Efficacy of postoperative prophylactic antibiotics in reducing permanent pacemaker infections

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1 Received: 16 December 2016 Accepted: 31 January 2017 DOI: /clc CLINICAL INVESTIGATIONS Efficacy of postoperative prophylactic antibiotics in reducing permanent pacemaker infections Wen-Huang Lee 1 Ting-Chun Huang 2 Li-Jen Lin 3 Po-Tseng Lee 1 Chih-Chan Lin 1 Cheng-Han Lee 1 Ting-Hsing Chao 1 Yi-Heng Li 1 Ju-Yi Chen 1 1 Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 2 Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital Dou-Liou Branch, Tainan, Taiwan 3 Department of Pharmacology, Institute of Clinical Pharmacy and Biopharmaceutical Science, School of Medicine, National Cheng Kung University, Tainan, Taiwan Correspondence: Ju-Yi Chen, MD, PhD, Associate Professor of Medicine Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan juyi@mail.ncku.edu.tw Background: Despite limited evidence, postoperative prophylactic antibiotics are often used in the setting of permanent pacemaker implantation or replacement. The aim of this study is to investigate the efficacy of postoperative antibiotics. Hypothesis: Postoperative prophylactic antibiotics may be not clinically useful. Methods: We recruited 367 consecutive patients undergoing permanent pacemaker implantation or generator replacement at a tertiary referral center. Baseline demographics, clinical characteristics, and procedure information were collected, and all patients received preoperative prophylactic antibiotics. Postoperative prophylactic antibiotics were administered at the discretion of the treating physician, and all patients were seen in follow-up every 3 to 6 months for an average follow-up period of 16 months. The primary endpoint was device-related infection. Results: A total of 110 patients were treated with preoperative antibiotics only (group 1), whereas 257 patients received both preoperative and postoperative antibiotics (group 2). After a mean follow-up period of 16 months, 1 patient in group 1 (0.9%) and 4 patients in group 2 (1.5%) experienced a device-related infection. There was no significant difference in the rate of infection between the 2 groups (P = 0.624). In the univariate analysis, only the age (60 11 vs years, P < 0.001) was significantly different between the infected and noninfected groups. In the multivariate analysis, younger age was an independent risk factor for infective complications (odds ratio = 1.08, P = 0.016). Conclusions: Patients treated with preoperative and postoperative antibiotics had a similar rate of infection as those treated with preoperative antibiotics alone. Further studies are needed to confirm these preliminary findings. KEYWORDS Pacemaker, Infection, Antibiotics 1 INTRODUCTION Infections related to cardiac implantable electronic devices (CIEDs), such as permanent pacemakers (PPM), cardiac resynchronization therapy (CRT), and implantable cardioverter-defibrillators (ICDs), have increased over the past several years disproportionately to the number of CIED implantations observed. 1,2 When these events occur, current guidelines recommend appropriate systemic antibiotics and complete CIED system removal. 3 Hence, this often leads to prolonged hospital stay, higher mortality, and increased financial burden. 2,4 Given prior studies, 5 there is general agreement on the benefits of preoperative prophylactic antibiotics, but little is known on whether adjuvant postoperative prophylactic antibiotics can provide additional benefit. Despite this and concerns of bacterial resistance related to antibiotic overuse, many physicians administer prolonged postoperative prophylactic antibiotics in the real world. 6 We aim to further investigate whether patients treated with a single dose of prophylactic antibiotics before the procedure compared to those Clinical Cardiology. 2017;40: wileyonlinelibrary.com/journal/clc 2017 Wiley Periodicals, Inc. 559

2 560 LEE ET AL. receiving both preprocedural and postprocedural antibiotics differed in the rate of CIED-related infections. 2 METHODS 2.1 Study population and study design This is a prospective, observational case control study. From September 2013 to October 2015, we prospectively enrolled 367 consecutive patients undergoing a new PPM implantation or generator replacement. Patients who received ICDs or CRT were excluded from the study. All baseline demographics, baseline biochemistry, indications for PPM, clinical, and procedure data, and infective complications were carefully collected. Patients were treated at the discretion of the implanting physician with some receiving preoperative prophylactic antibiotic only (group 1) and others receiving both preoperative and postoperative antibiotics (group 2). Almost all patients (95.6%) received an intravenous cefazolin 1-g infusion within 1 hour of device implantation. The study protocol was approved by the National Cheng Kung University Hospital ethics committee on human subject study, and all patients provided signed informed consent. 2.2 Antiseptic preparation, surgical procedure, postoperative care, and follow-up Four cardiologists who had at least 10 years and 1 cardiologist having 3 years experience with PPM implantation at a tertiary referral center with 200 implantations/year performed all of the procedures. For group 1, 1 electrophysiologist having more than 10 years experience and 3 cardiologists having 1 to 3 years experience under his supervision, performed the procedures. For group 2, 2 electrophysiologists having more than 10 and 3 years experience, respectively, and 2 cardiologists having more than 10 years experience performed the procedures. Fellows training in electrophysiology or general cardiology assisted in the procedures. All procedures were performed in the catheterization laboratory, and preoperative prophylactic antibiotics was administrated within 1 hour before the procedure. All patients were prepped with a 10% povidone iodine/75% alcohol solution and prepped and draped in the usual sterile fashion. Device implantation was performed with local anesthesia utilizing standard implanting techniques. The leads and generator were secured with nonabsorbable silk suture and the pocket carefully inspected prior to closure for bleeding. A hemostatic sponge was used as needed to maintain hemostasis. The incision was closed with absorbable sutures in the usual fashion. A 10-pound sandbag was placed over the wound for approximately 40 minutes, followed by a 20-minute ice pack over the wound site to ensure hemostasis and reduce local swelling. This was repeated for 4 hours. The bandages were not removed until the next morning. Intravenous or oral antibiotics were continued postoperatively in group 2. Patients were seen in the outpatient clinic within 1 week after discharge, and every 3 to 6 months thereafter. Patients were advised to visit the clinic if they encountered any problem with the wound or device. 2.3 Diagnosis and management According to the latest American Heart Association scientific report, 3 a PPM infection is defined as local inflammatory signs at the generator pocket including erythema, purulent discharge, wound dehiscence, or skin erosion. In this study, patients diagnosed with superficial or incisional infection were not counted toward the primary endpoint. For those presenting with CIED-related infection, 2 sets of blood cultures were drawn before the administration of antibiotics, and all patients underwent transesophageal echocardiography if blood cultures were positive. PPM endocarditis was confirmed by positive lead or valvular vegetation or meeting the Duke criteria. PPM removal was performed in patients diagnosed as PPM endocarditis or pocket infection, with abscess formation or lead/generator erosion. Pocket culture and lead tip culture were obtained when the PPM was removed. The choice of antibiotics was dictated by the in vitro susceptibility results and the duration of antimicrobial therapy administrated as per current clinical practice guidelines Statistical analysis Data were expressed as mean standard deviation. In comparison between patients with or without postoperative antibiotics, χ 2 test was used for categorical variables, and independent t test was used for continuous variables. A P value <0.05 was considered statistically significant. A multivariate logistic regression analysis was used to identify the independent factors associated with PPM infections. The analysis was performed using SPSS 17.0 for Window (IBM, Armonk, NY). 3 RESULTS 3.1 Patient characteristics There were total of 367 patients included in this study. The average age of the study population was years old (range, years), and 45.5% of patients were male. Thirty-three (9%) patients underwent regular hemodialysis; 17 (4.6%) and 47 (12.8%) patients took immunosuppressants and anticoagulants, respectively. The majority of implants were dual-chamber systems (n = 288, 78%), whereas 71 (19.3%) patients underwent temporary pacemaker insertion. Thirty percent of patients underwent generator replacement. Baseline characteristics, procedure information, indication, and complications are noted in Table 1. There were 110 patients in group 1 (only preoperative antibiotics), and 257 patients in group 2 (preoperative and different-days postoperative antibiotics) with no significant differences in baseline characteristics. Only 1 patient in group 1 and 5 patients in group 2 experienced a hematoma. The mean follow-up periods were months and months for group 1 and 2, respectively. 3.2 Risk factors of permanent pacemaker infection Univariate analysis of PPM infection risk factors is summarized in Table 2. Among 367 patients, 5 (1 in group 1; and 4 in group 2)

3 LEE ET AL. 561 TABLE 1 Characteristics of patients with preoperative antibiotics (group 1) and preoperative plus postoperative antibiotics (group 2) Group 1, n = 110 Group 2, n = 257 P Value Age, y Male gender, n (%) 46 (42) 121 (47) Underlying diseases, n (%) Diabetes 41 (37) 87 (34) Hypertension 79 (72) 162 (63) Hyperlipidemia 30 (27) 55 (21) Coronary artery disease 23 (21) 48 (19) Congestive heart failure 6 (5) 23 (9) VHD 17 (15) 30 (12) PAOD 2 (1.8) 2 (0.8) ESRD 10 (9) 23 (9) COPD 6 (5) 10 (4) Malignancy 11 (10) 30 (12) Liver cirrhosis 4 (4) 4 (2) Hepatitis 10 (9) 24 (9) Old stroke 10 (9) 26 (10) Smoking 9 (8) 28 (11) Alcoholism 1 (1) 5 (2) Drugs, n (%) Aspirin 23 (21) 60 (23) Clopidogrel or ticagrelor 14 (13) 32 (12) Oral anticoagulants 10 (9) 37 (14) Steroid 3 (3) 14 (5) Insertion of TPM 16 (15) 55 (21) Laboratory data WBC, mm Hemoglobin, mg/dl Platelet, mg/dl PT APTT Serum creatinine, mg/dl Left ventricular ejection fraction, % Implantation procedures, n (%) Medtronic 94 (85) 227 (88) Left subclavian 99 (90) 221 (86) Generator replacement 36 (33) 75 (29) Dual-chamber system 89 (81) 199 (77) Indication, n (%) SSS 67 (60.9) 139 (54.1) AVB 37 (33.6) 101 (39.3) Both SSS and AVB 4 (3.6) 7 (2.7) Atrial fibrillation 2 (1.8) 10 (3.9) Follow-up periods, mo Complications, n (%) Pneumothorax 0 2(0.78) Lead dislodgement 0 1(0.39) Lead insulation break 0 1(0.39) Subclavian vein stenosis 0 1(0.39) Hematoma, n (%) 1 (0.9) 5 (1.9) Infection rate, n (%) 1 (0.9) 4 (1.5) Abbreviations: APTT, activated partial thromboplastin time; AVB, atrioventricular block; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; PAOD, peripheral arterial occlusion disease; PT, prothrombin time; SSS, sick sinus syndrome; TPM, temporary pacemaker; VHD, valvular heart disease; WBC, white blood count.

4 562 LEE ET AL. developed PPM infection, and the total infection rate was 1.4%. Univariate analysis revealed that only age (60 11 vs years old, P < 0.001) was significantly different between these 2 groups. Host factors, such as diabetes mellitus, heart failure, end-stage renal disease (ESRD) or using steroids or anticoagulants, and procedurerelated factors, including temporary pacemaker insertion, dualchamber system, or replacement, were all not statistically different between these 2 groups. Moreover, hematoma complication was not a risk factor of PPM infection, and the use of postoperative antibiotics did not prevent PPM infection. After multivariate logistic TABLE 2 Comparison of characteristics of infected patients and non-infected patients Infection (n = 5) No infection, n = 362 P Value Age, y <0.001 Male gender, n (%) 2 (40) 165 (46) Underlying diseases, n (%) Diabetes 1 (20) 128 (35) Hypertension 4 (80) 237 (66) Hyperlipidemia 1 (20) 84 (23) Coronary artery disease 0 (0) 71 (20) Congestive heart failure 1 (20) 28 (8) VHD 1 (20) 46 (13) PAOD 0 (0) 4 (1) ESRD 1 (20) 32 (9) COPD 0 (0) 16 (4) Malignancy 0 (0) 41 (11) Liver cirrhosis 0 (0) 8 (2) Old stroke 0 (0) 36 (10) Smoking 0 (0) 37 (10) Alcoholism 0 (0) 6 (2) Drugs Aspirin 1 (20) 82 (23) Clopidogrel or ticagrelor 1 (20) 45 (12) Oral anticoagulants 0 (0) 40 (11) Steroid 0 (0) 17 (5) Insertion of TPM 2 (40) 69 (19) Laboratory data WBC, mm Hemoglobin, mg/dl Platelet, mg/dl PT APTT Serum creatinine, mg/dl Left ventricular ejection fraction, % Implantation procedures, n (%) Medtronic 4 (80) 317 (88) Left subclavian 4 (80) 316 (87) Generator replacement, n (%) 0 (0) 111 (31) Dual-chamber system, n (%) 5 (100) 283 (78) Indication, n (%) SSS 3 (60) 203 (56) AVB 2 (40) 136 (38) Both SSS and AVB 0 (0) 11 (3) Atrial fibrillation 0 (0) 12 (3) Follow-up periods, mo Hematoma, n (%) 0 (0) 6 (2) Postprocedure antibiotic use, n (%) 4 (80) 253 (70) Abbreviations: APTT, activated partial thromboplastin time; AVB, atrioventricular block; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; PAOD, peripheral arterial occlusion disease; PT, prothrombin time; SSS, sick sinus syndrome; TPM, temporary pacemaker; VHD, valvular heart disease; WBC, white blood count.

5 LEE ET AL. 563 regression analysis, only young age was an independent risk factor for PPM infection (odds ratio = 1.08, P = 0.016). 3.3 Antibiotics regimen Intravenous cefazolin was the predominant antibiotic used in group 1 (108, 98.2%). Among those in group 2, cefazolin was used in 93.8%, the remaining being treated with vancomycin (0.8%) and others (5.4%). Postoperative antibiotics were used at the discretion of the treating physician and are summarized in the Figure. He was diagnosed with an infected hematoma. Vancomycin administration for 6 weeks initially followed by wound dehiscence and need for PPM removal. No pathogens were identified in blood or wound cultures. Patient 5 had poor personal hygiene and frequently scratched the wound site. Pocket site infection with abscess formation developed 10 days after operation. The PPM system was extracted successfully. 4 DISCUSSION 3.4 Detail characteristics of infected patients Five patients experienced a CIED infection, and all underwent complete system extraction. The clinical characteristics and microbiology data are summarized in Table 3. Patient 1 had a late infection. There was abscess formation at pocket site and lead erosion 328 days after PPM implantation. No specific pathogens were isolated from the wound or blood cultures. Patient 2 had chronic hepatitis C infection under interferon therapy at the time of PPM implantation. PPM infection developed 5 months later, and she was continued on interferon therapy during this period. Patient 3 had a bleeding diathesis, malnutrition, ESRD, and underwent regular hemodialysis. She was initially admitted for permanent catheter infection and gastrointestinal bleeding. Oxacillin sensitive Staphylococcus aureus was isolated in initial blood cultures. Transthoracic echocardiography did not disclose any vegetation adherent to valves or perivalvular abscess. She was successfully treated, and after surveillance blood cultures were negative for 3 consecutive days, PPM implantation was performed. Unfortunately, a low grade fever, hematoma, and abscess developed at the pocket site 9 days after implantation. Blood cultures yielded multidrug-resistant Enterobacter cloacae. However, the patient refused further transesophageal echocardiography, and colistin plus amikacin were administrated. Patient 4 underwent hepatectomy for hepatocellular carcinoma 11 months after pacemaker implantation that was complicated by a subphrenic hematoma. Persistent oxacillin-resistant S aureus bacteremia and fever was noted about 2 weeks after surgery. There was no vegetation or perivalvular abscess on transthoracic echocardiography. 4.1 Main findings Previous studies demonstrating that antibiotics prophylaxis prior to PPM implantation prevents PPM infection 5,7 11 have shaped the current practice guidelines to recommend the use of preoperative prophylactic antibiotics. However, there are no data to support the use of postoperative prophylactic antibiotics. Prolonged use of antibiotics may increase financial cost, the selection of drug-resistant bacteria, drug allergy, and the total duration of hospitalization. 3 The main finding of this study was that there was no difference in CIED-related infections between patients treated with preoperative antibiotics only vs those treated with both preoperative and postoperative antibiotic administration. 4.2 Risk factors In our study, younger age was the only independent risk factor of PPM infection. After reviewing these patients, immunocompromised status and comorbidity might be other confounding factors. One patient had chronic hepatitis C infection under interferon therapy, 1 had end-stage renal disease, and 1 was associated with posthepatectomy complications. A previous study of systemic review and meta-analysis 11 identified the CIED infection risk factors, including temporary pacemaker insertion, replacement, dual-chamber system, early reintervention of hematoma, taking steroids or anticoagulants, heart failure, and diabetes mellitus. However, these factors did not appear to affect risk in our study. Compared with the other studies, the ratio of dual-chamber TABLE 3 Characteristics of infected patients Patient Age, y Gender M F F M F Days until infection Local manifestation Abscess formation Inflammation Abscess formation Inflammation Abscess formation Hematoma No No Yes No No Fever No Yes Yes Yes No TEE No No No No No Blood culture N/A N/A MDR E cloacae ORSA N/A Wound culture N/A N/A MDR E cloacae ORSA E cloacae Preoperative antibiotics Cefazolin Cefazolin Oxacillin Cefazolin Cefazolin Postoperative antibiotics Cephalexin Cephalexin Oxacillin Cefazolin N/A Abbreviations: F, female; M, male; MDR E Cloacae, multidrug resistant Enterobacter cloacae; N/A, not available; ORSA, oxacillin resistant Staphylococcus aureus; TEE, indicates transesophageal echocardiography.

6 564 LEE ET AL. operation duration in each procedure was not recorded. In our laboratory, the average duration was about 60 minutes. 5 CONCLUSION Our study demonstrated that the efficacies of prevention of PPM infection of different-days postoperative antibiotics in real-world practice appeared to be similar to those treated with preoperative antibiotics only. Younger age was an independent risk factor of infection complications, and a longer duration of antibiotic treatment may be considered in such cases. Otherwise, only preoperative antibiotic prophylaxis may be sufficient and effective to prevent PPM infections, and may further reduce the length of hospitalization and total costs. FIGURE 1 The percentage of different postoperative antibiotic regimens. Abbreviations: IV, intravenous; PO, by mouth. system and temporary pacemaker insertion is larger, and the total rate Conflicts of interest The authors declare no potential conflicts of interest. of hematoma and infection in our study is smaller (1.6% and 1.4%, respectively). In addition, we performed all implantations in the cardiac catheterization laboratory, not in the surgical operating room. A possible reason why these factors are not related to PPM infection is proper preoperative antiseptic preparation and adequate hemostasis in our study population. After skin antiseptic preparation, we applied Steri- Drapes on the operation site. We checked bleeders before closing the pocket, and we put a hemostatic sponge into the pocket for at least 10 minutes in patients with difficulty in hemostasis. Moreover, we did 40-minute sand bag compression and 20-minute ice packing alternatively for at least 4 hours after surgery. Another possible confounder in our study is the difference in operator volume between the 2 groups, which is defined as the cumulative number of PPM implantations or annual implantations per operator. The operator volume appears to be more related to complications than the annual hospital volume. More than 100 PPM implantations seem to have been necessary to achieve a low complication rate. 12,13 There is also an inverse relationship between the yearly number of cases per operator or experience in terms of years of PPM implantation and complication rate; operators doing >40 cases/year and/or >10 years of experience had the lowest complication rates Limitations Several limitations exist that should be taken into consideration when interpreting the findings of this study. First, this is not a double-blind, randomized study. However, this study was a prospective, welldesigned case control study including a medium-sized population, and the mean follow-up period was long enough to identify late infection. Second, there was diversity in the postoperative antibiotic regimen used. With that said, the majority of postoperative antibiotics regimen in our study reflected agents used commonly in daily practice. Third, due to small numbers of infected patients, the confounding factors and bias should be taken into consideration before drawing the conclusion of PPM infection risk factors. Finally, the REFERENCES 1. Voigt A, Shalaby A, Saba S. 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