Cell Wall Antibiotics - Gartenberg 5/3/16 Flashcards
penicillin
penicillin G
amoxacillin
cloxacillin
beta lactamase inhibitors
clavulanic acid
avibactam
cephalosporins
cefazolin (1gen)
cefamandole (2gen)
ceftazidime (3gen)
cefepime (4gen)
ceftolozane (latest)
cephalosporins for MRSA
ceftaroline
monobactam
aztreonam
carbapenem
imipenem
glycopeptides
vancomycin
oritavancin
dalbavancin
lipopeptides
daptomycin (pore former)
polymyxin (membrane disruptor)
inhibitors of peptidoglycan precursors
fosfomycin
bacitracin
D-cycloserine
life threatening infection
what’s the treatment protocol?
treat immediately with broad spectrum
use cultures and testing to determine sensitivites of serious/mysterious infections
once pathogen identified, switch to narrow spectrum
bacterial cell wall
Gram + : thick peptidoglycan
- enzymes synthesizing peptidoglycans would make good targets
Gram - : thin peptidoglycan sandwiched between pl mem and outer lipid mem
- peptidoglycan can only be targeted if enzymes can permeate the outer mem to get to it
broad spectrum
extended spectrum
broad spectrum: works against Gram + and Gram - bacteria
extended spectrum: drug with broadened selectivity due to chemical modification
chemical structure of peptidoglycan
polysacch chains (NAGlucosamine, NAMuramic acid) with peptide linkers hanging off
-
Gly hanging off of Lys is used to crosslink peptide chains → results in the loss of an Ala (from the end: D-Ala-D-Ala)
- Gram + = 5 Gly
- Gram - = 0 Gly
why do bacterial use D a.a.s?
oftentimes, enzymes responsible for degrading a.a.s only recog L a.a.s → D a.a.s act as defense mech to avoid recog
assembly of peptidoglycan
NAM-NAG with peptide linker is synthesized on inside of the pl mem, then flipped to outside
transglycosylase enzymes join sugars to make polysacch chains
transpeptidase enzymes cross link peptide chains (with removal of a D-Ala from the linker being added)
- target for beta lactams (ex. penicillins)
beta lactam antibiotics
core structures of primary beta lactam families:
- penicillin (mimics D-Ala-D-Ala of peptide linker)
- monobactam
- cephalosporin
- carbapenam
mechanism of action:
typically, transpeptidase (with Ser) kicks off terminal D-Ala → Gly from second peptide linker kicks off Ser, attaches to form cross link
- penicillin irreversibly binds transpeptidase (bc it looks like D-Ala-D-Ala) → “dead” enzyme → no crosslinking
- bacteria that are growing can’t get the structural integrity they need → lysis
bacterial beta lactamases
serine beta lactamases are similar to transpeptidases BUT are able to use water to cleave a Ser-lactam linkage
- hydrolyzed beta lactam : no activity → drug no longer effective
metallo beta lactamases hydrolyze lactams via diff mech
beta lactamase inhibitors
clavulanic acid
sulbactam
tazobactam
no antibacterial activity in and of themselves → combined with beta lactams to extend half life
- covalently bind beta lactamases, irreversibly inactivate them
lactamases can be of two types:
- chromosomoally encoded : inducible expression
- plasmid encoded : constitutively expressed
avibactam
broad spectrum beta lactamase inhibitor
Ser beta lactamases come in class A, C, D
- traditional beta lactamase inhibitors work mostly on A
- avibactam works on A, C, and some D
coformulated with cephalosporin, ceftazidime
**does not contain beta-lactam core
what’s the difference between…
common penicillins
anti-staphylococcal penicillins
extended-spectrum penicillins
common penicillin - penicillin G
- acid labile
- beta lactamase susceptible
anti-staph penicillin - oxacillin, cloxacilin, dicloxacillin (0, 1, 2 Cl)
- acid stable
- beta lactamase resistant
- not suitable for Enterococci or Gram negative cocci/bacilli
extended-spectrum penicillin - amoxicilin
- acid stable
- ability to penetrate outer membrane → greater activity against Gram -
- inactivated by lactamases
penicillins
- administration
- elimination
- adverse rxn
- resistance
administration
- oral (1 hr before or after food - avoid binding food proteins), IV, IM w/ anesthetic
elimination
- rapid active secretion (80% of dose can be cleared 3-4 hours post-admin)
- probenecid completely inhibits active secretion → increases steady state level and half life
- can cause toxicity in renal failure
adverse rxn
- diarrhea, nausea, urticaria, superinfection
- allergic rxn in 10% of patients
- all penicillins are cross reacting
- 2gen+ cephalosporin can sub
resistance
- upregulation of chromosomal beta-lactamases
- acquisition of beta-lactamases via horizontal gene transfer
- mutation of PBP (transpeptidases) to reduce their affinity
cephalosporins
broader spectrum bc have increased resistance to beta lactamases
- not active against Enterococci, Klebsiella, Listeria, E. coli : have extended-spectrum beta-lactamases
1gen: cefazolin
- broad spectrum; better for Gram+
- used for surgical prophylaxis
- doesnt cross CNS
2gen: cefamandole
- heterogenous class with individ specificities
- extended coverage over Gram- (compared to 1gen)
- no allergic cross-reactivity with penicillin
3gen: ceftazidine
- extended Gram- activity at expense of Gram+ activity
- some cross blood brain barrier
- effective against inducible beta lactamase production; NOT constitutive beta lactamase production
- Avycaz: ceftazidine + avibactin (beta lactamase inhibitor)
4gen: cefepime
- more resistant to inducible/constitutive beta lactamases AND better activity against Gram+ and Gram- : true broad spectrum drugs
- penetrate CNS
- good activity against lots of bacteria
cephalosporins
- administration
- elimination
- clinical use
- adverse rxn
- newest member
administration
some oral, some IV
elimination
via kidney : renal insufficiency → elevated levels → seizures
clinical use
sinusitis, otitis, lower resp tract infections
4gen : MRSA
adverse rxn
may elicit hypersensitivity rxn
superinfection with Candida
latest member: ceftolozane/tazobactam combo (Zerbaxa)
- tx of Gram- bacteria that are resistant, esp Pseudomonas
- compliated UTIs
- complicated intra-abd infection (+ metronidazole)
- tazobactam = beta lactamase inhibitor that extends half life of ceftolozane
cephalosporins with activity against MRSA
ceftaroline
- high affinity for unique transpeptidase commonly encoded by MRSA
- works on both Gram+, Gram- bacteria
- effective against skin/skin structure infections
- IV admin
- side effects: diarrhea, nausea, rash
monobactam
monocyclic core
relatively resistant to beta lactamases
active against Gram- rods (pseudomonas, serratia)
- NO ACTIVITY AGAINST GRAM+ or ANAEROBES
admin: IV
excretion: rapid
no penicillin cross reactivity
adverse rxn: none. occasional skin rash
carbapenems
broad spectrum antibiotics
- good activity against Gram-, Gram+, anaerobes
- used for mixed infections
resistant to Ser beta-lactamases but not metallo beta-lactamases
imipenem inactivated by dehydropeptidases in renal tubules
- cilastatin inhibits renal dehydropeptidase → increases half life
meropenem is resistant to dehydropeptidases
all excretion is renal ( → IV dose must be adjusted in pt with renal insufficiency)
adverse rxn: nausea, vomiting, diarrhea, skin rashes; seizures with renal insufficiency
might get cross reactivity with penicillin allergies
non-beta-lactam cell wall synthesis inhibitors
vancomycin
active against Gram+, esp Staph
binds cell wall (as opposed to enzymes used to make it)
- bind peptide linker chain (D-Ala-D-Ala) and prevent transglycosylation and transpeptidase activity
- weakened cell wall → susceptibility to lysis → bactericidal in actively growing cells
why are enterococci resistant?
D-Ala-D-Ala → D-Ala-D-Lactic acid
- (lose a key H bond that vancomycin would form; decreases affinity 1000x)
vancomycin
admin: 7-10d IV; oral for enterocolitis
common indications: methicillin resistant endocarditis or sepsis, anti-staph
elimination: kidney (high levels: risk for nephrotox)
combos: often combined with aminoglycosides and gentamicin for tx of enterococcal infection
related drugs: telcoplanin, televancin
latest glycopeptide drugs
dalbavancin : as effective as vancomycin by less dosing
oritavancin : similar efficacy to vancomycin, long half life (which permits single dose)
daptomycin
bacterial cell membrane pore former
- forms pores in bacterial membranes → K loss, NO TOXIN RELEASE
- Gram+ skin and SSTIs involving MRSA
polymyxins
class of lipopeptides that bind lipopolysacch molecule specific to outer membrane of Gram- bacteria → permeability of both inner and outer membranes
drugs targeting assembly of peptidoglycan precursors inside cell
fosfomycin
inhibits first committed step:
NAG-UDP → NAM-UDP
- drug covalently binds Cys active site of MurA enzyme
resistance occurs usually when drug cant be transported into cell
- TB MurA is naturally resistant
elimination: kidney
active against Gram+ and Gram-
drugs targeting assembly of peptidoglycan precursors inside cell
bacitracin
inhibits lipid phosphatase resp for dephosphorylating lipid carrier of peptidoglycan subunits
admin: topical only bc too nephrotoxic for other routes
active against Gram+
drugs targeting assembly of peptidoglycan precursors inside cell
D-cycloserine
competitively inhibits Ala racemase, D-Ala ligase
second-line drug with serious adverse rxn: dose-dep CNS effects
