4th Generation Cephalosporins 

• Introduction 

• Illustrated mechanism of action 

• Examples of Medication Brand Names (with Images)

• Indication

• Side Effects 

• Precautions & Contraindications 

• Monographs

• Reference 

The fourth generation of cephalosporins represents a class of broad-spectrum beta-lactam antibiotics that were developed to overcome resistance mechanisms affecting earlier generations. These antibiotics are particularly effective against both Gram-positive and Gram-negative bacteria, including organisms that produce beta-lactamases—enzymes that break down beta-lactam antibiotics. Introduction and Development Fourth-generation cephalosporins were introduced in the late 1980s and early 1990s to address the limitations of third-generation cephalosporins, especially resistance due to beta-lactamase production. They possess enhanced ability to penetrate the outer membrane of Gram-negative bacteria and have increased resistance to beta-lactamase enzymes. Key Features Broad-spectrum activity. Improved stability against beta-lactamases. Good penetration into the cerebrospinal fluid (CSF), making them useful in treating meningitis. Active against Pseudomonas aeruginosa, which is resistant to many other antibiotics. Examples Cefepime is the most well-known and widely used fourth-generation cephalosporin. Cefpirome is another agent in this class (available in some countries but not widely used in the U.S.). ‎<This message was edited> 

Mechanism of action

Detailed Mechanism: 1. Binding to Penicillin-Binding Proteins (PBPs): Cephalosporins target and bind to PBPs located in the bacterial cytoplasmic membrane. These proteins are critical enzymes involved in the final stages of peptidoglycan synthesis, the key structural component of the bacterial cell wall. 2. Inhibition of Peptidoglycan Cross-Linking: Once bound, cephalosporins block the transpeptidation reaction necessary for forming cross-links between peptidoglycan chains. This disrupts the integrity and rigidity of the bacterial cell wall. 3. Cell Lysis and Bacterial Death: The weakened cell wall cannot withstand osmotic pressure, leading to cell lysis and ultimately bacterial death. Thus, fourth-generation cephalosporins have a bactericidal effect. 4. Enhanced Features of the 4th Generation: Greater resistance to beta-lactamases, especially those produced by Gram-negative bacteria. Improved penetration through the outer membrane of Gram-negative bacteria. Activity against organisms like Pseudomonas aeruginosa, which are resistant to many other antibiotics. 

Common Clinical Indications: 1. Hospital-acquired (nosocomial) pneumonia Including ventilator-associated pneumonia (VAP) Active against Pseudomonas aeruginosa

 2. Febrile neutropenia Common in cancer patients undergoing chemotherapy Used as empirical broad-spectrum therapy 

3. Complicated urinary tract infections (UTIs) Including pyelonephritis Often used when resistance to simpler antibiotics is suspected 

4. Complicated intra-abdominal infections Often used in combination with metronidazole to cover anaerobes

 5. Skin and soft tissue infections Especially in diabetic foot infections or infections caused by resistant organisms 

6. Sepsis and bacteremia Effective for bloodstream infections caused by Gram-negative rods

 7. Meningitis (off-label use) Due to good penetration into cerebrospinal fluid (CSF) 

Common Side Effects: 1. Gastrointestinal: Nausea Vomiting Diarrhea Abdominal pain 

2. Hypersensitivity Reactions: Rash Urticaria (hives) Pruritus (itching) Anaphylaxis (rare, but possible especially in patients allergic to penicillins) 

3. Injection Site Reactions (IV/IM use): Pain Redness Inflammation 

Serious Side Effects: 1. Neurotoxicity (especially in renal impairment): Encephalopathy Confusion Seizures Myoclonus (More common in elderly or patients with kidney dysfunction if dosing is not adjusted) 

2. Clostridioides difficile–associated diarrhea (CDAD): Due to alteration of normal gut flora 

3. Hematologic Effects: Leukopenia Neutropenia Thrombocytopenia (rare) 

4. Elevated liver enzymes: Transient increases in AST, ALT, and bilirubin 

1. Precautions: a. Renal Impairment Cefepime and similar agents are primarily excreted by the kidneys. Dose adjustment is mandatory in patients with decreased renal function to prevent: Neurotoxicity (e.g., encephalopathy, seizures, confusion)

 b. Elderly Patients Increased risk of central nervous system (CNS) side effects, especially when renal function is compromised.

 c. History of Seizure Disorders Cephalosporins can lower the seizure threshold, particularly at high doses or in renal dysfunction.

 d. Prolonged Use May lead to superinfections, including fungal overgrowth or Clostridioides difficile colitis. 

e. Hematologic Monitoring Long-term use may rarely lead to blood dyscrasias (e.g., neutropenia, anemia, thrombocytopenia), so CBC monitoring is advised. 

2. Contraindications: Known hypersensitivity to cephalosporins Any history of severe allergic reaction (e.g., anaphylaxis, Stevens-Johnson Syndrome) to cephalosporins. Cross-reactivity with penicillins Caution in patients with a history of penicillin allergy due to possible cross-reactivity, especially with IgE-mediated reactions

1. FDA Prescribing Information for Maxipime (Cefepime): https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050679s021lbl.pdf 

2. Medscape – Cefepime Precautions and Interactions 

3. PubMed – Cefepime-induced Neurotoxicity in Renal Impairment