Transplantation One-shot versus multidose perioperative antibiotic prophylaxis after kidney transplantation: A randomized, controlled clinical trial Giuseppe Orlando, MD, PhD,a Tommaso Maria Manzia, MD, PhD,b Roberto Sorge, PhD,c Giuseppe Iaria, MD, PhD,b Roberta Angelico, MD,b Daniele Sforza, MD,b Luca Toti, MD, PhD,b Andrea Peloso, MD,a Timil Patel, MD,a Ravi Katari, BS,a Joao Paulo Zambon, MD, PhD,a Andrea Maida, MD,d Maria Paola Salerno, MD,b Katia Clemente, BS,e Pierpaolo Di Cocco, MD,e Linda De Luca, MD, PhD,e Laura Tariciotti, MD, PhD,e Antonio Famulari, MD,e Franco Citterio, MD,d Giuseppe Tisone, MD,b Francesco Pisani, MD,e and Jacopo Romagnoli, MD, PhD,d Winston Salem, NC, and Rome and L’Aquila, Italy
Background. There is no consensus on the optimal perioperative antibiotic prophylaxis regimen for renal transplant recipients. Some studies have reported that irrigation of the wound at the time of closure without systemic antibiotics may suffice to minimize the risk for surgical site infection (SSI), but many centers still use long-term, multidose regimens in which antibiotics are administered until removal of foreign bodies occur, such as the urethral catheter, drain and central line. Methods. We designed a prospective, randomized, multicenter, controlled trial to compare a single dose versus a multidose regimen of systemic antibiotic prophylaxis in adult, nondiabetic, non-morbidly obese patients undergoing renal transplantation. The primary endpoint was the incidence of SSI; the assessment of other infection in the first postoperative month was the secondary endpoint. Results. Two hundred five patients were enrolled and randomized to receive either a single (n = 103) or multidose antibiotic regimen (n = 102) for prophylaxis. The incidences of SSI and urinary tract infection were similar in both groups. Conclusion. As the dramatic increase in antibiotic resistance has mandated the implementation of global programs to optimize the use of antibiotic agents in humans, we believe that the single dose regimen is preferred, at least in nondiabetic, non-morbidly obese, adult renal transplant recipients. (Surgery 2015;157:104-10.) From the Wake Forest School of Medicine,a Winston Salem, NC; the Department of Surgery,b Section of Transplantation, and the Biometrics Laboratory,c Tor Vergata University of Rome; the Department of Surgery,d Renal Transplantation Unit, Catholic University, Rome; and the Department of Surgery,e Section of Transplantation, University of L’Aquila, L’Aquila, Italy
AS THE DRAMATIC INCREASE IN ANTIBIOTIC RESISTANCE has become ‘‘a major public health problem in both developed and developing countries throughout There are not conflicts of interest of any of the authors. Accepted for publication June 12, 2014. Reprint requests: Giuseppe Orlando, MD, PhD, Marie Curie Fellow, Assistant Professor of Surgery Director of Translational Research Department of General Surgery, Section of Transplantation Wake Forest Baptist Health Wake Forest School of Medicine Medical Center Boulevard Winston-Salem, NC 27157-1095. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.06.007
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the world,’’1 the World Health Organization urges strongly the implementation of global programs to optimize the use of antibiotic agents in humans. Perioperative antibiotic preoperative antibiotic prophylaxis is given to prevent surgical site infections (SSI), defined as an infection occurring within 30 days of renal transplantation (RT), which may become manifest in the presence of one of the clinical findings listed in Table I.2,3 After RT, the incidence of SSI ranges from 2 to 20% and occurs more frequently when expanded criteria donor grafts are used, cold ischemia time is >30 hours, delayed graft function is present, or the duration of the operation is >200 minutes; other risk factors for SSI
Surgery Volume 157, Number 1
Table I. The Centers for Disease Control and Prevention (CDC) National Nosocomial Infection Surveillance System (NNIS) definition of a surgical site infection (SSI) Superficial incisional SSI Purulent drainage Organisms isolated from culture of fluid or tissue from the surgical site One of the following clinical signs/symptoms: Pain, localized swelling, redness, and heat Superficial incision deliberately opened by surgeon, unless wound culture is negative Diagnosis of superficial incisional SSI by surgeon or attending physician Deep incisional SSI Purulent drainage Deep incision that spontaneously dehisces or is deliberately opened by the surgeon Abscess is found on clinical examination, radiographic examination, or reoperation Diagnosis of deep incision SSI by surgeon or attending physician Organ space SSI Purulent drainage from a drain placed into the organ space Organisms isolated from culture of organ space Abscess is found on clinical examination, radiographic examination, or reoperation Diagnosis of organ space SSI by surgeon or attending physician Adapted from Mangram et al.3
are diabetes mellitus or morbid obesity in the recipient.4 In addition, RT patients are at high risk for SSI, because they meet the criteria established by the Study of Efficacy of Nosocomial Infection Control to predict SSI, namely, an abdominal operation lasting >2 hours and >3 discharge diagnostic codes.5 Last, RT is at increased for infection, because it is a clean-contaminated procedure, and uremia per se impairs systemic immune function. Nevertheless, advances in asepsis protocols, perioperative patient management, and operative technology and techniques have led to the point that a single administration of perioperative prophylactic antibiotics may be sufficient in immunosuppressed patients. The recommended agent for patients undergoing RT is cefazolin for 24 hours at most.6 Furthermore, uremia-related impairment of the immune system should have only a minor effect on the risk of transplant operation-related infections if efficient dialysis is enforced. Current literature on preoperative antibiotic prophylaxis in RT is incongruent and lacks multicenter, randomized, controlled trials. In a survey conducted by the University of Oslo, it was discovered that 11% of the RT centers worldwide
Orlando et al 105
were not using any preoperative antibiotic, and had the same incidence of SSI as centers where prophylaxis is given.7 In addition, the author reported that 84% of their RT had been performed without antibiotic prophylaxis with an SSI rate of 3.4%. Similar data were reported by other groups.8-10 The University of Buffalo assessed the clinical course of 442 consecutive RT in patients who received only trimethoprim/sulfamethoxazole, which was given for anti–Pneumocystis jiroveci prophylaxis; only 9 patients (2%) developed SSI.9 In an elegant metaanalysis, Bowater et al11 stated that, ‘‘in surgery there is a general prevailing attitude that preoperative antibiotic prophylaxis should be assumed to be ineffective unless its effectiveness has been experimentally proven beyond doubt for the specific type of surgery being considered.’’11 Because transplant operations differ from general operations in that patients are already immunosuppressed before incision, we cannot similarly endorse that attitude. Rather, we prefer to assume that preoperative antibiotic prophylaxis is effective in decreasing the risk of wound infection after RT until the contrary can be demonstrated. Therefore, efforts should be made to assess the optimal regimen of preoperative antibiotic prophylaxis that is able to (1) prevent SSI, but also minimize antibiotic exposure; (2) prevent the development of resistant bacterial strains; (3) decrease the cost of health care; and (4) minimize toxicity to patients. In this context, we designed a randomized, controlled, multicenter trial to assess whether a single-dose antibiotic regimen is as effective as the multiple-dose regimen in preventing SSI after RT. This study may provide a platform for revision of guidelines regarding perioperative antibiotic prophylaxis after RT. PATIENTS AND METHODS Selection of patients. Patients were enrolled at 3 different transplant centers: Tor Vergata University, Rome (TVU), Catholic University of the Sacred Heart, Rome (CU), and the University of L’Aquila (ULA), all in Italy. Inclusion criteria were adult recipient of a deceased or living donor kidney allograft, no history of infection related to the last 18 months of dialysis treatment, and a signed consent form. Exclusion criteria were age 30 kg/m2, hemoglobin levels
Background. There is no consensus on the optimal perioperative antibiotic prophylaxis regimen for renal transplant recipients. Some studies have reported that irrigation of the wound at the time of closure without systemic antibiotics may suffice to minimize the risk for surgical site infection (SSI), but many centers still use long-term, multidose regimens in which antibiotics are administered until removal of foreign bodies occur, such as the urethral catheter, drain and central line. Methods. We designed a prospective, randomized, multicenter, controlled trial to compare a single dose versus a multidose regimen of systemic antibiotic prophylaxis in adult, nondiabetic, non-morbidly obese patients undergoing renal transplantation. The primary endpoint was the incidence of SSI; the assessment of other infection in the first postoperative month was the secondary endpoint. Results. Two hundred five patients were enrolled and randomized to receive either a single (n = 103) or multidose antibiotic regimen (n = 102) for prophylaxis. The incidences of SSI and urinary tract infection were similar in both groups. Conclusion. As the dramatic increase in antibiotic resistance has mandated the implementation of global programs to optimize the use of antibiotic agents in humans, we believe that the single dose regimen is preferred, at least in nondiabetic, non-morbidly obese, adult renal transplant recipients. (Surgery 2015;157:104-10.) From the Wake Forest School of Medicine,a Winston Salem, NC; the Department of Surgery,b Section of Transplantation, and the Biometrics Laboratory,c Tor Vergata University of Rome; the Department of Surgery,d Renal Transplantation Unit, Catholic University, Rome; and the Department of Surgery,e Section of Transplantation, University of L’Aquila, L’Aquila, Italy
AS THE DRAMATIC INCREASE IN ANTIBIOTIC RESISTANCE has become ‘‘a major public health problem in both developed and developing countries throughout There are not conflicts of interest of any of the authors. Accepted for publication June 12, 2014. Reprint requests: Giuseppe Orlando, MD, PhD, Marie Curie Fellow, Assistant Professor of Surgery Director of Translational Research Department of General Surgery, Section of Transplantation Wake Forest Baptist Health Wake Forest School of Medicine Medical Center Boulevard Winston-Salem, NC 27157-1095. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.06.007
104 SURGERY
the world,’’1 the World Health Organization urges strongly the implementation of global programs to optimize the use of antibiotic agents in humans. Perioperative antibiotic preoperative antibiotic prophylaxis is given to prevent surgical site infections (SSI), defined as an infection occurring within 30 days of renal transplantation (RT), which may become manifest in the presence of one of the clinical findings listed in Table I.2,3 After RT, the incidence of SSI ranges from 2 to 20% and occurs more frequently when expanded criteria donor grafts are used, cold ischemia time is >30 hours, delayed graft function is present, or the duration of the operation is >200 minutes; other risk factors for SSI
Surgery Volume 157, Number 1
Table I. The Centers for Disease Control and Prevention (CDC) National Nosocomial Infection Surveillance System (NNIS) definition of a surgical site infection (SSI) Superficial incisional SSI Purulent drainage Organisms isolated from culture of fluid or tissue from the surgical site One of the following clinical signs/symptoms: Pain, localized swelling, redness, and heat Superficial incision deliberately opened by surgeon, unless wound culture is negative Diagnosis of superficial incisional SSI by surgeon or attending physician Deep incisional SSI Purulent drainage Deep incision that spontaneously dehisces or is deliberately opened by the surgeon Abscess is found on clinical examination, radiographic examination, or reoperation Diagnosis of deep incision SSI by surgeon or attending physician Organ space SSI Purulent drainage from a drain placed into the organ space Organisms isolated from culture of organ space Abscess is found on clinical examination, radiographic examination, or reoperation Diagnosis of organ space SSI by surgeon or attending physician Adapted from Mangram et al.3
are diabetes mellitus or morbid obesity in the recipient.4 In addition, RT patients are at high risk for SSI, because they meet the criteria established by the Study of Efficacy of Nosocomial Infection Control to predict SSI, namely, an abdominal operation lasting >2 hours and >3 discharge diagnostic codes.5 Last, RT is at increased for infection, because it is a clean-contaminated procedure, and uremia per se impairs systemic immune function. Nevertheless, advances in asepsis protocols, perioperative patient management, and operative technology and techniques have led to the point that a single administration of perioperative prophylactic antibiotics may be sufficient in immunosuppressed patients. The recommended agent for patients undergoing RT is cefazolin for 24 hours at most.6 Furthermore, uremia-related impairment of the immune system should have only a minor effect on the risk of transplant operation-related infections if efficient dialysis is enforced. Current literature on preoperative antibiotic prophylaxis in RT is incongruent and lacks multicenter, randomized, controlled trials. In a survey conducted by the University of Oslo, it was discovered that 11% of the RT centers worldwide
Orlando et al 105
were not using any preoperative antibiotic, and had the same incidence of SSI as centers where prophylaxis is given.7 In addition, the author reported that 84% of their RT had been performed without antibiotic prophylaxis with an SSI rate of 3.4%. Similar data were reported by other groups.8-10 The University of Buffalo assessed the clinical course of 442 consecutive RT in patients who received only trimethoprim/sulfamethoxazole, which was given for anti–Pneumocystis jiroveci prophylaxis; only 9 patients (2%) developed SSI.9 In an elegant metaanalysis, Bowater et al11 stated that, ‘‘in surgery there is a general prevailing attitude that preoperative antibiotic prophylaxis should be assumed to be ineffective unless its effectiveness has been experimentally proven beyond doubt for the specific type of surgery being considered.’’11 Because transplant operations differ from general operations in that patients are already immunosuppressed before incision, we cannot similarly endorse that attitude. Rather, we prefer to assume that preoperative antibiotic prophylaxis is effective in decreasing the risk of wound infection after RT until the contrary can be demonstrated. Therefore, efforts should be made to assess the optimal regimen of preoperative antibiotic prophylaxis that is able to (1) prevent SSI, but also minimize antibiotic exposure; (2) prevent the development of resistant bacterial strains; (3) decrease the cost of health care; and (4) minimize toxicity to patients. In this context, we designed a randomized, controlled, multicenter trial to assess whether a single-dose antibiotic regimen is as effective as the multiple-dose regimen in preventing SSI after RT. This study may provide a platform for revision of guidelines regarding perioperative antibiotic prophylaxis after RT. PATIENTS AND METHODS Selection of patients. Patients were enrolled at 3 different transplant centers: Tor Vergata University, Rome (TVU), Catholic University of the Sacred Heart, Rome (CU), and the University of L’Aquila (ULA), all in Italy. Inclusion criteria were adult recipient of a deceased or living donor kidney allograft, no history of infection related to the last 18 months of dialysis treatment, and a signed consent form. Exclusion criteria were age 30 kg/m2, hemoglobin levels
