Epidemiology of carbapenem-resistant Klebsiella pneumoniae bloodstream infections after renal transplantation from donation after cardiac death in a Chinese hospital: a case series analysis

Renal transplantation has long been deemed to be the best therapeutic option for the treatment of the end stage of kidney failure. However, the deficiency of donors has been the enormous obstacle for the development of renal transplantation in China [1]. The main channel of renal transplantation basically comes from two resources, corpses and living organs [2]. In recent years, under more favorable conditions from aspects of ethics, law and the resources of transplantation, the renal transplantation from donation after cardiac death (DCD) has been widely performed in China. Along with the increasing demanding of organ donors and the technological advancements in the field of organ transplantation, the renal transplantation from DCD has achieved great progression in China, however many unusual complications following transplantation have been reported to date. The rupture or thrombus of the renal transplant artery, and the infection of the surrounding tissues caused by bacteria, especially Gram-negative bacteria [3], or fungus have been regard as two of the hard-handled complications in the early stage (within 3 months) following renal transplantation. Donor-transmitted infection (DTI), including bacterial or fungal infections, has also been frequently reported from kidney recipients from DCD, characterized by Gram-negative predominant donor-derived infection, with higher crude mortality and graft loss than those without donor-derived infection [4].

As the frequently reported pathogen among the donor-transmitted infections associated with kidney transplantation from DCD, Carbapenem resistant Klebsiella pneumonia (CRKP) is a Gram-negative bacterial pathogen responsible for severe diseases, such as septicemia, pneumoniae, urinary tract infection and soft tissue infection, associated with community and hospital acquired infection [5], and characterized by high mortality, high transmissibility and multidrug resistance [6]. It has been reported that high mortality rates, ranging from 20 to 40%, were related to patients with Klebsiella pneumonia bloodstream infection (KP-BSI) [7], but this mortality was reported to rise up to 67.6% for intensive care unit (ICU) patients [8]. Through various mechanisms, such as production of carbapenem-hydrolyzing enzymes (carbapenemases) or changes in membrane permeability, carbapenem resistance can occur [9].

The patients who has undergone the renal transplantation are susceptible to CRKP, attributed to multifaceted factors, ranging from the surgery, the use of immunosuppressant therapy, mechanical ventilation, prolonged use of invasive devices, use of antimicrobial agents and the high sequential organ failure assessment (SOFA) score at admission [10‐17]. In the early stage of post-transplantation, especially the first 3 months after renal transplantation, the incidence and severity of illness is directly related to the utilization of immunosuppression and its modulation that primarily intend to lessen the risk of rejection after transplantation [15].

Klebsiella pneumoniae (KP), with the characteristics of hypervirulent, highly transmissible and high mortality, has attracted a lot of attention in recent years, together with the worldwide spread of multidrug resistant KP strains. As the most lethal type of infection, Klebsiella pneumoniae bloodstream infection (KP-BSI), with the alarming high mortality in ICU, has been placed in the focus of various researches worldwide, showing the complex relationships with various factors, ranging from solid organ or stem cell transplantation, the frequent use of invasive devices, surgery, hematological malignancy to the previous use of antibiotics. In China, the CHINET data showed that the rate of carbapenem resistance of K. pneumoniae isolates rose steadily from 10.8% in 2012 to 17.9% in 2016. The rate of CRKP has also increased dramatically worldwide over the past 10 years [27], and in the areas of high CRKP endemicity, such as United States, Israel, Italy, and Greece, the percentage of CRKP-BSI was shown to be 18–68% [19, 28‐33]. Compared with these results, we observed a rapid increase in CRKP-BSI rates in our hospital after 2013, and the obtained data showed that these rates were higher than the average rates in China after 2014, especially among ICU patients, rising up to 47.7% in 2015, but declined to 46.3% in 2016 owing to the preventative measurements for the infection. In this research, the incidence of CRKP-BSI in the early stage (within 3 months) after renal transplantation from DCD was about 1.1% (3/275) in our hospital, approximating to the result of nationwide surveillance study of the incidence of carbapenem-resistant gram negatives (CRGN) in Italian transplant recipients performed by Lanini S et al., which comes to the Incidence rates were 1.23, 0.51 and 0.16 per 1000 recipient-days at 0–30, 31–60, and 61–90 days after solid organ transplantation (SOT), respectively [31].

Just as Fig. 4 shown, considering the renal transplantation performed in the foreign hospital and the confirmed infection of CRKP following renal transplantation, there is a possibility that Case 1 plays the role as the exogenous source, associated with the following series of CRKP-BSIs in our hospital in the next year. The result of ERIC-PCR has substantiated the supposition that there is certain level of nosocomial clonal spread, disseminating the pathogen from the exogenous resources, and highlighting the necessity of implementation of thorough surveillance of recipients of renal transplantation before transferring from foreign hospital.

Clinical characteristics associated with CRKP-BSI patients after renal transplantation in our study has been attributed to the various aspects. All of the patients had received the renal transplant from donation after cardiac death (DCD). Undoubtedly, compared with the living donor, as the supplement mean for transplantation, the renal transplants from DCD has satisfied the increasing demanding of the resource of kidney nowadays and accelerated the advancement of technology and conception of renal transplants. However, there is controversy with respect to the infection risk of renal transplantation from DCD worldwide. Sousa SR et al. had come to conclusion that renal transplants from decreased donors and a prolonged cold ischemia time were important risk factors for infections following renal transplantation [32]. Fernández-Ruiz M et al. performed a prospective cohort study of 291 KT patients, drawing the conclusion that uncontrolled DCD policies were safe in terms of the risk of post-transplant infection in spite of higher rate of delayed graft function (DGF) and the use of ATG-containing sequential therapy [33]. In our study, we had observed that in the early stage after renal transplantation (3 months), the CRKP induced rupture/thrombus of the artery of the transplanted kidney occurred. During the course of treatment, the predominant features of all the cases included the placement of catheters, the use of antibiotics, renal transplantation, prolonged stay of ICU department, and the high dose immunosuppressive therapy, predisposing to the vulnerability of CRKP-BSI. Additionally, the most common site of CRKP isolation, in our study, was organ-space surgical site, followed by urinary tract and pneumoniae. In a study of LTx recipients, in the first month after transplantation, 71% of the KPC-Kp-HAIs had abdominal infections [34]. In other studies of KTx recipients, the most common foci of infection have been found to be the surgical wound and the urinary tract [35]. These studies suggest that various site/type of infection, for instance abdominal effusion, surgical wound, urinary tract and so on, can be the susceptible sites of CRKP-BSIs as the manifestation of the systemic infection on specific site, serving as part of the systemic infection. The peri-renal infection can lead to the rupture or thrombus of the renal transplant artery, with the consequence of the excision of transplanted kidney, and be reckoned as the severe complication after kidney transplantation. In our research, all of the five cases have close relationship with CRKP, with one case (Case 2) associated with the mixed infection of CRKP and aspergillus that confirmed by the pathologic report (Fig. 5), therefore administrating different antibiotic regimen with the wide coverage for aspergillus. Xu MJ et al. reported 5 KTRs occurring the infectious rupture of renal transplant artery, with 1 KTR infected with CRKP, while other KTRs infected with fungus [36]. Wan Q et al. reported 3 of 154 KTRs developed confirmed donor-derived CRKP infections, with 1 CRKP-BSI and 1 CRKP died due to the rupture of renal transplant artery, coming to the conclusion that Klebsiella pneumoniae was the most probable causative microorganism leading to the episode of renal artery rupture [4].

When it comes to the treatment for CRKP-BSI after renal transplantation, a multidisciplinary therapy, combined with the surgical therapy and the combinational antibiotic therapy, especially regimens including a carbapenem, has been proven beneficial for the patient, demonstrated in several retrospective studies of general population [37, 38]. From the cases, we learn that it is critical to obtain the positive result of culture in the early stage of treatment, guiding the following definitive antibiotic therapy. Usually, a combined treatment (Tigecycline + Carbapenem, Tigecycline + Fosfomycin, Fosfomycin + Aminoglycoside, Third generation cephalosporin +β-lactamases inhibitors etc.) can be prescribed for the treatment of CRKP-BSI. If permitting, high dose Tigecycline (100 mg, q12h after 200 mg loading dose) scheme is worth recommending to bring a satisfactory outcome for the patient [39], and in Case 1 and 5, the respective scheme had been applied. Based on the differential result of antibiotic susceptibility and the evidence of growth of aspergillus on the transplanted kidney, the renal transplant artery and external iliac artery, plus with the infection of Candida, the antibiotic regimen, consisted of Meropenem, Tigecycline, Amikacin, Voriconazole and Amphotericin B, was prescribed for Case 2. Important of all, utilization of properly mini-invasive surgical approaches, for example the indwelling catheter drainage for the abdominal fluids, can alleviate the severity of the disease to a large extent and extend the survival, combined with the appropriate combined antibiotic therapy. Last but not least, the cooperation between multiple medical departments is also vital for the treatment, not only demonstrating the necessary coordination between departments for the therapy, but also enhancing the efficacy of treatment and avoiding the incompleteness and shortage of medical knowledge and techniques for one department.

In United states and Europe, there are myriad of clinical reports regarding the application of Ceftazidime, Avibactam and Polymyxin B, obtaining surprising and satisfactory therapeutic effect. Nevertheless, Polymyxin B came into Chinese market in December 2017, while Avibactam had not appeared on the Chinese market yet. In the absence of international newly developed drugs, the antibiogram for treating CRKP fundamentally was based on the combined treatment, consisted of Carbapenem/Aminoglycoside/Fosfomycin and Tigecycline, until now in China. In the near future, in light of pharmacokinetic/pharmacodynamic (PK/PD) profile of the CRKP-BSIs after KTx, it is worth adopting the multi-drugs combinational antibiotic strategy to elevate the cure rate for the KTRs infected with CRKP-BSI, taking advantage of the beneficial therapeutic approach including the high-dose prolonged-infusion (3–4 h) regimen to drive the PK/PD to acceptable exposures [40].

Our study has several limitations. Clinical data were obtained retrospectively from medical records, and therefore, there may exist some differences in physician practices or accuracy of information. Additionally, the data for patients who may have had significant BSI symptoms such as septic shock and hyperpyrexia, but were not tested owing to the patient refusal or because their blood culture was negative, were not included. Finally, this was a single-center study, showing all the 5 recorded CRKP-BSIs with detailed clinical analysis. A large-scale of study on the clinical characteristics of CRKP-BSIs after renal transplantation from donation after cardiac death is underway to provide more evidence on the clinical significance of the hard-handled multi-resistant superbug. Most important of all, the investigation of transmission of bacterial or fungal infection to kidney transplant recipients from DCD has also been on the way to clarify the etiology of CRKP-BSI after renal transplantation and help designate an effective strategy to eliminate the possibility of bacterial infection before transplantation for the surgeons and physicians in the ICU and transplant department.

As the recipients of renal transplantation from donation after cardiac death, many factors can interact modifying the risk for infection, such as the immunosuppression profile used, the post-operative care, and the profile of epidemiological exposure to the susceptibility to CRKP [32]. It is critical to perform thorough surveillance of the source of kidney before transplantation, the protection of integrity of skin and mucosal barriers in the critically ill patients or the patients undergoing invasive procedures, and all necessary contact precautions should be employed by hospital staff caring these high-risk patients [41]. In conclusion, the thorough surveillance of sources of kidney before transplantation, early clinical identification of the infection of carbapenem resistant klebsiella pneumonia, the necessary preventative measurements and the use of the appropriate treatment are the reasonable strategy to treat the CRKP-BSI in the early stage after renal transplantation from DCD.

An increase in the occurrence of CRKP-BSIs among KTRs from DCD in our hospital was observed in our hospital during January 1, 2012 to December 31, 2016. Rupture/thrombus of the renal transplant artery was demonstrated to be associated with CRKP-BSI in the early stage after KTx from DCD. Despite the low incidence of CRKP-BSI (1.1%) after KTx from DCD, the high mortality (4/5) had been observed.