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Surgery Today

, Volume 49, Issue 10, pp 859–869 | Cite as

Antimicrobial prophylaxis for 1 day versus 3 days in liver cancer surgery: a randomized controlled non-inferiority trial

  • Tadatoshi TakayamaEmail author
  • Osamu Aramaki
  • Taro Shibata
  • Masaaki Oka
  • Toshiyuki Itamoto
  • Mitsuo Shimada
  • Shuji Isaji
  • Takashi Kanematsu
  • Shoji Kubo
  • Masato Kusunoki
  • Hidetaka Mochizuki
  • Yoshinobu Sumiyama
Original Article

Abstract

Purposes

This study compared the effectiveness of 1-day vs 3-days antibiotic regimen to prevent surgical site infection (SSI) in open liver resection.

Method

We performed a randomized controlled non-inferiority trial in 480 patients at 39 hospitals across Japan (registered as UMIN000002852). Patients with hepatocellular carcinoma scheduled to undergo resection were randomly assigned to receive either a 1-day regimen for antimicrobial prophylaxis, or a 3-day regimen. The primary endpoint was the incidence of SSI.

Results

Among 480 randomized patients, 232 assigned to the 1-day regimen and 235 to the 3-day regimen were included in the full analysis set. Baseline characteristics of the two groups were well balanced. SSI was diagnosed in 22 patients (9.5%) in the 1-day group vs 23 patients (9.8%) in the 3-day group (difference, – 0.30; 90% CI – 4.80 to 4.19% [95% CI – 5.66% to 5.05%]; one-sided P = 0.001 for non-inferiority), meeting the non-inferiority hypothesis. In both groups, remote site infection (16 [6.9%] vs 22 [9.4%], P ˂ 0.001 for non-inferiority) and drain-related infection (5 [2.2%] vs 4 [1.7%], P ˂ 0.001 for non-inferiority) were comparable.

Conclusion

To prevent SSI in liver cancer surgery, a 1-day regimen of flomoxef sodium is recommended for antimicrobial prophylaxis because of confirming the non-inferiority to longer usage.

Keywords

Liver surgery Hepatocellular carcinoma Surgical site infection Antimicrobial prophylaxis Randomized controlled non-inferiority trial 

Abbreviations

CDC

The Centers for Disease Control and Prevention

CI

Confidence interval

CT

Computed tomography

HCC

Hepatocellular carcinoma

MRI

Magnetic resonance imaging

SSI

Surgical site infection

Notes

Acknowledgements

Investigators who participated in this study: T. Itamoto (Hiroshima University Hospital, Hiroshima); O. Masaaki (Yamaguchi University Hospital, Yamaguchi); M. Shimada (Tokushima University Hospital, Tokushima); S. Isaji (Mie University Hospital, Mie); T. Kanematsu (Nagasaki University Hospital, Nagasaki); S. Kubo (Osaka City University Hospital, Osaka); K. Chijiiwa (Miyazaki University Hospital, Miyazaki); K. Dono (Toyonaka Municipal Hospital, Osaka); K. Yanaga (Jikei Medical University Hospital, Tokyo); Y. Doki (Osaka University Hospital, Osaka); I. Koyama (Saitama Medical University Hospital, Saitama); K. Hirata (Sapporo Medical University Hospital, Hokkaido); J. Iseki (Shizuoka General Hospital, Shizuoka); K. Miyazaki (Saga University Hospital, Saga); Yamaue (Wakayama Medical University Hospital, Wakayama); M. Miyazaki (Chiba University Hospital, Chiba); S. Uemoto (Kyoto University Hospital, Kyoto); Y. Nakajima (Nara Medical University Hospital, Nara); M. Unno (Tohoku University Hospital, Miyagi); H. Saitsu (National Kyushu Medical Center, Fukuoka); M. Yamamoto (Tokyo Women's Medical University Hospital, Tokyo); S. Kudo (Showa University Hospital, Yokohama); M. Watanabe (Kitasato University Hospital, Kanagawa); J. Nagao (Toho University Hospital Ohashi Medical Center, Tokyo); T. Nonami (Aichi Medical University Hospital, Aichi); S. Ono (National Defense Medical College Hospital, Saitama); M. Shibazaki (Tokyo Yamate Medical Center, Tokyo); K. Yamaguchi (University of Occupational and Environmental Health, Fukuoka); H. Baba (Kumamoto University Hospital, Kumamoto); I. Endo (Yokohama City University Hospital, Kanagawa); Y. Kitagawa (Keio University Hospital, Tokyo); S. Natsugoe (Kagoshima University Hospital, Kagoshima); K. Shirouzu (Kurume University Hospital, Fukuoka); G. Wakabayashi (Iwate Medical University Hospital, Iwate); H. Fujii (University of Yamanashi Hospital, Yamanashi); K. Hanazaki (Kochi Medical University Hospital, Kochi); Y. Sasaki (Yao Municipal Hospital, Osaka); K. Yoshida (Gifu University Hospital, Gifu).

We thank all patients and their relatives for participating in this study, and all medical staff at the 39 participating sites for their cooperation. We also thank Prof Yasuhiko Mohri, Department of Gastrointestinal and Pediatric Surgery, Mie University for his assistance with data management, Prof Yukinori Kurokawa, Department of Gastroenterological Surgery, Osaka University for providing a study protocol on antimicrobial prophylaxis in gastric cancer surgery, Prof Mitsuru Yanai, Department of General Medicine, Nihon University for his assistance with data interpretation, Prof Masashi Fujii, Department of Digestive Surgery, Nihon University for his statistical review, and Prof. Satoshi Hori, Department of Infection Control Science, Juntendo University for his critical review.

Author contributions

Concept and design: TT, MO, HM, and YS. Acquisition or interpretation of data: TT, MO, TI, MS, SI, TK, and SK. Drafting of the manuscript: TT, and OA. Critical revision of the manuscript: TT, MO, Shibata, MK, and YS. Statistical analysis: TS.

Funding

This trial was funded by a grant from the Japan Society for Surgical Infection, Tokyo, Japan, which is a non-profit organization established to control surgery-related infections, initiated and sponsored this study, but had no role in the study design or the collection, analysis, and interpretation of data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Compliance with ethical standards

Conflict of interest

All authors declare no conflicts of interest.

Supplementary material

595_2019_1813_MOESM1_ESM.tif (96 kb)
Supplementary material 1 (TIF 97 kb)

References

  1. 1.
    Burke JP. Infection control—a problem for patient safety. N Engl J Med. 2003;348(7):651–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of Surgical Site Infection, Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control. 1999;27(2):97–132.CrossRefPubMedGoogle Scholar
  3. 3.
    Bratzler DW, Dellinger EP, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, Fish DN, Napolitano LM, Sawyer RG, Slain D, Steinberg JP, Weinstein RA, American Society of Health-System Pharmacists; Infectious Disease Society of America; Surgical Infection Society; Society for Healthcare Epidemiology of America. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195–283.CrossRefPubMedGoogle Scholar
  4. 4.
    Teillant A, Gandra S, Barter D, Morgan DJ, Laxminarayan R. Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study. Lancet Infect Dis. 2015;15(12):1429–37.CrossRefPubMedGoogle Scholar
  5. 5.
    Berríos-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, Reinke CE, Morgan S, Solomkin JS, Mazuski JE, Dellinger EP, Itani KMF, Berbari EF, Segreti J, Parvizi J, Blanchard J, Allen G, Kluytmans JAJW, Donlan R, Schecter WP, Healthcare Infection Control Practices Advisory Committee. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surg. 2017;152(8):784–91.CrossRefPubMedGoogle Scholar
  6. 6.
    Alexiou VG, Ierodiakonou V, Peppas G, Falagas ME. Antimicrobial prophylaxis in surgery: an international survey. Surg Infect (Larchmt). 2010;11(4):343–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Imamura H, Kurokawa Y, Tsujinaka T, Inoue K, Kimura Y, Iijima S, et al. Intraoperative versus extended antimicrobial prophylaxis after gastric cancer surgery: a phase 3, open-label, randomised controlled, non-inferiority trial. Lancet Infect Dis. 2012;12(5):381–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000;356(9232):802–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med. 2007;356(15):1545–59.CrossRefPubMedGoogle Scholar
  10. 10.
    Moreno Elola-Olaso A, Davenport DL, Hundley JC, Daily MF, Gedaly R. Predictors of surgical site infection after liver resection: a multicentre analysis using National Surgical Quality Improvement Program data. HPB (Oxford). 2012;14(2):136–41.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Nakahira S, Shimizu J, Miyamoto A, Kobayashi S, Umeshita K, Ito T, et al. Proposal for a sub-classification of hepato-biliary-pancreatic operations for surgical site infection surveillance following assessment of results of prospective multicenter data. J Hepatobiliary Pancreat Sci. 2013;20(5):504–11.CrossRefPubMedGoogle Scholar
  12. 12.
    Paruch JL, Merkow RP, Bentrem DJ, Ko CY, Posner MC, Cohen ME, et al. Impact of hepatectomy surgical complexity on outcomes and hospital quality rankings. Ann Surg Oncol. 2014;21(6):1773–800.CrossRefPubMedGoogle Scholar
  13. 13.
    Wu CC, Yeh DC, Lin MC, Liu TJ, Peng FK. Prospective randomized trial of systemic antibiotics in patients undergoing liver resection. Br J Surg. 1998;85(4):489–93.CrossRefPubMedGoogle Scholar
  14. 14.
    Togo S, Tanaka K, Matsuo K, Nagano Y, Ueda M, Morioka D, Endo I, Shimada H. Duration of antimicrobial prophylaxis in patients undergoing hepatectomy: a prospective randomized controlled trial using flomoxef. J Antimicrob Chemother. 2007;59(5):964–70.CrossRefPubMedGoogle Scholar
  15. 15.
    Hirokawa F, Hayashi M, Miyamoto Y, Asakuma M, Shimizu T, Komeda K, et al. Evaluation of postoperative antibiotic prophylaxis after liver resection: a randomized controlled trial. Am J Surg. 2013;206(1):8–15.CrossRefPubMedGoogle Scholar
  16. 16.
    Takagane A, Mohri Y, Konishi T, Fukushima R, Noie T, Sueyoshi S, et al. Randomized clinical trial of 24 versus 72 h antimicrobial prophylaxis in patients undergoing open total gastrectomy for gastric cancer. Br J Surg. 2017;104(2):e158–e164164.CrossRefPubMedGoogle Scholar
  17. 17.
    Gomi H, Solomkin JS, Takada T, Strasberg SM, Pitt HA, Yoshida M, Kusachi S, Mayumi T, Miura F, Kiriyama S, Yokoe M, Kimura Y, Higuchi R, Windsor JA, Dervenis C, Liau KH, Kim MH, Tokyo Guideline Revision Committee. TG13 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):60–70.CrossRefPubMedGoogle Scholar
  18. 18.
    Midorikawa Y, Takayama T, Nara S, Hashimoto T, Omichi K, Ebisawa K, et al. No Need of Immediate Treatment for Hypovascular Tumors Associated with Hepatocellular Carcinoma. World J Surg. 2016;40(10):2460–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Levy I, Greig PD, Gallinger S, Langer B, Sherman M. Resection of hepatocellular carcinoma without preoperative tumor biopsy. Ann Surg. 2001;234(2):206–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Liver Cancer Study Group of Japan. The clinical staging of hepatocellular carcinoma. In: Makuuchi M, editor. General rules for the clinical and pathological study of primary liver cancer. 3rd ed. Ltd, Tokyo: Kanehara & Co.; 2010. p. 26–27.Google Scholar
  21. 21.
    Takayama T, Makuuchi M, Kubota K, Harihara Y, Hui AM, Sano K, et al. Randomized comparison of ultrasonic vs clamp transection of the liver. Arch Surg. 2001;136(8):922–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Yamazaki S, Takayama T, Moriguchi M, Mitsuka Y, Okada S, Midorikawa Y, et al. Criteria for drain removal following liver resection. Br J Surg. 2012;99(11):1584–90.CrossRefPubMedGoogle Scholar
  23. 23.
    Ban KA, Minei JP, Laronga C, Harbrecht BG, Jensen EH, Fry DE, Itani KM, Dellinger EP, Ko CY, Duane TM. American College of Surgeons and Surgical Infection Society: Surgical Site Infection Guidelines, 2016 Update. J Am Coll Surg. 2017;224(1):59–74.CrossRefPubMedGoogle Scholar
  24. 24.
    Liu CL, Fan ST, Lo CM, Wong Y, Ng IO, Lam CM, et al. Abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases. Ann Surg. 2004;239(2):194–201.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Pelton JJ, Hoffman JP, Eisenberg BL. Comparison of liver function tests after hepatic lobectomy and hepatic wedge resection. Am Surg. 1998;64(5):408–14.PubMedGoogle Scholar
  26. 26.
    Kudo M, Izumi N, Ichida T, Ku Y, Kokudo N, Sakamoto M, et al. Report of the 19th follow-up survey of primary liver cancer in Japan. Hepatol Res. 2016;46(5):372–90.CrossRefPubMedGoogle Scholar
  27. 27.
    Ercolani G, Grazi GL, Ravaioli M, Del Gaudio M, Gardini A, Cescon M, et al. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg. 2003;237(4):536–43.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Dechartres A, Boutron I, Trinquart L, Charles P, Ravaud P. Single-center trials show larger treatment effects than multicenter trials: evidence from a meta-epidemiologic study. Ann Intern Med. 2011;155(1):39–51.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Tadatoshi Takayama
    • 1
    Email author
  • Osamu Aramaki
    • 1
  • Taro Shibata
    • 2
  • Masaaki Oka
    • 3
  • Toshiyuki Itamoto
    • 4
  • Mitsuo Shimada
    • 5
  • Shuji Isaji
    • 6
  • Takashi Kanematsu
    • 7
  • Shoji Kubo
    • 8
  • Masato Kusunoki
    • 9
  • Hidetaka Mochizuki
    • 10
  • Yoshinobu Sumiyama
    • 11
  1. 1.Department of Digestive SurgeryNihon University School of MedicineTokyoJapan
  2. 2.Biostatistics Division, Center for Research Administration and SupportNational Cancer CenterTokyoJapan
  3. 3.Department of Digestive Surgery and Surgical Oncology, Faculty of MedicineYamaguchi UniversityUbeJapan
  4. 4.Department of Gastroenterological and Transplant SurgeryHiroshima University School of MedicineHiroshimaJapan
  5. 5.Department of Digestive and Transplantation SurgeryTokushima University School of MedicineTokushimaJapan
  6. 6.Department of Hepatobiliary Pancreatic and Transplant SurgeryMie University Graduate School of MedicineTsu CityJapan
  7. 7.Department of SurgeryNagasaki University School of Biomedical SciencesNagasakiJapan
  8. 8.Department of Hepatobiliary Pancreatic SurgeryOsaka City University Graduate School of MedicineOsaka-CityJapan
  9. 9.Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life SciencesMie University Graduate School of MedicineTsuJapan
  10. 10.Department of SurgeryNational Defense Medical CollegeTokorozawaJapan
  11. 11.Chairman of the Board of DirectorsToho UniversityTokyoJapan

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