Kidney transplant patients are susceptible to infections due to their weakened immune response from prolonged immunosuppressive therapy (1). While preservation fluid (PF) plays a pivotal role in organ protection, it may concurrently act as a conducive medium for microbial growth. Early post-transplant infections and pathogens in PF have been linked in previous research (2–8). Furthermore, many studies recommend the use of antimicrobial or antifungal drugs as preemptive antibiotic therapy specifically targeting pathogens detected in PF (2, 9–13).

Donor-derived infections (DDIs) are a serious complication that can lead to significant graft loss, morbidity, and mortality (14). However, the risk of donor-transmitted infections varies among different pathogens. For instance, coagulase-negative staphylococci (CoNS) are relatively non-toxic gram-positive bacteria, presenting a lower transmission risk (4). Concurrently, prior studies have indicated that Enterococcus faecium, Enterococcus faecalis, and Staphylococcus aureus are associated with DDIs (4, 15). Gram-positive bacteria are frequently found in PF after renal transplantation, yet there are no well-established guidelines or consensus on their management. There is an urgent need for evidence regarding the risk stratification of gram-positive bacteria in PF.

Infections caused by multidrug-resistant organisms (MDROs) have emerged as a recent threat to solid organ transplantation (SOT) (16). Previous studies have indicated that multidrug-resistant-gram-positive bacteria (MDR-GP) accounted for three-quarters of MDROs on culture in solid organ transplantation donors (17). However, there is limited research on the impact of MDR-GP. Moreover, donors harboring MDR-GP are not typically considered unsuitable for transplantation. Therefore, it is imperative to investigate their role in post-transplant infections.

Preemptive antibiotic therapy in the perioperative period of kidney transplant varies widely (9, 18), particularly concerning gram-positive bacteria in PF. Commonly used agents include trimethoprim-sulfamethoxazole (TMP-SMX), first-and second-generation cephalosporins. However, due to intrinsic and acquired resistance mechanisms, these regimens do not reliably cover certain gram-positive bacteria (19, 20). Conventional antimicrobial drug regimens as a part of preemptive antibiotic therapy after kidney transplants have effective control of gram-negative bacteria (21). For some highly virulent gram-positive bacteria, incorporating anti-gram-positive antibiotic into preemptive antibiotic therapy is essential for effective infection management. However, scant research has investigated the impact of preemptive-anti-gram-positive antibiotic (P-antiGP) therapy against gram-positive bacteria in PF.

This study aimed to stratify the risk of gram-positive bacteria in PF. Furthermore, we investigated antibiotic resistance and its role in early post-kidney transplant infections. Lastly, we evaluated the efficacy of P-antiGP therapy.

We retrospectively analyzed 1,395 kidney transplant recipients in the First Affiliated Hospital of Sun Yat-sen University, China. Recipients without gram-positive bacteria in PF and those who underwent living donor kidney transplants were excluded. In addition, the clinical characteristics of donors and recipients, microbes in PF, infection events within 30 days post-transplantation, and preemptive antibiotic therapy were collected. Our study was approved by the research ethics committee of the First Affiliated Hospital of Sun Yat-sen University (approval number 2022439). All patient data were analyzed anonymously. Therefore, additional informed consent was waived. This study was conducted in accordance with the principles of the World Medical Association Declaration of Helsinki and the declaration of Istanbul.

Infection continues to be a major concern for kidney transplant recipients (1). Although DDIs are infrequent, their implications can be severe (29). Current routine antibiotics inadequately addresses gram-positive bacteria in PF after kidney transplantation. Thus, it is imperative to assess the pathogenicities of different gram-positive bacteria in PF and to explore the influence of antibiotics on them. High-risk recipients with E. faecium, S. aureus, and E. faecalis in the PF, exhibited a significantly higher incidence of P-DDIs and other infections than the low-risk group in our investigation. Furthermore, our research noted a decrease in P-DDIs and infections when employing P-antiGP therapy for high-risk recipients. In contrast, no notable benefit was observed in the low-risk cohort. These findings may provide evidence for the use of P-antiGP therapy for certain patients presenting with gram-positive bacteria in PF.

In our study, 31.2% of the recipients with gram-positive bacteria in the PF were classified as high-risk. The factors that influence the presence of high-risk pathogens in PF have not been extensively explored in existing literature. We observed that the high-risk group experienced longer cold (11.6 h vs. 10.0 h) and warm (4.7 min vs. 2.0 min) ischemia times. A prior study on pancreas transplantation reported that recipients with positive PF culture exhibited longer cold ischemia time and warm ischemia time (3). Notably, prolonged cold and warm ischemia times may increase the prevalence of high-risk pathogens in PF. The increased duration potentially enhances the transmission risk of these pathogens from the donor. Consequently, we advocate for a reduction in ischemia time. Furthermore, our research showed that CoNS represented 90% of the pathogens in the low-risk group. In contrast, other study has found Enterococcus species to be the primary pathogen, with CoNS in second place (4). This shift might be attributed to the inclusion of amikacin in the PF. However, most studies consistently identified CoNS as the predominant pathogen (3, 6, 8, 10). Additionally, donor cause of death may influence the risk of donor-derived infections, which can potentially be anticipated through PF analysis. In our cohort, no significant difference in donor cause of death was observed across PF risk groups. Prior reports indicate that drowning donors can harbor waterborne or opportunistic organisms, such as Aeromonas hydrophila and Legionella pneumophila (30, 31) In our study, Enterococcus faecium was detected in two of four drowning donors and CoNS in the other two cases. Although different from the specific pathogens previously described, this phenomenon remains noteworthy.

Our study observed a significantly increased incidence of infection events in the high-risk group, predominantly associated with E. faecium, E. faecalis, and S. aureus in PF. In addition, multivariate analysis identified high-risk classification as a risk factor for post-transplant infections. Notably, these pathogens accounted for all P-DDIs in our cohort. The abundant virulence factors of S. aureus, combined with its ability to acquire resistance both within and between species, render it a particularly formidable and adaptive human pathogen (32). In our cohort, one recipient developed a severe P-DDI caused by S. aureus and subsequently underwent graft nephrectomy. E. faecium is commonly implicated in healthcare-associated infections, particularly in those who are immunocompromised (33). Notably, both E. faecium and S. aureus are categorized as ESKAPE pathogens, known for their contribution to hospital-acquired infections (34). Yu et al. (4) identified a heightened risk of P-DDIs in recipients exhibiting ESKAPE-positive PF. Previous research indicates that E. faecalis is linked to significant donor-derived infection incidents (15). Similarly, E. faecalis-associated P-DDI transmission events were observed in our cohort. Furthermore, E. faecalis is also a major opportunistic pathogen for critically ill or immuno-compromised patients (35). For the low-risk group, CoNS have gained increasing attention in recent years due to their frequent detection in sterile body fluids and infection sites (36). Previous studies have considered CoNS to be a skin-colonizing and contaminating bacterium (37). Consistent with our findings, a recent prospective study reported that most PF isolates were low-virulence organisms such as coagulase-negative Staphylococcus, and no PF-positive case led to a concordant infection (38). Given that CoNS has fewer virulence factors, recipients with it in PF are deemed low-risk group. Consequently, we advocate for the classification of CoNS into the low-risk pathogen category. Furthermore, it is imperative to monitor recipients harboring E. faecium, E. faecalis, and S. aureus in PF more diligently, given their correlation with elevated post-transplant infection risks.

It is imperative to maintain constant vigilance against MDR-GP in PF and to emphasize special scrutiny for XDR-GP. Recipients with MDR-GP in PF exhibited an elevated risk of post-transplant infections. Notably, all P-DDIs in our cohort were caused by MDR-GP, with XDR-GP significantly associated with DDIs. However, most donors with MDROs are not considered a contraindication to donation (39). The relationship between MDROs in PF and post-transplant recipient infections warrants increased scrutiny in this context. A study from the United States indicated that MDR-GP accounted for three-quarters of MDROs on culture in solid organ transplantation donors (17). Notably, despite the high prevalence of MDR-GP, literature on gram-positive bacteria in PF remains scarce. In our study, over half of the recipients identified MDR-GP in the PF samples. We observed an increased incidence of infection events post-kidney transplantation associated with MDR-GP in PF. Interestingly, the proportion of recipients detecting XDR-GP in the PF samples surpassed 10%. Meanwhile, we found that recipients with XDR-GP in PF have a higher P-DDIs incidence. It is crucial to closely monitor XDR-GP in PF to avert DDIs events. A pathogenetic analysis following liver transplantation revealed that MRSCoNS was the predominant bacterium at the post-operative surgical site (40). However, there is a lack of exploration of the risk of MRSCoNS in PF. In our investigation, there was no significant difference in the rate of infectious events between groups with MRSCoNS and those without, and none of them suffered from P-DDIs. This suggests that the likelihood of MRSCoNS transmission from the donor appears minimal, and its association with post-transplant infectious events is limited.

P-antiGP therapy may be essential for the high-risk group, but its benefits for those in the low-risk group appear constrained. Our research detected a diminished frequency of infection events in high-risk group when treated with P-antiGP therapy. Remarkably, the adoption of P-antiGP therapy also substantially decreased the incidence of P-DDIs in high-risk group. Consistent with our findings, most studies have demonstrated that preemptive antimicrobial therapy for recipients with pathogen-positive preservation fluid significantly reduces the risk of donor-derived infection transmission (2, 10, 41). Importantly, E. faecium, S. aureus, and E. faecalis have increasingly been recognized for their high virulence and potential to cause donor-derived infections, and most studies suggest that targeted preemptive therapy against these pathogens can effectively reduce postoperative infection rates (2, 10, 13, 41). However, a national investigation from France disclosed that only a third of kidney transplant recipients with methicillin-susceptible Staphylococcus in PF received antimicrobial prescribing (9). Given the current circumstances, we consider P-antiGP therapy may be appropriate for recipients with high-risk pathogens. Linezolid exhibits a strong efficacy as a P-antiGP. Consistent with our results, prior research also demonstrated its efficacy against enterococci and staphylococci in transplant recipients (42). Moreover, Linezolid typically requires minimal dosage adjustment in kidney transplant patients (43). Nonetheless, caution is warranted due to its myelosuppressive effects, which may potentially lead to thrombocytopenia (44). The use of vancomycin is discouraged due to its nephrotoxic effects. In addition, teicoplanin has high protein binding affinity, potential nephrotoxicity, and slow onset of action (45, 46). In our study, Kaplan–Meier analysis showed that P-antiGP therapy, including Linezolid, was not associated with adverse effects on long-term death-censored graft survival, supporting its potential safety in high-risk recipients. Conversely, the administration of P-antiGP therapy showed no impact on the infection event rates among the low-risk group. Similarly, Picola Brau et al. found that CoNS in PF rarely received preemptive antimicrobial therapy and were not associated with any donor-to-recipient transmission events, supporting the view that such low-virulence organisms may not warrant routine intervention (12). However, previous report indicated that 8.3% recipients received preemptive antibiotic therapy for methicillin-susceptible Staphylococcus in PF (9), we consider that this strategy might be less than optimal. In addition, previous studies suggested that combination use of antimicrobial drugs may increase the risk of intestinal dysbiosis (47). Consequently, for kidney transplant recipients with pathogens such as E. faecium, E. faecalis, or S. aureus present in their PF, we advocate the consideration of P-antiGP therapy. Yet, those with low-risk gram-positive bacteria might find such a regimen less advantageous.

There are limitations to our study. Firstly, it was a retrospective study. In addition, DDIs were not eligible for detection, so we used the concept of P-DDIs instead. Finally, the absence of donor pathogenicity data in our study precluded any related analysis.

In conclusion, we considered that E. faecium, E. faecalis, and S. aureus should be considered as high-risk gram-positive bacteria in PF. Recipients with any of these pathogens should also be considered as a high-risk group. The occurrence rate of antibiotic resistance in gram-positive bacteria within PF is notably high, leading to an increased incidence for infection events after kidney transplant. Meanwhile, despite the high occurrence of MRSCoNS in PF, their influence on infection rates seems to be negligible. Moreover, we advocate for the use of linezolid as P-antiGP therapy in high-risk group. Concurrently, P-antiGP therapy might not be advisable for recipients harboring alternate pathogens in PF.