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) Side Effects GI: 2-5% Rash: 1-3% Neutropenia: <1% Seizures: <1%  Lactam antibiotics MOA: binds to PBP-inhibit bacterial cell wall synthesis Most agents are renally excreted Exception: Ceftriaxone

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, Cefoxitin GRAM + >60%: Strep: Pneumo, Viridans, MSSA 30-60%: 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

Carbapenems Imipenem, Meropenem, Ertapenem, Doripenem Bactericidal-Time dependent

Carbapenems Imipenem, 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 Effects GI: 4-5% Rash: 2-3% Infusion related: 3% Seizures: ~1% Bind to GABA Ertapenem:  infusion rxns (7-10%) CNS: confusion etc 5-10%) Coverage VERY BROAD SPECTRUM Gram + (NOT MRSA) Gram – (including pseudomonas) Anaerobes

Monobactams: Aztreonam Also a beta lactam MOA: inhibits bacterial cell wall synthesis Coverage: Gram – only Covers Pseudomonas Not used as often as other agents Well tolerated Bactericidal-Time dependent!

Gycopeptide-Vancomycin Bactericidal-Time dependent killer

Gycopeptides Vancomycin 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 / dL Poor oral bioavailability Side Effects: Red man syndrome Facial flushing and hypotension Histamine reaction related to rate of infusion Always infuse Vancomycin over ≥ 60 min

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

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 resistance VRE: Vancomycin resistant enterococci Linezolid (Zyvox)