Chronic kidney disease is a significant national public health problem in patients reaching end-stage renal failure. One of the most effective treatments is kidney transplantation (KT) (1). Despite noticeable progress in surgical procedures and immunosuppression after KT, urinary tract infection (UTI) remains an important problem in KT recipients (2–5). UTI is the most frequent infectious complication after KT, occurring in up to 86% of cases (6). Therefore, prevention of UTI must be considered for successful transplantation (7, 8).

The etiological pathogens in UTIs vary depending on environments, hosts' immune status, anatomical structure, virulence factors, or drug susceptibilities. In KT recipients, an emerging multi-drug resistant pathogen, especially Enterobacterales (EB), has been emerging and challenging in clinical practice (9). Uropathogenic Escherichia coli (UPEC) is a common bacterial pathogen causing UTIs in KT recipients. Several virulence factors have offered an opportunity to infect vulnerable hosts, mainly, Chaperone-Usher fibers (10, 11). Furthermore, fimbriae have been reported to affect biofilm growth, especially during the early course after KT since KT recipients are indwelled with a urinary catheter and ureteral stent placement (12, 13).

Extended-spectrum cephalosporin-resistant (ESC-R) EB such as E. coli and Klebsiella pneumoniae were pathogenic for UTI, causing high incidences of infection in KT patients in our setting and internationally (8, 14). Even when antibiotics are used peri-operatively, this pathogen can still survive because it has many mechanisms for antibiotic resistance. However, selecting an appropriate antibiotic is believed to decrease the chance of UTI from this particular bacterium (15). Cefuroxime has been utilized as routine perioperative prophylaxis for KT recipients at our center, although some clinicians sometimes switch to carbapenems due to a concern of an emerging ESC-R EB early UTI after the transplant lately at our institution. In the meantime, using broader spectrum antibiotics could place patients at risk of acquitting multi-drug resistant pathogens is concerning. Therefore, in the present study, we aimed to determine the impact of carbapenems given perioperatively on the incidence of ESC-R EB early UTI among KT recipients whether carbapenems proposed as an appropriate antibiotic that provide an adequate coverage could decrease the rate of ESC-R EB UTI in these vulnerable population.

We have reported a propensity score-matched cohort study involving adult KT recipients with similar baseline characteristics in a setting where an ESC-R UTI has been emerging among KT recipients. The results revealed that patients who received carbapenem perioperative prophylaxis had significantly decreased incidence of ESC-R EB UTI within 14 days after KT compared with patients who routinely received cefuroxime perioperative prophylaxis. The incidence of ESC-R EB infection increased the antibiotic duration and likely led to bloodstream infection after transplantation.

UTI is a common complication after KT that was reported to occur in 34–42% of cases (18, 19), similar to the incidence of 30% in the present cohort. A recent retrospective study revealed a significantly high incidence of UTI after KT. Specifically, approximately half of the patients developed UTI within the first month postoperatively, with a median onset of 5 days. Although female sex was identified as an independent factor for UTI (within 1 month after KT) among KT recipients in a single transplant center (20), which is comparable to the results of an analysis in a whole cohort, therefore, we decided to match gender as one of the factors to omit the confounding effect and truly investigate the effect of antibiotic agents. Additionally, KT recipients are subjected to innate immunity impairment, mainly toll-like receptors (TLR). TLR2, TLR4, and TLR5 are essential molecules in innate immunity to defend against pathogens in the genitourinary tract, and calcineurin inhibitors, especially tacrolimus, have been reported to decrease TLR5 expression in bladder macrophages while developing UTI (21, 22). Furthermore, most pathogens were Gram-negative bacilli which lately have been broader resistant to available antibiotics (20). Therefore, comprehensive prevention and treatment measures against known risk factors should be undertaken as early as possible to reduce UTI incidence. Due to a lacking of new effective antibiotics for multi-drug resistant Gram-negative pathogens, the properties of TLRs, as mentioned above, could provide an opportunity for ligand-drug alternatives (23).

A large meta-analysis of KT recipients found an overall rate of 10% for development of extended-spectrum beta-lactamase (ESBL)-producing EB UTI; however, this number could be as high as 33% among Asian KT recipients (24). A retrospective study from a single transplant center in China revealed rate of E. coli UTI in KT recipients of 12.5%, of that 73% were identified as having ESBL-producing pathogen and 64% carried adhesions-coding gene (25). In comparison, the incidence of ESC-R EB UTI in our cohort was relatively higher at 16%.

A previous retrospective propensity score-matched study revealed no significant impact of carbapenems compared with any other regimens within the first 72 h in preventing ESBL-producing EB bloodstream infection (26). Our recent study showed that carbapenems did not prevent ESC-R EB bloodstream infection (27). However, ESC-R EB was found to be the leading causative pathogen (50%) for bacteremia within the first year after KT, and 85% of the pathogens were considered to be derived from genitourinary sources (27).

ESC-R EB UTI was presented to be a cause of prolonged antibiotic duration both before and after matched analysis; these data emphasized a significant burden of antimicrobial stewardship, which could conserve patients' microbiome and avoid dysbiosis. However, the hospital stay was longer in the whole cohort, which was not substantially different in the propensity score-matched cohort. Therefore, the length of hospitalization is subjected to multiple factors, including infections and other transplant-related issues. ESC-R EB UTI was found to be associated with high mortality rates in several previous studies (28–30), while our results indicated that it did not increase mortality. Additionally, we also did not observe an increasing rate of carbapenem-resistant Enterobacterales, especially Metallo-ß-Lactamases, in our setting, which could threaten an emerging difficult-to-treat bacterial genitourinary tract infection in these vulnerable populations (31). Although no deaths were recorded during ESC-R EB-related UTI in our cohort, one patient developed allograft loss, and the rate of bacteremia was significantly higher in patients with ESC-R EB UTI, which could place patients at risk of unfavorable outcomes and morbidities.

The main strengths of the present study were the data from a large KT center with a high prevalence of ESC-R EB UTI and the presence of a preemptive urine analysis and culture monitoring protocol. This would have allowed us to retrieve the whole spectrum of UTI, including asymptomatic and symptomatic cases. However, our study had some limitations. The first was its retrospective design, which means that some of the collected patient data in the medical records may have been missing. The second was that the data did not enable us to postulate an effective method against ESBL-producing EB because phenotypic tests were not conducted to confirm ESBL enzyme production. The third was that although a relatively large number of participants were enrolled, the number of participants after matching was limited, which could have prevented us from exploring other risk factors. However, we corrected the unbalanced background characteristics between the two groups to accurately evaluate the effectiveness of carbapenems in preventing ESC-R EB UTI. Finally, the follow-up time was relatively short. Therefore, a prospective study design with a larger number of matched patients together with a more extended follow-up period would yield more statistically significant differences.

Furthermore, the American Society of Transplantation Infectious Diseases Community of Practice recommended using single first-generation cephalosporins such as cefazolin for perioperative prophylaxis in KT recipients (32). Instead, our data propose the potential use of antibiotic prophylaxis based on local epidemiology, predominant with ESC-R EB early UTI, which could lead to post-surgical complications.

In conclusion, ESC-R EB UTI is a potentially serious condition that can arise after KT. Consequently, prevention of this infection should be considered. In a well-balanced retrospective analysis, the present study showed that administration of carbapenem peri-transplant prophylaxis can significantly protect against ESC-R EB UTI early after KT. Appropriate antibiotics coverage during the peri-transplant period could potentially omit infection among KT recipients. Further prospective studies should focus on this particular infection prevention strategy. Furthermore, non-pharmacological interventions such as early urinary prosthesis removal should be encouraged to avoid complicated UTIs from the uropathogenic pathogen.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by Faculty of Medicine Ramathibodi Hospital, Mahidol University (MURA 2019/806). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

JB conceptualized and designed the study. SA, NA, PC, and JB collected the data. SA and JB analyzed data and draft manuscript. All authors reviewed and approved a final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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