Kathleen M. Mullane

Background: Few options are available for cytomegalovirus (CMV) treatment in transplant recipients resistant, refractory, or intolerant to approved agents. Letermovir (LET) is approved for prophylaxis in hematopoietic cell transplant (HCT) recipients, but little is known about efficacy in CMV infection. We conducted an observational study to determine the patterns of use and outcome of LET treatment of CMV infection in transplant recipients.Methods: Patients who received LET for treatment of CMV infection were identified at 13 transplant centers. Demographic and outcome data were collected.Results: Twenty‐seven solid organ and 21 HCT recipients (one dual) from 13 medical centers were included. Forty‐five of 47 (94%) were treated with other agents prior to LET, and 57% had a history of prior CMV disease. Seventy‐seven percent were intolerant to other antivirals; 32% were started on LET because of resistance concerns. Among 37 patients with viral load < 1000 international units (IU)/ml at LET initiation, two experienced >1 log rise in viral load by week 12, and no deaths were attributed to CMV. Ten patients had viral load > 1000 IU/ml at LET initiation, and six of 10 (60%) had a CMV viral load < 1000 IU/ml at completion of therapy or last known value. LET was discontinued in two patients for an adverse event.Conclusions: Patients treated with LET with viral load < 1000 IU/ml had good virologic outcomes. Outcomes were mixed when LET was initiated at higher viral loads. Further studies on combination therapy or alternative LET dosing are needed.

CMV reactivation is associated with significant morbidity and mortality in allo-HCT recipients and could be a resource intensive condition to manage. Limited data are available on the economic ramification of CMV reactivation in allo-HCT. Therefore, we aimed to examine healthcare cost and length of hospital stay (LOS) among allo-HCT recipients treated for CMV infection. We performed a retrospective cohort study that included 56 consecutive allo-HCT recipients who were diagnosed with CMV infection within 100 days post-transplant and admitted to two medical centers, University of Texas MD Anderson Cancer Center and University of Chicago, Department of Infectious Disease between January 2016 and December 2017. CMV-related hospitalization was determined as an inpatient admission with or for CMV reactivation within 100 days post-transplant. Data were limited to only the first CMV-related hospitalization. Descriptive statistics were reported on patient characteristics, first CMV-related hospitalization and costs. Most patients were 40 years or older (64%), female (55%), Caucasian (66%), CMV seropositive recipients (87%), received a matched unrelated donor HCT (49%) and had a myeloablative or reduced intensity conditioning regimen (65%) (Figure 1). The median duration of CMV episode was 40 days. Seventy-one percent of the patients were treated with foscarnet for CMV infection. Acute kidney injury was the most frequent CMV treatment-related complication (67%) followed by myelosuppression (55%) and end-stage renal disease (36%). Of 56 encounters, 16% required admission to intensive care unit with a median duration of 9 days. The median length of stay for hospitalization was 23 days and healthcare cost for CMV-related hospitalization was $71,840. The median hospitalization cost and LOS varied by reason for hospitalizations, type of anti-CMV therapy and treatment-related complications (Figure 2). Figure 1. Baseline characteristics, CMV episodes, outcomes, and cost. Figure 2. CMV Outcomes among allo-HCT recipients Our study showed even a single episode of CMV-related hospitalization led to significant resource use and hospitalization costs. This study highlights the need for interventions to prevent of CMV-related hospitalization, thereby reducing associated cost and resource use. Kathleen Mullane, DO, Pharm D, FIDSA, FAST, MERCK (Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau) Ella Ariza Heredia, MD, Merck Sharp & Dohme (Grant/Research Support)Oxford Immunotec (Grant/Research Support) Yuexin Tang, PhD, Merck and Co., Inc. (Employee) Amit D. Raval, PhD, Merck and Co., Inc (Employee) Roy F. Chemaly, MD, MPH, FACP, FIDSA, Chimerix (Consultant, Research Grant or Support)Clinigen (Consultant)Merck (Consultant, Research Grant or Support)Novartis (Research Grant or Support)Oxford Immunotec (Consultant, Research Grant or Support)Shire/Takeda (Research Grant or Support)Viracor (Research Grant or Support)

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice address the prevention and management of Clostridium difficile infection in solid organ transplant (SOT) recipients. Clostridioides (formerly Clostridium) difficile infection (CDI) is among the most common hospital acquired infections. In SOT recipients, the incidence of CDI varies by type and number or organs transplanted. While a meta‐analysis of published literature found the prevalence of postoperative CDI in the general surgical population to be approximately 0.51%, the prevalence of CDI that is seen in the solid organ transplant population ranges from a low of 3.2% in the pancreatic transplant population to 12.7% in those receiving multiple organ transplants. There are no randomized, controlled trials evaluating the management of CDI in the SOT population. Herein is a review and summary of the currently available literature that has been synthesized into updated treatment guidelines for the management of CDI in the SOT population.

Clostridium difficile–associated diarrhea (CDAD) is common during hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. We evaluated fidaxomicin for prevention of CDAD in HSCT patients. In this double-blind study, subjects undergoing HSCT with fluoroquinolone prophylaxis stratified by transplant type (autologous/allogeneic) were randomized to once-daily oral fidaxomicin (200 mg) or a matching placebo. Dosing began within 2 days of starting conditioning or fluoroquinolone prophylaxis and continued until 7 days after neutrophil engraftment or completion of fluoroquinolone prophylaxis/clinically-indicated antimicrobials for up to 40 days. The primary endpoint was CDAD incidence through 30 days after study medication. The primary endpoint analysis counted confirmed CDAD, receipt of CDAD-effective medications (for any indication), and missing CDAD assessment (for any reason, including death) as failures; this composite analysis is referred to as “prophylaxis failure” to distinguish from the pre-specified sensitivity analysis, which counted only confirmed CDAD (by toxin immunoassay or nucleic acid amplification test) as failure. Of 611 subjects enrolled, 600 were treated and analyzed. Prophylaxis failure was similar in fidaxomicin and placebo recipients (28.6% vs 30.8%; difference 2.2% [-5.1, 9.5], P = .278). However, most failures were due to non-CDAD events. Confirmed CDAD was lower in fidaxomicin vs placebo recipients (4.3% vs 10.7%; difference 6.4% [2.2, 10.6], P = .0014). Drug-related adverse events occurred in 15.0% of fidaxomicin recipients and 20.0% of placebo recipients. While no difference was demonstrated between arms in the primary analysis, results of the sensitivity analysis demonstrated that fidaxomicin significantly reduced the incidence of CDAD in HSCT recipients. NCT01691248