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Clostridioides difficile infection in intestinal transplantation: The quest for better outcomes continues

C. Gomez,D. Florescu

Published 2023 in Transplant Infectious Disease

ABSTRACT

Compared with the general population, solid-organ transplant (SOT) recipients experience a greater incidence and severity of Clostridioides difficile infection (CDI), often leading to significant morbidity and mortality.1 Risk factors for recurrent CDI such as advanced age, immunocompromised state, and severe infection at initial presentation are well described in SOT recipients. Intestinal transplant recipients (ITRs) are particularly vulnerable to CDI and recurrent CDI, partially due to their heavy net state of immunosuppression and multiple preand posttransplant events that are detrimental to their gut microbiota.2,3 Indeed, in intestinal transplantation, the fertile grounds for CDI begin before the transplant procedure. Disorders leading to irreversible intestinal failure, such as Crohn’s disease and ulcerative colitis, and clinical interventions, such as enteral feeding, bowel ostomy surgery, and proton pump inhibitors, have all been associated with gut microbiota disruption.4,5 Moreover, patients with intestinal failure often endure lengthy hospitalizations and require several courses of broad-spectrum antimicrobial therapy for line-related sepsis and other complications of parenteral nutrition, thereby leading to dysbiosis before transplantation. During the first year posttransplant, ITRs often receive broad-spectrum antibiotics to treat or prevent infections from gastrointestinal (GI) translocation. Episodes of GI translocation with subsequent bacteremia result from loss of the integrity of the intestinal epithelium barrier, due to ischemia-reperfusion injury, rejection, intestinal bacterial overgrowth, and opportunistic infections (e.g., cytomegalovirus, adenovirus, and norovirus). Health-economic studies have described the financial problem of CDI in the US healthcare system,6 but reports focusing exclusively on the intestinal transplant population are lacking. In this issue of Transplant Infectious Diseases, Amjad et al. present a study on the burden of CDI in the intestinal transplant population and its impact on clinical outcomes and resource utilization.7 Levering the nation’s largest inpatient dataset of encounter-level hospital care and all-payer data (The National Readmission Database, 2010–2017), which provides ∼20% of the stratified sample of all hospitals in the United States, the authors analyzed 8442 index hospitalizations in ITRs, of which, 320 (3.8%) corresponded to CDIs. Only adult patients (>18-year age) were included in this study. Compared with ITRs without CDI, CDIpatients demonstrated a higher median hospitalization cost ($54430 vs. $48888, p= .04), and length of hospital stay (7 vs. 5 days, p= .026). Clinical outcomes such as overall mortality rate, malnutrition, renal failure, and other intestinal transplant complications were similar in both groups, although ITRs patients without CDI had greater rates of ICU admissions and lower GI bleeding rates. Of note, 30-day allcause readmission rate rose significantly from 2010 (7.7%) to 2017 (30%). Indeed, among ITRswithCDIduring indexedadmission,CDIwas the leading cause of 30-day readmission but overall, the 30-day readmission rate was comparable between CDI and non-CDI ITRs (36.7% vs. 38%, p = .95). Major predictors for 30-day readmission included a history of short bowel syndrome, malnutrition, acute renal failure, cirrhosis, heart failure, andmalignancy.Anonstatistically significant trend toward increasedmortality amongCDI versus non-CDI ITRswas noted (3% vs. 2.2%, p = .37). Lastly, the study reported a CDI incidence of 38 per 1000 ITRs during the index hospitalization. Two main take-home points can be extracted from Amjad’s study. First, during the last decade, the burden of CDI on intestinal transplantation has remained rampant, becoming an unrelenting factor that affects healthcare utilization and transplant-related outcomes, especially posttransplant hospital readmissions. Indeed, hospital readmissions following transplantation not just represent a burden in healthcare costs but have been associated with reduced patient and graft survival.8 Clinicians and administrators can attest to the “vicious cycle” of hospital readmission and its negative effect on patient frailty, healthcare infections, and future disposition plans. Second, the study findings are a wake-up call for implementing innovative strategies to address the unacceptably high rates of CDI recurrence in ITRs and SOT recipients in general. At baseline, rates for CDI recurrence are disproportionately high following an initial CDI episode (15%–25%) and evenmore significant in the context of two or more prior CDI episodes (∼60%).1,9 Extrapolating from the present study’s findings, a transplant clinician can reasonably expect that one in three ITRs will experience hospital readmission following a CDI-related index hospitalization, with CDI being themain culprit for hospital readmission. In the quest for better posttransplant outcomes, the paradigm for CDI management in SOT should focus on achieving rapid clinical improvement while providing sustained gut microbiota restoration— the key for recurrence prevention anyhow—in a cost-effective manner.10 Two pharmacological interventions endorsed by the IDSA/SHEA 2021 Clinical Practice Guidelines Update for the Management of CDI in Adults11 have gained traction to prevent CDI recurrence in high-risk groups. For instance, in a randomized controlled trial, fidaxomicin therapy in an extended-pulsed regimen (25 instead of a 10-day course) achieved high clinical-cure rate and the lowest recurrence rate ever reported (2% at day 40).12 Moreover, sustained clinical cure of fidaxomicin extended-pulsed regimen has been consistent across high-risk subgroups for recurrent CDI (e.g., advanced age, cancer diagnosis, and infection with PCR-ribotype

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