Cephalosporins

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Cefalosporin antibiotics; Cefalosporins; Cephalosporin antibiotics

Definition
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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)
  • Group 2 (Intermediate cephalosporins)
    • Cefuroximaxetil
  • Group 3 (Broadband cephalosporins)
  • 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.

Limited indication
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Pregnancy, lactation, atopic diathesis, impaired kidney function.

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

Gatrointestinal ADRs:

  • By far the most common are gastrointestinal complaints, especially diarrhoea.
  • Nausea/vomiting and various uncharacteristic abdominal complaints also occur.
  • However, diarrhoea and other gastrointestinal complaints are more common with amoxicillin/clavulanic acid 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 UWAs (in about 1% of patients):

Individual case reports are available:

Cephalosporin allergies (see also penicillin allergy)

  • Real allergic reactions to oral cephalosporins are rare. They occur almost only 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 of cephalosporins: In a larger study 6.8 anaphylactic reactions per 100 000 intravenous exposures were detected. The incidence of fatal anaphylaxis by 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
  • Cefepim, cefotaxime, ceftizoxime, ceftriaxone, cefuroxime: 9,3 anaphylaxis per 100 000 exposures
  • Cefoxitin, cefmetazol, cefminox and cefotiam: no anaphylactic reactions .
  • Cephalosporins are contraindicated in people who have had an anaphylactic reaction to penicillin. Skin tests do not allow reliable conclusions about a cephalosporin allergy.

Neurological ADRs (rare):

  • In a major review (Lacroix L et al (2019), 511 reports of severe neurological ADRs were analysed between 1987 and 2017. The 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 cefalosporins, which were mostly administered parenterally (87.3%):
  • The following neurological ADRs were diagnosed: encephalopathy (30.3%), confusion (19.4%), convulsions (15.1%), myoclonia (9.4%), status epilepticus (9.2%), coma (6.3%), hallucination (4.3%).

Haematological ADRs;

Hepatogenic ADRs:

  • The hepatotoxicity of cephalosporins is expressed by a slight 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 blood creatinine and urea levels.

Interactions
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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.

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

Note(s)
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Cefazolin is most effective against staphylococci.

Literature
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  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

Tables
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Essential interactions of cephalosporins

Aminoglycoside antibiotics

Nephrotoxicity of aminoglycosides ↑

Anticoagulants

Bleeding complications (in case of high dosage i.v.)

Colistin

Nephrotoxicity of colistin ↑

Ganciclovir

Seizures under high doses of cephalosporin

Contraceptives, oral

Contraceptive effect ↓ (influencing the intestinal flora)

polymyxin B

Nephrotoxicity of Polymyxin B ↑

Platelet aggregation inhibitor

Bleeding tendency ↑

Authors

Last updated on: 29.10.2020