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Antimicrobial stewardship programs (ASPs) have made immense strides in optimizing antibiotic, antifungal, and antiviral use in clinical settings. However, although ASPs are required institutionally by regulatory agencies in the United States and Canada, they are not mandated for transplant centers or programs specifically. Despite the fact that solid organ transplant recipients in particular are at increased risk of infections from multidrug-resistant organisms, due to host and donor factors and immunosuppressive therapy, there currently are little rigorous data regarding stewardship practices in solid organ transplant populations, and thus, no transplant-specific requirements currently exist. Further complicating matters, transplant patients have a wide range of variability regarding their susceptibility to infection, as factors such as surgery of transplant, intensity of immunosuppression, and presence of drains or catheters in situ may modify the risk of infection. As such, it is not feasible to have a “one-size-fits-all” style of stewardship for this patient population. The objective of this white paper is to identify opportunities, risk factors, and ASP strategies that should be assessed with solid organ transplant recipients to optimize antimicrobial use, while producing an overall improvement in patient outcomes. We hope it may serve as a springboard for development of future guidance and identification of research opportunities.

Clotrimazole troches are used as prophylaxis against oropharyngeal candidiasis post-transplant and have limited systemic absorption. Following several occurrences of tacrolimus concentration fluctuations after clotrimazole discontinuation, its use as prophylaxis was discontinued post-kidney transplant.We conducted a retrospective cohort study to evaluate the effect of clotrimazole prophylaxis on tacrolimus trough concentrations post-kidney transplant. The study included adult patients who received a kidney transplant at Cleveland Clinic Main Campus from August 1, 2019 to July 1, 2020 and were maintained on per-protocol, standard-dose tacrolimus through 90 days post-transplant. Patients were excluded if they received cyclosporine, systemic antifungals, strong CYP3A4 inhibitors or inducers, or a simultaneous multiorgan transplant. The primary objective was to compare tacrolimus trough concentrations before and after completion of clotrimazole prophylaxis. Secondary objectives were to compare the time to first post-transplant goal tacrolimus trough concentration, the rate of for-cause allograft biopsies within 90 days after transplant, and the incidence and type of candidiasis within 30 days after transplant, pre- and post-protocol change.Following clotrimazole discontinuation, the median tacrolimus trough concentration decreased from 10.5 ng/ml (IQR 8.4-12.2) to 6.6 ng/ml (IQR 5-8.7, p 0.0001). No statistically significant differences in the rate of for-cause allograft biopsies (4.9% vs. 9.7%, p = 0.264) or incidence of candidiasis (1.2% vs. 5.4%, p = 0.217) were observed between those who received clotrimazole and those who did not receive clotrimazole.Our study provides further evidence of a significant drug-drug interaction between tacrolimus and clotrimazole among kidney transplant recipients that can potentially lead to negative allograft outcomes.

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is an aggressive and biologically heterogeneous disease. Risk stratification and treatment algorithms vary based on stage of disease and bulk along with other clinical and biological factors, including the International Prognostic Index, cell of origin, and other molecular subsets. Rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the current standard of care and cures more than 60% of patients. The role of radiotherapy is largely restricted to patients with limited-stage disease. In elderly patients, geriatric assessments of baseline fitness and functional status help optimize therapy based on the balance of efficacy and toxicity. While numerous randomized trials have failed to improve upon R-CHOP, a recent press release from the POLARIX trial (NCT03274492) suggests that adding polatuzumab vedotin (Polivy) to rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) improves progression-free survival and may replace R-CHOP in eligible patients. Ongoing trials are exploring frontline therapy that integrates other novel agents, including various small molecules, bispecific antibodies, and chimeric antigen receptor T-cell therapy, with promising preliminary results. Defining a population of patients with high-risk disease in whom R-CHOP is not effective is critical. Patient selection based on refining molecular subsets, quantitative PET metrics such as metabolic tumor volume, and dynamic risk assessments using interim PET and circulating tumor DNA analysis may allow for a personalized, response-adapted approach that will further improve outcomes in DLBCL.

The goal of testosterone replacement therapy (TRT) is to return serum testosterone levels to within physiologic range and improve symptoms in hypogonadal men. Some of the symptoms aimed to improve upon include decreased libido, erectile dysfunction, infertility, hot flashes, depressed mood, and loss of muscle mass or hair. Clinical use of testosterone for replacement therapy began approximately 70 years ago. Over the decades, numerous preparations and formulations have been developed primarily focusing on different routes of delivery and thus pharmacokinetics (PKs). Currently the routes of delivery approved for use by the United States Food and Drug Administration encompasses buccal, nasal, subdermal, transdermal, and intramuscular (IM). Many factors must be considered when a clinician is choosing the most correct formulation for a patient. As this decision depends highly on the patient, active patient participation is important for effective selection. The aim of this review is to describe and compare all testosterone preparations currently available and approved by the United States Food and Drug Administration. Areas of focus will include pharmacology, PKs, adverse effects, and specifics related to individual delivery routes.

BACKGROUND Fusarium spp. infections have become an emerging and lethal threat to the immunocompromised patient population, especially those with neutropenia. Recently there have been increased reports in solid organ transplant recipients. Presentation is commonly as soft tissue infections several months post-transplant. With high morbidity and mortality, efficacious antifungal therapy is essential. This remains challenging with limited data and no established clinical breakpoints defined. CASE REPORT We report on a modified multi-visceral transplant patient that developed a Fusarium infection only 7 weeks post-transplant in the native hard palate and esophagus, without any soft tissue lesions, which persisted despite aggressive combination treatment with amphotericin B lipid complex and voriconazole. CONCLUSIONS Fusarium spp. infection in solid organ transplant is a significant challenge without clear diagnostic clinical indicators of infection, or specific time of onset, in addition to possible emergence of a more aggressive drug-resistant strain.

Background UTIs are the most common infection after renal transplant (RTx) with an incidence of 6–86%. Post-RTx UTI has been associated with risk for graft loss and mortality, and RTx recipients are at risk for multidrug-resistant (MDR) UTI given immunosuppression (IS) and instrumentation. We sought to evaluate the incidence, timing, microbiology, and MDR risk of post-RTx UTI, as well as to characterize asymptomatic bacteriuria (ASB) practices at our center. Methods This was a retrospective cohort of subjects with ≥1 positive culture (≥105 CFU/mL) during the first year post-RTx that were transplanted from September 1, 2012 to October 1, 2016. Each bacteriuria episode was adjudicated as cystitis, pyelonephritis, or ASB (Figure 1). Subjects without bacteriuria were excluded from primary analysis but used to calculate UTI incidence. The primary outcome was 1-year symptomatic UTI incidence. Secondary outcomes: incidence of cystitis, pyelonephritis, and ASB; time-to-first UTI; microbiologic trends; and presence of MDR risk factors. Results Baseline characteristics: 52% male, median age 57 years, 65% stented, 34% antithymocyte globulin induction, 94% standard IS regimen (tacrolimus/mycophenolate/prednisone), 93% trimethoprim/sulfamethoxazole prophylaxis, and 21% receipt of IV antibiotics for ≥48 hours within 90 days of first positive culture (IV Abx); Of 527 RTx subjects, 100 had ≥1 positive culture. The 100 subjects had 234 cultures representing 359 isolates. Primary outcome: 12.1% symptomatic UTI incidence. Secondary outcomes (1-year incidences): 18.6% positive culture, 4.3% cystitis, 8.6% pyelonephritis, 11.9% ASB. Time to the first symptomatic UTI was a median of 50 days. A summary of microbiologic results can be found in Figure 2. ASB occurred 130 times and was treated 74.6% of the time (Figure 3). Significant risk factors for MDR UTI included female gender (P = 0.005), IV abx (P = 0.001), and recurrent UTI (P = 0.017). Conclusion Incidence of symptomatic UTI at our center was lower than previous reports. E. coli and E. faecalis were the most common urinary pathogens identified. MDR risk factors identified were biologically plausible and consistent with prior literature. ASB treatment occurred frequently and is an area to target stewardship interventions. Disclosures All authors: No reported disclosures.

Stiction in control valves is one of the long-standing problems in the process industries which lead to oscillations in closed loop systems. Numerous methods have been developed to detect stiction in linear closed-loop systems. Almost all of these methods utilize the fact that the presence of stiction in control valves introduces nonlinearities in the closed loop control system. However, there exists no measure of reliability for the results provided by these techniques. In this work, using frequency domain analysis of closed loop systems, a measure of reliability is developed for model based stiction detection approaches.

Background Adherence rates for recommended pre-transplant (pre-txp) vaccinations in pediatric solid-organ transplant (SOT) patients are variable and practice-dependent. Cleveland Clinic Children’s Hospital (CCCH) pre-txp adherence rates for select vaccines have not been described. The purpose of this study was to evaluate pre-txp adherence rates for the following vaccines: hepatitis B, influenza, pneumococcal conjugate (PCV13), pneumococcal polysaccharide (PPSV23), and hepatitis A (if at-risk). Methods This retrospective cohort study included patients undergoing initial pediatric heart, kidney, liver, or intestine/multi-visceral transplant at CCCH between 1/1/14 and 7/31/17. Data collected from the electronic medical record and Ohio Department of Health Statewide Immunization Information System included demographics, transplant-related data, immunization administration history, and quantitative/qualitative values for titer/serology. The primary objective of vaccination adherence rate was defined as the aggregate of patients who had completed the vaccine series, had positive titer/serology data, or were ineligible to receive the vaccine due to age or administration restrictions. Data are descriptive in nature and reported as number (percent) or median (interquartile range), as appropriate. Results 64 pediatric SOT recipients met inclusion criteria. Median age was 7.9 (2.1, 15.8) years. Majority of patients were American (73%) and male (63%). Most common organ was heart (41%), followed by liver (25%), kidney (21%), and intestine/multi-visceral (13%). Sixty-three (98%) patients underwent ID pre-txp evaluation. CCCH adherence rates were highest for hepatitis B at 92%, followed by PCV13 and PPSV23 at 84%, and influenza at 72%. Thirty-two (50%) patients were indicated to receive the hepatitis A vaccine and the respective adherence rate was 91%. Vaccination adherence by SOT team is described in Figure 1. Conclusion CCCH pre-txp vaccination adherence rates are higher than previously reported. Opportunities for improvement include influenza vaccination adherence across all SOT teams and PCV13/PPSV23 vaccination adherence in intestine/multi-visceral transplant patients. Figure 1: CCCH SOT team vaccination adherence rates. Disclosures All authors: No reported disclosures.

Background There is a demand for stewardship implementation and research in ambulatory and SOT populations. Few studies focus on outpatient stewardship interventions, and none has focused on timely recognition of CMV in outpatient SOT recipients. This study sought to determine the effect of real-time CMV result notification paired with pharmacist intervention on virologic and clinical outcomes in outpatient SOT recipients. Methods Quasi-experimental study comprised of two 6-month phases. In the pre-intervention phase, pharmacists were not involved in management of outpatient CMV viremia. In the intervention phase, pharmacists received real-time email notification of positive blood CMV results for review and intervention as necessary. The primary endpoint was rate of viremia eradication at 21 days from therapy initiation. Secondary endpoints: time to antiviral initiation and viremia eradication, rate of CMV invasive disease and hospital admission, and adverse drug events. Results 88 of 213 screened patients were included in the primary analysis (n = 49 and 39 in the pre-intervention and intervention groups, respectively). Baseline characteristics were similar, including transplant type (34% vs. 41% liver, 24% vs. 28% kidney, 14% vs. 17% lung, 14% vs. 10% heart), CMV serostatus (53% vs. 64% D+/R-), and maintenance immunosuppression. A total of 73 recommendations were made with 89% acceptance. Baseline CMV viral load >10,000 IU/mL occurred in 12 (24%) vs. 6 (15%) patients (P = 0.29). Of treated patients, 42 (85%) vs. 32 (82%) achieved CMV eradication at 21 days (P = 0.64), 10 (20%) vs. 5 (12%) required admission for CMV management (P = 0.35), 7 (14%) vs. 3 (7%) developed CMV invasive disease (P = 0.50), and 29 (60%) vs. 25 (66%) received antiviral within 5 days (P = 0.61). There were no statistically significant differences in time to antiviral initiation (45 vs. 41 hours; P = 0.64) or viremia eradication (19 vs. 18 days; P = 0.44). Conclusion CMV eradication at 21 days was not significantly different between groups; however, fewer patients in the intervention experienced elevated baseline viral load, CMV invasive disease, and hospital admission. These secondary endpoints suggest possible benefit from the intervention and warrant further characterization and study. Disclosures All authors: No reported disclosures.