cephalosporins 9-18-24.pdf

Cephalosporins Jamie Allman, Pharm.D., BCPS Cell Wall Matrix Simplified Microbiology Gram Positive (3) Gram Negative (3 CATEGORIES) Weak/ Piddly In Between a.k.a FENCE BUGS SPACE Atypicals (3) Anaerobes (3) SPACE Bug Coverage Box and One Therapy Cell Wall Inhib = PCN...

Cephalosporins Jamie Allman, Pharm.D., BCPS Cell Wall Matrix Simplified Microbiology Gram Positive (3) Gram Negative (3 CATEGORIES) Weak/ Piddly In Between a.k.a FENCE BUGS SPACE Atypicals (3) Anaerobes (3) SPACE Bug Coverage Box and One Therapy Cell Wall Inhib = PCN, Ceph, Carbapenem, Monobactam DNA gyrase = FQN 30 S = Aminoglycosides Ace in the Hole = Aztreonam (Anaphylaxis) Cephalosporin Structure Cephalosporin Structure R1 – Spectrum of Activity, PBP affinity, B-lactamase susceptibility R2 – Stability, metabolism, adverse effects, drug interactions, protein binding, t1/2 Pharmacokinetic Properties Absorption Oral Agents Rapidly and completely absorbed Oral cephalosporins are available as prodrug esters and nonesterified compounds Prodrug esters Cefuroxime axetil (Ceftin-2nd generation) Cefpodoxime proxetil (Vantin PO- 3rd generation) Hydrolyzed in the intestines to the active drug Food enhances absorption Mechanism of Action Binds to Penicillin Binding Proteins (PBPs) Inhibits crosslinking of peptidoglycan strands Efficacy of each cephalosporin is related to affinity to PBPs Can be susceptible to some beta-lactamases Pharmacokinetic Properties Distribution Well distributed to a variety of body tissues and fluids CSF penetration especially with inflamed meninges 3rd generation cephalosporins are great choices for various bacteria that cause meningitis (Ceftriaxone) Requires high doses to be used (Ceftriaxone = 4x normal dose) Pharmacokinetic Properties Metabolism/Excretion Renal excretion All agents except the 2 listed below Dosage adjustments in patients with renal insufficiency Hepatic elimination Ceftriaxone, Cefoperazone Adverse Effects Hypersensitivity reaction: 5-15% cross-reactivity with Penicillins Generally safe in non-IgE-mediated (anaphylaxis) penicillin allergic patients (DO NOT USE IN THIS SITUATION!!!) Rash, drug fever Hematology Bleeding N-Methylthiotetrazole (NMTT) side chain Cefamandole & cefoperazone due to hypoprothrombinemia (disturbance in vitamin K dependent clotting factors) Alcohol, disulfiram-like intolerance Agents with NMTT side-chain (Cefamandole & Cefaperazone) Structure NMTT Side-chain Adverse Effects Gastrointestinal Diarrhea Pseudomembranous colitis Renal Interstitial nephritis (rare) Immunologic Serum sickness in children- Cefaclor (Ceclor-2nd generation) Drug Interactions Warfarin Potentiation of anticoagulant effects Alcohol Disulfiram-like reaction Agents with NMTT side-chain only Probenecid Prolongs excretion in cephalosporins that have tubular secretion Cephalosporin Generations Generation Common Oral Products Common Parenteral Products First Cephalexin (Keflex) Cefazolin (Ancef) Cefadroxil (Duricef) Second Cefuroxime (Ceftin) Cefuroxime (Zinacef) Cefprozil (Cefzil) Cefaclor (Ceclor) Second N/A Cefoxitin (Mefoxitin) (Cephamycins) Cefotetan (Cefotan) Third Cefixime (Suprax) Ceftriaxone (Rocephin) Cefdinir (Omnicef) Cefotaxime (Claforan) Cefopodoxilme (Vantin) Third N/A Ceftazidime (Fortaz) (Antipseudomonal) Cefoperazone (Cefobid) Fourth N/A Cefepime (Maxipime) Fifth Ceftaroline (Teflaro) Ceftaz-avibactam (Avycaz) Ceftolozane/tazo (Zerbaxa) Spectrum of Activity As generations increase, gram negative coverage increases New agents coverage have renal restrictions due to outcomes variability (see slides below) Cephalosporins generally DO NOT COVER Enterococcus (except Ceftaroline) MRSA (except Ceftaroline) Chlamydia, Mycoplasma, Legionella Listeria monocytogenes  Spectrum of Activity Generation Gram + Gram - Anaerobes (No Enterococcus) (Bacteroides) First Staph, Strep Piddly, Ecoli* No Second Staph, Strep Yes (H. flu, M. cat, No Proteus, E. coli,Kleb -PEK) Second Staph, Strep Yes (H. flu, M. cat, Yes (cephamycins) PEK) Third Strep Yes (SACE) No Third Poor Yes (SPACE) No (Antipseudomonal) Fourth Staph, Strep Yes (SPACE) No Fifth Staph, Strep SCE No *Enterococcus SPACE – Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter Ceftolozane/tazobactam (Zerbaxa) Cephalosporin with Beta lactamase inhibitor Approved for complicated Urinary Tract Infections including Pyelonephritis Combined with Metronidazole, complicated intra-abdominal infections Covers: Strep anginosus/salivarius/constellatus, Proteus mirabilis, E.coli, Klebsiella oxytoca &pneumoniae, Pseudomonas aeruginosa In vitro activity against ESBL and SOME Beta-lactamases (trials E.coli/Kleb pneumoniae when MIC