• Second Generation Cephalosporins:  Cefuroxime

Cefuroxime: Audio Overview

 

• 2D Cefuroxime (Ceftin, oral; Zinacef, injection)

•  

  3D Cefuroxime (Ceftin, oral; Zinacef, injection)

   

• Cefuroxime: Clinical Uses

 

• Introduction: Cefuroxime ^2,3,4

  • Cefuroxime represents a pivotal agent in the second-generation cephalosporin class, distinguished by its enhanced stability against β-lactamase hydrolysis and expanded spectrum against Gram-negative bacilli compared to first-generation compounds.

    • The drug exists in two primary formulations: cefuroxime sodium for parenteral administration and cefuroxime axetil, an acetoxyethyl ester prodrug that enables oral bioavailability through intestinal esterase hydrolysis.

    • This dual-route availability has positioned cefuroxime as a versatile option for transitioning patients from inpatient to outpatient therapy, particularly in community-acquired infections where antimicrobial stewardship principles favor step-down therapy to narrow-spectrum agents.

  Mechanism of Action: Cefuroxime.^2,3,5,6

   

  • Cefuroxime: Mechanism of Action

  • The bactericidal activity of cefuroxime originates from its high-affinity binding to penicillin-binding proteins (PBPs), essential enzymes responsible for the final cross-linking of peptidoglycan units during bacterial cell wall synthesis.

    • Cefuroxime demonstrates preferential affinity for PBP3, while maintaining inhibitory activity against PBP1a and PBP1b.

      • This binding occurs through the β-lactam ring structure, which sterically inhibits the transpeptidation reaction required for cell wall integrity.

        • Resulting inhibition prevents formation of the rigid peptidoglycan network that protects bacteria from osmotic lysis, leading to cell death through autolytic enzyme activation.

        • Cefuroxime is resistant to hydrolysis by many β-lactamases produced by Gram-negative organisms, a property that distinguishes it from earlier cephalosporins and penicillins.

          • This resistance to enzymatic degradation is particularly evident against TEM-type β-lactamases in Haemophilus influenzae and Neisseria gonorrhoeae, though it remains vulnerable to extended-spectrum β-lactamases (ESBLs) and AmpC cephalosporinases.

    • However, cefuroxime does not bind altered PBPs in Methicillin-Resistant Staphylococcus Aureus (MRSA) or penicillin-resistant Streptococcus pneumoniae, so these strains are inherently resistant.²  

      • The failure to bind PBP2a (encoded by mecA in MRSA) represents the basis for cefuroxime’s lack of efficacy against MRSA.² 

  • Antimicrobial Spectrum and Resistance^2,7,8,9  

    • Cefuroxime has a broad antibacterial spectrum encompassing many gram-positive and gram-negative organisms.

      • Cefuroxime is active against Staphylococcus aureus (methicillin-susceptible strains), Streptococcus pyogenes, and S. pneumoniae, although activity against enterococci and MRSA is poor.

      • Cefuroxime covers many common gram-negative respiratory pathogens including Haemophilus influenzae (even ampicillin-resistant strains via β-lactamase production), Moraxella catarrhalis, and Neisseria gonorrhoeae (including penicillinase-producing strains).

      • This agent is also generally effective against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella, Shigella, Providencia, and others.

        • Cefuroxime exhibits good activity in vitro against many Enterobacter and Citrobacter species, but some strains of these organisms can inducibly express cephalosporinases that confer resistance.

        • Anaerobic coverage of cefuroxime is limited with some activity against some anaerobes (like Peptostreptococcus, Clostridium (non-C. difficile species), Fusobacterium), but it is ineffective against Bacteroides fragilis and Clostridioides difficile.

          • Cefuroxime is usually ineffective against Pseudomonas aeruginosa, certain Proteus (e.g. P. vulgaris), Campylobacter, Acinetobacter, and most Serratia, which are intrinsically resistant.

            • Main mechanisms of resistance to cefuroxime include bacterial production of β-lactamase enzymes that hydrolyze the drug (though cefuroxime is stable against many common plasmid β-lactamases), modifications of PBPs (e.g. PBP2a in MRSA), and reduced permeability of gram-negative outer membranes hindering drug entry.

      • Comparative Description of Gram-Negative Coverage

        Pathogen	Cephalexin (1st Gen)	Cefuroxime (2nd Gen)	Clinical Importance
        Escherichia coli	Active	Active	Both are effective for uncomplicated UTIs; however, resistance is growing for both (FDA Zinacef Labeling, 2024)11
        Klebsiella pneumoniae	Variable	Active	Cefuroxime provides more reliable coverage for community-acquired Klebsiella infections.12
        Proteus mirabilis	Active	Active	Common urinary pathogen covered by both generations.
        Haemophilus influenzae	Weak/Inactive	Highly Active	Cefuroxime is stable against many β-lactamases that render 1st Gen agents useless10
        Moraxella catarrhalis	Inactive	Highly active	Essential for treating acute otitis media and exacerbations of COPD.2
        Neisseria gonorrhea	Inactive	Activ	Historically used for gonorrhea, though third-generation agents are now the gold standard.
        Enterobacter species	Resistant	Variable/Weak	Generally, neither should be used for Enterobacter due to potential AmpC induction.

   

  • Cefuroxime: Pharmacokinetics 

    • Absorption and Bioavailability^2,3 

      • The oral form, cefuroxime axetil, is an acetoxyethyl ester prodrug that is poorly absorbed as the parent cefuroxime but becomes readily absorbed after conversion in the gut.

        • After oral administration, cefuroxime axetil is hydrolyzed by esterases in the intestinal mucosa to release active cefuroxime, which enters the circulation.

        • Absorption is significantly enhanced by food – the bioavailability of oral cefuroxime axetil is about 37% on an empty stomach, rising to approximately 52% when taken with food.

          • In adults, peak serum concentrations are reached about 2–3 hours after an oral dose, whereas in young children peak levels occur slightly later (around 3–4 hours).

      • Intramuscular or intravenous administration of cefuroxime bypasses this absorption step, and with IV infusion peak levels are achieved within minutes.

        • Parenteral administration achieves rapid therapeutic concentrations, with intravenous injection producing peak serum levels within 2-3 minutes and intramuscular injection reaching maximum concentration in 2-3 hours.

    • Distribution and Protein Binding^2,8,13 

      • Distribution

        • Cefuroxime has a moderate volume of distribution (~0.25–0.3 L/kg) and is roughly 33–50% bound to plasma proteins, distributing reasonably well into various tissues and body fluids. However, this agent exhibits less tissue penetration compared to the newer cephalosporins.

        • Therapeutically effective concentrations are attained in the respiratory tract (e.g. lung tissue, bronchial mucosa), ENT tissues (e.g. sinuses, tonsils, and middle ear effusions), and even the aqueous humor of the eye.

        • cefuroxime can penetrate into bone, which is useful for certain orthopedic or odontogenic infections.

        • Cefuroxime also crosses the inflamed meninges to reach the cerebrospinal fluid (CSF) at therapeutic levels, allowing it to be used for susceptible bacterial meningitis (although third-generation cephalosporins are more commonly preferred for CNS infections due to superior CSF penetration).

      • Protein Binding

        • Cefuroxime exhibits moderate protein binding, with approximately 33-50% of serum cefuroxime bound to albumin.

          • This binding is clinically advantageous, as it provides a reservoir of drug while maintaining sufficient free fraction for antimicrobial activity.

    • Metabolism and Elimination^2,13,14,16  

      • Cefuroxime undergoes minimal hepatic metabolism; the primary metabolic transformation involves cleavage of the axetil moiety in the intestinal mucosa to release active cefuroxime.

      • Unchanged drug is predominantly eliminated via renal excretion, with approximately 50% of the administered dose recovered in urine within 12 hours.

      • Renal tubular secretion accounts for 43-54% of total renal clearance, as demonstrated by probenecid-induced reductions in clearance of approximately 40%.

      • Eimination drug half-life is about 60-90 minutes in adults with normal renal function, extending to 1.4-1.9 hours in pediatric patients.¹⁵ 

      • In the presence of renal impairment, dose adjustments become necessary when creatinine clearance falls below 50 mL/min/1.73 m².

        • Special Populations^15,16

          • Patients with impaired renal function require systematic dose modifications to prevent accumulation and toxicity.

            • When creatinine clearance ranges from 30-49 mL/min, dosing intervals should extend to every 12 hours; at 10-29 mL/min, every 24 hours; and below 10 mL/min, every 48 hours.

            • For patients undergoing hemodialysis, 750 mg twice daily provides adequate coverage, while continuous arteriovenous hemofiltration may require 750 mg twice daily for high-flux systems.

            • Pediatric pharmacokinetics show similar elimination characteristics to adults beyond three weeks of age, though neonates exhibit prolonged half-lives due to immature renal function.

  • Cefuroxime: Pharmacodynamics^2,17 

    • Similar to other β-lactams, cefuroxime exhibits time-dependent killing (efficacy is linked to the duration plasma concentrations exceed the minimum inhibitory concentration of the pathogen).

      • Cefuroxime is generally bactericidal against susceptible bacteria and has a post-antibiotic effect of short duration.

        • Combining cefuroxime with a bacteriostatic agent is usually not problematic, but in severe infections cefuroxime may be used with an aminoglycoside for synergistic effect (especially to broaden coverage).

        • Probenecid can increase cefuroxime levels by blocking its tubular secretion .

          • This interaction has been used therapeutically to prolong β-lactam levels (but such combination must be accompanied by increased concern about drug exposure and toxicity.