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Cefpirome

Cefpirome: A Fourth-Generation Cephalosporin Powerhouse

Introduction

In the fight against severe and multidrug-resistant bacterial infections, advanced cephalosporins have emerged as vital therapeutic agents. Among them, Cefpirome—a fourth-generation cephalosporin—holds particular significance. Developed to extend the spectrum of activity and improve pharmacokinetic properties compared to earlier generations, cefpirome offers potent efficacy against both gram-negative and gram-positive pathogens, including Pseudomonas aeruginosa and certain strains producing extended-spectrum β-lactamases (ESBLs).

1. Overview and Chemical Profile

Chemical Identity

  • IUPAC Name: (6R,7R)-7-[[(2Z)-2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-[(E)-2-(4-methylpyridinium-1-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

  • Molecular Formula: C22H22N6O5S2

  • Molecular Weight: 530.58 g/mol

Cefpirome’s structure is characterized by a β-lactam ring fused to a dihydrothiazine ring, typical of cephalosporins, and additional side chains that confer enhanced β-lactamase resistance and improved membrane permeability in gram-negative bacteria.

Class: Fourth-generation cephalosporin

Mode of Administration: Intravenous (IV)

2. Mechanism of Action

Cefpirome, like other β-lactam antibiotics, exerts its bactericidal action by binding to penicillin-binding proteins (PBPs) located on the bacterial cell wall. This binding inhibits the final transpeptidation step in the synthesis of the bacterial cell wall, leading to cell lysis and death.

Cefpirome has high affinity for multiple PBPs, including PBP-2 and PBP-3 in gram-negative bacteria, which contributes to its potent antimicrobial activity.

3. Pharmacokinetics and Pharmacodynamics

Absorption

Cefpirome is not absorbed orally and is only available as a parenteral formulation, typically administered via intravenous infusion.

Distribution

  • Widely distributed in body fluids including pleural, peritoneal, and interstitial fluids.

  • Moderate cerebrospinal fluid (CSF) penetration, enhanced with inflamed meninges.

Protein Binding

  • Approximately 20–30%, which is relatively low compared to some other cephalosporins.

Metabolism

  • Not significantly metabolized; it remains mostly unchanged in circulation.

Elimination

  • Primarily excreted unchanged via renal filtration.

  • Dose adjustment is recommended in patients with renal impairment.

Half-Life

  • Around 2 hours in healthy adults, prolonged in renal dysfunction.

4. Spectrum of Antimicrobial Activity

Cefpirome is known for its broad-spectrum and β-lactamase-resistant profile, making it effective against a variety of aerobic gram-positive and gram-negative organisms.

4.1 Gram-Positive Bacteria

  • Staphylococcus aureus (including some methicillin-sensitive strains)

  • Staphylococcus epidermidis

  • Streptococcus pneumoniae

  • Streptococcus pyogenes

  • Enterococcus faecalis (limited activity)

4.2 Gram-Negative Bacteria

  • Escherichia coli

  • Klebsiella pneumoniae

  • Enterobacter cloacae

  • Serratia marcescens

  • Citrobacter freundii

  • Proteus spp.

  • Haemophilus influenzae

  • Neisseria meningitidis

  • Pseudomonas aeruginosa – a key advantage of cefpirome over earlier cephalosporins

4.3 Inactive Against

  • MRSA (Methicillin-resistant Staphylococcus aureus)

  • Acinetobacter baumannii (variable)

  • Most anaerobes (Bacteroides fragilis)

5. Clinical Indications

Cefpirome is reserved primarily for hospitalized patients with moderate to severe infections, often as empiric therapy before pathogen identification, and as definitive therapy for known susceptible organisms.

5.1 Hospital-Acquired Pneumonia (HAP)

  • Effective against Pseudomonas aeruginosa and other multidrug-resistant gram-negative bacilli.

5.2 Urinary Tract Infections (UTIs)

  • Used in complicated UTIs including pyelonephritis and catheter-associated infections.

5.3 Sepsis and Bacteremia

  • Broad-spectrum coverage makes cefpirome suitable for empirical management of sepsis, especially in intensive care settings.

5.4 Skin and Soft Tissue Infections

  • Used in complicated skin infections, especially with mixed flora.

5.5 Intra-Abdominal Infections

  • Often combined with metronidazole for anaerobic coverage in conditions like peritonitis or appendicitis.

5.6 Febrile Neutropenia

  • Cefpirome is a component of empirical regimens for immunocompromised patients, including those with malignancies or post-transplant status.

6. Dosage and Administration

Adult Dose

  • 1–2 g IV every 12 hours

  • In severe infections, dosage may be increased to every 8 hours.

Pediatric Use

  • Limited data; not typically used unless in special cases or clinical trials.

Renal Impairment

  • Dose adjustments required; monitoring of creatinine clearance is essential.

7. Safety and Tolerability

Common Side Effects

  • Diarrhea

  • Nausea

  • Injection site reactions

  • Skin rash

Less Common but Serious

  • Clostridioides difficile-associated diarrhea (CDAD)

  • Hypersensitivity reactions including anaphylaxis

  • Neutropenia or thrombocytopenia with prolonged use

  • Elevated liver enzymes (transaminases)

Cross-Reactivity

  • Patients with known penicillin allergies may exhibit hypersensitivity due to structural similarities.

8. Resistance Mechanisms

Although cefpirome is designed to resist hydrolysis by many β-lactamases, resistance has emerged due to:

8.1 ESBLs (Extended-Spectrum β-Lactamases)

  • Produced by E. coli, Klebsiella, and Proteus, rendering cefpirome less effective.

8.2 AmpC β-Lactamases

  • Expressed by Enterobacter, Serratia, and Citrobacter, leading to moderate resistance.

8.3 Carbapenemases

  • Cefpirome is not effective against carbapenemase-producing organisms (e.g., KPC, NDM).

8.4 Efflux Pumps and Porin Mutations

  • Common in P. aeruginosa, leading to reduced intracellular concentrations of the drug.

9. Comparative Advantage Over Other Cephalosporins

Cefpirome distinguishes itself through:

Feature Cefotaxime Ceftriaxone Ceftazidime Cefpirome
Generation 3rd 3rd 3rd 4th
Pseudomonas coverage No No Yes Yes
ESBL resistance Moderate Moderate Low Higher
CNS penetration Good Excellent Moderate Moderate
β-lactamase stability Moderate Moderate Low High

10. Cefpirome vs Cefepime

Cefepime is the only FDA-approved fourth-generation cephalosporin in widespread use in the U.S., while cefpirome is approved in Europe and other regions. Both agents share similarities, but differences exist:

Attribute Cefepime Cefpirome
CNS Penetration Excellent Moderate
Dosing Every 8–12 hrs Every 12 hrs
Activity vs P. aeruginosa Strong Strong
Anaerobic Coverage Limited Limited

11. Regulatory and Availability

Cefpirome is not approved by the U.S. FDA, but is available in Europe, India, and parts of Asia and South America under brand names like Cefrom and Broact. Its restricted availability is due not to efficacy concerns, but due to marketing strategies and availability of comparable agents like cefepime and carbapenems.

12. Role in Antimicrobial Stewardship

Cefpirome is classified as a Reserve Group Antibiotic in the WHO AWaRe classification, meaning it should be used with caution and only in cases where narrower-spectrum agents are not appropriate.

Key stewardship principles include:

  • Use only with culture/sensitivity guidance

  • De-escalation once pathogen identified

  • Avoid routine use for mild or self-limiting infections

Conclusion

Cefpirome represents an important advancement in cephalosporin antibiotics, especially for tackling serious nosocomial infections caused by resistant organisms. Its broad-spectrum activity, especially against Pseudomonas and gram-negative rods, makes it valuable in critical care and immunocompromised patients.However, like all powerful antibiotics, cefpirome must be used judiciously to combat the growing threat of antimicrobial resistance. Through appropriate clinical use and antimicrobial stewardship, cefpirome can continue to serve as a potent weapon in the fight against life-threatening bacterial infections.

References

  1. World Health Organization (WHO) Model List of Essential Medicines

  2. Sanford Guide to Antimicrobial Therapy

  3. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases

  4. European Medicines Agency (EMA) Product Data for Cefpirome

  5. Clinical and Laboratory Standards Institute (CLSI) Guidelines