7th

Cephalosporins

Four Generations! Bactericidal & Time-Dependent!

Cephalosporins

A B-lactam Analogous to PCN in Binding to specific PCN-binding proteins Inhibition of cell wall synthesis by blocking the transpeptidase step of peptidoglycan Bactericidal & Time-Dependent!

Cephalosporins

Tissue Penetration: very good Lung, kidney, muscle, synovial, pericardial, peritoneal and pleural fluids 5-10% cross reactivity rate with PCN allergies Specific resistance rates differ widely based on chemical structure (see cross reactivity article)
 Lactam antibioticsMOA: binds to PBP-inhibit bacterial cell wall synthesisMost agents are renally excretedException: Ceftriaxone Side Effects GI: 2-5% Rash: 1-3% Neutropenia: <1% Seizures: <1%

Spectrum Activity

In general a  in gram + and an  in gram - activity are observed as you move through generations 1-3.Cefepime (4th generation) maintains an excellent gram + and - activity.

1st Generation Cephalosporins

Cefazolin, Cefaclor (PO), Cephalexin (PO), Cefadroxil (PO)
GRAM + >60%: Strep Pneumo, Strep ABCG, Strep viridans, MSSA 30-60%: Staph epidermidis Moderate GRAM - coverage >60%: Proteus, E. Coli, Klebsiella Salmonella, Shigella, Neisseria gonorrheae, H. Influenzae



2nd Generation Cephalosporins
Cefuroxime (IV, PO), Cefotetan, CefoxitinGRAM +>60%: Strep: Pneumo, Viridans, MSSA30-60%: Staph epidermidis Gram - coverage vs. 1st gen>60%: Proteus, E. Coli, Klebsiella, Moraxella, Neisseria gonorrheae, H. Influenzae, Serratia.30-60%: Citrobacter, Enterobacter.Cefotetan/Cefoxitin:  anaerobic coverage>60%: Clostridium (not difficile), B. fragilis

3rd Generation Cephalosporins

IV: Ceftriaxone, Ceftazidime, Cefotaxime PO: Cefpodoxime, Cefixime, Cefdinir, Ceftobiprole
Gram +: same as 1st & 2nd ( bit less with Ceftaz)Good activity against Streptococci! Less activity against Staph than 1st and 2nd generation.  Gram - coverage vs. 2nd gen>60%: Proteus, E. Coli, Klebsiella, Moraxella, H. Influenzae, Serratia, Citrobacter, Enterobacter, Salmonella, Shigella, Pseudomonas (Ceftaz)30-60%: Neisseria gonorrheae (best with Ceftriaxone).

4th Generation Cephs: Cefepime

Very broad coverage of both Gram + and Gram - Like 3rd generations, but: Very good against all strains of neisseria (>60%) Better vs. acinetobacter (30-60%) Not active against anaerobes

CarbapenemsImipenem, Meropenem, Ertapenem, Doripenem

Bactericidal-Time dependent

CarbapenemsImipenem, Meropenem, Ertapenem, Doripenem

Beta-lactams, but have somewhat different chemical structure vs. PCNs and CEPHs MOA: cause lysis of bacterial cell wall Highly stable to beta-lactamases!! Only available in IV form Have PAE against Gram - bugs Tissue penetration: good Renally eliminated (require adjustment)

Carbapenems Imipenem, Meropenem, Ertapenem, Doripenem

Side EffectsGI: 4-5%Rash: 2-3%Infusion related: 3%Seizures: ~1%Bind to GABAErtapenem:  infusion rxns (7-10%)CNS: confusion etc 5-10%) CoverageVERY BROAD SPECTRUMGram + (NOT MRSA)Gram – (including pseudomonas)Anaerobes


Monobactams: Aztreonam
Also a beta lactamMOA: inhibits bacterial cell wall synthesisCoverage: Gram – onlyCovers PseudomonasNot used as often as other agentsWell toleratedBactericidal-Time dependent!

Gycopeptide-Vancomycin

Bactericidal-Time dependent killer

GycopeptidesVancomycin

MOA: Inhibit bacterial cell wall synthesis by binding to the D-ala-D-ala terminus of the pentapeptide, sterically interfering in the elongation of the cell wall polymer. Toxicities:Ototoxicity <1%Renal Dysfunction <1%Want trough levels ~ 5 - 15 mg / dLPoor oral bioavailability Side Effects: Red man syndromeFacial flushing and hypotension Histamine reaction related to rate of infusionAlways infuse Vancomycin over ≥ 60 min

ONLY COVERS GRAM + Treatment of choice for MRSA currently or Serious Gram + infection in PCN allergic patients.
GycopeptidesVancomycin

How does resistance to Vancomycin develop?

Primarily through plasmid-mediated changes in permeability to the drug, and  binding of vancomycin to receptor molecules.Widespread use leading to resistanceVRE: Vancomycin resistant enterococciLinezolid (Zyvox)