Pharmaceutical Research

, 35:116 | Cite as

Efficacious Cefazolin Prophylactic Dose for Morbidly Obese Women Undergoing Bariatric Surgery Based on Evidence from Subcutaneous Microdialysis and Populational Pharmacokinetic Modeling

  • Eduardo Celia Palma
  • Nelson Guardiola Meinhardt
  • Airton Tetelbom Stein
  • Isabela Heineck
  • Maria Isabel Fischer
  • BibianaVerlindo de Araújo
  • Teresa Dalla Costa
Research Paper



To determine the efficacious cefazolin prophylactic dose for bariatric surgery using free subcutaneous concentrations accessed by microdialysis after 2 g or 3 g i.v. bolus dosing to morbidly obese women and POPPK modeling.


A POPPK model with variable plasma and subcutaneous tissue protein binding was developed to simultaneously describe plasma and tissue data sets. The outcomes was predicted for common surgical site infection (SSI) bacteria over 3, 4, 5 and 6 h periods postdose, as probability of target attainment (PTA) using Monte Carlo simulation.


CFZ 2 g warrant up to 5 h SSI prophylaxis for bacteria with MICs ≤1 mg/L such as Escherichia coli and Staphylococcus aureus. For species such as Klebsiella pneumoniae, which present MIC distribution frequency of 2 mg/L, the maintenance of PTA ≥ 90% occurs with a 3 g dose for surgeries lasting up to 5 h, and 2 g dose provide an adequate response up to 4 h (PTA of 89%).


Effectiveness of CFZ 2 g is similar to 3 g against bacteria with a MIC up to 2 mg/L, especially if the surgery does not last for more than 4 h.


cefazolin β-lactam morbid obesity microdialysis populational pharmacokinetics 



American society of health-system pharmacists


Area under curve of unbound plasma concentration


Area under curve of total plasma concentration


Area under curve of unbound subcutaneous tissue concentration


Area under curve of total subcutaneous tissue concentration


Maximal binding capacity of CFZ to plasma albumin


Maximal binding capacity of CFZ to tissue albumin


Body mass index




Total body clearance


Total plasma cefazolin concentration


Tissue distribution factor


Dilution factor of albumin concentration in interstitial space fluid

fT > MIC

Unbound tissue CFZ concentration above the minimum inhibitory concentration


Unbound plasma fraction


Unbound subcutaneous tissue fraction


Nossa Senhora da Conceição Hospital


High-performance liquid chromatography


Dissociation constant for CFZ binding to plasma albumin


Dissociation constant for CFZ binding to tissue albumin


Minimum inhibitory concentration


Non-compartmental pharmacokinetic analysis


Populational pharmacokinetics


Probability of target attainment


Inter-compartmental clearance


Surgical site infection


Volume of distribution of the central compartment


Volume of distribution of the subcutaneous tissue compartment


Visual predictive check



This work was supported by the PPSUS/FAPERGS, Rio Grande do Sul, Brazil [#1298–255/13–8].

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

Supplementary material

11095_2018_2394_Fig5_ESM.gif (55 kb)
Supplementary Figure S1

Individual and population fitted total (upper panel), free plasma (middle panel) and free subcutaneous tissue (lower panel) profiles using nonlinear mixed-effect modeling approach. Patients received a single 2 g (1–4) or 3 g (5–6) intravenous bolus dose of CFZ. Black dots: observations; solid line: individual model predictions; dashed line: population model. (GIF 54 kb)

11095_2018_2394_MOESM1_ESM.tif (253 kb)
High Resolution Image (TIFF 253 kb)


  1. 1.
    Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. Jama [Internet]. 2016;315(21):2284–91. Available from: CrossRefGoogle Scholar
  2. 2.
    BRASIL. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância de Doenças e Agravos não Transmissíveis e Promoção da Saúde. Vigitel Brazil 2016: surveillance of risk and protective factors for chronic diseases by telephone survey: estimates of sociodemographic frequency and distribution of risk and protective factors for chronic diseases in the capitals of the 26 Brazilian sta [Internet]. Brasília: Ministério da Saúde; 2017. Available from:
  3. 3.
    De Oliveira ML, Santos LMP, Silvada EN. Direct healthcare cost of obesity in Brazil: an application of the cost-of-illness method from the perspective of the public health system in 2011. PLoS One. 2015;10(4):1–15.Google Scholar
  4. 4.
    Santos LMP, De Oliveira IV, Peters LR, Conde WL. Trends in morbid obesity and in bariatric surgeries covered by the Brazilian public health system. Obes Surg. 2010;20(7):943–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Maggard MA, Shugarman LR, Suttorp M, Maglione M, Sugerman HJ, Livingston EH, et al. Clinical guidelines meta-Analysis : surgical treatment of obesity. Clin Guidel. 2005;142(7):547–59.Google Scholar
  6. 6.
    Colquitt JL, Pickett K, Loveman E, Frampton GK. Surgery for weight loss in adults (review). Cochrane Database Syst Rev. 2014;8(8):1–241.Google Scholar
  7. 7.
    Johnson EE, Simpson AN, Harvey JB, Simpson KN. Bariatric surgery implementation trends in the USA from 2002 to. Implement Sci [Internet]. 2012;2016:1–9. Available from: Google Scholar
  8. 8.
    Winfield RD, Reese S, Bochicchio K, Mazuski JE, Obesity BGV. The risk for surgical site infection in abdominal surgery. Am Surg. 2016;82(4):331–6.PubMedGoogle Scholar
  9. 9.
    Topaloglu S, Avsar FM, Ozel H, Babacan M, Berkem H, Yildiz Y, et al. Comparison of bariatric and non-bariatric elective operations in morbidly obese patients on the basis of wound infection. Obes Surg. 2005;15(9):1271–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Heal Pharm. 2013;70(3):195–283.CrossRefGoogle Scholar
  11. 11.
    Brill MJE, Houwink API, Schmidt S, Van dongen EPA, Hazebroek EJ, Van ramshorst B, et al. Reduced subcutaneous tissue distribution of cefazolin in morbidly obese versus non-obese patients determined using clinical microdialysis. J Antimicrob Chemother. 2014;69(3):715–23.CrossRefPubMedGoogle Scholar
  12. 12.
    Edmiston CE, Krepel C, Kelly H, Larson J, Andris D, Hennen C, et al. Perioperative antibiotic prophylaxis in the gastric bypass patient: do we achieve therapeutic levels? Surgery. 2004;136(4):738–47.CrossRefPubMedGoogle Scholar
  13. 13.
    Anlicoara R, Ferraz ÁAB, Da P, Coelho K, De Lima Filho JL, Siqueira LT, et al. Antibiotic prophylaxis in bariatric surgery with continuous infusion of cefazolin: determination of concentration in adipose tissue. Obes Surg. 2014;24(9):1487–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Fischer MI, Dias C, Tetelbom Stein A, Guardiola Meinhardt N, Heineck I. Antibiotic prophylaxis in obese patients submitted to bariatric surgery. A systematic review. Acta Cir Bras. 2014;29(3):209–17.CrossRefPubMedGoogle Scholar
  15. 15.
    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 [Internet]. 2017;27(3):626–9. Available from: CrossRefGoogle Scholar
  16. 16.
    van Kralingen S, Taks M, Diepstraten J, Van De Garde EM, Van Dongen EP, Wiezer MJ, et al. Pharmacokinetics and protein binding of cefazolin in morbidly obese patients. Eur J Clin Pharmacol. 2011;67(10):985–92.CrossRefPubMedGoogle Scholar
  17. 17.
    Alves IA, Staudt KJ, Silva C de M, Lock G de A, Costa TD, Verlindo B, et al. Influence of experimental Cryptococcal meningitis in Wistar rats on Voriconazole brain penetration assessed by Microdialysis. Antimicrob Agents Chemother 2017;61(7).Google Scholar
  18. 18.
    Palma EC, Araújo BV de, Laureano JV, Meinhardt NG, Stein AT, Dalla Costa T. Fast and sensitive HPLC/UV method for cefazolin quantification in plasma and subcutaneous tissue microdialysate of humans and rodents applied to pharmacokinetic studies in obese individuals. Biomed Chromatogr. 2018. (Under revision).Google Scholar
  19. 19.
    Moine P, Fish DN. Pharmacodynamic modelling of intravenous antibiotic prophylaxis in elective colorectal surgery. Int J Antimicrob Agents [Internet]. 2013;41(2):167–73. Available from: CrossRefPubMedGoogle Scholar
  20. 20.
    The European Committee on Antimicrobial Susceptibility Testing - EUCAST 2017. EUCAST MIC distributions [Internet]. MIC distributions and ECOFFs. 2013 [cited 2017 Mar 1]. Available from:
  21. 21.
    De Cock RFW, Smits A, Allegaert K, de Hoon J, Saegeman V, Danhof M, et al. Population pharmacokinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates. J Antimicrob Chemother. 2014;69(5):1330–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Berezhkovskiy LM. On the Accuracy of Determination of Unbound Drug Fraction in Tissue Using Diluted Tissue Homogenate. 2012;101(5):1909–1916.Google Scholar
  23. 23.
    Berezhkovskiy LM. On the Accuracy of Estimation of Basic Pharmacokinetic Parameters by the Traditional Noncompartmental Equations and the Prediction of the Steady-State Volume of Distribution in Obese Patients Based Upon Data Derived from Normal Subjects. J Pharm Sci [Internet]. 2011 [cited 2017 Mar 30];100(6):2482–97. Available from:
  24. 24.
    Young OM, Shaik IH, Twedt R, Binstock A, Althouse AD, Venkataramanan R, et al. Pharmacokinetics of cefazolin prophylaxis in obese gravidae at time of cesarean delivery. Am J Obstet Gynecol 2015;213(4):541.e1–541541.e7.Google Scholar
  25. 25.
    Grupper M, Kuti JL, Swank ML, Maggio L, Hughes BL, Nicolau DP. Population pharmacokinetics of cefazolin in serum and adipose tissue from overweight and obese women undergoing cesarean delivery. J Clin Pharmacol. 2016;0(November):1–8.Google Scholar
  26. 26.
    Vella-Brincat JWA, Begg EJ, Kirkpatrick CMJ, Zhang M, Chambers ST, Gallagher K. Protein binding of cefazolin is saturable in vivo both between and within patients. Br J Clin Pharmacol. 2007;63(6):753–7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Smits A, Roberts JA, Vella-Brincat JWA, Allegaert K. Cefazolin plasma protein binding in different human populations: more than cefazolin-albumin interaction. Int J Antimicrob Agents. 2014;43(2):199–200.CrossRefPubMedGoogle Scholar
  28. 28.
    Tetsuya T, Norishige I, Kazunoru N, Akira T. Age-related change of cefazolin binding to rat serum proteins and its relation to the molar ratio of free fatty acid to serum albumin. Aust J Pharm. 1986;9:81–7.Google Scholar
  29. 29.
    Tsuji A, Yoshikawa T, Nishide K, Minami H, Kimura M, Nakashima E, et al. Physiologically based pharmacokinetic model for β-lactam antibiotics I: tissue distribution and Elimanation rates. J Pharm Sci [Internet]. 1983;72(11):1239–52. Available from: CrossRefGoogle Scholar
  30. 30.
    Housman ST, Sutherland CA, Nicolau DP. Pharmacodynamic profile of commonly utilised parenteral therapies against meticillin-susceptible and meticillin-resistant Staphylococcus aureus collected from US hospitals. Int J Antimicrob Agents [Internet]. 2014;44(3):235–41. Available from: CrossRefGoogle Scholar
  31. 31.
    Ho VP, Nicolau DP, Dakin GF, Pomp A, Rich BS, Towe CW, et al. Cefazolin dosing for surgical prophylaxis in morbidly obese patients. Surg Infect. 2012;13(1):33–7.CrossRefGoogle Scholar
  32. 32.
    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) [Internet]. 2016;18(0):1–6. Available from: Google Scholar
  33. 33.
    Allegranzi B, Zayed B, Bischoff P, Kubilay NZ, de Jonge S, de Vries F, et al. New WHO recommendations on intraoperative and postoperative measures for surgical site infection prevention: an evidence-based global perspective. Lancet Infect Dis [Internet]. 2016;16(12):e288–303. Available from: CrossRefGoogle Scholar
  34. 34.
    Allegranzi B, Bischoff P, de Jonge S, Kubilay NZ, Zayed B, Gomes SM, et al. New WHO recommendations on preoperative measures for surgical site infection prevention: an evidence-based global perspective. Lancet Infect Dis [Internet]. 2016;16(12):e276–87. Available from: CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Eduardo Celia Palma
    • 1
  • Nelson Guardiola Meinhardt
    • 2
  • Airton Tetelbom Stein
    • 2
  • Isabela Heineck
    • 3
  • Maria Isabel Fischer
    • 3
  • BibianaVerlindo de Araújo
    • 1
  • Teresa Dalla Costa
    • 1
  1. 1.Pharmacokinetics and PK/PD Modeling Laboratory, Pharmaceutical Sciences Graduate Program, Faculty of PharmacyFederal University of Rio Grande do SulPorto AlegreBrazil
  2. 2.Center for Obese Class III CareNossa Senhora Conceição Hospital (HNSC)Porto AlegreBrazil
  3. 3.Pharmaceutical Sciences Graduate Program, Faculty of PharmacyFederal University of Rio Grande do SulPorto AlegreBrazil

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