Surgical Site and Early Urinary Tract Infections in 1000 Kidney Transplants With Antimicrobial Perioperative Prophylaxis E. Capocasalea, E. De Vecchia, M.P. Mazzonia, R. Dalla Vallea, C. Pellegrinoa, S. Ferrettib, M. Sianesia, and M. Iariaa,* a Division of General Surgery and Organ Transplantation, Department of Surgery, Parma University Hospital, Parma, Italy; and bDivision of Urology, Department of Surgery, Parma University Hospital, Parma, Italy
ABSTRACT Surgical site infections (SSIs) and early urinary tract infections (UTIs) are well recognized postoperative kidney transplant complications. These complications seldom lead to graft loss, although they may result in significant morbidity with prolonged hospitalization. Thus, perioperative antibiotic prophylaxis (PAP) has traditionally been used in this setting. Between April 1988 and December 2012, we identified 1000 kidney transplant recipients (33 from living donors) who underwent prophylaxis with ceftriaxone before the surgical procedure. A retrospective analysis was conducted to evaluate both the incidence rate and outcome of SSIs and UTIs. Recipients who developed SSIs were also assessed to identify risk factors and potential correlations with different immunosuppressive regimens. A total of 20 SSIs (2%) and 93 UTIs (9.3%) were observed. The most significant risk factor for SSIs was urine leak (15.38%; odds ratio [OR], 12.3; P < .0001) followed by sirolimus-based maintenance immunosuppression therapy (5%; OR, 2.97; P ¼ .04) and induction therapy with either antithymocyte globulin or basiliximab (3.18%; OR, 3.45; P ¼ .01). Sex was identified as the only risk factor for UTI (female vs male, 17.1% vs 4.6%; P < .0001). We believe universal ceftriaxone-based prophylaxis is useful for preventing SSIs and UTIs, considering its effectiveness and safety profile.
R
ENAL transplantation is routinely performed, with low morbidity and mortality as a consequence of refinements in surgical techniques along with the use of newer immunosuppressant agents. However, transplant recipients are still exposed to infection-related morbidities, which may negatively affect the patient’s health and be a financial burden. Indeed, surgical site infections (SSIs) and early urinary tract infections (UTIs) represent common complications occurring within the first month after transplant [1e4]. Immunosuppressive agents, the nature of surgery (clean/contaminated), and postoperative complications have traditionally been considered major predisposing factors to such issues [5e9]. Antimicrobial prophylaxis, as well as timely diagnosis and proper treatment, is critical in such a setting. The present article reports the results of a single-center retrospective study of 1000 renal transplant recipients who underwent antimicrobial prophylaxis with ceftriaxone. SSI and UTI incidence rates and outcomes were evaluated. Recipients who developed SSIs were also assessed to identify
risk factors and potential correlations with different immunosuppressive regimens. PATIENTS AND METHODS A retrospective analysis of 1000 kidney transplants performed between April 1988 and December 2012 was conducted (967 from deceased donors, 33 from living donors). A total of 626 recipients were male (62.6%), and 374 were female (37.4%). Mean recipient age at the time of transplant was 43.7 years (range, 11e76 years). Kidney transplantation was performed according to standard techniques. Briefly, the allograft was implanted extraperitoneally either in the right or the left iliac fossa through a “hockey stick” incision. Vascular anastomoses were conducted on the iliac vessels and an ureteroneocystostomy was completed by using the extravesical Lich-Gregoire technique. Only 8 cases required an ureteroureteral anastomosis (0.8%). A double-J stent was selectively used (7.6%). At the time of surgery, a Foley catheter was inserted into the
*Address correspondence to Maurizio Iaria, MD, PhD, Via Linati, 6, 43121 Parma, Italy. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.07.071
Transplantation Proceedings, 46, 3455e3458 (2014)
3455
3456 bladder and removed within 7 days. A retroperitoneal drain was routinely left in place and subsequently pulled out 24 hours after Foley removal. Perioperative antibiotic prophylaxis (PAP) was administered as 2 g of ceftriaxone given intravenously 2 hours before the transplant followed by 1 g 24 hours later in the first 170 recipients [10]. The next 830 recipients received a single dose of ceftriaxone (2 g) 2 hours before the procedure (ultra-short prophylaxis). Several immunosuppressive regimens have been used throughout the study period. Calcineurin inhibitors such as cyclosporine or tacrolimus (717 vs 283) were associated with mycophenolate mofetil (MMF) or azathioprine or mammalian target of rapamycin inhibitors (sirolimus) and corticosteroids. Azathioprine was administered to 601 recipients (60.1%) and MMF to 319 (31.9%); sirolimus was used in 80 patients (8%). The use of induction therapy (antithymocyte globulin [ATG] or basiliximab [BSX]) was first used in 1994. In the present study, induction therapy was initiated in 471 patients (47.1%). A total of 272 patients (57.7%) received 2 doses of BSX (day of transplantation and posttransplant day 4) at the standard dose of 20 mg; in 199 (42.3%), ATG were administered starting intraoperatively at a dosage of 1.5 mg/kg and was generally continued for 4 days. Acute rejection episodes were treated with corticosteroids and/or ATG. Urinalysis and urine cultures were obtained in all patients once the bladder catheter was removed. UTIs were diagnosed on the basis of positive urine culture results with 105 CFU/mL from a clean-catch urine collection. The wound was checked daily until the patient’s discharge and twice a week during outpatient follow-up visits. According to the criteria of the Centers for Disease Control and Prevention [11], SSIs are defined as infections occurring within 30 days of surgery and involving the skin or subcutaneous or deep soft tissues at the surgical wound site, with at least 1 of the following: purulent discharge from the incision with or without laboratory confirmation, organisms isolated from an aseptically obtained culture of fluid or tissue, and 1 feature of infection (eg, pain/tenderness, swelling, redness, heat) with positive culture results or diagnosis of infection by the surgeon or attending physician. For each patient, several variables were recorded, including age, sex, type of donor, body mass index (BMI), diabetes, chronic glomerulonephritis, retransplant, urinary leak, reoperation, and induction and maintenance immunosuppressive therapy. Transplant recipients with and without SSIs and UTIs were compared by using the c2 test corrected by means of the Fisher exact test, and potential risk factors specific for SSI were analyzed. Differences at 2-tailed P values of .05 were considered statistically significant.
RESULTS Surgical Site Infections
Of 1000 kidney transplant recipients, 20 (2%) were diagnosed with an SSI (9 female subjects and 11 male subjects). In 8 patients, wound culture results were positive for bacterial infection (3 Staphylococcus epidermidis, 2 Pseudomonas aeruginosa, 2 Escherichia coli, and 1 Enterococcus faecalis). The median age at presentation was 47.2 years. No significant differences were related to age, sex, BMI, diabetes, retransplant, and chronic glomerulonephritis as a cause of end-stage renal disease. No SSIs were found in patients receiving livingdonor transplants. Six (15.38%) of the 39 recipients diagnosed with a urinary fistula developed an SSI (odds ratio [OR], 12.3; P < .0001). Other significant risk factors were the use of sirolimus for immunosuppression maintenance (OR,
CAPOCASALE, DE VECCHI, MAZZONI ET AL
2.97; P ¼ .045) and induction (OR, 3.45; P ¼ .011) therapy, with no substantial difference between ATG (OR, 3.26; P ¼ .041) and BSX (OR, 3.59; P ¼ .015) (Table 1). SSIs were generally resolved by the use of local wound care management, including drainage and irrigation along with culture resulteguided antimicrobial therapy in 6 patients (30%). Early UTIs
UTIs developed in 93 patients (9.3%; 64 female subjects and 29 male subjects). Female subjects had significantly more UTIs than male subjects (17.1% vs 4.6%; P < .0001). No other variable had an impact on the UTI incidence rate. Gram-positive bacteria (66.6%) were the most common causative agents in our cohort, with a predominance of E faecalis (38.7%) and staphylococci (27.9%). Clinically, UTI presented mostly as uncomplicated acute cystitis. Infectious episodes were approached with targeted antibiotic therapy without consequences for the patient or the allograft. DISCUSSION
There has been a significant decrease in complications related to kidney transplants over the years. Nonetheless, transplant recipients are still exposed to infectious morbidities; bacterial SSIs and UTIs are among the most common infections [12,13]. These rarely lead to graft loss or patient death, although they can result in prolonged hospitalization and rising costs. Systemic risk factors coupled with immunosuppressive agents and routine surgical steps of the transplant (eg, bladder catheterization, lymphatic dissection, ureteroneocystostomy, intraoperative ureteral stenting) may promote bacterial contamination of the operative field [3,6e9,14]. Therefore, the majority of transplant centers worldwide use PAP, although the antimicrobial agent of choice and length of prophylaxis vary among centers. In contrast, only a few centers use PAP selectively or not at all. Table 1. Potential Risk Factors for SSIs Variable
Age >60 y vs 30 kg/m2 vs 60 years or with a BMI >35 kg/m2. Midtvedt et al [15] performed 377 kidney transplants without any form of PAP. They reported an overall infection rate of 3.4% in the first postoperative week, including 9 UTIs and 3 cases of pneumonia. No SSIs were recorded in this population. More recently, other authors have confirmed a low SSI incidence rate (2%) in kidney transplant recipients not receiving PAP [23]. In our series, we adopted a universal prophylaxis strategy with either a short course (first 170 transplants) or an ultra-short course (830 transplants) of PAP, with a resulting SSI incidence rate of 2%. We believe that such SSI control has been
3457
achieved because PAP was associated with both ideal surgical techniques (including thorough hemostasis and careful ligation of lymphatics) and accurate perioperative wound care. Distinctive risk factors for SSI in the kidney transplant setting have been noted repeatedly in the literature. They include postoperative urinary fistula, older age, diabetes, obesity, lymphoceles, long-term dialysis, delayed graft function, and immunosuppressive therapy (steroids, MMF, and mammalian target of rapamycin inhibitors) [6,7,14]. Reoperation is reportedly a major risk factor for SSIs, most likely because of the contamination due to repeated handling of the surgical site [7]. In our cohort, urine leak was the strongest risk factor for SSI (OR, 12.3). Spillage of urine into the retroperitoneum may play a role in promoting either deep or superficial wound infections. Induction therapy seemed to be another risk factor for SSIs (OR, 3.45), with no significant difference between ATG (OR, 3.26) and BSX (OR, 3.59) treatment. No other immunosuppressive agent had an impact on the SSI incidence rate, with the exception of sirolimus (OR, 2.97). This association has been previously reported and is conceivably related to impaired wound healing due to the antiproliferative properties of sirolimus [24]. As a consequence, some transplant centers prefer to delay administration of sirolimus until the wound is completely healed, especially when a steroid-sparing regimen is not used [22]. Traditionally, risk factors for UTIs have included female sex, diabetes, allograft trauma, prolonged pretransplant dialysis, surgical manipulation of the urinary tract, ureteral stent, and urologic complications [25,26]. In addition, bladder catheterization up to 7 days may promote postoperative UTI development [1] because this time lapse could be long enough to advance growth of the pathogen bacteria [27]. Few studies have investigated the incidence of UTIs in kidney transplant recipients with and without PAP. In the immediate postoperative transplant period, Renoult et al [8] reported a 73.7% incidence rate in a large cohort not receiving prophylaxis. Cohen et al [28] found a lower incidence rate during the first 5 days posttransplant in PAP recipients compared with those not receiving PAP (11% vs 42%; P ¼ .04); after 14 days, however, this difference was no longer evident (P ¼ NS). Robles et al [29] found a reduced early UTI incidence rate in transplant patients receiving ceftriaxone-based PAP compared with those not receiving PAP (25% vs 35%), whereas the cefotaxime-based PAP group and the no-PAP group exhibited an equivalent infection rate (35%). Under universal ceftriaxone prophylaxis, our incidence of UTIs was low (9.3%) despite longer bladder catheterization times compared with other centers [30e32]. According to previous reports [2,8,33], female subjects are significantly more affected than male subjects; this was true in our study as well (17.1% vs 4.6%; P < .0001), similar to the general population’s pattern of distribution. The present study had significant limitations, including its retrospective nature and the long study period (24 years), which is noteworthy because immunosuppression protocols have changed over time. Nevertheless, we found no impact of
3458
the different immunosuppressive agents on the development of SSIs and UTIs, except for induction therapy and sirolimus. In addition, the lack of a control group makes it harder to draw conclusions regarding the true value of universal ceftriaxone-based PAP. In conclusion, our analysis highlights the safety of ceftriaxone-based PAP due to the virtual absence of drugrelated adverse events, and it provides exceptional results in terms of control of SSIs and early UTIs in a large cohort. A universal PAP strategy coupled with high-quality surgical techniques and a thorough perioperative management plan proved to be effective in maintaining considerably low SSI and UTI incidence rates after kidney transplant. Ceftriaxone seems to be an excellent antimicrobial agent because of its targeted coverage against the most common bacteria involved in this setting, its persistent therapeutic tissue concentration (long-acting), and its safety profile. REFERENCES [1] Dantas SR, Kuboyama RH, Mazzali M, Moretti ML. Nosocomial infections in renal transplant patients: risk factors and treatment implications associated with urinary tract and surgical site infections. J Hosp Infect 2006;63:117e23. [2] Maraha B, Bonten H, van Hoof H, et al. Infectious complications and antibiotic use in renal transplant recipients during a 1-year follow-up. Clin Microbiol Infect 2001;7:619e25. [3] Alangaden GJ, Thyagarajan R, Gruber SA, et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transplant 2006;20:401e9. [4] Alangaden GJ. Urinary tract infections in renal transplant recipients. Curr Infect Dis Rep 2007;9:475e9. [5] Kyriakides GK, Simmons RL, Najarian JS. Wound infections in renal transplant wounds: pathogenetic and prognostic factors. Ann Surg 1975;182:770e5. [6] Lapchik MS, Castelo Filho A, Pestana JO, Silva Filho AP, Wey SB. Risk factors of nosocomial urinary tract and postoperative wound infections in renal transplant patients: a matched-pair casecontrol study. J Urol 1992;147:994e8. [7] Menezes FG, Wey SB, Peres CA, Medina-Pestana JO, Camargo LF. Risk factors for surgical site infection in kidney transplant recipients. Infect Control Hosp Epidemiol 2008;29: 771e3. [8] Renoult E, Aouragh F, Mayeux D, et al. Factors influencing early urinary tract infections in kidney transplant recipients. Transplant Proc 1994;26:2056e8. [9] Humar A, Matas AJ. Surgical complications after kidney transplantation. Semin Dial 2005;18:505e10. [10] Capocasale E, Mazzoni MP, Tondo S, D’Errico G. Antimicrobial prophylaxis with ceftriaxone in renal transplantation. Prospective study of 170 patients. Chemotherapy 1994;40:435e40. [11] Horan TC, Gaynes RP, Martone WJ, Jarvis WR, Emori TG. CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections. Infect Control Hosp Epidemiol 1992;13:606e8. [12] Simon DM, Levin S. Infectious complications of solid organ transplantations. Infect Dis Clin North Am 2001;15:521e49. [13] Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998;338:1741e51. [14] Humar A, Ramcharan T, Denny R, Gillingham KJ, Payne WD, Matas AJ. Are wound complications after a kidney
CAPOCASALE, DE VECCHI, MAZZONI ET AL transplant more common with modern immunosuppression? Transplantation 2001;72:1920e3. [15] Midtvedt K, Hartmann A, Midtvedt T, Brekke IB. Routine perioperative antibiotic prophylaxis in renal transplantation. Nephrol Dial Transplant 1998;13:1637e41. [16] Guglielmo BJ, Hohn DC, Koo PJ, Hunt TK, Sweet RL, Conte JE. Antibiotic prophylaxis in surgical procedures. A critical analysis of the literature. Arch Surg 1983;118:943e55. [17] Woodfield JC, Beshay N, van Rij AM. A meta-analysis of randomized, controlled trials assessing the prophylactic use of ceftriaxone. A study of wound, chest and urinary infections. World J Surg 2009;33:2538e50. [18] Menezes FG, Wey SB, Peres CA, Medina-Pestana JO, Camargo LF. What is the impact of surgical site infection on graft function in kidney transplant recipients? Transpl Infect Dis 2010;12: 392e6. [19] Ramos A, Asensio A, Muñez E, Torre-Cisneros J, Montejo M, Aguado JM, et al. Incisional surgical site infection in kidney transplantation. Urology 2008;72:119e23. [20] Rioja Sanz LA, Lièdana Torres JM, Roncalès Badal A, et al. Surgical complications in kidney transplantation. Analysis of our series (300 transplantations, 1986-1995). Arch Esp Urol 1996;49: 1053e62. [21] Valente JF, Hrickik D, Weigel K, et al. Comparison of sirolimus versus mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003;3:1128e34. [22] Laftavi MR, Rostami R, Feng L, Said M, Kohli R, Dayton M, et al. The role of antibiotic prophylaxis in the new era of immunosuppression. Transplant Proc 2011;43:533e5. [23] Laftavi MR, Rostami R, Patel S, et al. Universal perioperative antimicrobial prophylaxis is not necessary in kidney transplantation. Clin Transplant 2012;26:437e42. [24] Fortun J, Martin-Davila P, Pascual J, et al; RESITRA Transplant Network. Immunosuppressive therapy and infection after kidney transplantation. Transpl Infect Dis 2010;12: 397e405. [25] Takai K, Tollermar J, Wilczek HE, Groth CG. Urinary tract infections following renal transplantation. Clin Transplant 1998;12: 19e23. [26] Munoz P. Management of urinary tract infections and lymphocele in renal transplant recipients. Clin Infect Dis 2001;33(Suppl 1):S53e7. [27] de Oliveira LC, Lucon AM, Nahas WC, Ianhez LE, Arap S. Catheter-associated urinary infection in kidney post-transplant patients. Sao Paulo Med J 2001;119:165e8. [28] Cohen J, Rees AJ, Williams G. A prospective randomized controlled trial of perioperative antibiotic prophylaxis in renal transplantation. J Hosp Infect 1988;11:357e63. [29] Robles NR, Gallego E, Anaya F, Franco A, Valderrábano F. Antibiotic prophylaxis before kidney transplantation. Enferm Infecc Microbiol Clin 1990;8:74e7 [in Spanish]. [30] Glazer ES, Akhavanheidari M, Benedict K, James S, Molmenti E. Cadaveric renal transplant recipients can safely tolerate removal of bladder catheters within 48h of transplant. Int J Angiol 2009;18:69e70. [31] Glazer ES, Benedict K, Akhavanheidari M, James S, Molmenti E. Living donor renal transplant recipients tolerate early removal of bladder catheters. Int J Angiol 2009;18:67e8. [32] Rabkin DG, Stifelman MD, Birkhoff J, et al. Early catheter removal decreases incidence of urinary tract infections in renal transplant recipients. Transplant Proc 1998;30:4314e6. [33] Brayman KL, Stephanian E, Matas AJ, et al. Analysis of infectious complications occurring after solid-organ transplantation. Arch Surg 1992;127:38e48.
ABSTRACT Surgical site infections (SSIs) and early urinary tract infections (UTIs) are well recognized postoperative kidney transplant complications. These complications seldom lead to graft loss, although they may result in significant morbidity with prolonged hospitalization. Thus, perioperative antibiotic prophylaxis (PAP) has traditionally been used in this setting. Between April 1988 and December 2012, we identified 1000 kidney transplant recipients (33 from living donors) who underwent prophylaxis with ceftriaxone before the surgical procedure. A retrospective analysis was conducted to evaluate both the incidence rate and outcome of SSIs and UTIs. Recipients who developed SSIs were also assessed to identify risk factors and potential correlations with different immunosuppressive regimens. A total of 20 SSIs (2%) and 93 UTIs (9.3%) were observed. The most significant risk factor for SSIs was urine leak (15.38%; odds ratio [OR], 12.3; P < .0001) followed by sirolimus-based maintenance immunosuppression therapy (5%; OR, 2.97; P ¼ .04) and induction therapy with either antithymocyte globulin or basiliximab (3.18%; OR, 3.45; P ¼ .01). Sex was identified as the only risk factor for UTI (female vs male, 17.1% vs 4.6%; P < .0001). We believe universal ceftriaxone-based prophylaxis is useful for preventing SSIs and UTIs, considering its effectiveness and safety profile.
R
ENAL transplantation is routinely performed, with low morbidity and mortality as a consequence of refinements in surgical techniques along with the use of newer immunosuppressant agents. However, transplant recipients are still exposed to infection-related morbidities, which may negatively affect the patient’s health and be a financial burden. Indeed, surgical site infections (SSIs) and early urinary tract infections (UTIs) represent common complications occurring within the first month after transplant [1e4]. Immunosuppressive agents, the nature of surgery (clean/contaminated), and postoperative complications have traditionally been considered major predisposing factors to such issues [5e9]. Antimicrobial prophylaxis, as well as timely diagnosis and proper treatment, is critical in such a setting. The present article reports the results of a single-center retrospective study of 1000 renal transplant recipients who underwent antimicrobial prophylaxis with ceftriaxone. SSI and UTI incidence rates and outcomes were evaluated. Recipients who developed SSIs were also assessed to identify
risk factors and potential correlations with different immunosuppressive regimens. PATIENTS AND METHODS A retrospective analysis of 1000 kidney transplants performed between April 1988 and December 2012 was conducted (967 from deceased donors, 33 from living donors). A total of 626 recipients were male (62.6%), and 374 were female (37.4%). Mean recipient age at the time of transplant was 43.7 years (range, 11e76 years). Kidney transplantation was performed according to standard techniques. Briefly, the allograft was implanted extraperitoneally either in the right or the left iliac fossa through a “hockey stick” incision. Vascular anastomoses were conducted on the iliac vessels and an ureteroneocystostomy was completed by using the extravesical Lich-Gregoire technique. Only 8 cases required an ureteroureteral anastomosis (0.8%). A double-J stent was selectively used (7.6%). At the time of surgery, a Foley catheter was inserted into the
*Address correspondence to Maurizio Iaria, MD, PhD, Via Linati, 6, 43121 Parma, Italy. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.07.071
Transplantation Proceedings, 46, 3455e3458 (2014)
3455
3456 bladder and removed within 7 days. A retroperitoneal drain was routinely left in place and subsequently pulled out 24 hours after Foley removal. Perioperative antibiotic prophylaxis (PAP) was administered as 2 g of ceftriaxone given intravenously 2 hours before the transplant followed by 1 g 24 hours later in the first 170 recipients [10]. The next 830 recipients received a single dose of ceftriaxone (2 g) 2 hours before the procedure (ultra-short prophylaxis). Several immunosuppressive regimens have been used throughout the study period. Calcineurin inhibitors such as cyclosporine or tacrolimus (717 vs 283) were associated with mycophenolate mofetil (MMF) or azathioprine or mammalian target of rapamycin inhibitors (sirolimus) and corticosteroids. Azathioprine was administered to 601 recipients (60.1%) and MMF to 319 (31.9%); sirolimus was used in 80 patients (8%). The use of induction therapy (antithymocyte globulin [ATG] or basiliximab [BSX]) was first used in 1994. In the present study, induction therapy was initiated in 471 patients (47.1%). A total of 272 patients (57.7%) received 2 doses of BSX (day of transplantation and posttransplant day 4) at the standard dose of 20 mg; in 199 (42.3%), ATG were administered starting intraoperatively at a dosage of 1.5 mg/kg and was generally continued for 4 days. Acute rejection episodes were treated with corticosteroids and/or ATG. Urinalysis and urine cultures were obtained in all patients once the bladder catheter was removed. UTIs were diagnosed on the basis of positive urine culture results with 105 CFU/mL from a clean-catch urine collection. The wound was checked daily until the patient’s discharge and twice a week during outpatient follow-up visits. According to the criteria of the Centers for Disease Control and Prevention [11], SSIs are defined as infections occurring within 30 days of surgery and involving the skin or subcutaneous or deep soft tissues at the surgical wound site, with at least 1 of the following: purulent discharge from the incision with or without laboratory confirmation, organisms isolated from an aseptically obtained culture of fluid or tissue, and 1 feature of infection (eg, pain/tenderness, swelling, redness, heat) with positive culture results or diagnosis of infection by the surgeon or attending physician. For each patient, several variables were recorded, including age, sex, type of donor, body mass index (BMI), diabetes, chronic glomerulonephritis, retransplant, urinary leak, reoperation, and induction and maintenance immunosuppressive therapy. Transplant recipients with and without SSIs and UTIs were compared by using the c2 test corrected by means of the Fisher exact test, and potential risk factors specific for SSI were analyzed. Differences at 2-tailed P values of .05 were considered statistically significant.
RESULTS Surgical Site Infections
Of 1000 kidney transplant recipients, 20 (2%) were diagnosed with an SSI (9 female subjects and 11 male subjects). In 8 patients, wound culture results were positive for bacterial infection (3 Staphylococcus epidermidis, 2 Pseudomonas aeruginosa, 2 Escherichia coli, and 1 Enterococcus faecalis). The median age at presentation was 47.2 years. No significant differences were related to age, sex, BMI, diabetes, retransplant, and chronic glomerulonephritis as a cause of end-stage renal disease. No SSIs were found in patients receiving livingdonor transplants. Six (15.38%) of the 39 recipients diagnosed with a urinary fistula developed an SSI (odds ratio [OR], 12.3; P < .0001). Other significant risk factors were the use of sirolimus for immunosuppression maintenance (OR,
CAPOCASALE, DE VECCHI, MAZZONI ET AL
2.97; P ¼ .045) and induction (OR, 3.45; P ¼ .011) therapy, with no substantial difference between ATG (OR, 3.26; P ¼ .041) and BSX (OR, 3.59; P ¼ .015) (Table 1). SSIs were generally resolved by the use of local wound care management, including drainage and irrigation along with culture resulteguided antimicrobial therapy in 6 patients (30%). Early UTIs
UTIs developed in 93 patients (9.3%; 64 female subjects and 29 male subjects). Female subjects had significantly more UTIs than male subjects (17.1% vs 4.6%; P < .0001). No other variable had an impact on the UTI incidence rate. Gram-positive bacteria (66.6%) were the most common causative agents in our cohort, with a predominance of E faecalis (38.7%) and staphylococci (27.9%). Clinically, UTI presented mostly as uncomplicated acute cystitis. Infectious episodes were approached with targeted antibiotic therapy without consequences for the patient or the allograft. DISCUSSION
There has been a significant decrease in complications related to kidney transplants over the years. Nonetheless, transplant recipients are still exposed to infectious morbidities; bacterial SSIs and UTIs are among the most common infections [12,13]. These rarely lead to graft loss or patient death, although they can result in prolonged hospitalization and rising costs. Systemic risk factors coupled with immunosuppressive agents and routine surgical steps of the transplant (eg, bladder catheterization, lymphatic dissection, ureteroneocystostomy, intraoperative ureteral stenting) may promote bacterial contamination of the operative field [3,6e9,14]. Therefore, the majority of transplant centers worldwide use PAP, although the antimicrobial agent of choice and length of prophylaxis vary among centers. In contrast, only a few centers use PAP selectively or not at all. Table 1. Potential Risk Factors for SSIs Variable
Age >60 y vs 30 kg/m2 vs 60 years or with a BMI >35 kg/m2. Midtvedt et al [15] performed 377 kidney transplants without any form of PAP. They reported an overall infection rate of 3.4% in the first postoperative week, including 9 UTIs and 3 cases of pneumonia. No SSIs were recorded in this population. More recently, other authors have confirmed a low SSI incidence rate (2%) in kidney transplant recipients not receiving PAP [23]. In our series, we adopted a universal prophylaxis strategy with either a short course (first 170 transplants) or an ultra-short course (830 transplants) of PAP, with a resulting SSI incidence rate of 2%. We believe that such SSI control has been
3457
achieved because PAP was associated with both ideal surgical techniques (including thorough hemostasis and careful ligation of lymphatics) and accurate perioperative wound care. Distinctive risk factors for SSI in the kidney transplant setting have been noted repeatedly in the literature. They include postoperative urinary fistula, older age, diabetes, obesity, lymphoceles, long-term dialysis, delayed graft function, and immunosuppressive therapy (steroids, MMF, and mammalian target of rapamycin inhibitors) [6,7,14]. Reoperation is reportedly a major risk factor for SSIs, most likely because of the contamination due to repeated handling of the surgical site [7]. In our cohort, urine leak was the strongest risk factor for SSI (OR, 12.3). Spillage of urine into the retroperitoneum may play a role in promoting either deep or superficial wound infections. Induction therapy seemed to be another risk factor for SSIs (OR, 3.45), with no significant difference between ATG (OR, 3.26) and BSX (OR, 3.59) treatment. No other immunosuppressive agent had an impact on the SSI incidence rate, with the exception of sirolimus (OR, 2.97). This association has been previously reported and is conceivably related to impaired wound healing due to the antiproliferative properties of sirolimus [24]. As a consequence, some transplant centers prefer to delay administration of sirolimus until the wound is completely healed, especially when a steroid-sparing regimen is not used [22]. Traditionally, risk factors for UTIs have included female sex, diabetes, allograft trauma, prolonged pretransplant dialysis, surgical manipulation of the urinary tract, ureteral stent, and urologic complications [25,26]. In addition, bladder catheterization up to 7 days may promote postoperative UTI development [1] because this time lapse could be long enough to advance growth of the pathogen bacteria [27]. Few studies have investigated the incidence of UTIs in kidney transplant recipients with and without PAP. In the immediate postoperative transplant period, Renoult et al [8] reported a 73.7% incidence rate in a large cohort not receiving prophylaxis. Cohen et al [28] found a lower incidence rate during the first 5 days posttransplant in PAP recipients compared with those not receiving PAP (11% vs 42%; P ¼ .04); after 14 days, however, this difference was no longer evident (P ¼ NS). Robles et al [29] found a reduced early UTI incidence rate in transplant patients receiving ceftriaxone-based PAP compared with those not receiving PAP (25% vs 35%), whereas the cefotaxime-based PAP group and the no-PAP group exhibited an equivalent infection rate (35%). Under universal ceftriaxone prophylaxis, our incidence of UTIs was low (9.3%) despite longer bladder catheterization times compared with other centers [30e32]. According to previous reports [2,8,33], female subjects are significantly more affected than male subjects; this was true in our study as well (17.1% vs 4.6%; P < .0001), similar to the general population’s pattern of distribution. The present study had significant limitations, including its retrospective nature and the long study period (24 years), which is noteworthy because immunosuppression protocols have changed over time. Nevertheless, we found no impact of
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the different immunosuppressive agents on the development of SSIs and UTIs, except for induction therapy and sirolimus. In addition, the lack of a control group makes it harder to draw conclusions regarding the true value of universal ceftriaxone-based PAP. In conclusion, our analysis highlights the safety of ceftriaxone-based PAP due to the virtual absence of drugrelated adverse events, and it provides exceptional results in terms of control of SSIs and early UTIs in a large cohort. A universal PAP strategy coupled with high-quality surgical techniques and a thorough perioperative management plan proved to be effective in maintaining considerably low SSI and UTI incidence rates after kidney transplant. Ceftriaxone seems to be an excellent antimicrobial agent because of its targeted coverage against the most common bacteria involved in this setting, its persistent therapeutic tissue concentration (long-acting), and its safety profile. REFERENCES [1] Dantas SR, Kuboyama RH, Mazzali M, Moretti ML. Nosocomial infections in renal transplant patients: risk factors and treatment implications associated with urinary tract and surgical site infections. J Hosp Infect 2006;63:117e23. [2] Maraha B, Bonten H, van Hoof H, et al. Infectious complications and antibiotic use in renal transplant recipients during a 1-year follow-up. Clin Microbiol Infect 2001;7:619e25. [3] Alangaden GJ, Thyagarajan R, Gruber SA, et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transplant 2006;20:401e9. [4] Alangaden GJ. Urinary tract infections in renal transplant recipients. Curr Infect Dis Rep 2007;9:475e9. [5] Kyriakides GK, Simmons RL, Najarian JS. Wound infections in renal transplant wounds: pathogenetic and prognostic factors. Ann Surg 1975;182:770e5. [6] Lapchik MS, Castelo Filho A, Pestana JO, Silva Filho AP, Wey SB. Risk factors of nosocomial urinary tract and postoperative wound infections in renal transplant patients: a matched-pair casecontrol study. J Urol 1992;147:994e8. [7] Menezes FG, Wey SB, Peres CA, Medina-Pestana JO, Camargo LF. Risk factors for surgical site infection in kidney transplant recipients. Infect Control Hosp Epidemiol 2008;29: 771e3. [8] Renoult E, Aouragh F, Mayeux D, et al. Factors influencing early urinary tract infections in kidney transplant recipients. Transplant Proc 1994;26:2056e8. [9] Humar A, Matas AJ. Surgical complications after kidney transplantation. Semin Dial 2005;18:505e10. [10] Capocasale E, Mazzoni MP, Tondo S, D’Errico G. Antimicrobial prophylaxis with ceftriaxone in renal transplantation. Prospective study of 170 patients. Chemotherapy 1994;40:435e40. [11] Horan TC, Gaynes RP, Martone WJ, Jarvis WR, Emori TG. CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections. Infect Control Hosp Epidemiol 1992;13:606e8. [12] Simon DM, Levin S. Infectious complications of solid organ transplantations. Infect Dis Clin North Am 2001;15:521e49. [13] Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998;338:1741e51. [14] Humar A, Ramcharan T, Denny R, Gillingham KJ, Payne WD, Matas AJ. Are wound complications after a kidney
CAPOCASALE, DE VECCHI, MAZZONI ET AL transplant more common with modern immunosuppression? Transplantation 2001;72:1920e3. [15] Midtvedt K, Hartmann A, Midtvedt T, Brekke IB. Routine perioperative antibiotic prophylaxis in renal transplantation. Nephrol Dial Transplant 1998;13:1637e41. [16] Guglielmo BJ, Hohn DC, Koo PJ, Hunt TK, Sweet RL, Conte JE. Antibiotic prophylaxis in surgical procedures. A critical analysis of the literature. Arch Surg 1983;118:943e55. [17] Woodfield JC, Beshay N, van Rij AM. A meta-analysis of randomized, controlled trials assessing the prophylactic use of ceftriaxone. A study of wound, chest and urinary infections. World J Surg 2009;33:2538e50. [18] Menezes FG, Wey SB, Peres CA, Medina-Pestana JO, Camargo LF. What is the impact of surgical site infection on graft function in kidney transplant recipients? Transpl Infect Dis 2010;12: 392e6. [19] Ramos A, Asensio A, Muñez E, Torre-Cisneros J, Montejo M, Aguado JM, et al. Incisional surgical site infection in kidney transplantation. Urology 2008;72:119e23. [20] Rioja Sanz LA, Lièdana Torres JM, Roncalès Badal A, et al. Surgical complications in kidney transplantation. Analysis of our series (300 transplantations, 1986-1995). Arch Esp Urol 1996;49: 1053e62. [21] Valente JF, Hrickik D, Weigel K, et al. Comparison of sirolimus versus mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003;3:1128e34. [22] Laftavi MR, Rostami R, Feng L, Said M, Kohli R, Dayton M, et al. The role of antibiotic prophylaxis in the new era of immunosuppression. Transplant Proc 2011;43:533e5. [23] Laftavi MR, Rostami R, Patel S, et al. Universal perioperative antimicrobial prophylaxis is not necessary in kidney transplantation. Clin Transplant 2012;26:437e42. [24] Fortun J, Martin-Davila P, Pascual J, et al; RESITRA Transplant Network. Immunosuppressive therapy and infection after kidney transplantation. Transpl Infect Dis 2010;12: 397e405. [25] Takai K, Tollermar J, Wilczek HE, Groth CG. Urinary tract infections following renal transplantation. Clin Transplant 1998;12: 19e23. [26] Munoz P. Management of urinary tract infections and lymphocele in renal transplant recipients. Clin Infect Dis 2001;33(Suppl 1):S53e7. [27] de Oliveira LC, Lucon AM, Nahas WC, Ianhez LE, Arap S. Catheter-associated urinary infection in kidney post-transplant patients. Sao Paulo Med J 2001;119:165e8. [28] Cohen J, Rees AJ, Williams G. A prospective randomized controlled trial of perioperative antibiotic prophylaxis in renal transplantation. J Hosp Infect 1988;11:357e63. [29] Robles NR, Gallego E, Anaya F, Franco A, Valderrábano F. Antibiotic prophylaxis before kidney transplantation. Enferm Infecc Microbiol Clin 1990;8:74e7 [in Spanish]. [30] Glazer ES, Akhavanheidari M, Benedict K, James S, Molmenti E. Cadaveric renal transplant recipients can safely tolerate removal of bladder catheters within 48h of transplant. Int J Angiol 2009;18:69e70. [31] Glazer ES, Benedict K, Akhavanheidari M, James S, Molmenti E. Living donor renal transplant recipients tolerate early removal of bladder catheters. Int J Angiol 2009;18:67e8. [32] Rabkin DG, Stifelman MD, Birkhoff J, et al. Early catheter removal decreases incidence of urinary tract infections in renal transplant recipients. Transplant Proc 1998;30:4314e6. [33] Brayman KL, Stephanian E, Matas AJ, et al. Analysis of infectious complications occurring after solid-organ transplantation. Arch Surg 1992;127:38e48.
