Cephalosporins

Cephalosporins are beta-lactam antibiotics organized into five generations, each broadening gram-negative coverage while generally narrowing gram-positive coverage. First-generation agents (cefazolin, cephalexin) are the workhorses for gram-positive skin and soft tissue infections and surgical prophylaxis. Second-generation (cefoxitin, cefuroxime) adds anaerobic and broader gram-negative activity. Third-generation (ceftriaxone, ceftazidime) targets serious gram-negative infections including meningitis and gonorrhea — ceftriaxone is first-line for bacterial meningitis and gonorrhea (single IM dose). Note: ceftazidime, unlike ceftriaxone, covers Pseudomonas. Fourth-generation (cefepime) covers Pseudomonas and resistant gram-negatives. Fifth-generation (ceftaroline) uniquely covers MRSA among cephalosporins. Cross-reactivity with penicillin is approximately 1–2% overall, driven primarily by R1 side-chain similarity rather than generation number alone. First-generation cephalosporins (cephalexin, cefadroxil) share an R1 side chain with aminopenicillins (amoxicillin, ampicillin) and carry the highest cross-reactivity risk. Third- and fourth-generation agents with dissimilar side chains have negligible cross-reactivity. If the penicillin reaction was anaphylaxis, avoid cephalosporins with similar side chains; agents with dissimilar side chains may be given under appropriate evaluation. Ceftriaxone is unique in biliary excretion and does not require renal dose adjustment. Ceftriaxone is contraindicated in neonates receiving calcium-containing IV solutions due to risk of fatal precipitates. All cephalosporins carry risk of C. difficile-associated diarrhea — monitor for watery or bloody stools.