Adverse Drug Reactions of Cephalosporins

1. Hypersensitivity Reactions

• Anaphylaxis - immediate, IgE-mediated (rare but life-threatening)
• Urticaria and bronchospasm
• Maculopapular rash - most common, usually appears after several days of therapy; may be accompanied by fever and eosinophilia
• Drug-induced fever
• Granulocytopenia / bone marrow depression (rare)
• Hemolytic anemia - positive Coombs test is common at high doses, but overt hemolysis is rare
• Nephritis (interstitial nephritis) - immune-mediated

• 1st and 2nd generation: ~10% cross-reactivity in penicillin-allergic patients (Fitzpatrick's)
• 3rd generation: ~2-3%
• Patients with mild or temporally distant penicillin allergy: low risk
• Patients with severe immediate penicillin reaction: require skin testing before use

2. Gastrointestinal Effects

• Diarrhea - most common GI side effect; more frequent with cefoperazone (due to high biliary excretion)
• Nausea / Vomiting
• Acute pancreatitis (rare)
• Biliary pseudolithiasis - ceftriaxone precipitates in bile as a calcium salt; reversible on stopping the drug. Ceftriaxone's high protein binding can also displace bilirubin - potentially causing jaundice in neonates (cefotaxime preferred in neonates)

3. Local Reactions

• Pain at IM injection site
• Thrombophlebitis after IV injection

4. Neurological Effects

• Seizures / Encephalopathy - especially with cefepime (4th generation) in high doses or patients with renal dysfunction or pre-existing brain injury (nonconvulsive status epilepticus reported)
• Seizures can occur even at therapeutic dosages with some agents

5. Hypoprothrombinemia and Bleeding

• Drugs: Cefamandole, Cefmetazole, Cefotetan, Cefoperazone
• Mechanism: Inhibit vitamin K epoxide reductase (warfarin-like effect) --> impaired clotting factor synthesis
• Clinically significant bleeding can occur, especially in patients on anticoagulants or with vitamin K deficiency
• Prevention: Oral Vitamin K 10 mg twice weekly

6. Disulfiram-like Reaction

• Cefamandole, Cefotetan, Cefoperazone, Cefmetazole
• When co-administered with alcohol - severe flushing, hypotension, nausea, tachycardia
• Alcohol must be strictly avoided during therapy with these agents

7. Nephrotoxicity

• Cephalosporins alone in recommended doses rarely cause significant renal toxicity
• Interstitial nephritis and tubular necrosis may occur uncommonly (Katzung's)
• Risk increases when combined with aminoglycosides or loop diuretics

8. Superinfection

• Broad-spectrum 2nd, 3rd, and 4th generation cephalosporins have little activity against Gram-positives (especially enterococci) and fungi
• Prolonged use may lead to superinfection with enterococci or Candida (Jawetz)

9. Long-term / High-dose Effects

• Serum sickness-like syndrome
• Drug-induced hepatitis (hepatocellular injury)
• Antibiotic-associated colitis (C. difficile) - with prolonged use disrupting normal flora

10. Drug Interactions of Note (Fitzpatrick's)

Quick Memory Mnemonics

• MTT group drugs (Disulfiram + Hypoprothrombinemia): "Can Care Cows Moo?" = Cefotetan, Cefoperazone, Cefamandole, Cefmetazole
• Cefepime = seizures (esp. in renal failure)
• Ceftriaxone = biliary sludge / pseudolithiasis, bilirubin displacement in neonates