Open Forum Infectious Diseases MAJOR ARTICLE The Impact of Culturing the Organ Preservation Fluid on Solid Organ Transplantation: A Prospective Multicenter Cohort Study I. Oriol,1,2,3 N. Sabe,1,2,3 J. Càmara,4,5 D. Berbel,4,5 M. A. Ballesteros,6 R. Escudero,7 F. Lopez-Medrano,8,9 L. Linares,3,10 O. Len,11,12 J. T. Silva,8,9,13 E. Oliver,14 L. Soldevila,1 S. Pérez-Recio,1 L. L. Guillem,1 D. Camprubí,1 L. LLadó,15 A. Manonelles,16 J. González-Costello,17 M. A. Domínguez,2,4,18 M. C. Fariñas,19 N. Lavid,20 C. González-Rico,19 L. Garcia-Cuello,19 F. Arnaiz de las Revillas,19 J. Fortun,7 J. M. Aguado,8,9 C. Jimenez-Romero,8,9 M. Bodro,3,10 M. Almela,3,10 D. Paredes,3,10 A. Moreno,3,10 C. Pérez-Cameo,12,21 A. Muñoz-Sanz,13 G. Blanco-Fernández,22 J. A. Cabo-González,23 J. L. García-López,24 E. Nuño,24 and J. Carratalà1,2,3 Downloaded from https://academic.oup.com/ofid/article/6/6/ofz180/5480175 by guest on 17 February 2022 1 Infectious Disease Department, Hospital Universitari de Bellvitge – IDIBELL; L’Hospitalet de Llobregat, Barcelona, Spain; 2Spanish Network for Research in Infectious Diseases (REIPI); 3Clinical Science Department, Faculty of Medicine, University of Barcelona, Barcelona; 4Microbiology Department, Hospital Universitari de Bellvitge-Universitat de Barcelona-IDIBELL, L’Hospitalet de Llobregat, Spain; 5CIBER de Enfermedades Respiratorias (CIBERes), Madrid, Spain; 6Intensive Care Unit, Marqués de Valdecilla Hospital, University of Cantabria, IDIVAL, Santander, Spain; 7 Infectious Diseases Department, Hospital Universitario Ramón y Cajal, Madrid, Spain. IRYCIS; 8Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain; 9School of Medicine, Universidad Complutense, Madrid, Spain; 10Infectious Diseases Department, Hospital Clínic-IDIBAPS, Barcelona, Spain; 11Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 12Universitat Autònoma de Barcelona, Barcelona, Spain; 13Department of Infectious Diseases, Hospital Universitario de Badajoz, Spain; 14Donor Coordination Unit, Bellvitge University Hospital, Barcelona, Spain; 15Liver Transplant Unit, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat (Barcelona), Spain; 16Department of Nephrology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat (Barcelona), Spain; 17Department of Cardiology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat (Barcelona), Spain; 18Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona; 19 Infectious Diseases Unit, Marqués de Valdecilla Hospital, University of Cantabria, IDIVAL, Santander, Spain; 20Donor Coordination Unit, Marqués de Valdecilla Hospital, University of Cantabria, IDIVAL, Santander, Spain; 21Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 22Liver Transplant Unit, Hospital Universitario de Badajoz, Spain; 23Kidney Transplant Unit, Hospital Universitario de Badajoz, Spain; 24Donor Coordination Unit, Hospital universitario de Badajoz, Spain Background. We analyzed the prevalence, etiology, and risk factors of culture-positive preservation fluid and their impact on the management of solid organ transplant recipients. Methods. From July 2015 to March 2017, 622 episodes of adult solid organ transplants at 7 university hospitals in Spain were prospectively included in the study. Results. The prevalence of culture-positive preservation fluid was 62.5% (389/622). Nevertheless, in only 25.2% (98/389) of the cases were the isolates considered “high risk” for pathogenicity. After applying a multivariate regression analysis, advanced donor age was the main associated factor for having culture-positive preservation fluid for high-risk microorganisms. Preemptive antibiotic therapy was given to 19.8% (77/389) of the cases. The incidence rate of preservation fluid–related infection was 1.3% (5 recipients); none of these patients had received preemptive therapy. Solid organ transplant (SOT) recipients with high-risk culture-positive preservation fluid re- ceiving preemptive antibiotic therapy presented both a lower cumulative incidence of infection and a lower rate of acute rejection and graft loss compared with those who did not have high-risk culture-positive preservation fluid. After adjusting for age, sex, type of trans- plant, and prior graft rejection, preemptive antibiotic therapy remained a significant protective factor for 90-day infection. Conclusions. The routine culture of preservation fluid may be considered a tool that provides information about the contami- nation of the transplanted organ. Preemptive therapy for SOT recipients with high-risk culture-positive preservation fluid may be useful to avoid preservation fluid–related infections and improve the outcomes of infection, graft loss, and graft rejection in trans- plant patients. Keywords. preemptive antibiotic therapy; preservation fluid; preservation fluid–related infection; solid organ transplantation. In spite of many advances, early postoperative infections re- prevention, diagnosis, and management of infections have be- main a significant cause of morbidity and mortality among come one of the main challenges of transplantation. solid organ transplant (SOT) recipients [1]. Therefore, the Early post-transplant infections are usually derived from the donor or recipient or from technical complications of surgery [2]. The organ donated may be contaminated either by an in- Received 19 February 2019; editorial decision 4 April 2019; accepted 17 April 2019. Correspondence: I. Oriol Bermúdez, Infectious Diseases Department, Hospital Universitari fection from the donor or as a consequence of the manipulation de Bellvitge, Feixa llarga s/n. 08907, L’Hospitalet de Llobregat, Barcelona, Spain of the organ in the time between extraction and implantation (isaoriolbermudez@gmail.com). [3–6]. Moreover, due to its biochemical characteristics, the Open Forum Infectious Diseases® © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society organ preservation fluid (PF) can keep microorganisms alive of America. This is an Open Access article distributed under the terms of the Creative Commons and also facilitate their growth [7]. This is why some transplant Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. centers now take intra-operative cultures of the PF to detect DOI: 10.1093/ofid/ofz180 infection promptly and avoid its transmission to the recipient. Impact of Culturing the Organ PF on SOT • ofid • 1 However, there are no widely accepted guidelines for the evalu- identified. Similarly, SOT patients received perioperative anti- ation of PF or for the use of prophylactic antibiotics [8]. Reliable bacterial prophylaxis, as well as prophylaxis for opportunistic evidence in support of this practice is scarce and is mainly based infections, in accordance with the protocol of each center. on retrospective studies and case reports. The study was approved by the ethics committees of all The role of culture-positive PF in the management of trans- participating institutions and conformed to the STROBE plant recipients has not been fully elucidated. In fact, it is not checklist. clear whether the organ PF should be cultured during the trans- plant procedure or whether preemptive antibiotic treatment Definitions (PE-T) is required in SOT recipients with culture-positive PF. Culture-positive PF was defined as growth of any microor- In a recent meta-analysis, our group found a high incidence of ganism in the PF culture. PF cultures in which the following culture-positive PF, and although few SOT recipients with PF microorganisms grew were considered to be “high risk”: cultures are positive for pathogenic microorganisms, they may gram-negative bacilli, Staphylococcus aureus, β-hemolytic develop a PF-related infection with high mortality [9]. However, streptococci, Streptococcus pneumoniae, enterococci, any spore- Downloaded from https://academic.oup.com/ofid/article/6/6/ofz180/5480175 by guest on 17 February 2022 this meta-analysis was based on the few studies available, which forming anaerobic gram-positive bacteria, Bacteroides species, were mainly retrospective; indeed, prospective studies of this and Candida spp. All the other culture-positive PF were clas- subject are lacking. sified as “low risk,” including coagulase-negative staphylococci This prospective multicenter study with a large patient popu- (CNS), Corynebacterium spp., and Streptococcus viridans group lation aims to analyze the incidence, etiology, and risk factors of [5]. PE-T was considered as an immediate post-transplant culture-positive PF and their clinical impact in order to indicate targeted antibiotic or antifungal treatment against the isolates of areas for improvement in the management of SOT recipients. culture-positive PF without any clinical signs of active infection in the recipient. PF-related infection was defined as documented METHODS infection in the recipient by the same microorganism isolated in Setting and Study Population the PF culture. Infections were defined according to the Centers We conducted a prospective multicenter cohort study at 7 ter- for Disease Control and Prevention/National Healthcare Safety tiary university referral hospitals in Spain with active transplan- Network guidelines [10]. Multidrug resistance (MDR) was de- tation programs (kidney, liver, heart, lung, or pancreas). From fined as acquired nonsusceptibility to at least 1 agent in 3 or July 2015 to March 2017, episodes of SOT in adults were in- more antimicrobial categories [11]. AGR was considered to be cluded if the patients or legal surrogates provided written in- present when proven by biopsy, and 90-day mortality was de- formed consent. Episodes in which the PF was not cultured, in fined as death by any cause within the first 90 days after the which the recipient died/lost the organ donated within the first onset of SOT. 24 hours, or in which informed consent was not provided were not included. Microbiological Studies The primary study end point was to assess the incidence Grafts were routinely preserved, mainly in 1 of the following rate of PF-related infections. Secondary end points included PFs: Celsior, Wisconsin, Perfadex, and Custodiol. PF culture the prevalence of culture-positive PF, the incidence risk ratio was obtained under sterile conditions just before implantation. of PF-related infection between SOT recipients who received PF samples were processed by the BACTEC FX method PE-T and those who did not, and the cumulative incidence of (Becton-Dickinson Microbiology Systems, Sparks, MD). The bacterial infections at 90 days and other outcomes at 90 days: inoculated bottles were incubated for 5 days at 35ºC before graft loss, acute graft rejection (AGR), and mortality. being discharged. Microbial identification was performed using Data regarding the transplant surgery, as well as the baseline commercially available panels (MicroScan, Beckman Coulter; characteristics of SOT donors and SOT recipients, were care- Brea, CA; or Vitek, Biomérieux, Marcy-L’Étoile, France; or by fully recorded in an electronic database. All patient data were matrix-assisted laser desorption ionization [MALDI-TOF], entered anonymously. To reduce measurement errors, a process Bruker Daltonik, Bremen, Germany). Antibiotic suscepti- of data quality evaluation was used. bility was tested using the microdilution method following Clinical follow-up was performed daily during the post- EUCAST guidelines [12]. Molecular typing was performed transplant hospital admission period and then periodically through pulse field gel electrophoresis after restriction with at outpatient appointments, with a post-transplant follow-up XbaI (enterobacteriaceae) or SmaI (staphylococci) following period of 3 months. There was no formal or institutional con- the criteria described by Tenover [13]. The screening of MDR sensus regarding PE-T; the choice was left to the discretion of phenotypes including methicillin-resistant S. aureus, ampicillin- each attending physician. In cases where PE-T was administered, resistant enterococci, extended-spectrum β-lactamase produc- it was started as soon as the PF culture was found to be positive tion (ESBL), and carbapenemase production was performed in and was adapted to the resistance profile of the microorganism accordance with EUCAST recommendations. 2 • ofid • Oriol et al Statistical Analysis Table 1. Baseline Demographic and Clinical Characteristics of SOT We estimated the prevalence of culture-positive PF, the in- Donors and SOT Recipients, Including Surgery-Related Data cidence rate of PF-related infections, the incidence risk ratio, Characteristics n = 622 and the risk difference of PF-related infections between SOT Donor features recipients who received PE-T and those who did not, with con- Age, y 61 (49–72) fidence intervals. Male sex 348 (56.0) To compare episodes of SOT by the result of the culture- Living donors 39 (6.3) positive PF, we used the chi-square test with continuity cor- Brain death donors 449 (72.2) rection for categorical variables and the Student t test and Donors after circulatory death 134 (21.5) Mann-Whitney U test for continuous variables. Multivariate Length of ICU stay, d 2 (1–5) Need for vasoactive drugs 412 (66.2) conditional regression analysis of factors potentially associated Prior colonization by resistant microorganisms or fungi 6 (1) with high-risk culture-positive PF was performed, including Donor infection 112 (18.0) all statistically significant variables in the univariate analysis, Respiratory tract infection 85 (13.7) Downloaded from https://academic.oup.com/ofid/article/6/6/ofz180/5480175 by guest on 17 February 2022 sex and age, and all clinically important variables regardless of Urinary tract infection 7 (1.1) whether they were statistically significant. Odds ratio (ORs) and Central nervous system 7 (1.1) Other 13 (2.1) 95% confidence interval (CIs) were calculated. Donor positive cultures 87 (14.0) Cumulative incidence of bacterial infection among SOT Surgery-related features recipients, depending on the result of their PF culture and Red blood cell transfusion 205 (33.0) the decision to give PE-T, was estimated in a competing risk Fresh-frozen plasma transfusion 94 (15.1) model in which death and graft loss were modeled as competing Platelet transfusion 93 (15.0) events. Patients included were censored at the time of (a) death, Cold ischemia time, min 470 (280–1055)   KT 940 (320–1260) (b) graft loss, or (c) end of study follow-up. We tested for   LT 376 (285–480) differences between groups using Fine-Gray regression models   HT 195 (151–225) [14]. Other secondary outcome variables were compared using   PT 350 (295–405) the Fisher exact test. Length of surgery, min 200 (150–335) All the statistical management was performed using STATA   KT 155 (135–185) statistical software, release 13.0 (STATA Corp., College Station,   LT 375 (313–430)   HT 312 (244–413) TX). All statistical tests were 2-tailed, and the threshold of sta-   PT 300 (250–360) tistical significance was P < .05. Length of antibiotic prophylaxis, h 24 (24–48) Type of PF Celsior 356 (57.2) RESULTS Wisconsin 116 (18.7) Perfadex 43 (6.9) During the study period, 622 episodes of SOT were prospec- Custodiol 22 (3.5) tively included (kidney 362, liver 166, lung 51, heart 32, and Other 85 (13.7) multi-organ 11). Baseline demographic and clinical characteris- Recipient features tics of SOT donors and SOT recipients, including the operation- Male sex 416 (66.9) related data, are summarized in Table 1. Age 59 (51–66) The prevalence of culture-positive PF was 62.5% (389/622). Prior colonization by resistant microorganisms or fungi 30 (4.8) Most of the isolates were considered “low-risk” microorganisms All data are presented as No. (%) or median (interquartile range). Abbreviations: HT, heart transplant; ICU, intensive care unit; KT, kidney transplant; LT, liver (291/622), and only 15.8% (98/622) were considered “high-risk” transplant; MT, multi-organ transplant; PF, preservation fluid; PT, lung transplant; SOT, solid pathogens. Only in 3 cases were the isolates considered MDR. organ transplant. The microorganisms isolated are detailed in full in Table 2. Table 3 summarizes the risk factors for high-risk culture- positive PF. After applying a backward stepwise logistic regres- the culture-positive PF cases (51 due to high-risk and 26 due sion model, advanced donor age (OR, 1.88; 95% CI, 1.16–3.05) to low-risk microorganisms). The percentage of high-risk cases was found to be an independent risk factor for culture-positive that received PE-T varied according to the transplanted organ: PF by high-risk microorganisms. 13% (2/15) in lung transplant, 54% (18/33) in liver transplant, The median length of antibiotic prophylaxis (interquartile 60% (28/47) in kidney transplant, and 100% (1/1) in heart range [IQR]) was 24 (24–48) hours. The isolated microorganisms transplant. The median length of PE-T (IQR) was 6 (4–12) days. were sensitive to the antibiotic prophylaxis administered The median duration of PE-T (IQR) was different according to during transplantation in 74% of high-risk SOT recipients. the microorganisms isolated in the PF culture: 5 (4–7) days for PE-T covering the PF isolate was given to 19.8% (77/389) of CNS isolation, 5 (3–8) days for S. aureus isolation, 4 (3–18) days Impact of Culturing the Organ PF on SOT • ofid • 3 Table 2. Microorganisms Isolated in the PF Culture of SOT in risk of PF-related infection due to high-risk pathogens be- tween patients who received PE-T and those who did not was Culture-Positive PF (N = 389) No. (%) 8.5% (95% CI, 0.5%–16.5%; P = .033). High riska 98 (15.8) Figure 1 shows the cumulative incidences of infection in SOT Monomicrobial 71 (11.4) recipients depending on the result of the PF culture and the de- Gram-positive bacteria Staphylococcus aureus 19 (4.9) Enterococcus faecalis 7 (1.8) cision to carry out PE-T. Enterococcus faecium 2 (0.5) SOT recipients with culture-positive PF experienced a Streptococcus pneumoniae 1 (0.2) higher cumulative incidence of infection than the other group Streptococcus agalactiae 1 (0.2) (Supplementary Table 1). Analyzing only SOT recipients with Gram-negative bacilli Escherichia coli 10 (2.6) culture-positive PF, the 90-day cumulative incidence of in- Enterobacter cloacae 5 (1.3) fection was lower in the PE-T group. Likewise, among SOT Klebsiella spp. 4 (1.0) Pseudomonas spp. 3 (0.8) recipients with culture-positive PF high-risk microorganisms, Serratia spp. 2 (0.5) the 90-day cumulative incidence of infection was lower in the Downloaded from https://academic.oup.com/ofid/article/6/6/ofz180/5480175 by guest on 17 February 2022 Haemophilus influenzae 2 (0.5) PE-T group. No differences between groups were detected in Otherb 10 (2.6) the low-risk group. Anaerobes Bacteroides spp. 1 (0.2) After adjusting for sex, age of SOT recipient, type of trans- Fungi Candida spp.c 4 (1.0) plant, and prior episode of AGR, the Fine-Gray analyses re- Polymicrobial (high-risk +/- low-risk isolates) 27 (6.9) Low riskd 291 (46.8) vealed that SOT recipients with culture-positive PF by high-risk Monomicrobial 243 (39.1) microorganisms receiving PE-T had a lower cumulative inci- Gram-positive bacteria CNS 225 (57.8) dence of infection (subhazard ratio, 0.46; 95% CI, 0.24–0.88) Othere 15 (3.9) (Supplementary Table 2) Anaerobes Otherf 3 (0.5) There were no significant differences either in the rate of Polymicrobial (only low-risk microorganisms) 48 (12.3) ESBL-producing strains (25.9% vs 16.2%, P = .227) or in MDR Abbreviations: CNS, coagulase-negative staphylococci; CP, culture positive; PF, preserva- tion fluid. isolates (7.4% vs 6.9%, P = .929) between the infections in SOT a High risk: gram-negative bacilli, Staphylococcus aureus, β-hemolytic Streptococcus spe- recipients who received PE-T and those who did not. cies, Streptococcus pneumoniae, Enterococci, Bacteroides, any spore-forming anaerobic gram-positive bacteria, and Candida spp. The Supplementary Data (Supplementary Table 3) show b Other gram-negative bacilli: Citrobacter freundii (1), Burkholderia cepacia (1), the comparison of other outcomes between SOT recipients Stenotrophomonas maltophilia (1), Cupriavidus gilardii (1), Hafnia alvei (1), Raultella planticola (1), Rothia mucilaginosa (1), other nonspecified gram-negative bacilli (3). depending on the result of the PF culture and the decision to c Candida spp.: C. glabrata (2), C. albicans (1), C. tropicalis (1). carry out PE-T. SOT recipients with culture-positive PF had d e All microorganisms except those classified as high risk. a higher rate of AGR and mortality than those with culture- Other gram-positive bacteria: viridans group streptococci (3), Bacillus cereus (2), Corynebacterium spp. (3), Lactobacillus (1), Micrococcus (3), Aerococcus viridans (1), other negative PF. Among SOT recipients with culture-positive (2). f PF, those who received PE-T had a lower risk of AGR. SOT Anaerobes: Prevotella (1), Bacteroides (1), Propionibacterium (1), Peptoniphilus harei (1). recipients with culture-positive PF high-risk microorganisms who received PE-T experienced a lower frequency of AGR and for Enterococci, 8 (5–13) days for Enterobacteriaceae, 14 (6–17) graft loss than those who did not. No differences in outcomes days for Pseudomonas spp., and 13 (13–46) days in those SOT between groups were detected in the low-risk group. No recipients with growth of Candida spp. in their PF. adjusted analysis was applied due to the small number of events. PF-related infection occurred in 5 recipients, representing a DISCUSSION cumulative incidence of 1.3% of SOT recipients with culture- positive PF. The median time from transplantation to the onset This prospective multicenter cohort study is the largest carried of PF-related infection was 6 days. The clinical characteris- out so far to analyze the incidence rate and outcomes of culture- tics of PF-related infections are summarized in Table 4. In the positive PF. We found a high incidence of culture-positive PF, case of Enterobacter cloacae, PF-related infection clonality was although high-risk microorganisms were isolated in only 15.8% demonstrated between the strains of the PF culture and the bio- of the cases. Although prior data were mainly derived from logical sample by the molecular epidemiology study. retrospective cohorts and showed a wide variability between The incidence risk ratio of PF-related infection between studies, our results are similar to those of previous prospective treated and untreated SOT recipients could not be calculated studies and support their findings [4, 15]. because no PF-related infections were detected in the PE-T Advanced donor age was the main associated factor for PF that group. No statistically significant differences were detected was culture-positive for high-risk microorganisms. Previous when analyzing the difference in risk of PF-related infection studies have hinted at an association between older donors and between treated and untreated culture-positive PF, nor when PF contamination but have been unable to demonstrate statis- analyzing the low-risk group separately. However, the difference tical significance in their multivariate analyses. Unlike Cerutti 4 • ofid • Oriol et al Table 3. Univariate and Multivariate Analyses of Factors Associated With High-risk Culture-Positive PF High-risk PFa Low-riskb or Culture-Negative PF Adjusted OR Variables (n = 98, 15.6%) (n = 524, 84.2%) P Value (95% CI) P Value Sex of donors (male) 53 (54.1) 295 (56.1) .656 Type of donation .141 Living donors 10 (10.2) 29 (5.5) Brain death donors 73 (74.5) 374 (71.4) Donation after circulatory death 15 (15.3) 119 (22.7) Type of transplant KT 47 (48.0) 315 (60.1) .025 0.51(0.11–2.51) .411 LT 33 (33.7) 133 (25.4) .089 0.86 (0.17–4.27) .852 HT 1 (1.0) 31 (5.9) .044 0.15 (0.01–1.86) .140 PT 15 (15.3) 36 (6.9) .005 1.77 (0.34–9.31) .501 MT 2 (2.0) 9 (1.7) .824 Downloaded from https://academic.oup.com/ofid/article/6/6/ofz180/5480175 by guest on 17 February 2022 Donor infection 12 (12.2) 100 (19.2) .103 Mean ischemia time 578 (485–672) 678 (603–753) .259 Advanced donor agec 81 (82.7) 383 (73.1) .046 1.88 (1.16–3.05) .010 ICU days of donor 3.1 (2.3–3.9) 3.6 (3.2–3.9) .317 All data are presented as No. (%) or median (interquartile range). Abbreviations: CI, confidence interval; HT, heart transplant; ICU, intensive care unit; KT, kidney transplant; LT, liver transplant; MT, multi-organ transplant; OR, odds ratio; PF, preservation fluid; PT, lung transplant. a High risk: gram-negative bacilli, Staphylococcus aureus, β-hemolytic Streptococcus species, Streptococcus pneumoniae, Enterococci, Bacteroides, any spore-forming anaerobic gram-pos- itive bacteria, and Candida spp. b All microorganisms except those classified as high risk. c Donor older than 60 years. et al., we did not find an association between prolonged ICU PE-T in those SOT recipients with growth of microorganisms stay and fluid contamination [7]. Interestingly, Sotiropoulos in their PF culture [24–26]. et al. analyzed data from 976 SOT donors and concluded that We did not detect any PF-related mortality. This conflicting only donor leukocyte count was independently associated with result may be explained, at least in part, by the fact that we did contamination of the PF in SOT [16]. Regrettably, we did not not detect any PF-related infection by Candida spp., whose include this variable in our analysis. mortality rate (and the rate of graft loss described in case series In our study, PF-related infections were detected in only and cohort studies) is between 50% and 100% of cases [7, 26– 1.3% of all SOT recipients with culture-positive PF, although 28]. The prospective nature of the study may have contributed the rate increased to 8.5% in the case of SOT recipients with to the greater diagnostic sensitivity and to the earlier initiation high-risk culture-positive PF without PE-T. These rates are of treatment. consistent with previous reports [17–20]. The high incidence A striking finding of this study was the fact that SOT of culture-positive PF and the low rate of PF-related infec- recipients with culture-positive PF had worse outcomes than tion are the reasons why some authors do not recommend those with culture-negative PF. The difference in mortality was routine PF culture; they argue that the benefit of treatment at the limit of statistical significance. Our results confirm pre- is low and that the risk of selecting resistant microorganisms vious findings by Yansouni et al., who in a retrospective series may be increased [15, 21]. Nevertheless, the mortality rate of detected a greater number of infections in SOT recipients with PF-related infections reported in other studies [7, 22, 23] has culture-positive PF and a higher mortality rate in liver trans- encouraged some authors to recommend a short course of plant recipients with culture-positive PF [5]. In contrast, Janny Table 4. Clinical Characteristics of PF-Related Infections Sex of Days From Days of 90-Day Type of SOT Age of Transplant to Microorganism ICU Graft Mor- Cases Transplant Recipient Recipient, y Infection Isolated Type of Infection Post-transplant AGR Loss Re-intervention tality 1 LT Male 47 5 E. faecium Intra-abdominal infection 6 No No Yes No 2 HT Male 19 7 S. epidermidis Surgical site infection 14 No No Yes No 3 PT Female 58 28 S. aureus Respiratory tract infection 11 Yes No No No 4 PT Male 28 6 E. cloacae Respiratory tract infection 10 Yes No No No 5 PT Male 64 2 S. marcescens Respiratory tract infection 90 No No No No Abbreviations: AGR, acute graft rejection; ICU, intensive care unit; HT, heart transplant; LT, liver transplant; PT, lung transplant; SOT, solid organ transplant. Impact of Culturing the Organ PF on SOT • ofid • 5 0.6 Cumulative incidence of infection, % 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 60 70 80 90 Downloaded from https://academic.oup.com/ofid/article/6/6/ofz180/5480175 by guest on 17 February 2022 Days after transplantation CN High-risk no PE-T High-risk PE-T Low-risk no PE-T Low-risk PE-T Figure 1. Cumulative incidence of infection on solid organ transplant recipients depending on the result of the preservation fluid culture and the decision to carry out PE-T. Abbreviations: CN, culture-negative preservation fluid; PE-T, preemptive antibiotic therapy. et al. did not detect significant differences between culture- of culture-positive PF and infection. Moreover, length of PE-T positive and culture-negative PF bacteremia, although this was not preestablished. Furthermore, we were unable to per- may have been due to the small sample size in their study [27]. form molecular epidemiology studies in most of the cases that Likewise, Chaim et al. detected a higher frequency of AGR were considered PF-related infections. among SOT recipients with culture-positive PF than in those In conclusion, the routine culture of the organ preservation with culture-negative PF [22]. An increase in the frequency of fluid may be considered as a tool that provides information AGR is probably seen when immunosuppressive treatment is about the contamination of the transplanted organ, whether reduced in order to ​​avoid post-transplant infection. However, at transmitted by the donor or secondary to the transplant pro- present little is known about the relation of rejection and infec- cedure. Preemptive antibiotic therapy for SOT recipients with tion, and studies addressing this issue are lacking. high-risk culture-positive PF may be useful to avoid preser- The reasons why SOT recipients of an organ with culture- vation fluid–related infections and to improve the outcomes positive PF have worse outcomes have not been established. of infection, graft loss, and acute graft rejection in transplant However, the result of the PF culture might be considered as patients. Further studies are required to establish the optimal an overall indicator of the quality of the SOT (including the length of PE-T days and long-term outcomes. donated organ and the transplant procedure). Supplementary Data Our results show that PE-T only improves the outcomes of Supplementary materials are available at Open Forum Infectious Diseases infection, graft loss, and AGR in the case of high-risk culture- online. Consisting of data provided by the authors to benefit the reader, positive PF. Furthermore, the administration of PE-T in these the posted materials are not copyedited and are the sole responsibility of SOT recipients did not increase the percentage of ESBL isola- the authors, so questions or comments should be addressed to the corre- sponding author. tion and MDR strains in subsequent infections. It should be noted that the median duration of PE-T was less than a week, Acknowledgments and the median of transplant antibiotic prophylaxis did not The authors would like to acknowledge Xavier Barroso for his kind assis- reach 2 days. tance with the creation of the database. Financial support. This work was supported by research grants Among the strengths of this study are its prospective design, from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos the inclusion of the largest number of SOT episodes described III and Ministerio de Ciencia e Innovación, Instituto de Salud Carlos so far, and the fact that the study replicates usual clinical prac- III, co-financed by the European Development Regional Fund “A way to tice. Nevertheless, our research has some limitations that achieve Europe” ERDF, the Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015), and the Institut d’Investigació Biomèdica should be noted. We analyzed a heterogeneous group of SOT de Bellvitge (IDIBELL). It was also partially supported by Ciber de recipients, who may have had their own specific incidence rates Enfermedades Respiratorias (CB06/06/0037 Ministry of Health, Instituto 6 • ofid • Oriol et al de Salud Carlos III, Madrid, Spain). I.O. is the recipient of a research grant for interim standard definitions for acquired resistance. Clin Microbiol Infect from the University of Barcelona. 2012; 18:268–81. Disclaimer. The funders had no role in the study design, data collec- 12. European Committee on Antimicrobial Susceptibility Testing Breakpoint tables for interpretation of MICs and zone diameters. http://www.eucast.org/fileadmin/ tion and analysis, decision to publish, or preparation of the manuscript. src/media/PDFs/EUCAST_files/Breakpoint_tables/v_8.0_Breakpoint_Tables. Potential conflicts of interest. The authors of this manuscript have no pdf. conflicts of interest related to the material presented. All authors: no re- 13. Tenover FC, Arbeit RD, Goering RV, et al. Interpreting chromosomal DNA re- ported conflicts of interest. All authors have submitted the ICMJE Form for striction patterns produced by pulsed-field gel electrophoresis: criteria for bacte- Disclosure of Potential Conflicts of Interest. Conflicts that the editors con- rial strain typing. J Clin Microbiol 1995; 33:2233–9. sider relevant to the content of the manuscript have been disclosed. 14. Austin PC, Fine JP. Accounting for competing risks in randomized controlled Author contributions. I.O., N.S., and J.C. designed the study; trials: a review and recommendations for improvement. Stat Med 2017; I.O. analyzed data; I.O., N.S., and J.C. wrote the manuscript; I.O. and 36:1203–9. N.S. coordinated the study; I.O., N.S., M.A.B., R.E., F.L.M., L.L., O.L., J.T.S., 15. Ruiz P, Gastaca M, Gonzalez J, et al. Incidence and clinical relevance of bacterial contamination in preservation solution for liver transplantation. Transplant Proc E.O., L.S., S.P., L.L.G., D.C., L.L.L., J.G.C., M.C.F., N.L., C.G.R., L.G.C., 2009; 41:2169–71. F.A.R., J.F., J.M.A., C.J.R., M.A., D.P., A.M., C.P.C., A.M.S., G.B.F., J.A.C.G., 16. Sotiropoulos GC, Steinmann J, Stern S, et al. Donor leucocytosis predicts bacterial J.L.G., and E.N. collected data; J.C.M., D.B., and M.A.D. contributed to an- and fungal contamination of the preservation solution in visceral organ trans- alytic tools; I.O., N.S., M.A.B., R.E., F.L.M., L.L., O.L., J.T.S., E.O., L.S., S.P., plantation. Prog Transplant 2018; 28:24–8. L.L.G., D.C., L.L.L., J.G.C., M.C.F., N.L., C.G.R., L.G.C., F.A.R., J.F., J.M.A., 17. Ranghino A, Diena D, Simonato F, et al. Clinical impact of bacterial contamina- Downloaded from https://academic.oup.com/ofid/article/6/6/ofz180/5480175 by guest on 17 February 2022 C.J.R., M.A., D.P., A.M., C.P.C., A.M.S., G.B.F., J.A.C.G., J.L.G., E.N., J.C.M., tion of perfusion fluid in kidney transplantation. Springerplus 2016; 5:7. D.B., M.A.D., and J.C. critically reviewed the final version of the manuscript. 18. Garcia-Zamora C, Segura J, Lopez-Lopez V, et al. Clinical significance of con- tamination of the preservation solution in liver transplantation. Transplant Proc 2015; 47:2322–3. References 19. Cotter MP, Smyth E, O’Gorman J, et al. Low predictive value of positive trans- 1. Dorschner P, McElroy LM, Ison MG. Nosocomial infections within the first plant perfusion fluid cultures for diagnosing postoperative infections in kidney month of solid organ transplantation. Transpl Infect Dis 2014; 16:171–87. and kidney-pancreas transplantation. J Clin Pathol 2012; 65:1132–5. 2. Fishman JA. From the classic concepts to modern practice. Clin Microbiol Infect 20. Sauget M, Verdy S, Slekovec C, et al. Bacterial contamination of organ graft pres- 2014; 20(Suppl 7):4–9. ervation solution and infection after transplantation. Transpl Infect Dis 2011; 3. Wakelin SJ, Casey J, Robertson A, et al. The incidence and importance of bacterial 13:331–4. contaminants of cadaveric renal perfusion fluid. Transpl Int 2005; 17:680–6. 21. Bertrand D, Pallet N, Sartorius A, et al. Clinical and microbial impact of screening 4. Grąt M, Ligocka J, Lewandowski Z, et al. Incidence, pattern and clinical relevance kidney allograft preservative solution for bacterial contamination with high- of microbial contamination of preservation fluid in liver transplantation. Ann sensitivity methods. Transpl Int 2013; 26:795–9. Transplant 2012; 17:20–8. 22. Chaim FH, Boin IF, Ataide EC, Stucchi RS. Perfusion fluid contamination in rela- 5. Yansouni CP, Dendukuri N, Liu G, et al. Positive cultures of organ preservation tion to recipient survival and acute cellular rejection in orthotopic liver transplan- fluid predict postoperative infections in solid organ transplantation recipients. tation: retrospective analysis. Transplant Proc 2011; 43:1313–5. Infect Control Hosp Epidemiol 2012; 33:672–80. 23. Bert F, Larroque B, Paugam-Burtz C, et al. Microbial epidemiology and out- 6. Oriol I, Lladó L, Vila M, et al. The etiology, incidence, and impact of preservation come of bloodstream infections in liver transplant recipients: an analysis of 259 fluid contamination during liver transplantation. PLoS One 2016; 11:e0160701. episodes. Liver Transpl 2010; 16:393–401. 7. Cerutti E, Stratta C, Romagnoli R, et al. Bacterial- and fungal-positive cultures in 24. Sharma AK, Smith G, Smith D, et al. Clinical outcome of cadaveric renal allografts organ donors: clinical impact in liver transplantation. Liver Transpl 2006; 12:1253–9. contaminated before transplantation. Transpl Int 2005; 18:824–7. 8. Audet M, Piardi T, Panaro F, et al. Incidence and clinical significance of bacterial 25. Janny S, Bert F, Dondero F, et al. Microbiological findings of culture-positive pres- and fungal contamination of the preservation solution in liver transplantation. ervation fluid in liver transplantation. Transpl Infect Dis 2011; 13:9–14. Transpl Infect Dis 2011; 13:84–8. 26. Rodrigues BF, Natário AS, Vizinho RS, et al. Candida species contamination of 9. Oriol I, Sabé N, Tebé C, et al. Clinical impact of culture-positive preservation fluid preservation fluid-outcome of renal transplantation in 6 patients. Transplant Proc on solid organ transplantation: a systematic review and meta-analysis. Transplant 2013; 45:2215–9. Rev (Orlando) 2018; 32:85–91. 27. Janny S, Bert F, Dondero F, et al. Microbiological findings of culture- 10. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health positive preservation fluid in liver transplantation. Transpl Infect Dis 2011; care-associated infection and criteria for specific types of infections in the acute 13:9–14. care setting. Am J Infect Control 2008; 36:309–32. 28. Levesque E, Paugam-Burtz C, Saliba F, et al. Fungal complications after Candida 11. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively preservation fluid contamination in liver transplant recipients. Transpl Int 2015; drug-resistant and pandrug-resistant bacteria: an international expert proposal 28:1308–16. Impact of Culturing the Organ PF on SOT • ofid • 7