33. Cell Envelope Abx Flashcards
what GN bug is usually hospital acquired with intrinsic resistance vs many of our Abx?
pseudomonas
principles for prescribing antibiotics? (there are 5)
- what is the syndrome?
- Is it a bacterial or viral cause?
- what bacteria are important?
- what antibiotics will be effective?
- choose the most narrow-spectrum effective antibiotic considering allergies, potential toxicities, PK/PD
what are the categories of beta-lactam agents?
penicillins, cephalosporins, carbapenems, monobactams
synthesis of the peptidoglycan layer?
transglycosylase inserts/links new peptidoglycan monomers
transpeptidase (PBP) forms stabilizing peptide cross links (to create layers of chains/meshlike structure)
constantly remodeled - AUTOLYSINS break linkages to allow for addition of new monomers
antimicrobial agents that act on the cell wall are often bactericidal and kill what types of cells?
actively growing cells ONLY
antimicrobial agents that act on the cell wall kill in a _____-dependent fashion.
time
mechanism of action of penicillins?
B-lactam ring resembles D-ala-D-ala of peptidoglycan monomer and covalently (irreversibly) binds transpeptidase (PBP) so that it can’t work, the cell wall is weakened, and the cell die by osmotic lysis. Autolysins continue to work.
PCNs mechanisms of resistance?
B-lactamases (hydrolyze B-lactam ring - eg penicillinases, cephalosporinases, carbepenemases, ESBL)
modified PBPs (like PBP2A encoded by MecA gene of MRSA)
PCNs PK/PD?
bactericidal, high TI, good tissue penetration
renally excreted (need DAF), short 1/2 life (freq dosing)
PCNs adverse effects?
hypersensitivity, acute interstitial nephritis, seizures at high dose
Penicillin G?
- IV, short 1/2 life
- resistance (penicillinase) common
- GN cocci only
- GP cocci/anaerobes
- spirochetes
use for Neisseria Meningitides, streptococci, dental abscess/human bites (GP oral anaerobes), syphilis
semi-synthetic PCNs?
nafcillin (IV) and dicloxacillin (PO)
bulky R group can’t fit into many B-lactamases so increased activity vs S. aureus
still resistance due to altered PBP (PBP2A by MecA in MRSA)
GP only!
used for infections due to methicillin susceptible S. aureus
aminopenicillins
ampicillin (IV) & amoxicillin (PO)
slightly better spectrum of activity of PCN because some penetration through GN porins (effective vs. H.flu, E.coli but NOT pseudomonas)
still susceptible to B-lactamases
PCN adverse effects + GI distress, and pts w/mono who are tx w/amoxicillin will get maculopapular rash
use for CA HEENT and URIs (otitis media, epiglottists, sinusitis, pharyngitis, bronchitis), CA UTIs
ESBLs
extended-spectrum B-lactamases (mutations that enable them to degrade some Abx designed to resist B-lactamase cleavage)
B-lactamases are encoded where?
carried on plasmids, or encoded on chromosome. Txn constitutively OR induced by exposure to B-lactam Abx
B-lactamase inhibitors?
Resemble B-lactam Abx but have little or no antimicrobial activity alone – designed to bind to the B-lactamases so that they are hydrolyzed while B-lactam Abx remain intact and able to exert effect
Used in combo w/B-lactam Abx to extend spectrum of Abx to include B-lactamase-producing bacteria
super broad spectrum
use for Polymicrobial infections (skin/ST, intra-abd, odontogenic) or Empiric therapy if the causative agent is unknown (severe infection) *DO NOT USE WHEN NARROW SPECTRUM AGENS WOULD SUFFICE
ampicillin-sulbactam and amoxicillin-clavulonic acid
IV - amp-sulbactam
PO - amox-clavulanic acid
overcomes penicillinase resistance of S.aureus (not MRSA), use for B-lactamase producing GNs and anaerobes
piperacillin-tazobactam
vs S. aureus (not MRSA)
vs B-lactamase producing GNs (INCL PSEUDOMONAS) and anaerobes
cephalosporins mechanism of action and resistance?
B-lactam agents (more resistant to B-lactamases than PCN but resistance still significant)
intrinsic resistance (Pseudomonas, enterococci) altereed membrane permeability (porins, pseudomonas) altered PBPs (most afents not effective vs MRSA) B-lactamases (AmpC and ESBLs)
adverse effects of cephalosporins?
minimal, well tolerated
hypersensitivity and cross-reactivity w/PCN allergy
cephalosporins spectrum of activity?
most GP but none vs enterococci and only one vs MRSA
increasing GN w/increasing generations
no anaerobic
cephalosporins 1st generation?
Cefazolin (IV q8h), cephalexin (PO)
excellent tx penetration
penetrate outer membrane of many GN bacilli
used for surgical prophylaxis, skin/soft tissue infections (limited/resistance due to MRSA so dicloxacillin often used instead)
2nd generation cephalosporins?
cefoxitin (IV)
cefotetan (PO)
increased GN activity
GOOD ANAEROBIC ACTIVITY - AN EXCEPTION
used for prophylaxis for intraabdominal surgery
3rd generation cephalosporins
ceftriaxone (IV, q24h) for CA pneumonia, meningitis, serious infections, and HA UTIs
ceftazidime (IV) for pseudomonas
excellent GN activity
excreted through biliary tract (no DAF needed unless liver failure)
4th generation cephalosporins
cefepime (IV)
highly resistant to B-lactamases
vs PSEUDOMONAS
use for serious or resistant infections
5th generation cephalosporins?
ceftaroline (IV)
overcomes MRSA resistance (binds to PBP2A) but susceptible to ESBLs
only ceph w/MRSA activity
not good vs Pseudomonas (similar to 3rd generation)
cephalosporin PLUS b-lactamase inhibitors?
ceftolozane/tazobactam
ceftazidime/avibactam
overcomes resistance to some B-lactamases (incl common ESBLs)
extend activity of cephalosporins
use for GN, incl pseudomonas
useful for resistant infections, UTI and intraabdominal infections
carbapenems?
imipenem (given w/cilastatin), meropenem, ertapenem (qd)
resistant to B-lactamases, but emergence of carbapenemases (incl KPC and metallo-B-lactamases) and multiple agents (islands), challenging to treat
bactericidal
IV, needs DAF
same adverse effects as PCN (cross-reactivity w/PCN allergy)
good vs GP (but ertapenem has no enterococci activity)
good vs GN incl pseudomonas and ESBL producers (but ertapenem has no activity vs pseudomonas or acinobacter)
good vs anaerobes
use EMPIRICALLY FOR SERIOUS INFECTION TREATMENT OR RESISTANT INFECTIONS
what % of reported PCN allergies are true allergies?
10-15
monobactams
aztreonam IV (needs DAF)
little hypersensitivty, but little potency, so use for pts w/TRUE PCN allergy
use for ALL GNs (incl pseudomonas and anaerobes) but NO GPs
Glycopeptides mechanism of action and resistance?
action: binds to terminal D-ala-D-ala so inibits transglycosylase and transpeptidase
resistance thanks to alteration of binding site (vanA changes to D-ala-D-lac, also vanB, vanC, vanD, and vanE genes)
OR thanks to thickened cell wall (decreased penetration: VISA = vancomycin intermediate susceptible staph aureus = GISA)
Glycopeptides PK/PD
vancomycin
bactericidal, IV (oral doesn’t penetrate GI tract so use for C.diff)
renally excreted (needs DAF)
glycopeptides adverse effects, spectrum, and uses?
vancomycin
adverse effects: red man syndrome, nephrotoxicity (avoid other nephrotoxic agents), dose dependent ototoxicity (so MONITOR LEVELS)
spectrum of activity: GP only (incl MRSA) - GP anaerobes like c.diff
use: inferior to B-lactams, use for severe GP infectoins or when there are allergies to PCN OR oral for c.diff
cyclic lipopeptides?
daptomycin (IV, qd)
lipophilic tail inserts into cell membrane, K+ efflux, cell death without lysis
failures re: increased MIC to both vanc and daptomycin (thanks to thickened cell wall)
bactericidal
inhibited by pulmonary surfactant (don’t use for pneumonia)
concentration dependent
adverse: GI distress, headache, eosinophillic pneymonia, elevated CPK/rhabdomyolysis w/BID dosing (monitor and avoid statins)
GP only (incl MRSA and VRE)
use for complicated GP infections (skin/st; bacteremia; endocarditis)
polymixins?
polymixin B and colistin
binds to LPS and disrupts outer membrane
IV only or topical
NEPHROTOXICITY, neurotoxicity, bronchospasm if inhaled
GN only (not proteus, serratia, or burkholderia)
use for serious resistant GN infections (when no other choice)
bacitracin
topical, GP only
fosfomycin
oral powder, GP and GN, use for UTI only
oral cell envelope Abx?
amoxicillin, dicloxicillin, cephalexin
GP ONLY cell envelope Abx?
nafcillin, vancomycin, daptomycin, bacitracin
GN only cell envelope Abx?
aztreonam, polymixins
adverse events:
PCN?
vancomycin?
daptomycin?
PCN: hypersensitivity
Vancomycin: red man, nephro (oto) toxicity
daptomycin: rhabdomyolysis, eosinophilic pna
cell envelope Abx vs MRSA?
ceftaroline, vancomycin, daptomycin
