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Cefoperazone

Cefoperazone: A Potent Cephalosporin for Severe Gram-Negative Infections

Introduction

In the complex and evolving realm of infectious disease management, Cefoperazone stands out as a third-generation cephalosporin antibiotic known for its robust efficacy against a wide range of Gram-negative pathogens. Originally developed in the 1980s, Cefoperazone has maintained clinical relevance, particularly in hospital-acquired infections and polymicrobial settings, often in combination with beta-lactamase inhibitors such as sulbactam.

Pharmacological Overview

  • Drug Class: Third-generation cephalosporin

  • Type: Parenteral beta-lactam antibiotic

  • Chemical Formula: C25H27N9O8S2

  • Molecular Weight: 667.67 g/mol

  • Brand Names: Cefobid, Sulperazon (Cefoperazone + Sulbactam), Cefoperazone MEP

Cefoperazone is often used in combination with sulbactam, a beta-lactamase inhibitor, to broaden its spectrum of activity against beta-lactamase-producing bacteria.

Mechanism of Action

Like all beta-lactam antibiotics, Cefoperazone targets bacterial cell wall synthesis. It binds to penicillin-binding proteins (PBPs), which are essential for peptidoglycan cross-linking in the bacterial cell wall. Disruption of this process results in a weakened cell wall and bacterial cell lysis.

Cefoperazone is bactericidal, exerting time-dependent killing and demonstrating a strong post-antibiotic effect in some organisms. It is relatively stable to several beta-lactamases, but can be hydrolyzed by extended-spectrum beta-lactamases (ESBLs) and AmpC enzymes unless paired with an inhibitor.

Antibacterial Spectrum

Cefoperazone has a broad spectrum of activity, particularly against aerobic Gram-negative bacilli, while retaining modest Gram-positive activity.

Gram-Negative Bacteria

  • Pseudomonas aeruginosa

  • Escherichia coli

  • Klebsiella pneumoniae

  • Proteus mirabilis

  • Enterobacter spp.

  • Serratia marcescens

  • Neisseria gonorrhoeae

  • Haemophilus influenzae

Gram-Positive Bacteria

  • Staphylococcus aureus (methicillin-sensitive strains)

  • Streptococcus pneumoniae

  • Streptococcus pyogenes

Anaerobes

  • Limited activity alone

  • In combination with sulbactam, enhanced activity against:

    • Bacteroides fragilis

    • Peptostreptococcus

    • Clostridium spp.

Pharmacokinetics

  • Route of Administration: Intravenous (IV), Intramuscular (IM)

  • Half-life: ~2 hours (prolonged in hepatic impairment)

  • Plasma Protein Binding: 82–93%

  • Excretion: Primarily biliary (~70%), minor renal (~30%)

  • Peak Plasma Concentration: Achieved within 15–30 minutes (IV)

Because of its biliary excretion, Cefoperazone is ideal for treating biliary tract infections, and its pharmacokinetics remain relatively stable in patients with renal impairment.

Formulations and Dosage

Monotherapy (Cefoperazone)

  • Common adult dose: 1–2 g IV every 12 hours

  • Severe infections: Up to 4 g/day in divided doses

  • Pediatric dose: 50–100 mg/kg/day, divided every 8–12 hours

Cefoperazone-Sulbactam Combination

  • Usual ratio: 1:1 (e.g., 1 g Cefoperazone + 1 g Sulbactam)

  • Dosing: 2–4 g/day (of Cefoperazone) in divided doses

Dosage adjustment is required in hepatic impairment, not renal, unless both systems are compromised.

Clinical Indications

Cefoperazone, especially when paired with sulbactam, is widely used in hospital and ICU settings. It is reserved for serious, polymicrobial, or resistant infections.

1. Respiratory Tract Infections

  • Hospital-acquired pneumonia (HAP)

  • Ventilator-associated pneumonia (VAP)

  • Aspiration pneumonia (with anaerobic coverage from sulbactam)

2. Urinary Tract Infections

  • Complicated UTIs

  • Catheter-associated infections

  • Pyelonephritis

3. Intra-abdominal Infections

  • Peritonitis

  • Cholecystitis

  • Liver abscess

  • Biliary tract infections (ideal due to biliary excretion)

4. Skin and Soft Tissue Infections

  • Diabetic foot infections

  • Cellulitis (polymicrobial coverage with sulbactam)

5. Septicemia and Bacteremia

  • Broad coverage makes it useful empirically in ICU patients

6. Gynecological Infections

  • Pelvic inflammatory disease (PID)

  • Endometritis

7. Bone and Joint Infections

  • Osteomyelitis

  • Septic arthritis

8. Meningitis

  • Not first-line due to poor CNS penetration, but may be used in combination in susceptible organisms

Efficacy and Clinical Evidence

Several studies and clinical trials underscore the efficacy of Cefoperazone:

  • Respiratory Infections: In pneumonia, it shows comparable efficacy to third-generation cephalosporins like ceftriaxone, especially when combined with sulbactam.

  • Intra-abdominal Infections: High cure rates due to dual coverage (aerobes + anaerobes) with sulbactam.

  • Pseudomonas Infections: While not the most potent anti-pseudomonal agent, it retains efficacy, especially in non-MDR strains.

  • Biliary Infections: Its biliary excretion makes it ideal for infections localized to the gallbladder or liver.

Adverse Effects

Cefoperazone is generally well tolerated, but some specific concerns exist.

Common Side Effects

  • Diarrhea

  • Nausea

  • Injection site reactions

  • Rash

Notable Side Effects

  • Hypoprothrombinemia: Cefoperazone interferes with vitamin K metabolism; may cause bleeding in high-risk patients (elderly, malnourished, liver disease)

  • Disulfiram-like Reaction: Avoid alcohol due to inhibition of aldehyde dehydrogenase

  • Hepatic dysfunction: Elevated liver enzymes

  • Allergic Reactions: Cross-reactivity with penicillins

Rare Events

  • Anaphylaxis

  • Stevens-Johnson syndrome

  • Hematologic abnormalities (thrombocytopenia, neutropenia)

Drug Interactions

  • Anticoagulants (warfarin): Increased risk of bleeding

  • Alcohol: Disulfiram-like reaction (flushing, vomiting, hypotension)

  • Aminoglycosides: Synergistic antibacterial effects but increased nephrotoxicity risk

Resistance Considerations

Cefoperazone is susceptible to several bacterial resistance mechanisms:

  • Beta-lactamase production (ESBLs, AmpC)

  • Porin channel alterations

  • Efflux pumps

Common Resistant Pathogens

  • ESBL-producing Enterobacteriaceae

  • Pseudomonas aeruginosa (MDR strains)

  • Acinetobacter baumannii

  • MRSA and Enterococcus faecalis (intrinsically resistant)

Combining with sulbactam enhances activity against beta-lactamase producers and Acinetobacter spp.

Special Populations

Hepatic Impairment

  • Requires dose adjustment

  • Monitor liver enzymes and coagulation

Renal Impairment

  • Dose adjustment usually unnecessary unless coexisting hepatic dysfunction

Pediatrics

  • Safe and widely used; monitor for diarrhea and rash

Pregnancy

  • Category B; safe if clearly needed

Lactation

  • Excreted in small amounts in breast milk; use with caution

Advantages of Cefoperazone

  • Excellent activity against Gram-negative bacilli

  • Effective biliary penetration

  • Low renal excretion, safer in renal dysfunction

  • Synergistic action with sulbactam expands spectrum

  • Useful in mixed infections (aerobic/anaerobic)

Limitations

  • Limited Gram-positive and anaerobic coverage as monotherapy

  • Emerging resistance, particularly in nosocomial settings

  • Risk of bleeding and alcohol-related adverse effects

  • Parenteral-only use limits outpatient therapy

Cefoperazone in Antimicrobial Stewardship

Given rising resistance, Cefoperazone should be:

  • Reserved for moderate to severe infections

  • Used according to culture and sensitivity reports

  • De-escalated when possible

  • Avoided in viral infections or mild community-acquired infections

Combination with sulbactam should be guided by pathogen profiles and infection type.

Global Usage and Availability

Cefoperazone is widely available, especially in Asia, the Middle East, and Latin America, often in the form of Cefoperazone-Sulbactam. It is a workhorse antibiotic in ICUs where resistant Gram-negative infections are prevalent.

Research and Future Outlook

  • Development of fixed-dose combinations with other beta-lactamase inhibitors

  • Liposomal formulations and prolonged infusion strategies

  • Expanded use in MDR bacterial infections (esp. Acinetobacter spp.)

New diagnostic tools like rapid resistance testing will help optimize Cefoperazone use in the future.

Conclusion

Cefoperazone is a versatile and potent third-generation cephalosporin with strong Gram-negative activity and notable biliary excretion, making it invaluable in treating respiratory, abdominal, biliary, and urinary infections. When combined with sulbactam, its spectrum broadens significantly, making it an effective empirical and targeted therapy in hospital settings.