Pharmacology II: Cell Wall Inhibitors II

Cephalosporins Overview

• Cephalosporins share the same mechanism of action (MOA) as penicillins and have a similar resistance profile.
• They are more stable against bacterial lactamases but ineffective against MRSA, L.monocytogenes, Clostridium difficile, and enterococci.

First-Generation Cephalosporins

• Examples include cefazolin, cephalexin, and cefadroxil.
• Effective against MSSA due to resistance to staphylococcal penicillinase.

Second-Generation Cephalosporins

• Includes cefuroxime, cefotetan, cefoxitin, cefprozil, and cefaclor.
• Less potent against MSSA compared to first generation, but effective against gram-negative bacilli and enteric organisms.

Third-Generation Cephalosporins

• Agents include cefotaxime, ceftriaxone, and ceftazidime.
• More active against gram-negative pathogens; recommended for meningitis caused by pneumococci and meningococci, but not effective against L.monocytogenes.
• Ceftazidime has activity against Pseudomonas aeruginosa, though resistance is a growing concern.
• Associated with collateral damage affecting microbial flora.

Fourth-Generation Cephalosporins

• Cefepime is widely effective against methicillin-susceptible staphylococci and aerobic gram-negative organisms.
• Advanced generation cephalosporins like ceftaroline are effective against MRSA and used for complicated skin infections and community-acquired pneumonia.

Resistance and Side Effects of Cephalosporins

• Susceptible to extended-spectrum β-lactamases (ESBLs) from E.coli and K.pneumoniae.
• Potential adverse effects include hypersensitivity reactions, nephritis, skin rashes, and hematological issues.
• Cross-sensitivity exists between penicillins and first-generation cephalosporins.

Carbapenems

• Includes imipenem, meropenem, doripenem, and ertapenem, functioning as synthetic β-lactam antibiotics.
• Effective against a wide variety of bacteria including anaerobes and resistant gram-negative organisms like P.aeruginosa.
• Imipenem is often used for empirical therapy due to its robust activity.

Pharmacokinetics and Adverse Effects of Carbapenems

• Imipenem/cilastatin and meropenem penetrate well into body tissues, achieving therapeutic levels in conditions like bacterial meningitis.
• Adverse effects include gastrointestinal disturbances, eosinophilia, neutropenia, and potential seizures with high imipenem dosage.

Monobactams

• Aztreonam is the primary agent, featuring a unique β-lactam ring structure.
• Targets gram-negative bacteria, including Enterobacteriaceae and P.aeruginosa, with no effectiveness against gram-positive bacteria or anaerobes.
• Exhibits low toxicity, but can cause phlebitis, skin rash, and liver function abnormalities.
• Minimal cross-reactivity makes it a suitable alternative for patients allergic to other β-lactams.