal penicillins effective against
staph and strep
NOT enterococci, anaerobic and gram negative cocci and rods
what are extended spectrum penicillins effective against
greatest activity against gram + and gram - cocci and non beta lactamase producing anaerobes, improved activity against gram - organisms
what is the drug of choice for syphillis
penicillin
what is penicillin G or V effective against
NOT USED IN STAPH
strep, syphilis, g+ anaerobes except bacteriodes or c diff, neisseria, spirochetes
half life of penicillin
30-90min
when can pregnant women take penicillin?
if they have T palladium – is super effective against t pallidium
which are the aminopenicillins
ampicillin and amoxicillin
spectrum that aminopenicillins cover
non beta lactamase producing neisseria, escherichia, haemophilus, enterococci, listeria, h pylori, klebsiella
what if add beta lactamase to aminopenicillin?
cover h influenzae and enterobacteriaceae
what are aminopenicillins first line for?
acute otitis media, neonatal meningitis (with gentamicin), uncomplicated enterococcal or proteus mirabilis UTI, dental prophylaxis
what are the penicillinase-resistant penicillins
- oxacillin
- nafcillin
- cloxacillin
- methicillin
what are the penicillinase resistant penicillins against
antistaphylococcal – for confirmed staph infections – endocarditis, osteomyelitis, skin/soft tissue, pneumo
also for strep bacteria
what does naficillin cover
gram + only
which are the antipseudomonal penicillins?
ticarcillin
piperacillin
what has the broadest spectrum of penicillins
piperacillin when combined with tazobactam
what is the spectrum of antipseudomonal penicillins
staph aureus, coag negative strep, strep pneumo, strep species, h influenzae, moraxella catarrhalis, neisseria meningititis, neisseria gonorrheae, e coli, klebsiella, pseudomonas, enterobactericeae, bacteriodes
what can cause MSSA
beta lactamases
what can cause MRSA
is inherently resistant
how is amoxicillin absorbed?
extensively absorbed PO so not good for shigella or salmonella
are penicillins safe for pregnancy?
generally
most common resistance to penicillins
inactivation by beta lactamase
how do pneumococci and enterococci have resistance to penicillins
modification of target PBP
how do gram - have resistance to penicillins?
impaired penetration of drug to target PBP and increased antibiotic efflux
what are cephalosporins NOT effective against
- listeria monocytogenes
- atypical pathogens in pneumonia like mycoplasma or chlamydia
- MRSA except 5th gen
- enterococci
“LAME”
what are cephalosporins susceptable to
ESBL but not most “wimpy” beta lactamases
what are 1st gen cephalosporins effective against
gram +
some gram -
2nd gen cephs effective against
better gram -
less gram+
some anaerobes
3rd gen cephs effective against
better gram - than the 2nd
some anaerobes
less + than 1st
4th gen cephs effective against
better gram -
some anaerobes
less +
PSEUDOMONAS
5th gen cephs effective against
better gram -
some anaerobes
less +
MRSA
which are the 1st gen cephalosporins
- cephalexin
- cefazolin
don’t let the LEXicon FAZe you, 1st gen are the only ones with a PH
1st gen ceph effective against
gram + plus PEcK
proteus
e coli
klebsiella
UTI caused by these plus saprophyticus
2nd gen cephalosporins
cefprozil cefotetan cefoxitin cefuroxime cefaclor
she nearly FPROZ going through the TETons so she wore her FOX FUR FACe
what do 2nd cephs cover
gram + plus HENPEcK
haemophilus, enterobacter, neisseria, proteus, e coli, klebsiella
what 2nd gen may cover bacteroides fragilis? for abd or gyn surgeries
cefotetan and cefoxitin
tetans have foxes
what are cefuroxime/cefprozil used for
lymes, acute otitis media, URI
what are the 3rd gen cephalosporins
cefdinir
ceftriaxone
cefazidime
cefotaxime
what are 3rd gen cephs effective against
enterobacteriaceae, neisseria, h influenzae, pneumococci
which 3rd gen are helpful against pneumococci
ceftriaxone
cefotaxime
what 3rd gen ceph is used for pseudomonas
ceftaxidime
what is a 4th gen ceph
cefepime
what does cefepime cover
broad spectrum including PSEUDOMONAS
what is a 5th gen ceph
ceftaroline
what does ceftaroline cover
like ceftriaxone (pneumo-CAP) that covers MRSA
what are the carbapenams
- imipenem/cilastatin
- ertapenem
- doripenem
- meropenem
what are carbapenams not effective against
atypical pneumonia, legionella, MRSA, or carbapenamase producing strains
what are carbapenams effective against
ESBL gram - (but not carbapenamase +), PSEUDOMONAS, actinobacter, anaerobes
what is added to imipenem and why
cilastatin to prevent deactivation by dipeptidases in the renal brush borders – the inactivation results in low urinary concentration
adverse effects carbapenams
seizures (imipenem)
what is the monobactam
aztreonam
what is aztreonam safe in
safe even in severe beta lactam allergy (except ceftazidime bc has identical side chain)
profile of aztreonam
aerobic gram -, including PSEUDOMONAS
what to do if type I hypersensitivity to penicillin, cephalosporin, carbapenam?
avoid other classes (can use aztreonam) unless benefit outweighs risk
what to do if type IV hypersensitivity to beta lactams?
just switch to different class
use of cell wall agents in neonates
ceftriaxone may displace bilirubin so don’t use it, don’t give IV calcium with it
what cell wall agents are safe in pregnancy
vancomyin and beta lactams general safe
what are cephalosporins not effective against?
enterococcus, MRSA, listeria, atypical pneumonia
