Cefazolin - Drug Monograph

Introduction

Cefazolin is a first-generation cephalosporin antibiotic that has been a cornerstone of antimicrobial therapy since its introduction in the 1970s. As a beta-lactam antibiotic, it belongs to the cephalosporin class and is particularly valued for its broad-spectrum activity against Gram-positive bacteria and some Gram-negative organisms. Cefazolin is primarily administered parenterally and remains one of the most commonly used antibiotics for surgical prophylaxis and treatment of various infections.

Mechanism of Action

Cefazolin exerts its bactericidal activity by inhibiting bacterial cell wall synthesis. It binds to penicillin-binding proteins (PBPs) located in the bacterial cell wall, particularly PBP3, which interferes with the final transpeptidation step of peptidoglycan synthesis. This disruption leads to the activation of autolytic enzymes that cause cell lysis and death. The drug's mechanism is time-dependent, meaning its antibacterial activity correlates with the duration that drug concentrations remain above the minimum inhibitory concentration (MIC) of the target organism.

Indications

Cefazolin is FDA-approved for:

• Treatment of respiratory tract infections
• Urinary tract infections
• Skin and skin structure infections
• Bone and joint infections
• Septicemia
• Endocarditis
• Perioperative prophylaxis in various surgical procedures (particularly orthopedic, cardiac, and gastrointestinal surgeries)

Off-label uses include:

• Treatment of susceptible Gram-positive infections in penicillin-allergic patients (with appropriate caution)
• Prophylaxis against Group B Streptococcus in penicillin-allergic pregnant women

Dosage and Administration

• Mild to moderate infections: 250-500 mg every 8 hours
• Moderate to severe infections: 500 mg to 1 g every 6-8 hours
• Life-threatening infections: Up to 1-1.5 g every 6 hours
• Surgical prophylaxis: 1-2 g IV within 60 minutes before incision

• Renal impairment:

- CrCl 35-54 mL/min: Maximum 1 g every 8 hours - CrCl 10-34 mL/min: Maximum 500 mg every 12 hours - CrCl <10 mL/min: Maximum 500 mg every 18-24 hours

• Hemodialysis: 500 mg to 1 g after each dialysis session
• Pediatric patients: 25-100 mg/kg/day divided every 6-8 hours

• IV route preferred (slow IV push over 3-5 minutes or infusion over 30 minutes)
• IM administration possible but less common due to pain at injection site

Pharmacokinetics

• Volume of distribution: 0.12-0.2 L/kg
• Protein binding: 85-90%
• Crosses placenta and enters breast milk

• Half-life: 1.4-2.2 hours (prolonged in renal impairment)
• Clearance: Renal (glomerular filtration and tubular secretion)

Contraindications

• Known hypersensitivity to cefazolin or other cephalosporins
• History of anaphylactic reaction to any beta-lactam antibiotic
• Cross-sensitivity with penicillins (contraindicated in patients with immediate hypersensitivity to penicillins)

Warnings and Precautions

• Use with caution in patients with penicillin allergy (5-10% cross-reactivity)
• May cause Clostridium difficile-associated diarrhea (CDAD)
• Potential for superinfection and fungal overgrowth
• Use with caution in patients with renal impairment (dose adjustment required)
• May cause false-positive Coombs test
• Can prolong prothrombin time (monitor in patients with vitamin K deficiency)
• Exercise caution in patients with history of gastrointestinal disease, particularly colitis

Drug Interactions

• Probenecid: Decreases renal clearance of cefazolin, increasing serum concentrations
• Aminoglycosides: Potential increased nephrotoxicity (monitor renal function)
• Warfarin: May enhance anticoagulant effect (monitor INR)
• Ethanol: Disulfiram-like reaction possible
• Oral contraceptives: Potential decreased efficacy (use alternative contraception)
• Loop diuretics: Increased potential for nephrotoxicity

Adverse Effects

• Injection site reactions (pain, phlebitis)
• Diarrhea
• Nausea/vomiting
• Rash
• Pruritus
• Eosinophilia

• Anaphylaxis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Blood dyscrasias (neutropenia, thrombocytopenia)
• Hepatitis
• Acute interstitial nephritis
• Seizures (in renal impairment)
• Clostridium difficile-associated diarrhea
• Hemolytic anemia

Monitoring Parameters

• Complete blood count with differential
• Renal function tests (BUN, creatinine)
• Liver function tests
• Culture and susceptibility testing (when appropriate)

• Signs and symptoms of infection resolution
• Renal function (weekly in prolonged therapy)
• CBC weekly for courses >2 weeks
• Signs of hypersensitivity reactions
• Diarrhea (assess for CDAD)
• Coagulation parameters in at-risk patients
• Therapeutic drug monitoring in severe infections or renal impairment

Patient Education

• Complete the full course of therapy even if feeling better
• Report any signs of allergic reaction (rash, itching, swelling, difficulty breathing)
• Inform healthcare providers of any penicillin or cephalosporin allergies
• Report severe diarrhea, especially if containing blood or mucus
• Notify provider if pregnancy is suspected or if breastfeeding
• Be aware that cefazolin may affect certain lab tests (Coombs test, glucose tests)
• Avoid alcohol during treatment and for 72 hours after completion
• Use alternative contraception if taking oral contraceptives

References

1. Lexicomp Online. Cefazolin monograph. Wolters Kluwer Clinical Drug Information, 2023. 2. Micromedex Solutions. Cefazolin drug information. IBM Watson Health, 2023. 3. Gilbert DN, et al. The Sanford Guide to Antimicrobial Therapy. 52nd ed. Antimicrobial Therapy, Inc.; 2022. 4. Drug Facts and Comparisons. Facts & Comparisons [online]. 2023. 5. Clinical Pharmacology [database online]. Tampa, FL: Elsevier; 2023. 6. FDA Prescribing Information: Cefazolin for Injection. Revised 2022. 7. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020. 8. American Society of Health-System Pharmacists. AHFS Drug Information. Bethesda, MD: ASHP; 2023.