{"\ufeffEFFECTIVENESS OF INTEGRATED PROPHYLACTIC ANTIBIOTICS PRESCRIPTION IN PATIENTS UNDERGOING RADIOFREQUENCY AND MICROWAVE ABLATION OF LIVER TUMORS: A RETROSPECTIVE COHORT STUDY\nW.X. Pang1, K.C. Hung2, N.G.S. Chua2, S.J. Chung3, L. Sum4*\n1Lee Kong Chian School of Medicine, Nanyang Technological University-Imperial College London, Singapore\n2Department of Pharmacy, Singapore General Hospital, Outram Road, Singapore\n3Department of Infectious Diseases, Singapore General Hospital, Outram Road, Singapore \n4Department of Vascular and Interventional Radiology, Singapore General Hospital, Outram Road, Singapore\n\n*Corresponding author:  \nL. Sum, Department of Vascular and Interventional Radiology, Singapore General Hospital, Outram Road, Singapore 169608. Email: leong.sum@singhealth.com.sg\n\nDOI: https://doi.org/10.32896/tij.v3n4.1-11\nSubmitted: 07.09.2023\nAccepted: 21.11.2023\nPublished: 31.12.2023\n \nABSTRACT: \nAn institutionalised in-house antibiotic prophylaxis (AP) guideline was developed in May 2019 to standardize AP prescription. This retrospective cohort study evaluated the effectiveness and clinical outcomes of the newly launched AP guideline on patients undergoing radiofrequency (RFA) and microwave (MWA) ablation of the liver from November 2018 to March 2020. Patients without high risk of biliary tree contamination were recommended a single dose of 2g IV cefazolin (or 600mg IV clindamycin in cases of beta-lactam allergy). Univariate analysis was conducted to evaluate the clinical outcomes.\nThe study included 87 patients who underwent 93 procedures consisting of 18 RFAs and 75 MWAs for liver tumours.\u00a0Concordance with AP guidelines improved significantly (38.5% vs. 87.0%": null, " p<0.001). There were no ablation-related infections and mortality within 30 days post-ablation, and post-procedural nausea and vomiting were significantly reduced (15.4% vs. 1.9%": null, " p": "0.020). No significant difference in post-procedural fever (7.7% vs. 5.6%", " p-value": "0.693), chest and/or abdominal pain (5.1% vs. 7.4%", " while other methods include laser and ultrasound(2). Radiofrequency ablation (RFA) creates coagulative necrosis by current-induced ionic friction in tissue that occurs at the targeted tumour and surrounding hepatic parenchyma(3), while microwave ablation (MWA) causes coagulative necrosis leveraging on the electromagnetic field to agitate water molecules(4). MWA is sometimes chosen as a favourable alternative to RFA for several reasons: it can achieve higher intra-tumoral temperatures to treat multiple lesions simultaneously, has no need for grounding pads, less susceptibility to the sink phenomenon, ability to work on larger ablation zones with shorter ablation times and possibly better local tumour control(5). \n\nBy inoculating the bloodstream or causing post-ablative tissue necrosis, hyperthermal ablation procedures are associated with the risk of infection(6). Similar rates of liver abscesses are observed in the RFA(1.8%) and MWA(1.6%) groups(7). The presence of biliary-enteric anastomoses, sphincterotomies, and bile duct stents can lead to contamination of the biliary tree, putting patients at high risk of infection(8). There has been no evidence that antibiotic prophylaxis is beneficial without these high-risk factors(9), but international guidelines for percutaneous interventional radiology recommend it due to the potential bacterial seeding in necrotic tissue(10). Antibiotics were prescribed in a heterogeneous manner to patients undergoing liver ablation. In May 2019, AP prescription guideline was standardised based on published evidence and international guidelines, following discussions with the Department of Vascular and Interventional Radiology (DVIR) and antimicrobial stewardship unit. \n\nThe primary objective of this retrospective cohort study was to determine the compliance with the new DVIR antibiotic prophylaxis recommendation, before and after implementation, and the effect that the new guideline has on patient outcomes. The secondary objective assessed the safety of the current antibiotic prophylaxis regimen to determine the need to revise the guidelines and improve antibiotic prophylaxis prescription.\n\nMETHODOLOGY\n\nStudy Population and Design\nThis was a retrospective review of the compliance and clinical effects of the newly implemented in-house DVIR antibiotic prophylaxis guideline in May 2019 for RFA and MWA. Duration of post-procedural AP was considered compliant if it was prolonged due to suspicion of infection. In the implementation period, measures were taken to improve the prescription of APs. In July 2019, a Computerised Decision Support System (CDSS) enhancement was introduced to aid doctors with AP prescriptions, and an internal roadshow was held in September 2019 to increase awareness of the new guideline and CDSS. An analysis of AP prescription implementation pre- and post-implementation periods from November 2018 to April 2019 and October 2019 to March 2020 respectively was conducted for this study. \n\nInclusion and Exclusion Criteria\nAll patients above the age of 21 who underwent imaging-guided RFA and MWA within the study period were included. Patients with either an infection or suspected to have an infection before the IR procedure, who were being treated with antibiotics not intended for prophylaxis prior to the procedure, who had DVIR procedures in conjunction with other surgical procedures, or who had incomplete documentation of antibiotics, were excluded from the study.\n\nAntibiotic Prophylaxis\n2g of intravenous cefazolin was given prophylactically to all patients for its Gram-positive coverage for skin commensals such as Staphylococcal and Streptococcal organisms to reduce post-procedural infections(11). No oral or intravenous antibiotics were prescribed post-operatively. For patients with severe beta-lactam allergies, 600mg of intravenous clindamycin was prescribed": null, " patients with high-risk factors received 1.2g of intravenous co-amoxiclav before the procedure, and 1g twice daily for five days following the procedure due to a greater risk of reflux cholangitis(12). \n\nData collection\nData was extracted from electronic medical records. All percutaneous liver ablation procedures were guided by computed tomography (CT), and their reports were stored electronically. Patient demographics and clinical characteristics collected included age, gender, weight, past medical history, hyperthermic ablation modality, number of tumour(s), maximum diameter of each tumour, prophylactic antibiotics regimen administered, and clinical and laboratory data for inflammatory markers. \n\nData Analysis\nUnivariate data analysis was performed using IBM SPSS 26.0 software package (SPSS, Inc., Chicago, IL, USA). Continuous variables were checked for normality using the Shapiro-Wilk test and analysed with the independent t-test. Categorical discrete variables were analysed using the Chi-squared (\u03c72) test or Fischer\u2019s exact test, where appropriate. All tests for significance were 2-tailed, and p<0.05 indicates statistical significance.\n\nRESULTS\n\nDemographics and clinical characteristics \nWe retrospectively analysed the data of 147 cases of RFA and MWA procedures during the study period. After applying the exclusion criteria, a total of 54 patients were excluded, including 4 patients who were on antibiotics treatment not intended for prophylaxis prior to the procedures, 11 patients who underwent ablation concurrently with other surgical procedures, and 39 patients who had incomplete documentation of the antibiotics prescribed (Figure 1).  In total, 87 patients were included in this study. They underwent a total of  93 procedures, including 18 RFA and 75 MWA for 83 (89.2%) hepatocellular carcinomas, 9 (9.7%) liver metastases and 1 (1.1%) liver adenoma. Within the 93 cases of ablation, 70 (75.3%) had one tumour, 19 (20.4%) had two tumours and 4 (4.3%) had three tumours. Among these, 6 (6.90%) patients had undergone ablation twice, and 1 (1.1%) had high-risk factors of biliary-enteric anastomosis. The demographics and tumour characteristics of the two groups of ablation cases between pre-implementation (n": null, " p<0.001)": null, " choice of antibiotics selected was more aligned with the guidelines post-implementation (43.6% vs 90.7%": null, " p<0.001) but duration compliance was not significantly different (92.3% vs. 96.3%": null, " consequently, further clinic imaging and laboratory testing are necessary for its diagnosis(25). Our study showed no concurrent increase in serum PCT and positive blood cultures suggestive of infective complications in patients with post-ablation clinical symptoms. The newly implemented AP guidelines used in hyperthermal liver ablations did not adversely affect patient outcomes, and no liver abscesses or deaths resulted from the procedure. All patients who experienced clinical symptoms were discharged after close monitoring, and recoveries were uneventful.\n\nThere was a significant decrease in post-procedural nausea and vomiting in patients. One possible reason could be due to the choice of antibiotics used. Metronidazole was used commonly in conjunction with ceftriaxone prior to the implementation of AP guidelines. Since metronidazole is associated with a higher rate of nausea and vomiting (10-12%)(26) compared to cephalosporins (<4%)(27), omitting metronidazole from the new guidelines may have contributed to the reduction in incidences of post-ablation nausea and vomiting. Furthermore, combination antibiotics can increase the likelihood of adverse reactions (28).\n\nThis study had several limitations. Firstly, this was a retrospective study with a small sample size. Clinically significant conclusions about the effects of the newly implemented AP guidelines on post-ablation infection or mortality could not be drawn based on the small number of patients (n": null, "77(7):1254\u201362. \n2.\tBrace C. Thermal Tumor Ablation in Clinical Use. IEEE Pulse. 2011": null, "2(5):28\u201338. \n3.\tNakagomi R, Tateishi R, Mikami S, Wake T, Kinoshita MN, Nakatsuka T, et al. Infectious complications related to radiofrequency ablation of liver tumors: The role of antibiotics. PLoS ONE. 2021 Nov 19": null, "16(11):e0259641. \n4.\tShibata T, Niinobu T, Ogata N, Takami M. Microwave coagulation therapy for multiple hepatic metastases from colorectal carcinoma. Cancer. 2000": null, "89(2):276\u201384. \n5.\tShady W, Petre E, Do K, Gonen M, Yarmohammadi H, Brown K, et al. Percutaneous Microwave versus Radiofrequency Ablation of Colon Cancer Liver Metastases: Ablation with clear margins (A0) provides the best local tumor control. J Vasc Interv Radiol JVIR. 2018 Feb": null, "29(2):268-275.e1. \n6.\tRyan JM, Ryan BM, Smith TP. Antibiotic Prophylaxis in Interventional Radiology. J Vasc Interv Radiol. 2004 Jun 1": null, "15(6):547\u201356. \n7.\tSu XF, Li N, Chen XF, Zhang L, Yan M. Incidence and Risk Factors for Liver Abscess After Thermal Ablation of Liver Neoplasm. Hepat Mon. 2016 May 23": null, "16(7):e34588. \n8.\tWong SL, Mangu PB, Choti MA, Crocenzi TS, Dodd GD, Dorfman GS, et al. American Society of Clinical Oncology 2009 Clinical Evidence Review on Radiofrequency Ablation of Hepatic Metastases From Colorectal Cancer. J Clin Oncol. 2010 Jan 20": null, "28(3):493\u2013508. \n9.\tBhatia S, Spector S, Dalal R, Echenique A, Narayanan G. Is antibiotic prophylaxis necessary for percutaneous radiofrequency ablation of hepatocellular carcinoma. J Vasc Interv Radiol. 2014 Mar 1": null, "25(3):S180. \n10. Sutcliffe JA, Briggs JH, Little MW, McCarthy E, Wigham A, Bratby M, et al. Antibiotics in interventional radiology. Clin Radiol. 2015 Mar": null, "70(3):223\u201334. \n11. Yoshihara S, Yamana H, Akahane M, Kishimoto M, Nishioka Y, Noda T, et al. Association between prophylactic antibiotic use for transarterial chemoembolisation and occurrence of liver abscess: a retrospective cohort study. Clin Microbiol Infect. 2021 Oct 1": null, "27(10):1514.e5-1514.e10. \n12. Fang C, Cortis K, Yusuf GT, Gregory S, Lewis D, Kane P, et al. Complications from percutaneous microwave ablation of liver tumours: a pictorial review. Br J Radiol. 2019 Jul": null, "92(1099):20180864. \n13. Lissovoy G de, Fraeman K, Hutchins V, Murphy D, Song D, Vaughn BB. Surgical site infection: Incidence and impact on hospital utilisation and treatment costs. Am J Infect Control. 2009 Jun 1": null, "37(5):387\u201397. \n14. Antibiotic prophylaxis in surgery: a national clinical guideline. Edinburgh: Scottish Intercollegiate Guidelines Network": null, " 2014. \n15. Dale WB, Peter MH, for the Surgical Infection Prevention Guidelines Writers Workgroup. Antimicrobial Prophylaxis for Surgery: An Advisory Statement from the National Surgical Infection Prevention Project. Clin Infect Dis. 2004 Jun 15": null, "38(12):1706\u201315. \n16. Tan A, Rouse M, Kew N, Qin S, Paglia DL, Pham T. The appropriateness of ceftriaxone and metronidazole as empirical therapy in managing complicated intra-abdominal infection\u2014experience from Western Health, Australia. PeerJ. 2018 Aug 15": null, "6:e5383. \n17. Rawat D, Nair D. Extended-spectrum \u03b2-lactamases in Gram Negative Bacteria. J Glob Infect Dis. 2010": null, "2(3):263\u201374. \n18. Buckley AM, Moura IB, Altringham J, Ewin D, Clark E, Bentley K, et al. The use of first-generation cephalosporin antibiotics, cefalexin and cefradine, is not associated with induction of simulated Clostridioides difficile infection. J Antimicrob Chemother. 2021 Dec 24": null, "77(1):148\u201354. \n19. Zhang SX, Parisian F, Yau Y, Fuller JD, Poutanen SM, Richardson SE. Narrow-Spectrum Cephalosporin Susceptibility Testing of Escherichia coli with the BD Phoenix Automated System: Questionable Utility of Cephalothin as a Predictor of Cephalexin Susceptibility. J Clin Microbiol. 2007 Nov": null, "45(11):3762\u20133. \n20. Chehab MA, Thakor AS, Tulin-Silver S, Connolly BL, Cahill AM, Ward TJ, et al. Adult and Pediatric Antibiotic Prophylaxis during Vascular and IR Procedures: A Society of Interventional Radiology Practice Parameter Update Endorsed by the Cardiovascular and Interventional Radiological Society of Europe and the Canadian Association for Interventional Radiology. J Vasc Interv Radiol. 2018 Nov 1": null, "29(11):1483-1501.e2. \n21. Rhim H, Yoon KH, Lee JM, Cho Y, Cho JS, Kim SH, et al. Major Complications after Radio-frequency Thermal Ablation of Hepatic Tumors: Spectrum of Imaging Findings. RadioGraphics. 2003 Jan": null, "23(1):123\u201334. \n22. Sotto Mayor J, Robalo MM, Pacheco AP, Esperan\u00e7a S. Pyogenic liver abscess: uncommon presentation. BMJ Case Rep. 2016 May 11": null, "2016:bcr2016214841. \n23. \u00c7olak A, Y\u0131lmaz C, Toprak B, Akto\u011fu S. Procalcitonin and CRP as Biomarkers in Discrimination of Community-acquired Pneumonia and Exacerbation of COPD. J Med Biochem. 2017 Apr 22": null, "36(2):122\u20136. \n24. Jansen MC, van Wanrooy S, van Hillegersberg R, Rijken AM, van Coevorden F, Prevoo W, et al. Assessment of systemic inflammatory response (SIR) in patients undergoing radiofrequency ablation or partial liver resection for liver tumors. Eur J Surg Oncol EJSO. 2008 Jun 1": null, "34(6):662\u20137. \n25. Dodd GD, Napier D, Schoolfield JD, Hubbard L. 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Singapore Med J. 2019 Mar": null, "60(3):130\u20135. \n\n\nFIGURE LEGENDS:\n\n\n\nFigure 1: Flow diagram of study design\n\n\n\n\nTABLE LEGENDS:\n\nTable 1: Patient demographics and clinical characteristics\n\nPre-implementation\n(n": null, " MWA: microwave ablation": null, " RFA: radiofrequency ablation": null, " MRSA: methicillin-resistant Staphylococcus aureus": null, " TACE: Transcatheter arterial chemoembolization\n\n\n\n\n\n\n\n\n\nTable 2: AP prescription and compliance before and after implementation of AP guidelines\n\n\nPre-implementation\n(n": null, " 4 (44.4%) patients with extended antibiotics were considered compliant to duration due to suspicion of infection. Data presented as mean \uf0b1 standard deviation": null, " AP: Antibiotics prophylaxis\n\n\n\n\nTable 3: Comparison of post-RFA/MWA clinical outcomes \n\n\nPre-implementation\n(n": null}