Cephalosporins are among the most widely prescribed antibacterial medicines. Here in this guide, we review the must-know pharmacology about this widely used and effective drug class.
Cephalosporins were discovered in the mid-1940s, first isolated from the fungus Cephalosporium acremonium – a fungus that was found in the sewers of Sardinia. There are now dozens of approved cephalosporins – each of which can be found in one of the five generations that now exist:
Indications and Spectrum of Activity
In terms of cephalosporins and indications, here are some broad principles which apply to this drug class.
- Orally administered cephalosporins are second and third-line in the treatment of respiratory and urinary tract infections.
- Intravenously administered cephalosporins are used in the treatment of more severe infections – including antibiotic-resistant infections.
- Earlier cephalosporin generations – such as the first-generation – have greater activity against Gram-positive organisms. Their Gram-negative activity can be summarised through the mnemonic PEcK – Proteus mirabilis, some E. coli, and Klebsiella pneumoniae.
- As cephalosporin generations progress, they become more and more active against Gram-negative organisms.
- Second-generation agents have greater Gram-negative activity than first-generation drugs – with PEcK indications above plus HEN: Haemophilus influenza, Enterobacter, and some Neisseria.
- Third-generation agents can penetrate the central nervous system, making them effective against meningitis.
- Fourth-generation cephalosporins – such as cefepime – are extended-spectrum agents with similar Gram-positive activity as first-generation cephalosporins. They also possess greater resistance to beta-lactamases than third-generation drugs.
- Both fourth and fifth-generation agents are active against Pseudomonas aeruginosa except the fifth-generation drug, ceftaroline. The third-generation drugs – cefoperazone and ceftazidime – are also effective against P. aeruginosa.
- Fifth-generation cephalosporins are active against MRSA.
Mechanism of Action
Cephalosporins are beta-lactam antibacterial drugs – disrupting cell wall synthesis.
By targeting cell wall synthesis, cephalosporins disrupt the osmotic gradient necessary to retain the structural integrity of the microbe. As the osmotic gradient falls, bacteria begin to swell and lyse. Cephalosporins have, therefore, a bactericidal effect.
Cephalosporins inhibit the enzymes needed for peptidoglycan cross-linking of the bacterial cell wall. The final step of peptidoglycan synthesis involves cross-linking at the D-Ala-D-Ala site. Cephalosporins mirror this site – forbidding penicillin-binding proteins (PBPs) from binding to the D-Ala-D-Ala site.
Side effects with cephalosporins include:
- Gastrointestinal effects – nausea, rash, abdominal pain, diarrhea
- Injectable cephalosporins – pain and inflammation at the injection site.
- Hypersensitivity reactions
- Increased risk of seizures
Cephalosporins can also cause C. difficile-associated colitis.
The third-generation cephalosporin, ceftriaxone, also causes:
- Elevated blood urea nitrogen (BUN)
- Hemolytic anemia
- Elevated liver enzymes
The following two cephalosporins can cause a disulfiram-like reaction due to the presence of their N-methylthiotetrazole (NMTT) sidechains:
When we talk about the clinical pharmacology of cephalosporins, we must consider the following factors:
- Resistance to cephalosporins is rising steadily; resistance becoming more common with second and third-generation drugs. Fourth-generation agents exhibit greater resistance to beta-lactamases.
- Cephalosporins should be used with caution in patients with C. difficile colitis.
- Cephalosporins are contraindicated in patients who have experienced anaphylaxis after taking penicillin, cephalosporin, or a carbapenem.
- Patients with renal dysfunction should be prescribed a lower dose.
- Ceftolozane is used to treat complicated infections – such as complicated UTIs and intraabdominal infections. Due to multi-drug resistance, ceftolozane is typically administered alongside the beta-lactamase inhibitor tazobactam.
- Cephalosporins increase the risk of nephrotoxicity when taken with aminoglycosides.
- Because healthy gut flora synthesizes vitamin K (antagonist to the effects of warfarin), broad-spectrum cephalosporins that kill colonic gut flora and increase the risk of bleeding with warfarin.
That concludes our review of cephalosporins pharmacology. Check back to our pharmacy blog soon for more exclusive content to help you master the science of drugs and medicines!
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