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Ceftizoxime

Ceftizoxime: A Detailed Review of the Parenteral Third-Generation Cephalosporin

In the ever-evolving field of antimicrobial therapy, cephalosporins continue to serve as a crucial pillar in combating bacterial infections. Among the third-generation agents, Ceftizoxime stands out due to its broad spectrum of activity, particularly against Gram-negative bacteria, and its resistance to β-lactamases. Though not as widely used today due to the emergence of newer cephalosporins, ceftizoxime remains clinically relevant in various hospital settings.

Introduction

Ceftizoxime is a third-generation cephalosporin antibiotic developed for parenteral use. It was introduced into clinical practice in the 1980s under brand names like Cefizox. Unlike some of its oral counterparts, ceftizoxime is administered intravenously or intramuscularly, making it more suitable for hospital settings and moderate to severe infections. Ceftizoxime features enhanced activity against Gram-negative organisms, including many Enterobacteriaceae, and shows stability against a variety of β-lactamases. Its reliable pharmacokinetics, bactericidal action, and low toxicity profile make it a viable option in specific scenarios, especially in areas with low resistance prevalence.

Chemical Structure and Classification

  • Chemical Name: (6R,7R)-7-[[(2Z)-2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-[(E)-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

  • Molecular Formula: C16H16N6O7S2

  • Molecular Weight: 468.47 g/mol

  • Class: Third-generation cephalosporin

Ceftizoxime is structurally similar to cefotaxime and ceftriaxone, but it uniquely lacks an acetoxymethyl group at the 3-position, making it more resistant to hydrolysis by β-lactamases.

Mechanism of Action

Ceftizoxime, like other β-lactam antibiotics, exerts its bactericidal activity by inhibiting bacterial cell wall synthesis. It achieves this by binding to penicillin-binding proteins (PBPs), which are essential enzymes for the cross-linking of peptidoglycan chains.

This inhibition disrupts cell wall formation, leading to:

  • Compromised cell wall integrity

  • Osmotic instability

  • Bacterial lysis and death

Ceftizoxime demonstrates time-dependent killing, and maintaining adequate serum concentrations above the minimum inhibitory concentration (MIC) is critical for optimal effect.

Antibacterial Spectrum

Ceftizoxime is highly active against many Gram-negative organisms and shows moderate activity against select Gram-positive pathogens.

Gram-Negative Organisms (High Activity):

  • Escherichia coli

  • Klebsiella pneumoniae

  • Proteus mirabilis

  • Haemophilus influenzae

  • Neisseria gonorrhoeae

  • Enterobacter spp. (limited activity)

  • Citrobacter spp.

  • Salmonella and Shigella spp.

Gram-Positive Organisms (Moderate Activity):

  • Streptococcus pneumoniae

  • Streptococcus pyogenes

  • Staphylococcus aureus (methicillin-sensitive strains)

Anaerobes:

  • Limited activity against anaerobes; not a first-line option for anaerobic infections.

Not Effective Against:

  • Pseudomonas aeruginosa

  • Methicillin-resistant Staphylococcus aureus (MRSA)

  • Enterococcus spp.

Pharmacokinetics and Pharmacodynamics

Absorption:

As a parenteral drug, ceftizoxime is administered via intravenous (IV) or intramuscular (IM) injection.

Distribution:

  • Well-distributed into body fluids and tissues, including pleural, peritoneal, and synovial fluids.

  • Penetrates moderately into the cerebrospinal fluid (CSF) when meninges are inflamed.

  • Protein binding: ~30%

Metabolism and Elimination:

  • Not metabolized in the liver

  • Excreted unchanged in urine

  • Elimination half-life: ~1.5–2 hours in healthy adults

  • Prolonged in renal impairment, requiring dose adjustment

Dosage and Administration

Adults:

  • 1–2 g every 8–12 hours IV or IM

  • Severe infections may require up to 12 g/day in divided doses

Children:

  • 50–180 mg/kg/day, divided every 6–8 hours

  • Maximum dose: ~6–8 g/day

Renal Impairment:

  • Dosage must be adjusted based on creatinine clearance

  • Supplemental dose may be necessary post-hemodialysis

Clinical Indications

Ceftizoxime is approved or used for:

  1. Lower Respiratory Tract Infections

    • Pneumonia

    • Bronchitis

  2. Urinary Tract Infections (UTIs)

    • Complicated and uncomplicated

  3. Skin and Soft Tissue Infections

    • Cellulitis

    • Abscesses

  4. Gynecological Infections

    • Pelvic inflammatory disease

    • Endometritis

  5. Intra-abdominal Infections

    • Peritonitis

    • Appendicitis (in combination therapy)

  6. Septicemia

    • Particularly when the causative organism is susceptible

  7. Bone and Joint Infections

    • Osteomyelitis (off-label)

  8. Surgical Prophylaxis

    • Abdominal or gynecological procedures

Its role in treating hospital-acquired infections has diminished due to rising resistance and availability of broader-spectrum agents.

Adverse Effects

Ceftizoxime is generally well tolerated, with a low incidence of serious side effects.

Common:

  • Injection site reactions

  • Diarrhea

  • Rash

  • Nausea

Less Common:

  • Eosinophilia

  • Elevated liver enzymes (AST, ALT)

  • Headache

Rare but Serious:

  • Clostridioides difficile-associated diarrhea (CDAD)

  • Anaphylaxis or severe hypersensitivity

  • Neutropenia or thrombocytopenia with prolonged therapy

  • Interstitial nephritis (rare)

Caution is advised in patients with a history of allergy to penicillin or other β-lactams.

Drug Interactions

Ceftizoxime generally exhibits minimal drug interactions. However:

  • Probenecid may reduce renal clearance, increasing plasma levels.

  • Aminoglycosides and loop diuretics may increase nephrotoxicity risk when co-administered.

  • May interfere with urine glucose tests (false positives with certain methods).

Resistance Mechanisms

Despite its β-lactamase resistance, ceftizoxime is vulnerable to several resistance mechanisms:

  1. Extended-Spectrum β-Lactamases (ESBLs) – hydrolyze third-generation cephalosporins

  2. AmpC β-Lactamases – found in Enterobacter, Citrobacter, Serratia

  3. Altered PBPs – reduce binding affinity

  4. Efflux pumps and porin mutations – reduce intracellular accumulation

Resistance has curtailed ceftizoxime’s routine use in many hospitals, especially in regions with high prevalence of multidrug-resistant (MDR) organisms.

Comparison with Other Cephalosporins

Agent Generation Route CSF Penetration Pseudomonas Coverage Dosing Frequency
Ceftizoxime 3rd IV/IM Moderate No Every 8–12 hours
Cefotaxime 3rd IV/IM Good No Every 6–8 hours
Ceftriaxone 3rd IV/IM Good No Once daily
Ceftazidime 3rd IV/IM Moderate Yes Every 8 hours

Ceftizoxime's dosing frequency and lack of Pseudomonas coverage make it less favorable compared to ceftriaxone or ceftazidime in some settings.

Use in Special Populations

Pregnancy:

  • Category B: Animal studies do not show risk, but caution is advised

Lactation:

  • Trace amounts excreted in breast milk

  • Considered compatible with breastfeeding

Pediatrics:

  • Safe and effective with proper dosing adjustments

Geriatrics:

  • No specific contraindications, but renal function should be monitored

Clinical Trials and Efficacy

Several trials have confirmed ceftizoxime's efficacy in:

  • Community-acquired pneumonia: comparable to cefotaxime

  • UTIs and skin infections: high clinical and microbiological cure rates

  • Surgical prophylaxis: reduction in post-op infection rates, particularly in gynecological surgeries

However, most of this data predates the ESBL era, limiting current applicability.

Limitations and Challenges

  • Rising resistance due to ESBL and AmpC producers

  • Inferior pharmacokinetics compared to ceftriaxone

  • Limited use in outpatient settings (parenteral administration only)

  • Replaced in many guidelines by broader-spectrum or once-daily agents

Future Outlook

While no longer front-line, ceftizoxime still has a role in:

  • Targeted therapy when susceptibility is confirmed

  • Resource-limited settings

  • Combination regimens in mixed infections

Ongoing surveillance of antimicrobial susceptibility patterns will dictate its continued utility.

Conclusion

Ceftizoxime remains a valuable agent within the third-generation cephalosporin class, offering potent bactericidal activity against a range of Gram-negative pathogens. Though its clinical use has diminished in favor of more convenient or broader-spectrum alternatives, it still retains relevance in targeted hospital-based therapy. Rational, susceptibility-driven use can help maximize its benefits while minimizing resistance development.