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Sunday, August 10, 2025

Cephalosporins


1. Introduction

  • Cephalosporins are a large group of β-lactam antibiotics derived from the fungus Acremonium (formerly Cephalosporium).

  • They are structurally and functionally related to penicillins but generally more resistant to β-lactamases produced by certain bacteria.

  • Widely used for treatment and prophylaxis of bacterial infections due to their broad spectrum, good safety profile, and diverse formulations.

2. History and Development

  • Discovered in 1945 from cultures of Cephalosporium acremonium by Italian scientist Giuseppe Brotzu.

  • The naturally occurring compound cephalosporin C showed resistance to penicillinase.

  • Chemical modification of the 7-aminocephalosporanic acid (7-ACA) nucleus led to multiple synthetic and semi-synthetic derivatives.

  • Classification into “generations” developed to reflect spectrum changes and structural advancements.

3. Chemical Structure

  • Core structure: β-lactam ring fused to a six-membered dihydrothiazine ring.

  • Position 7 (acyl side chain on β-lactam ring): affects antibacterial activity and β-lactamase resistance.

  • Position 3 (side chain on dihydrothiazine ring): influences pharmacokinetics, metabolism, and stability.

4. Mechanism of Action

  • Bind to penicillin-binding proteins (PBPs) in bacterial cell membranes.

  • Inhibit transpeptidation step in peptidoglycan cross-linking during cell wall synthesis.

  • Weakened cell wall leads to osmotic instability and bacterial lysis.

  • Bactericidal and time-dependent activity: efficacy depends on duration above minimum inhibitory concentration (MIC).

5. Classification by Generation

First Generation

  • Examples: cefazolin, cephalexin, cefadroxil.

  • Spectrum: strong Gram-positive coverage (e.g., Streptococcus spp., MSSA); limited Gram-negative coverage.

  • Uses: skin infections, surgical prophylaxis, uncomplicated urinary tract infections.

Second Generation

  • Examples: cefuroxime, cefaclor, cefprozil, cefoxitin, cefotetan.

  • Broader Gram-negative activity, some anaerobic coverage (especially cefoxitin, cefotetan).

  • Uses: respiratory tract infections, intra-abdominal infections, gynecologic infections.

Third Generation

  • Examples: ceftriaxone, cefotaxime, ceftazidime, cefixime.

  • Expanded Gram-negative coverage; many agents cross the blood–brain barrier.

  • Ceftazidime active against Pseudomonas aeruginosa.

  • Uses: sepsis, meningitis, complicated urinary tract infections, pneumonia.

Fourth Generation

  • Example: cefepime.

  • Broad Gram-positive and Gram-negative coverage; more resistant to AmpC β-lactamases.

  • Uses: febrile neutropenia, hospital-acquired pneumonia, complicated intra-abdominal infections.

Fifth Generation

  • Example: ceftaroline.

  • Spectrum includes MRSA and resistant Streptococcus pneumoniae.

  • Uses: community-acquired pneumonia, acute bacterial skin and skin structure infections.

6. Pharmacokinetics

  • Administration: oral, intramuscular, intravenous depending on agent.

  • Distribution: good penetration into most tissues and fluids; some cross blood–brain barrier.

  • Elimination: primarily renal; dose adjustments needed in renal impairment.

  • Half-life varies: from less than 1 hour (cefazolin) to over 8 hours (ceftriaxone).

7. Clinical Uses

  • Respiratory tract infections (e.g., pneumonia, bronchitis, sinusitis).

  • Skin and soft tissue infections.

  • Urinary tract infections.

  • Bone and joint infections.

  • Intra-abdominal infections (with or without anaerobic coverage).

  • Sexually transmitted infections (e.g., gonorrhea).

  • Meningitis (third-generation agents).

  • Surgical prophylaxis.

8. Adverse Effects

Common

  • Diarrhea, nausea, vomiting.

  • Rash, pruritus.

  • Injection-site pain or inflammation.

Less Common / Serious

  • Hypersensitivity reactions (urticaria, angioedema, anaphylaxis).

  • Clostridioides difficile–associated diarrhea.

  • Hematologic effects (e.g., neutropenia, thrombocytopenia).

  • Hepatic enzyme elevations.

  • Seizures (high doses, especially with renal impairment).

9. Contraindications and Precautions

  • History of severe allergic reaction to cephalosporins.

  • Caution in patients with serious penicillin allergy (cross-reactivity risk, though low).

  • Adjust dosing in renal impairment.

  • Monitor for superinfection with prolonged use.

10. Resistance Mechanisms

  • Production of β-lactamases that hydrolyze cephalosporins (ESBLs, AmpC).

  • Altered PBPs with reduced affinity for β-lactams.

  • Reduced permeability due to porin channel modifications.

  • Efflux pumps expelling the antibiotic from bacterial cells.

11. Role in Antimicrobial Stewardship

  • Selection should be based on culture and susceptibility data when possible.

  • Reserve advanced generations for serious or resistant infections.

  • De-escalate to narrower-spectrum agents once pathogen and sensitivity are known.

  • Avoid unnecessary use to prevent further resistance development.




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