Abx targeting cell envelope

Question 1

Types of Beta-Lactams

Answer 1

• Penicillins
  
  • Natural penicillins
  • anti-staph penicillins
  • aminopenicillins
  • beta-lactamase inhibitors + penicillins/ extended spectrium penicillins
  • extended spectrum penicillins
• Cephalosporins
• Carbapenems
• Monobactam

Question 2

Natural Penicillins

Answer 2

• Penicillin V = PO
• Penicillin G = IV
  
  • Procaine Benzylpenicillin
    
    • duration is 15-20 hours
  • ​Benzathine Penicillin
    
    • low solubility
    • duration: 10-14 days
• ​​G+ with a few G- (N. meningitidis, Hflu)

Question 3

Anti-Staph Penicillins

Answer 3

• cover G+, but not G- activity
• bulky side chains prevent binding to beta-lactamases
• Nafcillin
• oxacillin
• dicloxacillin
• methicillin (no longer in use)
• not effective against MRSA- good for other S. aureus infections
• not used for strep or enterococci infections

Question 4

Aminopenicillins

Answer 4

• amino group = increase hydrophilic nature = can pass through porins of gram negative bacteria more easily
• Amoxicillin
• ampicillin
• tx: G+, and E.coli, Proteus, Salmonella, Shigella, H. Pylori, Listeria, N. meningitis
• susceptible to beta-lactamase (penicillinase)
• many gram negative bacteria have beta-lactamase = resistance

Question 5

Beta-lactimase inhibitors

Answer 5

• mimic penicillin and bind to the beta-lactamase which inhibits the beta-lactamase (penicillinase)
  
  • allows the drug to target the PBPs
• Cluvalanate
• Sulbactam and Tazobactam

Question 6

Extended Spectrum Penicillins

Answer 6

• polar side chain allows greater penetration into gram negative bacteria
• more resistant to gram negative beta-lactamases
  
  • still susceptible to beta-lactimase of staph
• more active against gram - bacteria including pseudomonas
• can be combined with beta-lactamase inhibitors
• Drugs:
  
  • Piperacillin
    
    • broader spectrum than ticarcillin
  • Ticarcillin

Question 7

SEs of Penicillins

Answer 7

• N/V/D
• drug fever, rash
• hepatotoxicity
• neurologic toxicity
• Urticaria
• Angioedema

Question 8

Extended spectrum penicilins + beta-lactamase inhibitors

Answer 8

• broadest coverage, cover most enteric G- bacilli, and anaerobes

Question 9

Cephalosporins general info

Answer 9

• 2 benefits of their structure:
  
  • more resistant to beta-lactamases
  • two side chains → creates more variations
• Each generation covers broader aerobic G - (except 5th generation)

Question 10

2nd generation cephalosporins

Answer 10

• True Cephalosporins
  
  • PO: Cefaclor, Cefprozil, Cefuroxime axetil
  • IV: Cerufroxime sodium
  • active against G+ (same as 1st gen)
  • also covers G-: Hflu, Neisseria, and PEK
• Cephamycins:
  
  • Cefotetan, Cefoxitin
  • methoxy group
    
    • resistant to beta-lactamases of anaerobes
    • loss of activity against staph and strep → methoxy group reduces affinity for PBPs

Question 11

3rd gen cephalosporins

Answer 11

• PO: cefdinir, cefixime, ceftibuten
• IV: cefotaxime, ceftazidime, ceftriaxone
• covers HEN PEK–Hflu, Enterobacter, Neisseria
  
  • ​Proteus, E.coli, Klebsiella
• **no activity against pseudomonas →adding a bulky side chain increases pseudomonas activity (ceftazidime) but makes you lose activity against G+

Question 12

4th generation Cephalosporins

Answer 12

• Cefepime IV
• Ceftolozane/tazobactam (IV)
• modified R2 side chain improves activity against enterobacters (i.e. Klebsuekkam E.coli, salmonella, shigella)
• **no loss of activity against G+ (unlike 3rd gen)
• very limited anaerobic activity
• covers: staph, strep, HEN PEK + Pseudomonas

Question 13

5th Generation Cephalosporins

Answer 13

• Ceftaroline IV
• cover staph, strep and MRSA
• HEN + PEK but no pseudomonas

Question 14

Cefiderocol

Answer 14

• MOA: 1st siderophore cephalosporin
• Indication: Complicated UTI and pyelonephritis
  
  • caused by G- bacteria
• Spectrum: G- aerobic/facultative
  
  • ​pseudomonas, Klebsiella pneumoniae carbapenemase (KPC)-producing enterobacteria
  • **no activity against G+ and anaerobes**
• Dose based on creatinine clearance
• SEs:
  
  • N/V/D/ C (leads to d/c of tx) and HA
  • infusion site rxn
  • rash
  • candidiasis, cdiff
  • cough
  • increase LFTs***/ HypoK ***
  • ***Hypersensitivity
  • thrombocytosis
  • stomatitis, seizure

Question 15

Cephalosporin Toxicity

Answer 15

• cross sensitivty with PCN allergy
• relatively safe
• rash, urticaria, anaphylaxis
• reversible neutropenia, thrombocytosis, elevated LFTs
• Cefotetan = hypothrmobinemia, disulfiram-like rxn
• ceftriaxone = elimibated by biliary excretion = biliary sludge

Question 16

Activity of 1st gen cephalosporin

Answer 16

staph, strep + PEK

Question 17

Activity of 2nd gen cephalosporin

Answer 17

• staph, strep + HaN PEK
• (Cefoxitin and cefotetan = mod anaerobic activity)

Question 18

Activity of 3rd gen cephalosporin

Answer 18

• staph, strep + HEN PEK

Question 19

Activity of 4th gen cephalosporin

Answer 19

• staph, strep + HEN + PEK +pseudomonas

Question 20

Activity of 5th gen cephalosporin

Answer 20

• staph (including MRSA), strep, + HEN PEK

Question 21

Carbapenems

Answer 21

• small molecules that use porins to gain accesss to periplasma of G- bacteria
  
  • structure is resistant to most beta-lactanases
  • broad range for PBPs from different bacteria
• imipenem: staph, strep, listeria, HEN + pseudomonas
• Doripenem: lower rate of resistance in pseudomonas
• Ertapenem: lessa ctive against G+
  
  • no pseudomonas, and acinetobacter activity
  • once a day dosing

Question 22

Monobactams

Answer 22

• Aztreonam: IV
• only covers Gram -
• completely synthetic
• bind well to PBPs and resistant to beta-lactamases
• excellent coverage of Hflu, Neisseria
• intermediate coverage of pseudomonas
• Toxicity:
  
  • rash,
  • toxic epiderma necrolysis
  • may induce eosinophilia
• okay to use in pts with PCN allergy

Question 23

Glycopeptides Overview

Answer 23

• structure is extremely large = cant pass through proins
• → activity only against G+ (nearly all staph including MRSA) and strep
• also good against anaerobic G+ (i.e. C.diff)
• ex: vancomycin, telavancin, dalbavancin, oritavancin

Question 24

Vancomycin

Answer 24

• glycopeptide (LARGE STRUCTURE)
• Toxicities:
  
  • due to contaminants during purification process
  • Red man syndrome → infusion related syndrome
  • phlebitis
  • ototoxicity (associated with peak level)
  • nephrotoxocity (associated with trough level)

Question 25

Telavancin

Answer 25

• glycopeptides
• lipophilic side chain: enhances binding to peptidoglycan
  
  • pore formation and cell leakage
• Toxicity:
  
  • Red Man Sxs
  • Diarrhea/N/V
  • Foamy urine
  • QT prolongation
  • Taste disturbances
  • interfere with coagulation test

Question 26

Daptomycin

Answer 26

• cyclic lipopeptide abx, IV only
• lipid portion inserts into the bacterial membrane creates channel →cell death
• no activity against G-
• activity against G+ including MRSA and some VRE
• Poor activity in lungs = do not use to treat PNA
  
  • ​inactivated by lung surfactant
• only use for skin and soft tissue infection (SSTI) and bacteremia/endocarditis
• toxicity:
  
  • reversibly myopathy (only at higher doses)
  • phlebitis, rash, and GI effects

Question 27

Colistin

Answer 27

• from the polymyxin group
• cyclic decapeptide plus a fatty acid side chain
• MOA:
  
  • positive charge bind to negative charge of lipopolysaccharide on outer membrane which dispaces calcium and magnesium →destabilizes the membrane
  • fatty acid tails inserts into membrane → increased permability →cell lysis
• covers pseudomonas