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Thursday, August 7, 2025

Fourth generation cephalosporins


Overview
Fourth-generation cephalosporins are advanced β-lactam antibiotics within the broader cephalosporin class, engineered to resist β-lactamases and to exhibit enhanced activity against both Gram-positive and Gram-negative organisms. They build on the pharmacological strengths of third-generation cephalosporins while adding improved stability against hydrolysis by β-lactamase enzymes and increased penetration of the bacterial outer membrane. These agents are critical in managing serious hospital-acquired and healthcare-associated infections, especially in the face of rising multidrug resistance.

Cephalosporins, including fourth-generation variants, are structurally and functionally similar to penicillins, sharing the β-lactam ring, and inhibit bacterial cell wall synthesis. However, their resistance to β-lactamase degradation and extended spectrum make them invaluable in critical care and resistant infections.

1. Core Fourth-Generation Cephalosporins

The fourth-generation cephalosporins currently in clinical use include:

  1. Cefepime (most widely used and clinically relevant)

    • Brand names: Maxipime (U.S.), Axepim

    • FDA-approved in 1996

  2. Cefpirome (approved and used in Europe and Asia, but not in the United States)

    • Brand names: Cefrom, Broact

Among these, cefepime is the prototypical fourth-generation cephalosporin and remains the cornerstone of therapy in this class.

2. Mechanism of Action

Fourth-generation cephalosporins act by inhibiting bacterial cell wall synthesis, specifically binding to penicillin-binding proteins (PBPs) that catalyze the cross-linking of peptidoglycan chains.

Mechanism details:

  • Disrupt transpeptidation reaction in bacterial peptidoglycan biosynthesis.

  • Induce bacterial cell lysis due to defective cell wall synthesis.

  • Exhibit bactericidal activity, especially against dividing bacteria.

Cefepime and cefpirome have enhanced ability to:

  • Penetrate the outer membrane of Gram-negative bacteria.

  • Resist hydrolysis by AmpC β-lactamases.

  • Bind with high affinity to multiple PBPs, including PBP3 in Enterobacteriaceae.

3. Antibacterial Spectrum

Fourth-generation cephalosporins are broad-spectrum agents, effective against both Gram-negative and Gram-positive pathogens.

A. Gram-Positive Activity:

  • Streptococcus pneumoniae (including penicillin-intermediate strains)

  • Streptococcus pyogenes

  • Staphylococcus aureus (methicillin-sensitive only; not MRSA)

  • Enterococcus faecalis (limited activity)

B. Gram-Negative Activity:

  • Escherichia coli

  • Klebsiella pneumoniae

  • Proteus mirabilis

  • Enterobacter spp.

  • Serratia spp.

  • Citrobacter spp.

  • Pseudomonas aeruginosa (notable advantage over 3rd gen)

C. Anaerobes:

  • Limited activity; not reliable against Bacteroides fragilis or other strict anaerobes.

D. Resistance Profile:

  • Stable against many β-lactamases, including:

    • Chromosomal AmpC β-lactamases (e.g., in Enterobacter spp.)

    • Some extended-spectrum β-lactamases (ESBLs), but not carbapenemases

4. Clinical Indications

Cefepime is approved and commonly used in the treatment of serious infections, including:

  • Febrile neutropenia (empiric monotherapy)

  • Nosocomial pneumonia, including ventilator-associated pneumonia

  • Complicated urinary tract infections (UTIs), including pyelonephritis

  • Complicated intra-abdominal infections (as part of combination therapy)

  • Skin and soft tissue infections (non-MRSA)

  • Sepsis and bacteremia, especially due to Gram-negative bacilli

  • Meningitis (off-label use due to good CSF penetration at high doses)

Cefpirome is used in some regions for similar indications, particularly in resistant infections.

5. Pharmacokinetics

ParameterCefepimeCefpirome (limited data)
AdministrationIV or IMIV
BioavailabilityNot applicable (parenteral only)IV only
DistributionWidely distributed; good CSF penetrationGood distribution
Protein Binding~16–19%~20%
Half-life~2 hours~2–3 hours
EliminationRenal (unchanged drug)Renal
Excretion>85% unchanged in urine>80% in urine


Requires dose adjustment in renal impairment.

  • Crosses blood-brain barrier in meningitis or high-dose therapy.

6. Adverse Effects

A. Common

  • Diarrhea

  • Rash

  • Injection site reactions

  • Nausea/vomiting

B. Central Nervous System (CNS)

  • Neurotoxicity: seizures, encephalopathy, confusion

    • Most common in renal failure due to drug accumulation.

    • Cefepime neurotoxicity is well-documented; monitor renal function closely.

C. Hematologic

  • Neutropenia

  • Thrombocytopenia

  • Eosinophilia

D. Hypersensitivity

  • Cross-reactivity with other β-lactams (~1–10%)

  • Caution in penicillin-allergic individuals

E. Others

  • Elevated liver enzymes (AST, ALT)

  • C. difficile-associated diarrhea (CDAD)

7. Contraindications

  • Known hypersensitivity to cephalosporins or other β-lactam antibiotics

  • Caution in:

    • Patients with a history of severe penicillin allergy

    • Seizure disorders, especially in renal impairment

    • Elderly with renal dysfunction

8. Drug Interactions

  • Aminoglycosides: increased risk of nephrotoxicity when co-administered.

  • Loop diuretics: may enhance nephrotoxicity risk.

  • Probenecid: may reduce cefepime excretion, increasing serum levels.

  • Warfarin: prolonged PT/INR has been observed with some cephalosporins; monitor closely.

No significant interaction with CYP450 enzymes—safe in polypharmacy contexts.

9. Dosage and Administration

IndicationCefepime DoseDuration (typical)
Febrile neutropenia2 g IV every 8 hours7–14 days
Nosocomial pneumonia2 g IV every 8 hours7–14 days
UTI (complicated)1–2 g IV every 12 hours7–10 days
Skin and soft tissue infections1–2 g IV every 12 hours7–14 days
Intra-abdominal infections2 g IV every 8–12 hours (w/ metronidazole)7–14 days


Renal Dose Adjustments (based on creatinine clearance):

  • CrCl 30–60 mL/min: 2 g every 12 hrs

  • CrCl 11–29 mL/min: 1 g every 12 hrs

  • CrCl ≤10 mL/min: 500 mg every 24 hrs

  • Hemodialysis: Dose post-dialysis

10. Resistance Concerns

While cefepime has increased resistance to β-lactamases, emerging resistance patterns include:

  • ESBL-producing Enterobacteriaceae

  • Carbapenem-resistant Enterobacteriaceae (CRE) – resistant due to carbapenemases (e.g., KPC, NDM)

  • Pseudomonas aeruginosa – porin mutations and efflux pumps

  • AmpC hyperproduction – may reduce cefepime efficacy

Susceptibility testing is essential before initiating monotherapy in high-risk or resistant environments.

11. Monitoring Parameters

  • Renal function (baseline and during therapy)

  • Neurological status in patients with renal dysfunction

  • Culture and sensitivity testing

  • Complete blood count (CBC) with prolonged use

  • Signs of superinfection, especially C. difficile

12. Comparative Advantages of Cefepime

  • Superior anti-Pseudomonal activity vs. third-generation cephalosporins.

  • Enhanced β-lactamase stability, including AmpC.

  • Useful in empiric therapy for febrile neutropenia and sepsis.

  • Lower resistance rates in many regions (though this is changing).

13. Limitations

  • Not effective against:

    • MRSA

    • Anaerobes (must add metronidazole for intra-abdominal infections)

    • Atypical pathogens (e.g., Mycoplasma, Chlamydia)

    • ESBL/CRE infections (depending on local resistance patterns)



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