Cephalosporins

Cephalosporins are β-lactams, so their mechanism is identical to the penicillins’: they bind penicillin-binding proteins (PBPs) and block the cross-linking of peptidoglycan, killing the bacterium by wall failure — bactericidal, and selective because human cells have no wall. What sets them apart is durability: their molecular structure makes them more stable against many β-lactamases, so they hold up against bacteria that would inactivate a plain penicillin.

Because that stability and spectrum improved step-by-step as chemists modified the molecule, cephalosporins are learned by generation — and there is one rule to anchor everything: as you go up the generations, coverage shifts from gram-positive toward broader gram-negative, and later agents penetrate the central nervous system better. The gram-positive strength narrows through the 3rd generation, then the 5th generation swings back to add MRSA coverage.

1st generation (cefazolin, cephalexin): best gram-positive cocci — cefazolin is the workhorse for surgical prophylaxis. 2nd generation (cefuroxime, plus the cephamycins cefoxitin/cefotetan): more gram-negatives and some anaerobes. 3rd generation (ceftriaxone, cefotaxime, ceftazidime, cefdinir): broad gram-negative reach, and two standouts — ceftriaxone crosses into the CNS (a mainstay for bacterial meningitis and, per CDC, first-line for gonorrhea), while ceftazidime is antipseudomonal.

4th generation (cefepime): broad coverage **including *Pseudomonas*, stable against many β-lactamases. 5th generation (ceftaroline): the first β-lactam with reliable MRSA** activity (but it does *not* cover *Pseudomonas*). Two teaching cautions worth carrying: antipseudomonal activity is drug-specific, not generation-wide (ceftazidime and cefepime yes; ceftriaxone no), and the β-lactamase stability is a trend, not an absolute — many older cephalosporins are still hydrolyzed by ESBLs.

Beyond the shared β-lactam allergy story (same side-chain-driven cross-reactivity with penicillins, and the same C. difficile risk from broad flora disruption), a few cephalosporin-specific dangers show up on exams and at the bedside. Ceftriaxone must never be combined with IV calcium in a neonate — the two form fatal crystalline precipitates in the lungs and kidneys, so it is contraindicated in neonates receiving calcium-containing IV fluids; ceftriaxone can also cause reversible biliary sludging. Cefotetan (and other agents bearing the NMTT side chain) causes a disulfiram-like reaction with alcohol (flushing, nausea, tachycardia) and hypoprothrombinemia/bleeding — so patients avoid alcohol during and for ~72 hours after, and PT/INR is watched. (Note: **cefazolin does *not* carry the NMTT side chain** — a common misconception.)

The last trap is cefepime neurotoxicity: because it is renally cleared, in renal impairment without dose adjustment it accumulates in the CNS and antagonizes GABA, causing encephalopathy, myoclonus, and nonconvulsive seizures. The remedy is simple and is pure nursing: adjust the dose for renal function. Reassuringly, like the penicillins, cephalosporins carry no class-wide boxed warning — the ceftriaxone-calcium rule is a contraindication, not a boxed warning.