Cephalosporins

Semi-synthetic antibiotics that are essentially derivatives of cephalosporin C isolated from Cephalosporium acremonium. Betalactam antibiotics.

The common basic structure of cephalosporins is the 7-aminocephalosporanic acid, whose characteristic backbone is a β-lactam ring in combination with a dihydrothiazine ring. This ring structure is very similar to that of penicillins.

The naturally occurring cephalosporin C shows only low antibiotic activity. Improved antibiotic activity is only achieved by derivatization at position 7. Changing the substituent at position 3 leads to altered pharmacological properties.

Oral cephalosporins:

• Group 1 (basic cephalosporins)
  • Cefalexin
  • cefaclor
  • Cefadroxil
• Group 2 (intermediate cephalosporins)
  • Cefuroxime axetil
• Group 3 (broad-spectrum cephalosporins)
  • Cefpodoxime
  • cefixime
  • Ceftibuten
  • Loracarbef
• Other cephalosporins
  • 4th generation cephalosporins
    • Cefepime (good efficacy in gram-positive (especially against staphylococci) and gram-negative (incl. Pseudomonas aeruginosa); serious life-threatening infections, sepsis, pneumonia, serious infections of the urinary or biliary tract, abdominal infections)
  • Cephalosporins of the 5th generation
    • Ceftaroline (good efficacy in the gram-positive and gram-negative range, efficacy against MRSA!)
  • Older cephalosporins: cefazolin, cefuroxime, cefotiam, cefoxitin
  • Cephalosporins for severe infections: cefotaxime, ceftazidime, cefepime

Note: Cephalosporins are ineffective against some important pathogens: enterococci (enterococcal gap), listeria, penicillin-resistant pneumococci, multi-resistant staphylococci (MRSA), intracellular bacteria (legionella, chlamydia), bacteria without a cell wall (mycoplasma), Campylobacter jejuni, Chlostridium difficile. They are largely stable against the enzymatic activity of penicillinases (subgroup of ß-lactamases). However, they are degraded to varying degrees by the ß-lactamases of gram-negative germs.

Pregnancy, lactation, atopic diathesis, impaired kidney function.

Cephalosporins are generally relatively well tolerated drugs. On average, around 10 % of those treated with oral cephalosporins complain of ADRs (adverse effects).

Gatrointestinal ADRs:

• By far the most common are gastrointestinal complaints, especially diarrhea.
• Nausea/vomiting and various uncharacteristic abdominal complaints also occur.
• However, diarrhea and other gastrointestinal complaints occur more frequently with amoxicillin/clavulanic acid, for example, than with most cephalosporins.
• All cephalosporins can occasionally lead to pseudomembranous colitis. It is not known whether this problem occurs more frequently than with other antibiotics. Although the influence of individual preparations on the gastrointestinal flora has been investigated, these studies are too small to lead to generally valid statements.

Dermatological ADR (in around 1 % of patients):

• Maculo-papular exanthema
• Urticaria (rarely angioedema)
• pruritus

Individual case reports are available:

• Toxic epidermal necrolysis (Harr T et al. 2010)

• AGEP (Lin YF et al. 2014)

Cephalosporin allergies (see also penicillin allergy)

• Genuine allergic reactions to oral cephalosporins are rare. They occur almost exclusively in people who are also allergic to penicillin. The incidence of clinically relevant cross-allergies between penicillin and cephalosporins is estimated at 2 to 10 %.

Anaphylaxis with cephalosporins: In a larger study, 6.8 anaphylactic reactions per 100,000 intravenous exposures were detected. The incidence of fatal anaphylaxis due to cephalosporins was 0.1 cases per 100,000 exposures (Kang DY, MS et al. 2018). The following incidences were found for the individual cephalosporins:

• Ceftizoxime: 13.0 anaphylaxis per 100,000 exposures
• Cefepime, cefotaxime, ceftizoxime, ceftriaxone, cefuroxime: 9.3 anaphylaxis per 100,000 exposures
• Cefoxitin, cefmetazole, cefminox and cefotiam: no anaphylactic reactions
• Cephalosporins are contraindicated in persons who have had an anaphylactic reaction to penicillin. Skin tests do not allow reliable conclusions to be drawn about a cephalosporin allergy.

Neurological ADR (rare):

• In a major review (Lacroix L et al. (2019), 511 reports of serious neurological ADRs between 1987 and 2017 were analyzed. The patients had an average age of 67.1 years (m:w= 1:1) and a mean creatinine clearance of 32.9 ml / min. The following frequencies were observed for cefalosporins, most of which were administered parenterally (87.3 %):
  • Cefepime (33.1 %)
  • Ceftriaxone (29.7 %)
  • Ceftazidime (19.6 %)
  • cefotaxime (9 %)
  • cefazolin (2.9 %)
• The following neurological ADRs were diagnosed: encephalopathies(30.3 %), confusion (19.4 %), convulsions (15.1 %), myoclonus (9.4 %), status epilepticus (9.2 %), coma (6.3 %), hallucinations (4.3 %)

Hematologic ADR:

• Eosinophilia
• rarely neutropenia

Hepatogenic ADR:

• The hepatotoxicity of cephalosporins manifests itself in an occasional to frequent increase in liver enzymes. Rare are cholestasis and hepatitis.

Nephrogenic ADRs:

• Nephrotoxic side effects are dose-dependent. They can be recognized by an increase in creatinine and urea levels in the blood.

Like other antibiotics, oral cephalosporins may interfere with the efficacy of oral contraceptives and live vaccines. Individual substances cause further interactions (see table). Probenecid inhibits the renal elimination of cephalosporins.

Hypersensitivity to cephalosporins (possibly cross-allergy with other β-lactam antibiotics, e.g. penicillins, see below penicillin allergy).

1. Ariza A et al (2015) Hypersensitivity reactions to ß-lactams: relevance of hapten-protein conjugates. J Investig Allergol Clin Immunol 25:12-25.
2. Harr T et al (2010) Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 5:39.

3. Kang DY, MS et al (2018) Incidence of cephalosporin-induced anaphylaxis and clinical efficacy of screening intradermal tests with cephalosporins: A large multicenter retrospective cohort study. Allergy 73:1833-1841.

4. Lacroix L et al (2019) Serious central nervous system side effects of cephalosporins: A national analysis of serious reports registered in the French Pharmacovigilance Databas. J Neurol Sci 398:196-201

5. Lin YF et al (2014) Severe cutaneous adverse reactions related to systemic antibiotics. Clin Infect Dis. 58:1377-1385.

6. Stryjewski ME et al (2007) Use of vancomycin or first-generation cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis 44: 190-196

Essential interactions of cephalosporins