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Background: Cytomegalovirus (CMV)-specific cell-mediated immunity is important for control of CMV after transplant. Assays exist to measure this, but their place in therapy is unclear, particularly in CMV high-risk recipients, without pretransplant exposure., Objective: The objective of this study was to evaluate predictive potential of a positive assay to determine freedom from DNAemia and describe subsequent 3-month CMV outcomes., Methods: Adult CMV high-risk kidney and/or pancreas transplant recipients were included if a CMV inSIGHT T Cell Immunity Panel (TCIP, Eurofins Viracor) was ordered and resulted between 1 August, 2019 and 30 July, 2022., Results: Seventy-six patients were included in our study; 49 tested during prophylaxis and 27 during treatment. Most TCIP assays obtained in the prophylaxis cohort were negative (n = 46, 93.9%). Rate of post-TCIP CMV infection was 10.2%. In those tested during treatment, 33.3% were positive and rate of post-TCIP CMV recurrence was 22.2%. The positive predictive value of the assay to successfully predict immunity was 66.7% during both prophylaxis and treatment. There were 4 cases of TCIP predictive failure with progressive CMV replication. At time of replication, 2 patients had concomitant clinical confounders thought to influence immune control of viral replication. All patients had intensification of immunosuppression prior to recurrent replication, but after TCIP was collected., Conclusion and Relevance: The data obtained from the TCIP are not static, immune control of CMV in latency can change and must be evaluated in clinical context. Timing of TCIP after transplant is significant, and patient-specific factors remain important to assess the likelihood of CMV in each unique patient-specific scenario. A CMV stewardship program can aid in application and interpretation of results., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients., Data Sources: A literature search of PubMed and the Cochrane Controlled Trials Register (1960 to early July 2022) was performed using the following search terms: maribavir, 1263W94 , and cytomegalovirus ., Study Selection and Data Extraction: All relevant English-language studies were reviewed and considered, with a focus on phase 3 trials., Data Synthesis: Maribavir, an orally available benzimidazole riboside with minimal adverse effects, was originally studied for universal prophylaxis in phase 3 trials but failed to demonstrate noninferiority over placebo and oral ganciclovir. It was effective for preemptive treatment in a dose-finding Phase 2 study. Maribavir is FDA approved for treatment of refractory/resistant CMV infection based on improved response rate at 8 weeks compared with investigator-assigned therapy (IAT) when initiated at median viral loads less than approximately 10 000 IU/mL (55.7% vs 23.9%, P < 0.001). Recurrence after 8-week treatment for refractory/resistant CMV was high (maribavir 50% vs IAT 39%). Significant drug interactions exist and must be managed by a pharmacotherapy expert to prevent harm., Relevance to Patient Care and Clinical Practice: The addition of maribavir to the antiviral armamentarium should improve the management of refractory/resistant CMV, allowing early transition from toxic, high-cost, intravenous agents such as foscarnet and outpatient management. Optimal timing of initiation, duration, and potential alternative uses are unclear., Conclusion: Future studies are needed to fully elucidate the role of maribavir in the management of CMV after transplant.

Background: Studies suggest that rabbit-antithymocyte globulin (rATG) decreases biliary complications (BCs) after donation-after-circulatory-death-donor liver transplantation (DCD LTx), but safety data are lacking. Objective: Our aim was to assess the safety of rATG for this indication. The secondary end point was efficacy of rATG for this indication. Methods: Adult recipients of DCD LTx were divided into 2 cohorts: protocolized use of rATG in the modern era (July 1, 2013, to December 31, 2016) and a historical control without rATG (January 1, 2005, to June 30, 2013). Incidence of infection, leukopenia, and thrombocytopenia were compared for the safety assessment, incidence of BCs, ischemic cholangiopathy (IC), and transplant outcomes for the efficacy assessment. Results: A total of 83 patients met inclusion criteria: 42 in the historical cohort and 41 in the modern cohort. The modern cohort had significantly fewer bacterial infections at 3 months (historical 54.8% vs modern 23%; P = 0.004) and 1 year (historical 62.1% vs modern 34.2%, P = 0.004). The modern cohort also had fewer fungal infections at these time points (historical 33.3% and 47.9% vs modern 15% and 15%; P = 0.001). There were no significant differences in platelet or white blood cell reduction between groups. There was a nonsignificant, but numerical, trend toward reduced IC/BC in the modern cohort at 1 year (IC: historical 30.1% vs modern 13.2%, P = 0.08; BC: historical 51% vs modern 37.5%, P = 0.13). There was no difference in graft/patient survival. Conclusion and Relevance: Our data suggest no major safety issues with rATG in DCD LTx. Our study should ease clinical apprehension surrounding rATG use for this indication. Future prospective studies are needed to further evaluate the role of rATG and its impact on efficacy end points.

Background: Modifiable risk-factors associated with Clostridioides difficile infection (CDI) in renal-transplant (RTX) have not been clearly established and peri-transplant risk has not been described., Objective: Evaluate epidemiology, risk-factors and outcomes after CDI occurring in the first 90 days after RTX (CDI-90). Methods: Observational cohort study/survival analysis of adult RTX recipients from 1/1/2012-12/31/2015. Primary outcome was CDI-90 incidence/risk-factors. Secondary outcome was evaluation of post-90 day transplant outcomes., Results: 982 patients met inclusion criteria; 46 with CDI-90 and 936 without (comparator). CDI incidence in the total population was 4.7% at 90 days, 6.3% at 1 year, and 6.4% at 3 years. Incidence of CDI-90 was 5%; time to diagnosis was 19.4±25 days (median 7). Risk-factors for CDI-90 were alemtuzumab induction (Hazard ratio [HR] 1.5, 95% CI(1.1-2.0), p = 0.005) and age at transplant (HR 1.007/year, 95% CI (1.002-1.012), p = 0.007). However, risk-factors for CDI at any time were different; donation-after-circulatory-death (DCD) donor (HR 2.5 95% CI (1.3-4.9), p = 0.008) and female gender (HR 1.6 95% CI (1.0-2.7), p = 0.049). On Kaplan-Meier, CDI-90 appeared to have an impact on patient/graft survival, however when analyzed in a multivariable stepwise Cox proportional hazards model, only age was significantly associated with survival ( p = 0.002)., Conclusion and Relevance: Incidence of CDI-90 is low, mostly occurring in the first post-operative month. Risk-factors vary temporally based on time from transplant. In the early post-op period induction agent and age at transplant are significant, but not after. Associations between CDI and negative graft outcomes appear to be largely driven by age. Future studies validating these risk-factors as well as targeted prophylaxis strategies and their effect on long term graft outcomes and the host microbiome are needed.

Background: Biologic agents inhibiting the tumor necrosis factor α pathway (TNFα-Is) are used to treat systemic inflammatory diseases. The best management of these agents after renal transplantation is unknown., Objective: Evaluate peritransplant use of TNFα-Is and associated outcomes., Methods: Retrospective, single-center study of adult renal-transplant-recipients (RTRs) transplanted between 1/1/1998-12/31/2017, who received TNFα-Is for inflammatory disease prior to transplant. Qualifying patients were divided into 2 cohorts: patients who resumed TNFα-Is after transplant and those who did not. Outcomes were evaluated., Results: A total of 5256 renal transplants occurred in the study window; 14 patients met inclusion criteria. Primary indication for TNFα-I was Crohn's-disease (CD; 57.1%). Infliximab was utilized most frequently (50%). Seven RTRs resumed TNFα-I posttransplant; mean time to resumption of 10.6±4.35 months (median=6 months), 85.7% for CD. Immunosuppression was modified in 2 patients (28.6%) in response to restarting TNFα-I therapy. Seven RTRs did not resume TNFα-Is following transplant; the majority of these had rheumatic diseases. There was no significant difference in time to first bacterial or fungal infection, rejection, or patient survival between the 2 groups. Last measured estimated glomerular-filtration-rate was similar between groups (TNFα-I: 41 ± 14.2 vs 48.6 ± 8.6, P = 0.25). No patient had cytomegalovirus infection; however, 42.8% of each cohort had documented BK virus infection. Malignancy occurred more frequently in the cohort that resumed TNFα-Is (42.8% vs 14.3%, P = 0.24); however, this was not statistically significant. Conclusion and Relevance: TNFα-I therapy prior to renal-transplant is relatively uncommon. The decision to continue therapy after transplant must balance risks of infection and malignancy against inflammatory disease recurrence. A multidisciplinary treatment approach is necessary as use of TNFα-I affects immunosuppressive management and appears to affect transplant outcomes. Future studies are needed to further clarify the role of TNFα-I therapy use in RTRs with inflammatory disorders focusing on its correlation with both BK and malignancy.

Background: Ganciclovir-resistant cytomegalovirus (GR-CMV) is a serious complication of transplantation. Recurrence after primary infection is common. Little is known about CMV drug resistance and latency., Objective: Review CMV genotype during episodes of recurrent CMV viremia after prior documentation of ganciclovir resistance to evaluate if resistance is redemonstrated., Methods: All adult transplant recipients with history of GR-CMV viremia from January 1, 2011, to December 31, 2015, were screened; those with subsequent laboratory evidence of recurrent CMV viremia and genotyping were included., Results: A total of 23 patients had genetically confirmed GR-CMV within the study time period; 14 were excluded due to lack of repeat resistance testing at recurrence and 4 due to of lack of negativity between testing, leaving 5 patients with 7 episodes of recurrent viremia to evaluate. At first recurrent viremia, 4 patients (80%) demonstrated resistant genotype; 1 patient had wild type. Two patients went on to have a second viremia recurrence; both demonstrated wild-type genotype, despite the fact that the first recurrence in these patients was resistant genotype., Conclusion: In transplant recipients with history of GR-CMV, it appears that there is strain variability in latency: repeat genetic testing in patients with recurrent viremia after GR-CMV should be conducted. In the setting of wild-type repopulation, use of GCV should be considered.

Background: Incidence of primary and recurrent Clostridium difficile infection (CDI) is higher in solid-organ transplant recipients than in the average hospitalized patient. Strategies for preventing recurrent CDI are limited. Prophylaxis with oral vancomycin (VPPx) for preventing recurrent CDI may be beneficial, but there is limited evidence supporting its use., Objective: To examine the impact of VPPx (125 mg twice daily) for the prevention of recurrent CDI in renal transplant recipients (RTX) receiving high-risk broad spectrum antibiotics (BSAs)., Methods: Adult RTX with history of CDI, hospitalized with receipt of BSAs during a unit-specific CDI outbreak period-January 1, 2012, to December 31, 2015-were divided into 2 matched cohorts: patients who received VPPx concomitantly with BSAs and patients who did not. The primary objective was incidence of CDI recurrence, defined as CDI occurring ≤30 days after receipt of BSAs but ≥48 hours after beginning VPPx. Univariate analysis was performed., Results: Baseline characteristics were similar; however, the VPPx group had more severe primary CDI and were receiving BSAs for more severe infections. There were no cases of CDI recurrence in the VPPx group (0% [0/12] vs 8% [2/24], P = 0.54)., Conclusion: Although sufficient power was not obtained to detect statistically significant differences between the intervention and control groups, a 0% incidence of recurrent CDI while receiving VPPx in this high-risk patient population is compelling because it pertains to the avoidance of CDI-related morbidity and mortality in transplant recipients. Future prospective studies are needed to better evaluate the impact of this preventive strategy.

Background: Following abdominal solid organ transplant (aSOT), valganciclovir (VGC) is recommended for cytomegalovirus (CMV) prophylaxis. This agent is associated with efficacy concerns, toxicity, and emergence of ganciclovir resistance., Objective: To evaluate the incidence of high-dose acyclovir (HD-A) prophylaxis failure in seropositive aSOT recipients (R+)., Methods: This was a retrospective, single-center study of R+ transplanted without lymphocyte-depleting induction between January 1, 2000, and June 30, 2013, discharged with 3 months of HD-A prophylaxis (800 mg 4 times daily). The primary outcome was incidence of prophylaxis failure. Secondary outcomes were incidence of biopsy-proven tissue-invasive disease and prophylaxis failure for each allograft subgroup., Results: A total of 1525 patients met inclusion criteria: 944 renal (RTX), 108 simultaneous pancreas-kidneys (SPK), 462 liver (LTX), and 11 pancreas (PTX) transplant recipients. The composite rate of HD-A prophylaxis failure was 7%; incidence of tissue-invasive disease was 0.4%. Failure rates were 4.5%, 6.1%, 11%, and 20% in the RTX, SPK, LTX, and PTX populations, respectively; tissue-invasive disease rates were 0.2%, 0%, 0.7%, and 10%. Failure occurred more frequently in the LTX and PTX populations ( P < 0.0001, HR = 2.6; P = 0.04 HR = 4.4). Incidence of tissue-invasive disease was minimal and not different in the RTX, LTX and SPK populations ( P = 0.34). When evaluating recipients of seronegative allografts (D-), the composite failure rate was 3.4% with no significant difference between allograft subgroups ( P = 0.45)., Conclusion: HD-A may be a reasonable prophylaxis alternative for D-/R+ recipients, in the absence of lymphocyte-depleting induction, if low incidence viremia is tolerable. Future studies are needed to determine the long-term impact of CMV viremia in the setting of this prophylaxis approach.

Background: Urinary tract infection (UTI) after abdominal solid organ transplantation (SOT) is associated with significant morbidity and mortality. Fosfomycin tromethamine (FOS), a uroselective antibiotic, is FDA approved for uncomplicated UTIs in women and is used off-label for complicated UTIs and prostatitis in men. Literature supporting the use of FOS in the SOT population is limited, and efficacy is questioned in the setting of renal dysfunction., Objective: To evaluate the success of FOS for the treatment of cystitis in SOT patients with renal dysfunction., Methods: This was a single-center, retrospective study using medical records. SOT recipients receiving at least 1 dose of FOS for treatment of cystitis between January 1, 2009, and April 30, 2015, were included. Treatment outcomes were analyzed with respect to renal function., Results: A total of 76 courses of FOS were identified in 64 patients. The renal dysfunction arm (creatinine clearance [CrCl] < 40 mL/min) included 33 patients with 39 FOS courses; the normal renal function arm (CrCl ≥ 40 mL/min) included 31 patients with 37 FOS courses. Mean CrCl was 23.3 ± 9.7 mL/min for the renal-dysfunction group and 65 ± 29.3 mL/min for the normal renal function group ( P < 0.01). No significant difference in treatment success was noted between CrCl <40 mL/min and CrCl ≥40 mL/min (31 [80%] vs 34 [92%], P = 0.12) in a unilateral analysis. After adjusting for confounders in a multivariable analysis, there was no difference in the risk of failure between CrCl <40 mL/min and CrCl ≥40 mL/min groups ( P = 0.70)., Conclusion: FOS appears to be successful for the treatment of cystitis in SOT recipients in the setting of renal dysfunction.

Objective: To review the pharmacology, microbiology, chemistry, in vitro activity, pharmacokinetics, clinical efficacy, safety, dosage, and administration of ceftaroline fosamil (Teflaro, Forest Laboratories, Inc.), a novel parenteral broad-spectrum cephalosporin approved by the Food and Drug Administration (FDA) on October 29, 2010, for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP)., Data Sources: A search of MEDLINE (1966-July 2011) using the search terms ceftaroline fosamil, ceftaroline, TAK-599, PPI-0903, PPI-0903M, and T-91825 was performed. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, European Congress on Clinical Microbiology and Infectious Diseases, and the Infectious Diseases Society of America from 2005 to 2010, as well as information available from the manufacturer's Web site., Study Selection and Data Extraction: All English-language articles identified from the data sources were evaluated. In vitro, preclinical, and Phase 1, 2, and 3 clinical trials were included., Data Synthesis: Clinical trials have been conducted evaluating use of ceftaroline for treatment of ABSSSI and CABP. Safety data from Phase 1, 2, and 3 clinical trials suggest that it is well tolerated and has a safety and tolerability profile common to the cephalosporin class. Ceftaroline has excellent in vitro activity against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), which makes it an attractive monotherapy for the treatment of ABSSSI. However, it lacks activity against problem gram-negative bacteria (eg, Pseudomonas spp.), which will likely limit its use for serious health care-associated infections. While its role in treating CABP is supported by excellent in vitro activity against Streptococcus pneumoniae and clinical efficacy data, currently available comparators may offer some advantages over ceftaroline. Finally, data are lacking to assess its role in the treatment of serious infections due to MRSA (eg, pneumonia, bacteremia)., Conclusions: These considerations should be part of the formulary review process; however, when considering the significant role MRSA plays in ABSSSI in both the community and hospital settings, we believe that ceftaroline will provide clinicians with a welcome option in addition to currently available anti-MRSA therapies for the treatment of ABSSSI.