Cefazolin exerts its antimicrobial effect through a well-characterized mechanism of bacterial cell wall inhibition.^3,4  

• Similar to all beta-lactam antibiotics, cefazolin possesses a four-membered beta-lactam ring structure that enables it to function as a structural analog of the D-alanine-D-alanine motif present in bacterial peptidoglycans.

  • The drug binds covalently to penicillin-binding proteins (PBPs), which are bacterial transpeptidases responsible for catalyzing the formation of isopeptide cross-linkages between peptidoglycan strands, the terminal step in bacterial cell wall synthesis.

  • By inhibiting this critical transpeptidation reaction, cefazolin prevents the cross-linking of peptidoglycan polymers, resulting in structural instability and weakness of the bacterial cell wall.

    • This destabilization triggers autolytic degradation of the cell wall, as bacteria continuously remodel their peptidoglycan matrix during growth and cell division.

    • The consequence is bacterial cell lysis and death, making cefazolin bactericidal rather than merely bacteriostatic.

      • Cefazolin demonstrates superior in vitro bactericidal activity compared to other first-generation cephalosporins such as cephalexin, with particularly enhanced potency against gram-negative organisms such as Escherichia coli and Klebsiella pneumoniae, where it demonstrates two to eightfold greater activity.^2,5

Cefazolin Spectrum of Activity

• The spectrum of activity of cefazolin encompasses primarily gram-positive organisms, particularly streptococci species and methicillin-susceptible Staphylococcus aureus (MSSA), resulting in its efficacy against the most common pathogens encountered in skin and soft tissue, bone and joint, and urinary tract infections.^6,7,8  

• The drug also demonstrates moderate but clinically useful activity against select gram-negative organisms including E. coli, Klebsiella pneumoniae, and Proteus mirabilis.

  • Cefazolin is ineffective against methicillin-resistant Staphylococcus aureus (MRSA), which possess the mecA gene encoding penicillin-binding protein 2A (PBP2A), a low-affinity PBP that does not effectively bind beta-lactam antibiotics.

    • Cefazolin lacks activity against enterococci, anaerobic organisms, and most Enterobacteriaceae that produce extended-spectrum beta-lactamases.

Cefazolin Pharmacokinetics and Distribution^9,10 

• Cefazolin is administered exclusively via parenteral routes, intravenously or intramuscularly, given its limited gastrointestinal bioavailability.

  • Oral administration does not reliably result in therapeutic levels.

  • Cefazolin following intravenous administration is rapidly distributed.

    •  Distribution half-life Is about 4 minutes.

      • Peak plasma concentrations are achieved rapidly following bolus injection, providing immediate bactericidal activity at tissue sites.

      • Volume of distribution is approximately 0.2 to 0.25 liters per kilogram, indicating confined distribution consistent with a hydrophilic molecule that does not extensively penetrate lipid-rich compartments.

• An important pharmacokinetic property of cefazolin is its high degree of protein binding in serum, which approaches 80 percent.^9,11 

  • This extent protein binding has critical implications for pharmacodynamic efficacy as only the unbound drug fraction possesses antimicrobial activity.

    • Protein binding of cefazolin demonstrates concentration-dependent characteristics as higher drug concentrations result in relatively decreased protein binding which may lead to higher unbound drug fractions at elevated doses.

      • In interstitial fluid accumulating within tissue-embedded spaces, approximately 30% of cefazolin remains protein-bound, compared to 80% in serum, resulting in significantly higher free drug concentrations at tissue sites.

• Elimination of cefazolin occurs primarily through renal excretion, with the drug being cleared predominantly by glomerular filtration, supplemented by active tubular secretion.^10,12,13

  • Serum elimination half-life in patients with normal renal function is approximately 1.5 to 2 hours, though more recent population pharmacokinetic studies suggest a terminal half-life of approximately 57.93 minutes.

    •  In anephric patients (those without renal function), the serum half-life extends dramatically to approximately 42 hours.

  • Total elimination constant and renal clearance of cefazolin vary linearly with creatinine clearance, indicating that as renal function declines, drug accumulation becomes proportionally significant.^12,14

  • More than 90 percent of an administered dose is recovered in the urine of patients with normal renal function during the first 24 hours.

    • Peak urine levels range from 60 to over 2,000 micrograms per milliliter, reflecting the renal concentration process.

• Cefazolin is not significantly metabolized by hepatic enzymes.¹⁵

• Cefazolin does not cross the blood-brain barrier to a clinically useful extent under normal circumstances, with cerebrospinal fluid (CSF) penetration being limited in the absence of meningeal inflammation.¹⁶

• Tissue Penetration and Compartment-Specific Pharmacokinetics

  • Cefazolin is especially important in perioperative prophylaxis.^8,17,18  

    • Bone tissue achieves particularly high concentrations of cefazolin, with peak bone concentrations occurring approximately 40 minutes after parenteral administration, with a bone tissue half-life of approximately 42 minutes compared to the serum half-life of 108 minutes.

      • Favorable bone penetration reflects the drug's hydrophilicity and its ability to accumulate in mineralized tissue through multiple mechanisms.

        • Recent pharmacokinetic studies indicates that optimal bone and soft tissue concentrations are achieved when cefazolin is administered between 10 and 30 minutes before tourniquet inflation during orthopedic procedures.

          • Median bone concentration-to-serum concentration ratio is approximately 0.25, with a reported range of 0.06 to 0.41.

            • In continuous infusion studies of cefazolin for bone and joint infections, median bone concentrations reached 13.5 micrograms per gram, with considerable individual variation.

  • The blood-brain barrier presents a significant limitation to cefazolin distribution in the absence of meningeal inflammation.¹⁰  

     

    • Protective barriers of the brain

      Attribution Protective barriers of the brain Stolp HB, Liddelow SA, Sá-Pereira I, Dziegielewska KM and Saunders NR, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Protective_barriers_of_the_brain.jpg

    • Until recently, cefazolin penetration into cerebrospinal fluid was thought prohibitively low.

      • Contemporary evidence suggests more nuanced penetration patterns.¹⁹ 

        • Even in the absence of meningeal inflammation, the cerebrospinal fluid distribution ratio of cefazolin may be approximately 3 to 5 percent of serum concentrations, which may nevertheless achieve therapeutic concentrations in certain clinical scenarios.

          • When meningeal inflammation is present, as occurs during meningitis or ventriculitis, the blood-brain barrier becomes more permeable, and CSF penetration improves substantially, potentially allowing therapeutic concentrations to be achieved.

            • Despite this finding, cefazolin is typically not considered a first-line agent for bacterial meningitis due to its generally limited CNS penetration, particularly in the prophylaxis or treatment of central nervous system infections in immunocompetent individuals.

             

    • Cefazolin: Pharmacokinetic Parameters

      Parameter	Value	Clinical Implication
      Bioavailability	Not applicable (parenteral administration)	Requires IV or IM administration
      Protein Binding	74%-86%23	High binding; only free drug is active; drug interacts with albumin levels.
      Half-life (t1/2)	1.8-2.0 hours22	Allows q8h dosing
      Volume of Distribution (Vd)	0.19 L/kg22	Drug mostly localized to the extracellular domain. Effective for blood/soft tissue infections
      Excretion	Renal (as unchanged drug)23	Requires dose adjustment if renal failure present; effective agent for urinary tract infections.
      CSF Penetration	<4%23	Contraindicated for treating meningitis

Cefazolin Pharmacodynamics and Time-Dependent Antimicrobial Activity

• Optimal cefazolin utilization depends on its pharmacodynamic profile.^20,21  

  • Cephalosporins, including cefazolin, exhibit time-dependent bactericidal activity, meaning that antimicrobial efficacy is determined primarily by the proportion of the dosing interval during which unbound drug concentrations remain above the minimum inhibitory concentration (T>MIC) of the target pathogen.

    • Unlike aminoglycosides, which demonstrate concentration-dependent killing, increasing the peak serum concentration of cefazolin beyond four times the minimum inhibitory concentration does not enhance bactericidal activity. Instead, increasing the concentration only results in enhanced adverse effect risk.

  •  This pharmacodynamic principle effects dosing strategy, as extended infusions or continuous infusions of cefazolin may optimize T>MIC and potentially improve clinical outcomes compared to standard bolus administration.²¹

    • Population pharmacokinetic analyses suggest that continuous infusion of cefazolin is associated with improved target attainment compared to bolus dosing.²⁰

• In summary, for cephalosporins, maximizing the time above MIC is critical.

  • The goal is typically to maintain free drug levels above the MIC for at least 50-60% of the dosing interval for bactericidal activity.

  • For serious infections (like endocarditis) or in neutropenic hosts, 100% T > MIC is often targeted to limit the likelihood of regrowth.

    • High peaks and 1.8-hour half-life of cefazolin facilitate achieving these targets with q8h dosing for most systemic infections, whereas continuous infusion strategies are sometimes employed for critical cases.²²