Comment on: Role of cephalosporins in the era of Clostridium difficile infection

Comment on: Role of cephalosporins in the era of Clostridium difficile infection Sir, The review of the role of cephalosporins in the era of Clostridium difficile infection (CDI) implies that cephalosporins, including those belonging to the same generation, are different when it comes to the risk of CDI.1 It states that the risk of CDI can be mitigated by careful selection of cephalosporins taking into account their differing pharmacokinetic parameters (achieved gut levels, which could be higher with cephalosporins that have substantial elimination via the biliary tree), effects on microbiota and impact on C. difficile growth and toxin production.1 I was surprised not to see the third-generation parental cephalosporin cefotaxime that is used in the UK, which has different pharmacokinetic properties to ceftriaxone, particularly biliary excretion (cefotaxime 1% versus ceftriaxone 30%–40%), in the review’s tables on pharmacokinetic parameters and pharmacodynamic properties.1 Similarly for the fourth-generation parental cephalosporin, cefepime, which is used in Europe, given that the review authors describe a meta-analysis indicating that, of the cephalosporins, fourth-generation cephalosporins may have a lower risk of CDI.2 This absence may be because cefotaxime and cefepime are not among the most commonly used cephalosporins across Europe as displayed in Table 1 of Wilcox et al.1 I do notice that the other category in this table ranges widely from country to country, from <0.05% to 40.7% of total cephalosporin use.1 It is also possible that the authors decided to leave out cefotaxime and cefepime from the tables in the review for brevity. Table 1 Summary of pharmacokinetic parameters, pharmacodynamic properties and in vitro susceptibility of C. difficile to cefotaxime and cefepime   Parameter  Cefotaxime  Cefepime  Summary of pharmacokinetic parameters and pharmacodynamic properties  serum t½, h  1.23  2.03  protein binding, %  353  203  urinary excretion, %  60%, further 24% as antibacterially active metabolite desacetyl-cefotaxime4  883  biliary excretion, %  13  –  bile concentration, mean ± SD (range), mg/L  34.5 ±15.3  [T], 49.3 ±17.0 [T] for desacetyl-cefotaxime5  19.8 ±12.9 [G]6  dose (number of doses)a  15 mg/kg body weight5  2000 mg6  route of elimination  same as urinary excretion, % above  primarily excreted unchanged in urine7  distribution  high concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile4  achieved high concentrations in bile and gall bladder tissue6  effect on intestinal microbiota  increase in enterococci, Candida spp. stay the same with decrease in Escherichia coli8  decrease in E. coli and bifidobacteria in faeces, slight increase in Bacteroides spp. and clostridia9  faecal concentration  –  –  In vitro susceptibility of C. difficile  isolates tested, n  7510  –  MIC range, mg/L  4–512  no data  MIC50, mg/L  >128  no data  MIC90, mg/L  256  no data    Parameter  Cefotaxime  Cefepime  Summary of pharmacokinetic parameters and pharmacodynamic properties  serum t½, h  1.23  2.03  protein binding, %  353  203  urinary excretion, %  60%, further 24% as antibacterially active metabolite desacetyl-cefotaxime4  883  biliary excretion, %  13  –  bile concentration, mean ± SD (range), mg/L  34.5 ±15.3  [T], 49.3 ±17.0 [T] for desacetyl-cefotaxime5  19.8 ±12.9 [G]6  dose (number of doses)a  15 mg/kg body weight5  2000 mg6  route of elimination  same as urinary excretion, % above  primarily excreted unchanged in urine7  distribution  high concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile4  achieved high concentrations in bile and gall bladder tissue6  effect on intestinal microbiota  increase in enterococci, Candida spp. stay the same with decrease in Escherichia coli8  decrease in E. coli and bifidobacteria in faeces, slight increase in Bacteroides spp. and clostridia9  faecal concentration  –  –  In vitro susceptibility of C. difficile  isolates tested, n  7510  –  MIC range, mg/L  4–512  no data  MIC50, mg/L  >128  no data  MIC90, mg/L  256  no data  G, concentration in gall bladder bile; T, concentration in bile obtained from a T-tube or drain tube. Bile concentration data are shown for patients either undergoing or following cholecystectomy or with cholecystolithiasis, unless otherwise indicated. Concentrations in bile obtained from a T-tube or drain tube (indicated by T) are peak concentrations unless otherwise stated. a Single dose, unless otherwise indicated. In Table 1 of this article I have tried to summarize the pharmacokinetic parameters, pharmacodynamic properties and in vitro susceptibility of C. difficile to cefotaxime and cefepime, which are adapted from tables in the review. I have left out the fourth-generation cephalosporin cefpirome due to space constraints. I feel this adds further information to the review, which discusses how the differing properties of cephalosporins could help with deciding which ones to use to mitigate CDI risk and increase diversity of antibiotic use. When use of the novel cephalosporin/β-lactamase inhibitors (e.g. ceftolozane/tazobactam and ceftazidime/avibactam) becomes more established it will be interesting to see what role they play in the era of CDI. Transparency declarations None to declare. References 1 Wilcox MH, Chalmers JD, Nord CE et al.   Role of cephalosporins in the era of Clostridium difficile infection. J Antimicrob Chemother  2017; 72: 1– 18. Google Scholar CrossRef Search ADS PubMed  2 Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother  2014; 69: 881– 91. Google Scholar CrossRef Search ADS PubMed  3 Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc  1999; 74: 187– 95. Google Scholar CrossRef Search ADS PubMed  4 Wockhardt UK Ltd. Cefotaxime 2g Powder for Solution for Injection or Infusion—Summary of Product Characteristics. https://www.medicines.org.uk/emc/medicine/12154. 5 Jehl F, Peter JD, Picard A et al.   Investigation of the biliary clearances of cefotaxime and desacetylcefotaxime by an original procedure in cholecystectomised patients. Infection  1987; 15: 450– 4. Google Scholar CrossRef Search ADS PubMed  6 Petrikkos G, Kastanakis M, Markogiannakis A et al.   Pharmacokinetics of cefepime in bile and gall bladder tissue after prophylactic administration in patients with extrahepatic biliary diseases. Int J Antimicrob Agents  2006; 27: 331– 4. Google Scholar CrossRef Search ADS PubMed  7 Van der Auwera P, Santella PJ. Pharmacokinetics of cefepime: a review. J Antimicrob Chemother  1993; 32 Suppl B: 103– 15. Google Scholar CrossRef Search ADS PubMed  8 Van der Leur JJ, Thunnissen PL et al.   Effects of imipenem, cefotaxime and cotrimoxazole on aerobic microbial colonization of the digestive tract. Scand J Infect Dis  1993; 25: 473– 8. Google Scholar CrossRef Search ADS PubMed  9 Bächer K, Schaeffer M, Lode H et al.   Multiple dose pharmacokinetics, safety, and effects on faecal microflora, of cefepime in healthy volunteers. J Antimicrob Chemother  1992; 30: 365– 75. Google Scholar CrossRef Search ADS PubMed  10 Goudarzi M, Goudarzi H, Alebouyeh M et al.   Antimicrobial susceptibility of Clostridium difficile clinical isolates in Iran. Iran Red Crescent Med J  2013; 15: 704– 11. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Comment on: Role of cephalosporins in the era of Clostridium difficile infection

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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0305-7453
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10.1093/jac/dkx377
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Abstract

Sir, The review of the role of cephalosporins in the era of Clostridium difficile infection (CDI) implies that cephalosporins, including those belonging to the same generation, are different when it comes to the risk of CDI.1 It states that the risk of CDI can be mitigated by careful selection of cephalosporins taking into account their differing pharmacokinetic parameters (achieved gut levels, which could be higher with cephalosporins that have substantial elimination via the biliary tree), effects on microbiota and impact on C. difficile growth and toxin production.1 I was surprised not to see the third-generation parental cephalosporin cefotaxime that is used in the UK, which has different pharmacokinetic properties to ceftriaxone, particularly biliary excretion (cefotaxime 1% versus ceftriaxone 30%–40%), in the review’s tables on pharmacokinetic parameters and pharmacodynamic properties.1 Similarly for the fourth-generation parental cephalosporin, cefepime, which is used in Europe, given that the review authors describe a meta-analysis indicating that, of the cephalosporins, fourth-generation cephalosporins may have a lower risk of CDI.2 This absence may be because cefotaxime and cefepime are not among the most commonly used cephalosporins across Europe as displayed in Table 1 of Wilcox et al.1 I do notice that the other category in this table ranges widely from country to country, from <0.05% to 40.7% of total cephalosporin use.1 It is also possible that the authors decided to leave out cefotaxime and cefepime from the tables in the review for brevity. Table 1 Summary of pharmacokinetic parameters, pharmacodynamic properties and in vitro susceptibility of C. difficile to cefotaxime and cefepime   Parameter  Cefotaxime  Cefepime  Summary of pharmacokinetic parameters and pharmacodynamic properties  serum t½, h  1.23  2.03  protein binding, %  353  203  urinary excretion, %  60%, further 24% as antibacterially active metabolite desacetyl-cefotaxime4  883  biliary excretion, %  13  –  bile concentration, mean ± SD (range), mg/L  34.5 ±15.3  [T], 49.3 ±17.0 [T] for desacetyl-cefotaxime5  19.8 ±12.9 [G]6  dose (number of doses)a  15 mg/kg body weight5  2000 mg6  route of elimination  same as urinary excretion, % above  primarily excreted unchanged in urine7  distribution  high concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile4  achieved high concentrations in bile and gall bladder tissue6  effect on intestinal microbiota  increase in enterococci, Candida spp. stay the same with decrease in Escherichia coli8  decrease in E. coli and bifidobacteria in faeces, slight increase in Bacteroides spp. and clostridia9  faecal concentration  –  –  In vitro susceptibility of C. difficile  isolates tested, n  7510  –  MIC range, mg/L  4–512  no data  MIC50, mg/L  >128  no data  MIC90, mg/L  256  no data    Parameter  Cefotaxime  Cefepime  Summary of pharmacokinetic parameters and pharmacodynamic properties  serum t½, h  1.23  2.03  protein binding, %  353  203  urinary excretion, %  60%, further 24% as antibacterially active metabolite desacetyl-cefotaxime4  883  biliary excretion, %  13  –  bile concentration, mean ± SD (range), mg/L  34.5 ±15.3  [T], 49.3 ±17.0 [T] for desacetyl-cefotaxime5  19.8 ±12.9 [G]6  dose (number of doses)a  15 mg/kg body weight5  2000 mg6  route of elimination  same as urinary excretion, % above  primarily excreted unchanged in urine7  distribution  high concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile4  achieved high concentrations in bile and gall bladder tissue6  effect on intestinal microbiota  increase in enterococci, Candida spp. stay the same with decrease in Escherichia coli8  decrease in E. coli and bifidobacteria in faeces, slight increase in Bacteroides spp. and clostridia9  faecal concentration  –  –  In vitro susceptibility of C. difficile  isolates tested, n  7510  –  MIC range, mg/L  4–512  no data  MIC50, mg/L  >128  no data  MIC90, mg/L  256  no data  G, concentration in gall bladder bile; T, concentration in bile obtained from a T-tube or drain tube. Bile concentration data are shown for patients either undergoing or following cholecystectomy or with cholecystolithiasis, unless otherwise indicated. Concentrations in bile obtained from a T-tube or drain tube (indicated by T) are peak concentrations unless otherwise stated. a Single dose, unless otherwise indicated. In Table 1 of this article I have tried to summarize the pharmacokinetic parameters, pharmacodynamic properties and in vitro susceptibility of C. difficile to cefotaxime and cefepime, which are adapted from tables in the review. I have left out the fourth-generation cephalosporin cefpirome due to space constraints. I feel this adds further information to the review, which discusses how the differing properties of cephalosporins could help with deciding which ones to use to mitigate CDI risk and increase diversity of antibiotic use. When use of the novel cephalosporin/β-lactamase inhibitors (e.g. ceftolozane/tazobactam and ceftazidime/avibactam) becomes more established it will be interesting to see what role they play in the era of CDI. Transparency declarations None to declare. References 1 Wilcox MH, Chalmers JD, Nord CE et al.   Role of cephalosporins in the era of Clostridium difficile infection. J Antimicrob Chemother  2017; 72: 1– 18. Google Scholar CrossRef Search ADS PubMed  2 Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother  2014; 69: 881– 91. Google Scholar CrossRef Search ADS PubMed  3 Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc  1999; 74: 187– 95. Google Scholar CrossRef Search ADS PubMed  4 Wockhardt UK Ltd. Cefotaxime 2g Powder for Solution for Injection or Infusion—Summary of Product Characteristics. https://www.medicines.org.uk/emc/medicine/12154. 5 Jehl F, Peter JD, Picard A et al.   Investigation of the biliary clearances of cefotaxime and desacetylcefotaxime by an original procedure in cholecystectomised patients. Infection  1987; 15: 450– 4. Google Scholar CrossRef Search ADS PubMed  6 Petrikkos G, Kastanakis M, Markogiannakis A et al.   Pharmacokinetics of cefepime in bile and gall bladder tissue after prophylactic administration in patients with extrahepatic biliary diseases. Int J Antimicrob Agents  2006; 27: 331– 4. Google Scholar CrossRef Search ADS PubMed  7 Van der Auwera P, Santella PJ. Pharmacokinetics of cefepime: a review. J Antimicrob Chemother  1993; 32 Suppl B: 103– 15. Google Scholar CrossRef Search ADS PubMed  8 Van der Leur JJ, Thunnissen PL et al.   Effects of imipenem, cefotaxime and cotrimoxazole on aerobic microbial colonization of the digestive tract. Scand J Infect Dis  1993; 25: 473– 8. Google Scholar CrossRef Search ADS PubMed  9 Bächer K, Schaeffer M, Lode H et al.   Multiple dose pharmacokinetics, safety, and effects on faecal microflora, of cefepime in healthy volunteers. J Antimicrob Chemother  1992; 30: 365– 75. Google Scholar CrossRef Search ADS PubMed  10 Goudarzi M, Goudarzi H, Alebouyeh M et al.   Antimicrobial susceptibility of Clostridium difficile clinical isolates in Iran. Iran Red Crescent Med J  2013; 15: 704– 11. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Feb 1, 2018

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