Cephalosporins

Semi-synthetic antibiotics which are essentially derivatives of cephalosporin C isolated from Cephalospoium acremonium. Betalactam antibiotics.

The common basic structure is the 7-aminocephalosporanic acid, which has a ring structure based on a betalactam ring linked to a dihydrothiazine ring. This ring structure is very similar to that of penicillins.

The naturally occurring cephalosporin C shows only a low antibiotic activity. An improved antibiotic activity is only achieved by derivatization at position 7. Changing the substituent at position 3 leads to an altered pharmacological property.

Oral cephalosporins:

• Group 1 (basic cephalosporins)
  • Cefalexin
  • Cefaclor
  • Cefadroxil
• Group 2 (Intermediate cephalosporins)
  • Cefuroximaxetil
• Group 3 (Broadband cephalosporins)
  • Cefpodoxime
  • Cefixim
  • Ceftibuten
  • Loracarbef
• Other cephalosporins
  • 4th generation cephalosporins
    • Cefepim (good efficacy in the gram-positive (especially against staphylococci) and gram-negative area (incl. against Pseudomonas aeruginosa), severe life-threatening infections sepsis, pneumonia, severe infections of the urinary or biliary tract, infections of the abdominal cavity)
  • 5th generation cephalosporins
    • Ceftarolin (good effectiveness in the gram-positive and gram-negative range, effective against MRSA!)
  • Older cephalosporins: cefazolin, cefuroxime, cefotiam, cefoxitin.
  • Cephalosporins for serious infections: Cefotaxim, Ceftazidim, Cefepim.

Note: Cephalosporins are ineffective against some important infectious agents: Enterococci ((Enterococcus gap), Listerin, Penicillin-resistant Pneumococci, Multi-resistant Staphylococcus (MRSA), intracellularly growing bacteria (Legionella, Chlamydia), bacteria without cell wall (Mycoplasma), Camphylobacter 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 bacteria.

Pregnancy, lactation, atopic diathesis, impaired kidney function.

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

Gatrointestinal UAWs:

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

Dermatologic UWAs (in about 1% of patients):

• Maculo-papular exanthema.
• Urticaria (rarely angioedema)
• Pruritus

Isolated case reports are available:

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

• AGEP (Lin YF et al 2014).

Cephalosporin allergies (see also penicillin allergy).

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

Anaphylaxis to cephalosporins: In one major study, 6.8 anaphylactic reactions per 100 000 intravenous exposures were reported. The incidence of fatal anaphylaxis from cephalosporin was 0.1 cases per 100 000 exposures (Kang DY, MS et al. 2018). The following incidences were found for each cephalosporin:

• 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 a single anaphylactic reaction to penicillin. Skin tests do not reliably infer cephalosporin allergy.

Neurologic UAWs(rare):

• In a major review (Lacroix L et al. (2019), 511 reports of serious neurologic UAWs were analyzed between 1987 and 2017. Patients had a mean age of 67.1 years (m:w= 1:1) with a mean creatinine clearance of 32.9 ml / min. These were observed with the following mostly parenterally administered (87.3%) cefalosporins:
  • Cefepime (33.1%)
  • Ceftriaxone (29.7%)
  • Ceftazidime (19.6%)
  • Cefotaxime (9%)
  • Cefazolin (2.9%)
• The following neurological UAWs were diagnosed: encephalopathy (30.3%),confusional state (19.4%), convulsions (15.1%), myoclonia (9.4%), status epilepticus (9.2%), coma (6.3%), hallucination (4.3%).

Hematologic UAWs;

• Eosinophilia
• rarely neutropenia

Hepatogenic UAWs:

• Hepatotoxicity of cephalosporins manifests as occasional to frequent elevation of liver enzymes. Cholestasis and hepatitis are rare.

Nephrogenic UAWs:

• Nephrotoxic adverse reactions are dose-dependent. They are recognizable by an increase in blood creatinine and urea levels.

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