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Microbiology > Cell Wall Antibiotics - Gartenberg 5/3/16 > Flashcards

Cell Wall Antibiotics - Gartenberg 5/3/16 Flashcards

1
Q

penicillin

A

penicillin G

amoxacillin

cloxacillin

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2
Q

beta lactamase inhibitors

A

clavulanic acid

avibactam

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3
Q

cephalosporins

A

cefazolin (1gen)

cefamandole (2gen)

ceftazidime (3gen)

cefepime (4gen)

ceftolozane (latest)

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4
Q

cephalosporins for MRSA

A

ceftaroline

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5
Q

monobactam

A

aztreonam

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6
Q

carbapenem

A

imipenem

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7
Q

glycopeptides

A

vancomycin

oritavancin

dalbavancin

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8
Q

lipopeptides

A

daptomycin (pore former)

polymyxin (membrane disruptor)

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9
Q

inhibitors of peptidoglycan precursors

A

fosfomycin

bacitracin

D-cycloserine

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10
Q

life threatening infection

what’s the treatment protocol?

A

treat immediately with broad spectrum

use cultures and testing to determine sensitivites of serious/mysterious infections

once pathogen identified, switch to narrow spectrum

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11
Q

bacterial cell wall

A

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
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12
Q

broad spectrum

extended spectrum

A

broad spectrum: works against Gram + and Gram - bacteria

extended spectrum: drug with broadened selectivity due to chemical modification

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13
Q

chemical structure of peptidoglycan

A

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

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14
Q

assembly of peptidoglycan

A

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)
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15
Q

beta lactam antibiotics

A

core structures of primary beta lactam families:

  1. penicillin (mimics D-Ala-D-Ala of peptide linker)
  2. monobactam
  3. cephalosporin
  4. 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
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16
Q

bacterial beta lactamases

A

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

17
Q

beta lactamase inhibitors

A

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
18
Q

avibactam

A

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

19
Q

what’s the difference between…

common penicillins

anti-staphylococcal penicillins

extended-spectrum penicillins

A

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
20
Q

penicillins

  • administration
  • elimination
  • adverse rxn
  • resistance
A

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
21
Q

cephalosporins

A

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
22
Q

cephalosporins

  • administration
  • elimination
  • clinical use
  • adverse rxn
  • newest member
A

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
23
Q

cephalosporins with activity against MRSA

A

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
24
Q

monobactam

A

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

25
Q

carbapenems

A

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

26
Q

non-beta-lactam cell wall synthesis inhibitors

vancomycin

A

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)
27
Q

vancomycin

A

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

28
Q

latest glycopeptide drugs

A

dalbavancin : as effective as vancomycin by less dosing

oritavancin : similar efficacy to vancomycin, long half life (which permits single dose)

29
Q

daptomycin

A

bacterial cell membrane pore former

  • forms pores in bacterial membranes → K loss, NO TOXIN RELEASE
  • Gram+ skin and SSTIs involving MRSA
30
Q

polymyxins

A

class of lipopeptides that bind lipopolysacch molecule specific to outer membrane of Gram- bacteria → permeability of both inner and outer membranes

31
Q

drugs targeting assembly of peptidoglycan precursors inside cell

fosfomycin

A

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-

32
Q

drugs targeting assembly of peptidoglycan precursors inside cell

bacitracin

A

inhibits lipid phosphatase resp for dephosphorylating lipid carrier of peptidoglycan subunits

admin: topical only bc too nephrotoxic for other routes

active against Gram+

33
Q

drugs targeting assembly of peptidoglycan precursors inside cell

D-cycloserine

A

competitively inhibits Ala racemase, D-Ala ligase

second-line drug with serious adverse rxn: dose-dep CNS effects

Microbiology (13 decks)

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