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Cephalosporins - Complete Pharmacology Reference

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1. Composition / Chemical Structure

• A β-lactam ring fused to a dihydrothiazine ring (6-membered, unlike penicillin's 5-membered thiazolidine ring)
• R² side chain at the 7-position - determines antibacterial activity and spectrum
• R¹ side chain at the 3-position - modifies pharmacokinetic properties

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2. Mechanism of Action

• They are bactericidal and time-dependent agents (bacterial killing is maximized when drug concentrations remain above the Minimum Inhibitory Concentration [MIC] for the greatest proportion of the dosing interval)
• They inhibit bacterial cell wall synthesis by binding to Penicillin-Binding Proteins (PBPs) - enzymes responsible for cross-linking peptidoglycan chains
• Binding to PBPs prevents transpeptidation (the final cross-linking step of peptidoglycan), weakening the cell wall and causing osmotic lysis
• They are affected by the same resistance mechanisms as penicillins (β-lactamase hydrolysis, reduced PBP affinity)

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3. Generations, Examples, and Spectrum

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4. Dosage and Route of Administration

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5. Pharmacokinetics

• Absorption: Most oral agents are well absorbed; most IV/IM agents have poor oral bioavailability
• Distribution: Widely distributed to tissues, pleural fluid, and joint fluid. Most do not penetrate CSF - exception: third-generation agents (ceftriaxone, cefotaxime) achieve therapeutic CSF levels
• Metabolism: Minimal hepatic metabolism; mostly excreted unchanged
• Excretion: Primarily renal (glomerular filtration + tubular secretion). Exception: Ceftriaxone is significantly excreted in bile (can cause biliary sludging)
• Probenecid blocks tubular secretion, increasing and prolonging cephalosporin blood levels

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6. Indications

Surgical Prophylaxis

• Cefazolin (1st gen) is the gold-standard for most surgical prophylaxis (cardiac, orthopedic, abdominal procedures)

Infections

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7. Contraindications

• Known hypersensitivity to cephalosporins - absolute contraindication
• Known hypersensitivity to penicillin - use with caution (cross-reactivity ~3-5%, highest between penicillin and 1st-generation cephalosporins; determined by side chain similarity, not the β-lactam ring itself)
• Patients with Stevens-Johnson syndrome or toxic epidermal necrolysis from penicillins should NOT receive cephalosporins
• Patients with a negative penicillin skin test have no greater risk of cephalosporin reaction than the general population
• Caution in severe renal impairment (dose adjustment required)

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8. Drug Interactions

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9. Side Effects and Adverse Effects

Common Side Effects

• GI disturbances: Nausea, vomiting, diarrhea (more common with oral agents and broad-spectrum agents)
• Injection site reactions: Pain, phlebitis at IV site
• Diarrhea / Pseudomembranous colitis: Disruption of normal intestinal flora; C. difficile-associated colitis possible with all cephalosporins

Allergic / Hypersensitivity Reactions

• Urticaria, rash, pruritus (most common)
• Serum sickness-like reactions
• Anaphylaxis (rare but life-threatening)
• Cross-reactivity with penicillin allergy (~3-5%)

Hematologic Effects

• Thrombocytopenia, neutropenia, eosinophilia
• Hypoprothrombinemia (with cephalosporins containing N-methylthiotetrazole side chains: cefotetan, cefoperazone) - can prolong PT/INR
• Coombs-positive hemolytic anemia (rare)

Renal

• Nephrotoxicity (uncommon at standard doses; potentiated by concurrent aminoglycoside use)
• Acute interstitial nephritis (rare)

Neurological

• Seizures (rare, with very high doses or in patients with renal failure/CNS disease)
• Cefepime-associated encephalopathy - confusion, myoclonus, nonconvulsive status epilepticus, especially in renal impairment if dose is not adjusted

Biliary

• Biliary pseudolithiasis (biliary sludge): Seen particularly with ceftriaxone, especially in children - ceftriaxone precipitates as an insoluble calcium salt in bile

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10. Toxicity

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11. Role of the Nurse

Pre-Administration

1. Allergy assessment: Always inquire about penicillin AND cephalosporin allergy before administration; document the type of reaction (anaphylaxis vs. rash)
2. Baseline assessments: Obtain baseline renal function (BUN, serum creatinine), complete blood count, and LFTs for prolonged therapy
3. Culture collection: Ensure culture and sensitivity specimens are collected before the first dose
4. Reconstitution and compatibility: Verify correct reconstitution technique, concentration, and IV compatibility (avoid calcium-containing solutions with ceftriaxone, particularly in neonates)
5. Dose verification: Confirm dose is appropriate for the patient's weight, age, and renal function

During Administration

1. Infusion rate: Administer IV over 30-60 minutes (standard); use extended infusion over 3-4 hours when ordered for time-dependent optimization
2. Monitor IV site: Observe for phlebitis, extravasation, redness, or pain; rotate sites
3. Monitor for allergic reaction: Especially during the first 30 minutes - watch for urticaria, pruritus, wheezing, hypotension; have resuscitation equipment ready
4. IM injections: Administer deep into a large muscle (e.g., gluteus); warn patient about pain at injection site

Post-Administration Monitoring

1. Therapeutic response: Monitor WBC trends, temperature curves, clinical signs of infection improvement
2. Renal function: Monitor urine output, BUN, and creatinine, especially with aminoglycoside co-administration
3. Coagulation: Monitor PT/INR in patients on warfarin or receiving MTT-containing cephalosporins
4. Superinfection: Watch for signs of C. difficile-associated diarrhea (watery/bloody stools), oral candidiasis, or vaginal candidiasis
5. Cefepime neurotoxicity watch: Report confusion, myoclonus, or altered consciousness, particularly in renal impairment

Patient and Family Education

1. Oral agents: Take the full prescribed course even if feeling better; take with food if GI upset occurs
2. Iron/antacids: Separate cefdinir from iron supplements and antacids by at least 2 hours
3. Alcohol avoidance: Counsel patients on cefotetan or cefoperazone to avoid alcohol during therapy and for 72 hours after the last dose
4. Report symptoms: Advise immediate reporting of rash, difficulty breathing, severe diarrhea, yellowing of skin/eyes, or unusual bleeding
5. Breast-feeding/pregnancy: Inform the prescriber; cephalosporins are generally considered safe in pregnancy (Category B) but documentation is required

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• Lippincott Illustrated Reviews: Pharmacology, Chapter 29 (β-Lactam Antibiotics / Cephalosporins)
• Fitzpatrick's Dermatology, Contraindications and Precautions of Cephalosporin Therapy
• Red Book 2021: Report of the Committee on Infectious Diseases, Cephalosporin Cross-Reactivity
• Campbell's Operative Orthopaedics, 15th Ed, Antibiotic Treatment and Open Fracture Management
• The Washington Manual of Medical Therapeutics, Cefepime dosing