Lecture 4: Inhibitors of cell wall synthesis II

Cephalosporins advantage

Cephalosporins have beta-lactam ring structure

Advantage over Penicillins - 7-methyl group in cephalosporins increases cephalosporin resistance to beta-lactamase

Moraxella catarrhalis DOC

second or third generation Cephalosporin

Neisseria gonorrhoeae DOC

ceftriaxone, cefixime

E. coli, Klebsiella, Proteus DOC

first or second generation Cephalosporin

Salmonella DOC

third generation Cephalosporin

Penicillin resistant Streptococcus pneumoniae DOC

ceftriaxone

Late Borrelia burgdorferi DOC

ceftriaxone

alternative for penicillin-allergic individuals

Cephalosporins, but caution about cross-reactivity

First Generation Cephalosporins

Good activity against G+ bacteria

relatively moderate activity against G- organisms (E. coli, Klebsiella, Proteus)

Renal excretion

cefazolin – DOC for surgical prophylaxis

Cefazolin – IV, IM

Cephalexin – oral

Cefadroxil - oral

Second Generation Cephalosporins

lower activity against G+

increased activity against G- negatives (E.coli, Moraxella, Klebsiella, Proteus)

Cefaclor- Oral

Cefuroxime- I.M., I.V.

Cefprozil- Oral

Cefoxitin- I.M., I.V.

Cefotetan- I.M., I.V.

Third Generation Cephalosporins

less active against G+ cocci

increased G- coverage

excellent activity against Enterobacteriaceae

most excreted by the kidney

Ceftriaxone- CNS penetration, Neisseria, Borrelia – IV/IM → Contraindication: neonates, bilirubin displacement

Cefotaxime Sodium- CNS penetration – IV/IM

Ceftazidime- P. aeruginosa – IV/IM

Cefpodoxime, Cefdinir, Cefixime- Oral

Fourth Generation Cephalosporins

better G+ coverage

more resistant to beta-lactamases

Antipseudomonal

Penetrates the CSF

renal excretion

broadest coverage of the class: Enterobacteriaceae, MSSA, Pseudomonas

empirical therapy, particularly when resistance to β-lactamases are suspected

Cefepime- IV

“Fifth” Generation Cephalosporins

activity against G+ and G-, approved for CABP

renal excretion

no antipseudomonal activity

MRSA and VRSA coverage: the only beta lactam active against MRSA

Mechanistically, ceftaroline can bind to PBP2A with very high affinity – this is the mutated PBP that other beta-lactams cannot bind to

Ceftaroline fosamil- IV

Cephalosporin Adverse Effects

superinfection

disulfiram-like reaction

Allergy (cross sensitivity with pen)

Dose dependent renal tubular necrosis

Diarrhea

Imipenem, Meropenem and Ertapenem

Carbapenems

Imipenem is rapidly inactivated by renal tubule dihydropeptidases and must be given with cilastatin, a dihydropeptidase inhibitor

Imipenem & Meropenem

I.V.

broad spectrum, including anaerobes, G+ and G-, Pseudomonas (good for mixed infections)

relatively resistant to β-lactamases

Imipenem can cause seizures and should be used cautiously in patients with renal failure, brain lesions, head trauma, or a history of CNS disorders such as seizures

meropenem is less likely to cause seizures

potential for penicillin cross-reactivity

Ertapenem

less active against Pseudomonas, should not be used

I.V. or I.M

95% protein binding

Aztreonam

Monobactam

active only against aerobic G- rods

IM or IV

relatively resistant to β-lactamases

few side effects (phlebitis, skin rash, abnormal liver function)

No cross sensitivity with other β-lactams (good for pen allergic)