International Journal of Clinical Pharmacy

, Volume 40, Issue 5, pp 1059–1071 | Cite as

Pharmacodynamic model for β-lactam regimens used in surgical prophylaxis: model-based evaluation of standard dosing regimens

  • XiangQing SongEmail author
  • MingHui Long
Research Article


Background Continual evolution of resistance among bacteria against methods of surgical prophylaxis may make currently used beta-lactam regimens inadequate. Objective To re-evaluate beta-lactam regimens in surgical prophylaxis. Setting A pharmacodynamic Monte Carlo simulation (MCS) model based on a number of patients in China. Methods Pharmacodynamic profiling using Monte Carlo simulation up to 4 hours postinfusion was conducted for standard-dose, short-term (0.5 h) and prolonged (2 to 4 h) infusions of ampicillin, cefazolin, cefotaxime, cefoxitin, cefuroxime, ertapenem, and piperacillin/tazobactam in adult patients with normal renal function. Microbiological data were incorporated. Cumulative fraction of response (CFR) was determined for each regimen against populations of S. aureus, coagulase-negative staphylococci and E. coli. The optimal CFR was defined as ≥ 90% response. Main Outcome Measure Cumulative fractions of response of pharmacodynamic target attainment. Results During the first 2 hours postinfusion, piperacillin/tazobactam 3.375 g exhibited consistently optimal cumulative fractions against S. aureus, CoNS and E. coli. Ampicillin 2 g (2 h) also displayed optimal CFRs for S. aureus and E. coli but not for coagulase-negative staphylococci. Cefoxitin 2 g didnot achieve any optimal CFRs, even via 2-h prolonged infusion (maximum 72.8% CFR for S. aureus and 64.5% CFR for E. coli). Cefazolin 2 g (4 h) and cefuroxime 1.5 g (4 h) provided desired CFRs across 4 h postinfusion for S. aureus but provided poor CFRs for coagulase-negative staphylococci and E. coli. Only ertapenem 1 g for E. coli and S. aureus and cefotaxime 1 g for E. coli consistently yielded ≥ 90% CFRs for 4 hour postinfusion. Conclusions Certain dosing regimens may warrant adjustment for improved prevention efficiency and enhanced empirical antibiotic regimens for surgical prophylaxis.


Antibiotic prophylaxis Beta-lactam Cumulative fraction of response Model-based evaluation Monte Carlo simulation Pharmacodynamics Pharmacokinetics 



The authors are grateful to Prof. Liu Jing for her continuous support.



Conflicts of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    World Health Organization. Global guidelines for the prevention of surgical site infection. World Health Organization. 2016. Accessed 14 Jan 2018.
  2. 2.
    Berríos-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, et al. Centers for disease control and prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152:784–91.CrossRefGoogle Scholar
  3. 3.
    World Health Organization. WHO guidelines for safe surgery 2009: safe surgery saves lives World Health Organization. 2009. Accessed 14 Jan 2018.
  4. 4.
    Haripriya A. Antibiotic prophylaxis in cataract surgery–an evidence-based approach. Indian J Ophthalmol. 2017;65:1390–5.CrossRefGoogle Scholar
  5. 5.
    Zapata-Copete J, Aguilera-Mosquera S, García-Perdomo HA. Antibiotic prophylaxis in breast reduction surgery: a systematic review and meta-analysis. J Plast Reconstr Aesthet Surg. 2017;70:1689–95.CrossRefGoogle Scholar
  6. 6.
    Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283.CrossRefGoogle Scholar
  7. 7.
    McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T > MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31:345–51.CrossRefGoogle Scholar
  8. 8.
    Mattioli F, Fucile C, Del Bono V, Marini V, Parisini A, Molin A, et al. Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients. Eur J Clin Pharmacol. 2016;72:839–48.CrossRefGoogle Scholar
  9. 9.
    Johnson DP. Antibiotic prophylaxis with cefuroxime in arthroplasty of the knee. J Bone Jt Surg Br. 1987;69:787–9.CrossRefGoogle Scholar
  10. 10.
    Koomanachai P, Yungyuen T, Disthaporn P, Kiratisin P, Nicolau DP. Application of pharmacodynamic profiling for the selection of optimal β-lactam regimens in a large university hospital. Int J Infect Dis. 2016;46:22–6.CrossRefGoogle Scholar
  11. 11.
    Koomanachai P, Bulik CC, Kuti JL, Nicolau DP. Pharmacodynamic modeling of intravenous antibiotics against gram-negative bacteria collected in the United States. Clin Ther. 2010;32:766–79.CrossRefGoogle Scholar
  12. 12.
    Crader MF, Bhimji SS. Preoperative antibiotic prophylaxis. Treasure Island: StatPearls; 2017. Accessed 19 Jan 2018.
  13. 13.
    Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Infect Control Hosp Epidemiol. 1999;20:250–278; quiz 279–280.CrossRefGoogle Scholar
  14. 14.
    European Centre for Disease Prevention and Control. Annual epidemiological report for 2014–surgical site infections. European Centre for Disease Prevention and Control. 2016. Accessed 19 Jan 2018.
  15. 15.
    European Centre for Disease Prevention and Control. Annual epidemiological report for 2015–surgical site infections. European Centre for Disease Prevention and Control. 2017. Accessed 19 Jan 2018.
  16. 16.
    Eucast2 (online). Antimicrobial wild type distributions of microorganisms. 2017. Accessed 5 Oct 2017.
  17. 17.
    Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; CLSI supplement M100.Document M100-S27. Wayne: CLSI; 2017.Google Scholar
  18. 18.
    Moine P, Mueller SW, Schoen JA, Rothchild KB, Fish DN. Pharmacokinetic and pharmacodynamic evaluation of a weight-based dosing regimen of cefoxitin for perioperative surgical prophylaxis in obese and morbidly obese patients. Antimicrob Agents Chemother. 2016;60:5885–93.CrossRefGoogle Scholar
  19. 19.
    Suffoletta TJ, Jennings HR, Oh JJ, Stephens D, Poe KL. Continuous versus intermittent infusion of prophylactic cefoxitin after colorectal surgery: a pilot study. Pharmacotherapy. 2008;28:1133–9.CrossRefGoogle Scholar
  20. 20.
    Ferraz ÁAB, de Siqueira LT, Campos JM, de Araújo GC, Martins Filho ED, Ferraz EM. Antibiotic prophylaxis in bariatric surgery: a continuous infusion of cefazolin versus ampicillin/sulbactam and ertapenem. Arq Gastroenterol. 2015;52:83–7.CrossRefGoogle Scholar
  21. 21.
    Wang H, Zhang B, Ni Y, Kuti JL, Chen B, Chen M, et al. Pharmacodynamic target attainment of seven antimicrobials against gram-negative bacteria collected from China in 2003 and 2004. Int J Antimicrob Agents. 2007;30:452–7.CrossRefGoogle Scholar
  22. 22.
    Wildfeuer A, Müller V, Springsklee M, Sonntag HG. Pharmacokinetics of ampicillin and sulbactam in patients undergoing heart surgery. Antimicrob Agents Chemother. 1991;35:1772–6.CrossRefGoogle Scholar
  23. 23.
    Brown RM, Wise R, Andrews JM, Hancox J. Comparative pharmacokinetics and tissue penetration of sulbactam and ampicillin after concurrent intravenous administration. Antimicrob Agents Chemother. 1982;21:565–7.CrossRefGoogle Scholar
  24. 24.
    Bhalodi AA, Housman ST, Shepard A, Nugent J, Nicolau DP. Tissue pharmacokinetics of cefazolin in patients with lower limb infections. Antimicrob Agents Chemother. 2013;57:5679–83.CrossRefGoogle Scholar
  25. 25.
    Zhang Y, Wang F, Zhang J, Shi Y, Wang Z, Dai Z. Clinical pharmacokinetics research and dosage regimen of cephalosporins. Chin J Infect. 1995;13:195–8.Google Scholar
  26. 26.
    Buijk SE, Gyssens IC, Mouton JW, Metselaar HJ, Groenland TH, Verbrugh HA, et al. Perioperative pharmacokinetics of cefotaxime in serum and bile during continuous and intermittent infusion in liver transplant patients. J Antimicrob Chemother. 2004;54:199–205.CrossRefGoogle Scholar
  27. 27.
    van Zanten ARH, Oudijk M, Nohlmans-Paulssen MKE, van der Meer YG, Girbes ARJ, Polderman KH. Continuous vs. intermittent cefotaxime administration in patients with chronic obstructive pulmonary disease and respiratory tract infections: pharmacokinetics/pharmacodynamics, bacterial susceptibility and clinical efficacy. Br J Clin Pharmacol. 2007;63:100–9.CrossRefGoogle Scholar
  28. 28.
    Ko H, Cathcart KS, Griffith DL, Peters GR, Adams WJ. Pharmacokinetics of intravenously administered cefmetazole and cefoxitin and effects of probenecid on cefmetazole elimination. Antimicrob Agents Chemother. 1989;33:356–61.CrossRefGoogle Scholar
  29. 29.
    Emmerson AM. Cefuroxime axetil. J Antimicrob Chemother. 1988;22:101–4.CrossRefGoogle Scholar
  30. 30.
    Foord RD. Cefuroxime: human pharmacokinetics. Antimicrob Agents Chemother. 1976;9:741–7.CrossRefGoogle Scholar
  31. 31.
    Pletz MWR, Rau M, Bulitta J, De Roux A, Burkhardt O, Kruse G, et al. Ertapenem pharmacokinetics and impact on intestinal microflora, in comparison to those of ceftriaxone, after multiple dosing in male and female volunteers. Antimicrob Agents Chemother. 2004;48:3765–72.CrossRefGoogle Scholar
  32. 32.
    Burkhardt O, Brunner M, Schmidt S, Grant M, Tang Y, Derendorf H. Penetration of ertapenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers measured by in vivo microdialysis. J Antimicrob Chemother. 2006;58:632–6.CrossRefGoogle Scholar
  33. 33.
    Kinzig M, Sörgel F, Brismar B, Nord CE. Pharmacokinetics and tissue penetration of tazobactam and piperacillin in patients undergoing colorectal surgery. Antimicrob Agents Chemother. 1992;36:1997–2004.CrossRefGoogle Scholar
  34. 34.
    Landersdorfer CB, Bulitta JB, Kirkpatrick CMJ, Kinzig M, Holzgrabe U, Drusano GL, et al. Population pharmacokinetics of piperacillin at two dose levels: influence of nonlinear pharmacokinetics on the pharmacodynamic profile. Antimicrob Agents Chemother. 2012;56:5715–23.CrossRefGoogle Scholar
  35. 35.
    Price KE, McGregor DN. Basic design of beta-lactam antibiotics–cephalosporins. Scand J Infect Dis Suppl. 1984;42:50–63.PubMedGoogle Scholar
  36. 36.
    Bergan T. Pharmacokinetics of beta-lactam antibiotics. Scand J Infect Dis Suppl. 1984;42:83–98.PubMedGoogle Scholar
  37. 37.
    Sweetman SC, Pharm B, Pharms FR. Antibacterials. In: Sweetman SC, Pharm B, Pharms FR, editors. Martindale: the complete drug reference (ISBN 978 0 85369 840 1). London: Pharmaceuticale Press; 2009. p. 204–5, 222, 228–30, 269, 315–6.Google Scholar
  38. 38.
    European Centre for Disease Prevention and Control. Surveillance of antimicrobial resistance in Europe 2016. European Centre for Disease Prevention and Control 2017. Accessed 19 Jan 2018.
  39. 39.
    Isla A, Trocóniz IF, de Tejada IL, Vázquez S, Canut A, López JM, et al. Population pharmacokinetics of prophylactic cefoxitin in patients undergoing colorectal surgery. Eur J Clin Pharmacol. 2012;68:735–45.CrossRefGoogle Scholar
  40. 40.
    Moine P, Fish DN. Pharmacodynamic modelling of intravenous antibiotic prophylaxis in elective colorectal surgery. Int J Antimicrob Agents. 2013;41:167–73.CrossRefGoogle Scholar
  41. 41.
    Leng X, Zhao Y, Qiu H, Cao Y, Zhu W, Shen J, et al. Ertapenem prophylaxis of surgical site infections in elective colorectal surgery in China: a multicentre, randomized, double-blind, active-controlled study. J Antimicrob Chemother. 2014;69:3379–86.CrossRefGoogle Scholar
  42. 42.
    Grundmann H, Glasner C, Albiger B, Aanensen DM, Tomlinson CT, Andrasević AT, et al. Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study. Lancet Infect Dis. 2017;17:153–63.CrossRefGoogle Scholar
  43. 43.
    Chen X, Brathwaite CEM, Barkan A, Hall K, Chu G, Cherasard P, et al. Optimal cefazolin prophylactic dosing for bariatric surgery: no need for higher doses or intraoperative redosing. Obes Surg. 2017;27:626–9.CrossRefGoogle Scholar
  44. 44.
    Peppard WJ, Eberle DG, Kugler NW, Mabrey DM, Weigelt JA. Association between pre-operative cefazolin dose and surgical site infection in obese patients. Surg Infect (Larchmt). 2017;18:485–90.CrossRefGoogle Scholar
  45. 45.
    Ahmadzia HK, Patel EM, Joshi D, Liao C, Witter F, Heine RP, et al. Obstetric surgical site infections: 2 grams compared with 3 grams of cefazolin in morbidly obese women. Obstet Gynecol. 2015;126:708–15.CrossRefGoogle Scholar
  46. 46.
    Trent Magruder J, Grimm JC, Dungan SP, Shah AS, Crow JR, Shoulders BR, et al. Continuous intraoperative cefazolin infusion may reduce surgical site infections during cardiac surgical procedures: a propensity-matched analysis. J Cardiothorac Vasc Anesth. 2015;29:1582–7.CrossRefGoogle Scholar
  47. 47.
    European Centre for Disease Prevention and Control (ECDC), European Food Safety Authority (EFSA), European Medicines Agency (EMA). ECDC/EFSA/EMA second joint report on the integrated analysis of the consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from humans and food-producing animals: joint interagency antimicrobial consumption and resistance analysis (JIACRA) report. EFSA J. 2017.
  48. 48.
    Zelenitsky SA, Ariano RE, Harding GKM, Silverman RE. Antibiotic pharmacodynamics in surgical prophylaxis: an association between intraoperative antibiotic concentrations and efficacy. Antimicrob Agents Chemother. 2002;46:3026–30.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of PharmacyHunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityYuelu DistrictChina

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