Cefuroxime Monograph

Introduction

Cefuroxime is a second‑generation cephalosporin antibiotic that exhibits a broad spectrum of activity against Gram‑positive and Gram‑negative organisms. Its structural modifications, which include a 2‑hydroxyethyl side chain, confer enhanced stability against β‑lactamases and improved pharmacokinetic properties relative to first‑generation cephalosporins. The drug is commonly available as cefuroxime axetil, a prodrug formulation designed to improve oral bioavailability. Historically, cefuroxime was introduced in the early 1980s and has since become a staple in the empiric treatment of respiratory tract infections, skin and soft tissue infections, and certain sexually transmitted infections. The importance of cefuroxime within pharmacology and therapeutics stems from its favorable safety profile, ease of administration, and versatility across a range of clinical scenarios.

Learning objectives for this chapter include:

• Comprehending the structural and mechanistic basis of cefuroxime’s antibacterial activity.
• Understanding the pharmacokinetic parameters that influence dosing regimens.
• Recognizing clinical indications, contraindications, and safety considerations.
• Applying knowledge to construct appropriate therapeutic strategies in diverse patient populations.
• Integrating pharmacodynamic principles with clinical outcomes to optimize treatment efficacy.

Fundamental Principles

Structural Features and Chemical Classification

Cefuroxime belongs to the β‑lactam class of antibiotics, specifically the cephalosporin subclass. Its core β‑lactam ring is fused to a dihydrothiazine ring, forming the characteristic cephalosporin nucleus. The presence of a 2‑hydroxyethyl side chain at the 7‑position enhances resistance to β‑lactamase enzymes produced by many Gram‑negative bacteria. The prodrug cefuroxime axetil incorporates an acetate ester moiety that facilitates passive diffusion across the gastrointestinal epithelium; enzymatic hydrolysis within enterocytes releases the active cefuroxime molecule.

Mechanism of Action

Cephalosporins, including cefuroxime, exert bactericidal effects by inhibiting bacterial cell wall synthesis. Specifically, they bind to penicillin‑binding proteins (PBPs) located on the cytoplasmic membrane and interfere with the cross‑linking of peptidoglycan chains during cell wall assembly. The inhibition of transpeptidase activity results in weakened cell wall integrity, osmotic lysis, and ultimately bacterial death. Cefuroxime demonstrates high affinity for PBP3, which is essential for bacterial cell division, thereby contributing to its potency against a variety of pathogens.

Pharmacodynamic Considerations

The antibacterial activity of cefuroxime is time‑dependent, meaning that the duration of drug exposure above the minimum inhibitory concentration (MIC) is the primary determinant of efficacy. Therefore, maintaining serum concentrations above the MIC for a significant proportion of the dosing interval is critical. A commonly cited pharmacodynamic target is that the free drug concentration remains above the MIC for at least 40–50 % of the dosing interval (T>MIC). In cases of severe infection, a target of 70–80 % T>MIC may be pursued to enhance clinical success.

Detailed Explanation

Pharmacokinetics

Absorption

Oral cefuroxime axetil is absorbed in the small intestine after enzymatic conversion to the active drug. Peak plasma concentrations (C_max) are typically achieved within 2–4 hours following ingestion. Bioavailability of the prodrug formulation is approximately 40 % relative to intravenous cefuroxime, corresponding to a C_max of 1.5–2 mg/L for a 250 mg oral dose. Factors that may influence absorption include gastric pH, presence of food, and intestinal motility. Administration with food can improve tolerability without markedly altering systemic exposure.

Distribution

After reaching systemic circulation, cefuroxime distributes extensively into extravascular compartments, achieving tissue concentrations that are comparable to plasma levels for most sites. The volume of distribution (V_d) is approximately 0.6 L/kg, reflecting moderate penetration into body fluids. Cefuroxime is moderately bound to plasma proteins (≈30 %), meaning that a substantial fraction remains free to exert antimicrobial action. Distribution into the central nervous system is limited due to the blood‑brain barrier; concentrations in cerebrospinal fluid are typically <5 % of plasma levels, which restricts its use in meningitis unless hydrocephalus or inflammation increases permeability.

Metabolism

Metabolic transformation of cefuroxime is minimal. The drug is largely excreted unchanged, with negligible contribution from hepatic metabolism. Consequently, hepatic impairment does not necessitate dose adjustment for most patients, although caution is advised in severe liver disease due to potential accumulation of other β‑lactam metabolites.

Excretion and Clearance

Renal excretion accounts for the majority of cefuroxime elimination. The drug is filtered by the glomerulus and undergoes minimal tubular secretion or reabsorption. Mean effective renal clearance (Cl_renal) is approximately 5 L/h in healthy adults. The half‑life (t_1/2) is around 1.5–2 hours, but it can extend to 3–4 hours in patients with reduced glomerular filtration rate (GFR). The relationship between dose, clearance, and area under the concentration–time curve (AUC) can be expressed as:

AUC = Dose ÷ Clearance

When renal function declines, the AUC increases proportionally, raising the risk of toxicity if dosing is not appropriately adjusted.

Mathematical Modeling of Concentration–Time Profile

The concentration of cefuroxime in plasma over time can be described by a first‑order elimination model:

C(t) = C₀ × e⁻ᵏᵗ

where C₀ represents the initial concentration at the time of administration, k is the elimination rate constant (k = ln 2 ÷ t_1/2), and t is the elapsed time. By integrating this equation, the AUC from zero to infinity is calculated as:

AUC = C₀ ÷ k

These equations facilitate the prediction of drug exposure and support the design of dosing intervals that achieve desired pharmacodynamic targets.

Factors Influencing Pharmacokinetics

• Renal Function: Decline in GFR leads to reduced clearance and prolonged half‑life.
• Age: Elderly patients may exhibit decreased renal clearance, necessitating dose reduction.
• Body Weight: Obesity can increase the volume of distribution, potentially requiring higher doses for adequate exposure.
• Drug Interactions: Concomitant administration of nephrotoxic agents (e.g., aminoglycosides) may amplify renal toxicity risk.
• Gastrointestinal Factors: Altered pH or motility disorders can affect absorption of the prodrug.

Safety and Adverse Effects

Cephalosporins are generally well tolerated. Common adverse reactions include gastrointestinal upset (diarrhea, nausea), rash, and mild hepatotoxicity. Severe hypersensitivity reactions, such as Stevens–Johnson syndrome, are rare but have been reported. Because cefuroxime undergoes renal excretion, accumulation may precipitate neurotoxicity, manifested as seizures, particularly in patients with impaired renal function or in those receiving concurrent neurotoxic medications.

Resistance Considerations

Resistance to cefuroxime can arise through several mechanisms: production of β‑lactamases capable of hydrolyzing the cephalosporin core, alteration of PBPs reducing drug affinity, and decreased permeability due to porin loss. Monitoring local antibiograms and employing stewardship principles are essential to sustain cefuroxime effectiveness.

Clinical Significance

Therapeutic Indications

Cefuroxime is indicated for the treatment of community‑acquired pneumonia, acute sinusitis, acute otitis media, uncomplicated urinary tract infections, skin and soft tissue infections, and certain sexually transmitted infections such as gonorrhea. Its activity against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus (methicillin‑sensitive strains) renders it suitable for empiric therapy in many acute infections.

Dosing Regimens

Standard adult dosing for most indications involves 250–500 mg of cefuroxime axetil taken orally twice daily. For severe infections or impaired renal function, dose adjustments are recommended:

• Patients with GFR ≥ 60 mL/min: 500 mg bid.
• Patients with GFR 30–59 mL/min: 250 mg bid.
• Patients with GFR < 30 mL/min: 250 mg qd.

Intravenous cefuroxime is less commonly used but may be employed in hospital settings for patients unable to tolerate oral therapy. A typical IV dose of 1 g q12h is administered in patients with normal renal function; dose reductions mirror the oral adjustments described above.

Clinical Outcomes

Multiple randomized controlled trials have demonstrated non‑inferiority of cefuroxime compared with other β‑lactam agents in the treatment of uncomplicated cystitis and acute otitis media. Meta‑analyses indicate higher cure rates in patients receiving cefuroxime axetil for community‑acquired pneumonia when compared with amoxicillin, particularly in populations with high prevalence of β‑lactamase‑producing organisms.

Safety in Special Populations

• Geriatric Patients: Dose reduction is often warranted due to age‑related decline in renal function.
• Pregnancy: Classified as category B; cross‑placental transfer is limited, but caution is advised.
• Infants and Children: Pediatric dosing is weight‑based: 25 mg/kg/day divided into two doses for most indications.
• Patients with Renal Impairment: Monitoring of serum creatinine and dose adjustment are essential to prevent accumulation.

Clinical Applications/Examples

Case Scenario 1: Community‑Acquired Pneumonia in an Adult

A 45‑year‑old male presents with fever, productive cough, and dyspnea. Chest radiograph confirms lobar pneumonia. Empiric therapy is initiated with cefuroxime axetil 500 mg bid. The patient’s baseline serum creatinine is 1.0 mg/dL, corresponding to an estimated GFR of 90 mL/min. The patient tolerates therapy well, with clinical improvement within 48 hours. After 7 days, complete resolution of symptoms is achieved. This case illustrates the utility of cefuroxime in treating moderate pneumonia when β‑lactamase–producing pathogens are suspected.

Case Scenario 2: Uncomplicated Urinary Tract Infection in a Pregnant Woman

A 28‑year‑old woman in her second trimester is diagnosed with cystitis based on dysuria and positive dipstick urinalysis. Cefuroxime axetil 250 mg bid is prescribed for 7 days. No adverse events are reported. The patient remains symptom‑free at follow‑up. This scenario demonstrates cefuroxime’s safety profile during pregnancy and its effectiveness against common uropathogens.

Case Scenario 3: Skin and Soft Tissue Infection in a Diabetic Patient

A 60‑year‑old man with type 2 diabetes presents with erythema, swelling, and purulent drainage from a foot ulcer. Cultures grow Streptococcus pyogenes. Cefuroxime axetil 500 mg bid is started empirically while awaiting culture results. After 5 days, the ulcer shows marked improvement. The patient’s creatinine is 1.4 mg/dL (GFR ≈ 45 mL/min); dose adjustment to 250 mg bid is considered to reduce nephrotoxicity risk. This example underscores the importance of dose modification in patients with renal impairment.

Problem‑Solving Approach for Cefuroxime Dosing in Renal Impairment

1. Estimate patient’s GFR using the Cockcroft–Gault or MDRD equation.
2. Refer to dosing adjustment guidelines based on GFR thresholds.
3. Calculate the adjusted dose as: Adjusted Dose = (Target Dose ÷ Normal Clearance) × (Patient Clearance).
4. Monitor renal function periodically and reassess dosing each week.
5. Consider therapeutic drug monitoring if the infection is severe or if the patient exhibits atypical pharmacokinetics.

Summary/Key Points

• Cefuroxime is a second‑generation cephalosporin with enhanced β‑lactamase resistance due to a 2‑hydroxyethyl side chain.
• Its mechanism of action involves inhibition of PBPs, leading to bacterial lysis.
• Pharmacokinetic parameters: V_d ≈ 0.6 L/kg, protein binding ≈ 30 %, renal clearance ≈ 5 L/h, t_1/2 ≈ 1.5–2 h.
• Time‑dependent killing necessitates maintaining plasma concentrations above the MIC for a significant portion of the dosing interval; target T>MIC is 40–50 % for most infections.
• Dosing recommendations: 250–500 mg oral bid for adults; renal‑adjusted doses for patients with GFR < 60 mL/min.
• Adverse effects are generally mild; serious hypersensitivity reactions are rare.
• Resistance mechanisms include β‑lactamase production, PBP alteration, and reduced permeability.
• Clinical applications encompass respiratory, urinary, skin, and sexually transmitted infections; case examples illustrate dosing adjustments and therapeutic outcomes.
• Key pharmacodynamic target: C_free > MIC for ≥ 40 % of the dosing interval; higher targets may be pursued in severe disease.
• Monitoring of renal function and consideration of drug interactions are essential to maintain safety and efficacy.

References

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