What is the overview of 4th generation cephalosporins (4th gen ceph) for infection treatment?

Overview of 4th Generation Cephalosporins

Fourth-generation cephalosporins are broad-spectrum antibiotics with enhanced activity against both gram-positive and gram-negative bacteria, including many resistant strains, making them valuable options for treating serious infections when other antibiotics may be ineffective.

Key Characteristics

• Structure and Mechanism: Fourth-generation cephalosporins feature a quaternary nitrogen (positively charged) at the 3-position, creating a zwitterionic structure that enables more rapid penetration through gram-negative bacterial cell membranes 1
• Beta-lactamase Stability: They have low affinity for most type I beta-lactamases and are stable against many common plasmid- and chromosomally-mediated beta-lactamases 2, 3
• Poor Inducers: Unlike third-generation cephalosporins, they are poor inducers of AmpC beta-lactamases, reducing the risk of developing resistance during therapy 4

Antimicrobial Spectrum

Gram-Positive Coverage

• Active against Staphylococcus aureus (methicillin-sensitive)
• Effective against Streptococcus pneumoniae (including penicillin-sensitive, -intermediate, and -resistant strains)
• Similar gram-positive coverage to third-generation cephalosporins 4
• Not active against Enterococcus faecalis, Clostridium difficile, or methicillin-resistant S. aureus 1

Gram-Negative Coverage

• Excellent activity against Enterobacteriaceae, including strains resistant to third-generation cephalosporins
• Active against Pseudomonas aeruginosa (similar to ceftazidime) 4
• Retains activity against derepressed mutants of Enterobacter spp. 4
• More resistant to hydrolysis by extended-spectrum beta-lactamases (ESBLs) than third-generation cephalosporins 4

Anaerobic Coverage

• Poor activity against Bacteroides species 1

Available Agents

Currently, cefepime is the primary fourth-generation cephalosporin in clinical use:

Cefepime

• FDA-approved indications 5:
  • Pneumonia
  • Empiric therapy for febrile neutropenic patients
  • Uncomplicated and complicated urinary tract infections
  • Uncomplicated skin and skin structure infections
  • Complicated intra-abdominal infections (in combination with metronidazole)

Dosing and Administration

Standard Dosing for Cefepime 5

• Moderate to Severe Pneumonia: 1-2g IV every 8-12 hours for 10 days
  • For Pseudomonas aeruginosa: 2g IV every 8 hours
• Empiric therapy for febrile neutropenia: 2g IV every 8 hours until resolution of neutropenia
• Mild to Moderate UTI: 0.5-1g IV every 12 hours for 7-10 days
• Severe UTI: 2g IV every 12 hours for 10 days
• Skin and Skin Structure Infections: 2g IV every 12 hours for 10 days
• Complicated Intra-abdominal Infections: 2g IV every 8-12 hours for 7-10 days (with metronidazole)

Renal Adjustment

• Dosage adjustment required for patients with creatinine clearance ≤60 mL/min 5

Clinical Applications

Respiratory Infections

• Effective for community-acquired and nosocomial pneumonia
• Comparable efficacy to ceftazidime, ceftriaxone, or cefotaxime in clinical trials 4
• For Pseudomonas aeruginosa pneumonia, cefepime 2g IV every 8 hours is recommended 6

ESBL-Producing Enterobacteriaceae

• Use of cefepime for ESBL-producing organisms is controversial
• Safety in patients previously exposed to third-generation cephalosporins is not well documented 7
• Carbapenems are generally considered more reliable for ESBL infections 7

HACEK Microorganisms

• Cefepime may be substituted for ceftriaxone or other third-generation cephalosporins in the treatment of HACEK microorganism infections 7

Pseudomonas aeruginosa Infections

• Monotherapy with an anti-pseudomonal β-lactam agent (including cefepime) is recommended as first-line therapy 6
• Cefepime 2g IV every 8 hours is an appropriate option for Pseudomonas infections 7, 6

Advantages Over Third-Generation Cephalosporins

• Broader spectrum of activity against both gram-positive and gram-negative pathogens 2
• Greater stability against beta-lactamases 2
• Activity against Enterobacteriaceae resistant to third-generation cephalosporins 4
• Less likely to induce resistance during therapy 4

Adverse Effects

• Generally well-tolerated with a safety profile similar to other cephalosporins 4
• Most common adverse events (≥1%):
  • Local reactions at injection site
  • Positive Coombs' test
  • Decreased phosphorous
  • Increased ALT and AST
  • Increased PT and PTT
  • Rash 5
• At highest doses (2g every 8 hours), additional common adverse effects include:
  • Diarrhea
  • Nausea
  • Vomiting
  • Pruritus
  • Fever
  • Headache 5

Drug Interactions

• Aminoglycosides: Increased potential for nephrotoxicity and ototoxicity 5
• Potent diuretics (e.g., furosemide): Risk of nephrotoxicity 5

Practical Considerations

• Administer intravenously over approximately 30 minutes 5
• Linear pharmacokinetic profile with elimination half-life of approximately 2 hours 2
• Primarily excreted by renal mechanisms as unchanged drug 2
• Monitor renal function during therapy, especially in elderly patients or those with pre-existing renal impairment

Resistance Concerns

• To prevent development of resistance, fourth-generation cephalosporins should be used judiciously and only for appropriate indications
• Local resistance patterns should be monitored as they may affect efficacy 6
• Regular culture and susceptibility testing during therapy is recommended to ensure effective treatment 6