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Cephalosporins: Mechanism of Action, Side Effects and Contraindications

Four Generations of Cephalosporins

Cephalosporins are β-lactam antibiotics, which are grouped into four generations according to their antibiotic spectrum of activity:

• First generation: cefazolin
• Second generation: cefaclor, cefuroxime
• Third generation: cefotaxime, ceftriaxone, ceftazidime for parenteral application. Cefpodoxime and ceftibuten for oral formulations.
• Fourth generation: cefepime, ceftolozan (combined with tazobactam)

Mechanism of action of Cephalosporins

Cephalosporins are β-lactam antibiotics; they inhibit the peptidoglycan synthesis of the bacterial wall after binding to so-called penicillin-binding proteins (peptidoglycan synthetases) and inhibit the polymerization of the peptidoglycan and covalent cross-linking of the bacterial wall.

Antibiotic Spectrum of Different Cephalosporin Generations

The first generation has mainly gram-positive activity. The second and third generations have more gram-negative activity with decreased activity against gram-positive bacteria. The fourth generation of cephalosporins has a broad spectrum of activity.

Cephalosporins are generally ineffective against enterococci, Listeria, Legionella, Mycoplasma, and Chlamydia.

Side Effects of Cephalosporins

• Allergic reactions ranging from rash to anaphylaxis: 1–4%, the risk of cross-allergy to penicillin is approximately 10%.
• Gastrointestinal side effects: nausea and diarrhea are common, as are elevated liver enzymes; pseudomembranous enterocolitis is rare but possible.
• Rare but potentially serious side effects include cerebral seizures, severe cutaneous skin reactions, anaphylaxis, interstitial nephritis, cholestatic jaundice (especially ceftriaxone), hemolytic anemia, and thrombocytopenia.

Drug Interactions with Cephalosporins

• Increased nephrotoxicity when combined with aminoglycosides or loop diuretics.
• Probenecid inhibits renal tubular excretion and increases serum concentration.

Contraindications

Allergy to cephalosporins. Caution is necessary in patients with a history of penicillin allergy.

Cefazolin

Cefazolin is a first-generation cephalosporin.

Antibiotic Spectrum of Cefazolin

Staphylococci (but not MRSA), streptococci, E. coli, Proteus, and Klebsiella.

Urologic Indications for Cefazolin

Staphylococcal infections (wound infections), urinary tract infections (if proven effective in the antibiogram), and perioperative antibiotic prophylaxis.

Pharmacokinetics of Cefazolin

Cefazolin is only available for parenteral administration. The elimination half-life is 1.5 h, with 90% renal elimination.

Dosage of Cefazolin

In adults, the dosage of cefazolin is 1 g 1-1-1 i.v. Children receive a daily dose of 60 mg/kgBW, divided into three doses. Dose reduction is necessary for chronic kidney disease.

Cefuroxime

Cefuroxime is a second-generation cephalosporin available in oral and parenteral formulations.

Antibiotic Spectrum of Cefuroxime

Staphylococci (except MRSA), streptococci, Haemophilus, E. coli, Proteus, Klebsiella, Salmonella, Shigella, Citrobacter.

Urologic Indications of Cefuroxime:

Perioperative antibiotic prophylaxis, urinary tract infections (if proven effective in the antibiogram).

Pharmacokinetics of Cefuroxime

Cefuroxime can be prescribed orally and intravenously. However, the oral bioavailability of cefuroxime is only 30–50%, and it is best taken after meals. Half-life 1 hour. Renal elimination 70–90%.

Dosage of Cefuroxime

For urinary tract infections in adults: cefuroxime 250–500 mg p.o. 1-0-1 or 1.5 g 1-1-1 i.v. Children receive 25 mg/kgBW 1-1-1 i.v. In severe infections, parenteral administration should be preferred due to poor oral bioavailability.

A dose reduction is necessary for renal insufficiency with a GFR below 20 ml/min: 0.75 g cefuroxime twice daily, and below 10 ml/min once daily, 0.75 g.

Cefotaxime

Cefotaxime is a third-generation cephalosporin available for parenteral use.

Antibiotic Spectrum of Cefotaxime

Effective against streptococci, gonococci, meningococci, Haemophilus, and staphylococci. Cefotaxime has a high β-lactamase resistance and is, therefore, effective against gram-negative bacteria (Enterobacteriaceae). Only weak efficacy against Pseudomonas. No efficacy against enterococci, mycoplasmas, chlamydia, and MRSA.

Urologic Indications of Cefotaxime:

Severe complicated urinary tract infections and urosepsis.

Pharmacokinetics of Cefotaxime

Only parenteral administration of cefotaxime is possible. The half-life of cefotaxime is 1 hour, and significantly longer in patients with renal insufficiency. Hepatic metabolism to active metabolites, 80–90% renal elimination.

Dosage of Cefotaxime

The daily dosage of cefotaxime for adults is 3–6 g (children 50–100 mg/kgBW), divided into three individual doses, depending on the severity of the infection.

A dose reduction is necessary for patients with renal insufficiency. For a GFR below 50 ml/min, the daily dose (after the initial normal dose) is reduced to 50%. For a GFR below 10 ml/min, it is reduced to 25%.

Ceftriaxone

Ceftriaxone is a third-generation cephalosporin available for parenteral use.

Antibiotic Spectrum of Ceftriaxone

Comparable to cefotaxime, see above.

Urologic Indications for Ceftriaxone

Severe complicated urinary tract infections and urosepsis. Treatment of gonorrhea.

Pharmacokinetics of Ceftriaxone

Only parenteral administration of ceftriaxone is possible. High protein binding and good tissue penetration. The half-life of ceftriaxone is 6–9 hours. Modest hepatic metabolism. Biliary (40–50%) and renal (50–60%) elimination.

Dosage of Ceftriaxone

1–2 g ceftriaxone once daily i.v. for adults, depending on the severity of the infection. Children receive 50–80 mg/kgBW. For the treatment of gonorrhea, 500 mg ceftriaxone is administered i.m. or i.v. as a single dose. A dose reduction is not necessary for patients with renal insufficiency if liver function is not impaired.

Ceftibuten

Ceftibuten is an orally available third-generation cephalosporin.

Antibiotic Spectrum:

Compared to cefotaxime, it is highly effective against gram-negative bacteria but less effective against gram-positive bacteria.

Urological Indications of Ceftibuten

Outpatient treatment of urinary tract infections, also as oral step-down treatment after initial parenteral treatment of severe urinary tract infections.

Pharmacokinetics of Ceftibuten:

Good bioavailability when taken independently of meals, half-life 2.5–4 hours, low metabolism, and unchanged excretion via the urine.

Dosage of Ceftibuten:

For adults 400 mg 1-0-0, children 9 mg/kgBW 1-0-0. Halve the dosage for patients with a GFR of 50–30 ml/min. For a GFR of 29–5 ml/min, prescribe only a quarter of the normal dosage.

Cefixime

Cefixime is an orally available third-generation cephalosporin.

Antibiotic Spectrum of Cefixime:

Comparable to ceftibuten.

Urological Indications of Cefixime

Outpatient treatment of urinary tract infections, also as oral step-down treatment after initial parenteral treatment of severe urinary tract infections. Second-line treatment of gonorrhea.

Pharmacokinetics of Cefixime:

30–50% bioavailability independent of food intake, half-life 3–4 hours, modest metabolism, and unchanged excretion via the urine.

Dosage of Cefixime:

For adults 200 mg 1-0-1 or 400 mg 1-0-0, children 4 mg/kgBW 1-0-1 or 8 mg/kgBW 1-0-0. In patients with severe renal insufficiency (GFR <20 ml/min), the dose should be limited to 200 mg once daily.

Cefpodoxime

Cefpodoxime is an orally available third-generation cephalosporin.

Antibiotic Spectrum of Cefpodoxime:

Comparable to ceftibuten, it is slightly more effective against gram-positive bacteria (pneumococci or staphylococci).

Urological Indications of Cefpodoxime

Outpatient treatment of urinary tract infections, also as oral step-down treatment after initial parenteral treatment of severe urinary tract infections.

Pharmacokinetics of Cefpodoxime:

The prodrug (cefpodoxime proxetil) is hydrolyzed by the intestinal mucosa, with approximately 50% bioavailability when taken with food. Cefpodoxime has a half-life of 2.5 hours, low metabolism, and unchanged excretion via urine.

Dosage of Cefpodoxime:

For adults 100–200 mg 1-0-1 depending on the severity of the infection, children receive 4 mg/kgBW 1-0-1. In patients with renal insufficiency (GFR 40–10 ml/min), the dose should be limited to once daily. In severe renal insufficiency (GFR <10 ml/min), a single dose is administered every two days.

References

Gok u.a. 2001 GOK, F. ; DUZOVA, A. ; BASKIN, E. ; OZEN, S. ; BESBAS, N. ; BAKKALOGLU, A.: Comparative study of cefixime alone versus intramuscular ceftizoxime followed by cefixime in the treatment of urinary tract infections in children.
In: J Chemother
13 (2001), Nr. 3, S. 277–80

Ho u.a. 2001 HO, M. W. ; WANG, F. D. ; FUNG, C. P. ; LIU, C. Y.: Comparative study of ceftibuten and cefixime in the treatment of complicated urinary tract infections.
In: J Microbiol Immunol Infect
34 (2001), Nr. 3, S. 185–9

Ovalle u.a. 2000 OVALLE, A. ; MARTINEZ, M. A. ; WOLFF, M. ; CONA, E. ; VALDERRAMA, O. ; VILLABLANCA, E. ; LOBOS, L.: [Prospective, randomized, comparative study of the efficacy, safety and cost of cefuroxime versus cephradine in acute pyelonephritis during pregnancy].
In: Rev Med Chil
128 (2000), Nr. 7, S. 749–57

Simon und Stille 1997 SIMON, C. ; STILLE, W.: Antibiotika-Therapie in Klinik und Praxis.
9. Auflage.
Stuttgart New York : Schattauer, 1997

Vilaichone u.a. 2001 VILAICHONE, A. ; WATANA, D. ; CHAIWATANARAT, T.: Oral ceftibuten switch therapy for acute pyelonephritis in children.
In: J Med Assoc Thai
84 Suppl 1 (2001), S. S61–7

  Deutsche Version: Cephalosporine

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