Skip to main content

Pharmacokinetics of ampicillin–sulbactam and the renal function-based optimization of dosing regimens for prophylaxis in patients undergoing cardiovascular surgery

Abstract

Surgical site infections are a major cause of postoperative morbidity and mortality in cardiovascular surgery. Proper antibiotic prophylaxis can reduce the rate of such infections, but the concentration of antibiotic must be maintained at an adequate level throughout the operation. This study aimed to use renal function to determine the most appropriate timing for intraoperative repeated dosing of ampicillin–sulbactam, a commonly used prophylactic antibiotic, to maintain adequate concentrations throughout the course of surgery. The mean volume of distribution, elimination rate constant, elimination half-life, and total clearance of ampicillin were 13.2 l, 0.652 h−1, 1.32 h, and 8.45 l/h, respectively. A statistically significant (P < 0.0001) correlation (r = 0.771) was observed between the total clearance of ampicillin and creatinine clearance of the patients. Plasma concentrations of ampicillin were simulated with the pharmacokinetic parameters obtained. We developed a nomogram for adjusting the dosing interval according to renal function and predicted ampicillin trough concentrations. We revealed the best dosage and dosing interval for cardiovascular surgery by analyzing the perioperative pharmacokinetics of ampicillin–sulbactam administered prophylactically. We suggest that the dosage and dosing interval for ampicillin–sulbactam should be adjusted to optimize treatment efficacy and safety, on the basis of the MIC90 of methicillin-sensitive Staphylococcus aureus (MSSA) in each institution. Trial registration: UMIN000007356.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol. 1999;1999(20):250–78.

    Article  Google Scholar 

  2. Emori TG, Gaynes RP. An overview of nosocomial infections, including the role of the microbiology laboratory. Clin Microbiol Rev. 1993;6:428–42.

    PubMed  CAS  Google Scholar 

  3. Gårdlund B. Postoperative surgical site infections in cardiac surgery—an overview of preventive measures. APMIS. 2007;115:989–95.

    PubMed  Article  Google Scholar 

  4. Kirkland KB, Briggs JP, Trivette SL, Wilkinson WE, Sexton DJ. The impact of surgical-site infections in the 1990s: attributable mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol. 1999;20:725–30.

    PubMed  Article  CAS  Google Scholar 

  5. Broex EC, van Asselt AD, Bruggeman CA, van Tiel FH. Surgical site infections: how high are the costs? J Hosp Infect. 2009;72:193–201.

    PubMed  Article  CAS  Google Scholar 

  6. Houang ET, Ahmet Z. Intraoperative wound contamination during abdominal hysterectomy. J Hosp Infect. 1991;19:181–9.

    PubMed  Article  CAS  Google Scholar 

  7. Kreter B, Woods M. Antibiotic prophylaxis for cardiothoracic operations. Meta-analysis of thirty years of clinical trials. J Thorac Cardiovasc Surg. 1992;104:590–9.

    PubMed  CAS  Google Scholar 

  8. Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis. 2004;38:1706–15.

    PubMed  Article  Google Scholar 

  9. Owens CD, Stoessel K. Surgical site infections: epidemiology, microbiology and prevention. J Hosp Infect. 2008;70(suppl 2):3–10.

    PubMed  Article  Google Scholar 

  10. Gårdlund B, Bitkover CY, Vaage J. Postoperative mediastinitis in cardiac surgery: microbiology and pathogenesis. Eur J Cardiothorac Surg. 2002;21:825–30.

    PubMed  Article  Google Scholar 

  11. Kernodle DS, Kaiser AB. Efficacy of prophylaxis with beta-lactams and beta-lactam-beta-lactamase inhibitor combinations against wound infection by methicillin-resistant and borderline-susceptible Staphylococcus aureus in a guinea pig model. Antimicrob Agents Chemother. 1993;37:702–7.

    PubMed  Article  CAS  Google Scholar 

  12. Hampel B, Lode H, Bruckner G, Koeppe P. Comparative pharmacokinetics of sulbactam/ampicillin and clavulanic acid/amoxycillin in human volunteers. Drugs. 1988;35(suppl 7):29–33.

    PubMed  Article  CAS  Google Scholar 

  13. Martin C, Cotin A, Giraud A, Beccani-Argeme M, Alliot P, Mallet MN, et al. Comparison of concentrations of sulbactam-ampicillin administered by bolus injections or bolus plus continuous infusion in tissues of patients undergoing colorectal surgery. Antimicrob Agents Chemother. 1998;42:1093–7.

    PubMed  CAS  Google Scholar 

  14. Yamaoka K, Tanigawara Y, Nakagawa T, Uno T. A pharmacokinetic analysis program (multi) for microcomputer. J Pharmacobiodyn. 1981;4:879–85.

    PubMed  Article  CAS  Google Scholar 

  15. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.

    PubMed  Article  CAS  Google Scholar 

  16. Shimizu T. Studies on binding of cefazolin and other antibiotics. Jpn J Antibiot. 1974;27:296–301.

    PubMed  CAS  Google Scholar 

  17. Niki Y, Hanaki H, Matsumoto T, Yagisawa M, Kohno S, Aoki N, et al. Nationwide surveillance of bacterial respiratory pathogens conducted by the Japanese Society of Chemotherapy in 2008: general view of the pathogens’ antibacterial susceptibility. J Infect Chemother. 2011;17:510–23.

    PubMed  Article  Google Scholar 

  18. Kato D, Maezawa K, Yonezawa I, Iwase Y, Ikeda H, Nozawa M, et al. Randomized prospective study on prophylactic antibiotics in clean orthopedic surgery in one ward for 1 year. J Orthop Sci. 2006;11:20–7.

    PubMed  Article  CAS  Google Scholar 

  19. 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.

    PubMed  Article  CAS  Google Scholar 

  20. Takahashi Y, Takesue Y, Nakajima K, Nakajima K, Ichiki K, Wada Y, et al. Implementation of a hospital-wide project for appropriate antimicrobial prophylaxis. J Infect Chemother. 2010;16:418–23.

    PubMed  Article  CAS  Google Scholar 

  21. Higuchi Y, Takesue Y, Yamada Y, Ueda Y, Suzuki T, Aihara K, et al. A single-dose regimen for antimicrobial prophylaxis to prevent perioperative infection in urological clean and clean-contaminated surgery. J Infect Chemother. 2011;17:219–23.

    PubMed  Article  CAS  Google Scholar 

  22. Dehne MG, Mühling J, Sablotzki A, Nopens H, Hempelmann G. Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques. Orthopedics. 2001;24:665–9.

    PubMed  CAS  Google Scholar 

  23. Kosaka T, Hosokawa K, Shime N, Taniguchi F, Kokufu T, Hashimoto S, et al. Effects of renal function on the pharmacokinetics and pharmacodynamics of prophylactic cefazolin in cardiothoracic surgery. Eur J Clin Microbiol Infect Dis. 2012;31:193–9.

    PubMed  Article  CAS  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yasuo Takeda.

About this article

Cite this article

Yokoyama, Y., Matsumoto, K., Yamamoto, H. et al. Pharmacokinetics of ampicillin–sulbactam and the renal function-based optimization of dosing regimens for prophylaxis in patients undergoing cardiovascular surgery. J Infect Chemother 18, 878–882 (2012). https://doi.org/10.1007/s10156-012-0431-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10156-012-0431-6

Keywords

  • Ampicillin
  • Sulbactam
  • Cardiovascular surgery
  • Prophylaxis