Prophylaxis In Solid Organ Transplant Recipients Research Articles

636. Meningococcal Vaccination and Antibiotic Prophylaxis Practices in Solid Organ Transplant Recipients undergoing Eculizumab Therapy

Abstract Background Eculizumab, an inhibitor of terminal complement activation, has been utilized in pre-transplant desensitization, treatment of antibody-mediated rejection and thrombotic microangiopathy in solid organ transplant recipients (SOTR). Eculizumab is associated with meningococcal disease, leading to guidelines for vaccination against serogroups ACWY (menACWY) and B (menB) at least 2 weeks prior to eculizumab therapy. In persons requiring emergent use of eculizumab, prophylaxis for at least 2 weeks is recommended. SOTRs respond suboptimally to vaccination, raising consideration for pre-transplant vaccination and prolonged prophylaxis in those undergoing eculizumab therapy. We sought to describe meningococcal vaccination and prophylaxis practices among SOTRs receiving eculizumab. Methods We performed a retrospective chart review of meningococcal vaccination, including number and timing pre- or post-transplant, along with prophylaxis prescribing and duration in SOTRs receiving eculizumab across 3 distinct Mayo Clinic Enterprise sites (Rochester, Arizona, and Florida). Results 200 SOTRs receiving at least one dose of eculizumab between 1/1/2008 and 9/16/2021 were reviewed. Eculizumab indications included antibody mediated rejection (38%), desensitization (26%), and thrombotic microangiopathy (19%). 83% (166/200) of SOTRs received eculizumab for an unanticipated post-transplant complication. Vaccination rates were 82% (164/200) and 35.5% (71/200) for menACWY dose 1 and 2, respectively, and 54% (108/200) and 28.5% (57/200) for menB dose 1 and 2, respectively. The majority received their first vaccination post-transplant: menACWY 66.5% (133/200) and menB 2.5% (185/200). Among those without vaccination pre-eculizumab, 22.3% (41/184) were not prescribed prophylaxis. The median duration of prophylaxis was 62 (range 4-2651) days. Conclusion Most SOTRs underwent meningococcal vaccinations near the time of eculizumab administration post-transplant for an unanticipated complication. One-fifth of those meeting criteria were not provided meningococcal prophylaxis. These findings may support pre-transplant administration of meningococcal vaccinations and heightened awareness for meningococcal prophylaxis in SOTRs receiving eculizumab. Disclosures All Authors: No reported disclosures.

1702. Assessing the Safety and Efficacy of Valganciclovir Dosing for Cytomegalovirus Prophylaxis in Solid Organ Transplant Recipients on Hemodialysis

BackgroundValganciclovir is the standard of care used for the prevention of Cytomegalovirus (CMV) infections among solid organ transplant (SOT) recipients. Currently there is minimal guidance for prophylaxis in SOT recipients undergoing intermittent hemodialysis (IHD). At Mount Sinai Hospital (MSH), the current practice for CMV prophylaxis in SOT recipients on IHD is valganciclovir 450 mg every other day (Q48H) or three-times weekly (TIW). This study aims to evaluate the safety and effectiveness of these dosing regimens in SOT recipients on IHD.MethodsA single-center, retrospective chart review study was conducted among all MSH SOT recipients on valganciclovir 450 mg Q48H or TIW for CMV prophylaxis and undergoing IHD for at least 30 days. The primary study outcome was the safety of using these valganciclovir doses determined by the incidence of leukopenia, thrombocytopenia, and the administration of growth colony stimulating factor (GCSF). The secondary outcome were the incidences of CMV viremia and CMV disease while on prophylaxis.ResultsEighteen transplant encounters satisfied the inclusion and exclusion criteria. The majority were liver (7, 38.9%) and kidney (5, 27.8%) transplants. Thirteen (72.2%) recipients were on valganciclovir 450 mg Q48H dosing, while 5 (27.8%) were on valganciclovir 450 mg TIW dosing. Both the mean platelet count nadir (131 ± 93 vs 161 ± 115) and mean white blood cell count nadir (3.4 ± 2.5 vs 5.1 ± 3.8) were lower in the Q48H regimen. Four patients (22.2%) in the Q48H regimen group required GCSF vs none (0.0%) in the TIW regimen. No patient had a detectable CMV viral load while on either prophylactic dose. Two (11.1%) CMV high risk patients on the every other day dosing regimen and one (5.6%) CMV moderate risk patient on the three times weekly regimen developed CMV viremia about 2-3 months after their prophylaxis was stopped.Table 1. Baseline Demographics. Table 2. Primary Outcomes Table 3. Secondary Outcomes ConclusionValganciclovir 450 mg TIW may be safer than and as efficacious as Q48H dosing for prophylaxis in SOT recipients on chronic IHD. This data supports the use of three times weekly dosing as standardized practice at MSH, however more data is necessary to determine a conclusive result.Disclosures All Authors: No reported disclosures

Use of T Cell Mediated Immune Functional Assays for Adjustment of Immunosuppressive or Anti-infective Agents in Solid Organ Transplant Recipients: A Systematic Review.

Background: Defining the optimal dosage of the immunosuppressive or duration of anti-infective agents is a challenge in solid organ transplant (SOT) recipients. We aimed to systematically review the literature regarding the use of T cell mediated immune functional assays (IFAs) for adjustment of the immunosuppressive or anti-infective agents in SOT recipients.Methods: We systematically searched PubMed, Scopus, EMBASE, Web of Science (WOS), Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov to find human interventional studies or study protocols that used either in-house or commercially available IFAs for adjustment of the immunosuppressive or anti-infective agents in SOT recipients.Results: We included six clinical trials and six study protocols. Four out of the six clinical trials used interferon-γ release assays for cytomegalovirus (IGRA-CMV), and five out of the six registered study protocols planned to use IGRA-CMV for adjustment of anti-CMV antiviral (Valganciclovir) prophylaxis or preemptive therapy in SOT recipients. Primary or secondary anti-CMV prophylaxes were discontinued in SOT recipients who had positive IGRA-CMV results without an increase in the rate of CMV infection or reactivation. Among other IFAs, one clinical trial used interferon-γ release assays for tuberculosis (IGRA-TB), and one study used ImmuKnow for adjustment of the duration and dosage of isoniazid and tacrolimus, respectively.Conclusion: Our systematic review supports a promising role for the IGRA-CMVs for adjustment of the duration of anti-CMV antiviral prophylaxis in SOT recipients. There are limited data to support the use of IFAs other than IGRA-CMVs for adjustment of immunosuppressive or anti-infective agents. Further multicenter randomized clinical trials using IFAs other than IGRA-CMVs may help in personalized immunosuppressive or prophylactic anti-infective therapy in SOT recipients.

2646. Incidence of Myelosuppression Related to Valganciclovir Prophylaxis in Solid-Organ Transplant Recipients at High Risk of CMV Disease

BackgroundValganciclovir (VGCV) prophylaxis in solid-organ transplant patients (SOT) is limited by myelotoxicity. We aimed to analyze the impact of VGCV prophylaxis on myelotoxicity and risk factors for its occurrence.MethodsRetrospective single-center cohort study of adult CMV-seronegative recipients transplanted between July 2005 and November 2017. CMV D+/R− recipients received 3 to 6 months of VGCV prophylaxis whereas CMV D-/R- received no VGCV. Definitions: leukopenia < 3.5 × 109/L, significant neutropenia < 1.0 × 109/L and significant thrombocytopenia < 50 × 109/L.ResultsA total of 363 SOT recipients were included, 169 (47%) CMV D+/R− and 194 (53%) CMV D−/R−, with a mean age of 49.5 years and 275 (76%) males; types of organ transplant: 133 (37%) liver, 181 (50%) kidney, 37 (10%) simultaneous kidney-pancreas and 12 (3%) other. Although there was no difference in the incidence of significant neutropenia or thrombocytopenia per transplant type, leukopenia in the first year was more common in liver transplant patients (P < 0.001). New onset leukopenia post-SOT, significant neutropenia (Figure 1) and significant thrombocytopenia in the first year were more common in patients receiving VGCV: 116 D+/R− (69%) vs. 52 D−/R− (31%), P < 0.001; 86 (91%) vs. 9 (9%), P < 0.001; 8 (80%) vs. 2 (20%), P = 0.050; respectively. G-CSF was used more frequently in patients receiving prophylaxis (60% CMV D+/R− vs. 10% CMV D−/R−, P < 0.001). Significant neutropenia had no impact on long-term mortality adjusted by age and transplant type (HR 1.1, 95% CI 0.6–2.1, P = 0.709). Significant neutropenia led to decrease immunosuppression in 90% of patients (vs. 46%, P < 0.001) and was associated with increased risk of rejection (HR 8.5, P < 0.001). In multivariate analysis for significant neutropenia in the first year, VGCV prophylaxis was the only predictor of this outcome after adjusting for confounders (HR 15.1, 95% CI 7.5–30.1, P < 0.001).ConclusionVGCV prophylaxis increased the risk of significant neutropenia by 15-fold post-SOT. No other clinical variables were useful to predict this complication. Therefore, complete blood count monitoring is still needed for all SOT recipients receiving VGCV prophylaxis. Disclosures All authors: No reported disclosures.

357. Aspergillus Isolates Remain Largely Susceptible to Azoles and Other Antifungals at a Large Transplant Program Using Azole Prophylaxis

BackgroundThe emergence of azole resistance globally among Aspergillus species has major clinical and agricultural implications. At our center, isavuconazole (ISA), posaconazole (POS), and voriconazole (VOR) have been used as antifungal prophylaxis in solid-organ transplant recipients. We determined susceptibility to azoles and other antifungals among Aspergillus isolates from our center.MethodsFifty-two patient isolates of Aspergillus species were collected from the UPMC Microbiology Laboratory between December 2016 and April 2018. Minimum inhibitory concentrations (MICs) of ISA, POS, VOR, amphotericin B (AmB), and caspofungin (CAS) were measured using EUCAST Antimicrobial Susceptibility Testing methods. Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 were used as quality control.ResultsSeventy-one percent (37/52) of isolates were from solid-organ transplant recipients (34 lungs, two liver, and one heart). Aspergillus spp. were A. fumigatus (29), A. terreus (At, 6), A. niger, A. flavus and Aspergillus calidoustus (five of each species), and A. lentulus and A. thermomutatus (one of each species). Thirteen breakthrough (BT) isolates were recovered from patients on azoles: A. calidoustus (5), A. niger (4), A. flavus (2), A. fumigatus (1) and At (1). A. calidoustus, A. flavus, and A. niger were more likely than other species to be recovered from azole BT (75% (12/16) vs. 5% (2/36), P = 0.06). For all isolates, ISA, VOR, and POSA MIC50 were 0.25 µg/mL, 0.04 µg/mL, and 0.25 µg/mL, respectively. One A. calidoustus and one At were resistant to all antifungals (azoles, AmB, and caspofungin MICs were >16 µg/mL); both were associated with azole BT. ISA, POS, and VOR MIC50 vs. azole BT isolates (0.5, 0.125, and 0.5 µg/mL, respectively) were higher than those vs. non-BT isolates (0.25, 0.03, and 0.25 µg/mL, respectively; P < 0.01 for all).ConclusionDespite widespread use of azole prophylaxis in transplant recipients at our center, we did not observe high rates of resistance to azoles or other antifungals among Aspergillus isolates, although azole MICs were higher against BT isolates. Azole BT isolates were more likely to be non-A. fumigatus species. Clinicians should understand that antifungal resistance rates can vary by center and geographical location, and use their local epidemiology to guide decisions about the utility of specific agents in their populations. Disclosures All authors: No reported disclosures.

Varicella Zoster Virus (VZV) in Solid Organ Transplant Recipients

-herpesvirus family. VZV is presentworldwide and is highly infectious. Primary infection leadsto acute varicella or ‘chickenpox,’ usually from exposureeither through direct contact with a skin lesion or throughairborne spread from respiratory droplets (1,2). After initialinfection, VZV establishes lifelong latency in cranial nerveanddorsalrootganglia,andcanreactivateyearstodecadeslater as herpes zoster (HZ) or ‘shingles’ (3). More than90% of adults in the United States acquired the disease inchildhood, while the majority of children and young adultshave been vaccinated with the live virus vaccine (2,4).Primary varicella typically presents with fever, constitu-tional symptoms and a vesicular, pruritic, widely dissem-inated rash that primarily involves the trunk and face (5).Thesymptomsusuallyresolvewithin7–10days,butinrarecases primary varicella leads to more severe disease andvisceral invasion. Complications, such as hepatitis, pancre-atitis, pneumonitis and encephalitis are infrequent but canbelife-threatening;adultsandveryyoungchildrenaremorelikely to develop such complications from primary infection(6,7). Rates of hospitalization and mortality due to varicellahave dropped with the institution of routine childhood vari-cella vaccination (8,9).Nearly all patients with HZ develop an exanthem of vesic-ular lesions in a dermatomal distribution. The annual inci-dence of HZ in the general population is 1.5–3.0 cases per1000 persons (2), and is estimated to occur in up to 20%of individuals during their lifetime (10). Secondary compli-cations such as bacterial superinfection and postherpeticneuralgia (PHN), or chronic neuropathic pain at the site ofHZ, lead to increased morbidity (11).Over 90% of adult solid organ transplant (SOT) recipientswill be seropositive for VZV. Rates are lower in pediatrictransplants(12,13),butimmunitywillincreaseasuptakeofvaricella vaccine improves. Varicella is rare in adult SOT re-cipients,butcanbedevastating,withvisceralinvolvement,severe skin disease, and disseminated intravascular coag-ulation (14–19). HZ is a frequent infectious complication inSOT recipients with an incidence of approximately 8–11%during the first 4 years posttransplant (20–22). Invasive dis-ease and dissemination similar to that seen in primary VZVinfection are uncommon but have been reported in SOTand other immunocompromised populations, and level ofimmunosuppression may alter the risk of developing thesecomplications (17,23,24). Rates of PHN in SOT recipi-ents may also be higher than in immunocompetent popu-lations (22).

Anti-cytomegalovirus prophylaxis in solid-organ transplant recipients

Ganciclovir and its prodrug, valganciclovir, are more effective than acyclovir in preventing cytomegalovirus (CMV) infection and disease in solid-organ transplant recipients. However, the indirect effects of prophylactic use of ganciclovir and acyclovir are comparable, and the greater effectiveness of ganciclovir may be compensated for by less drug-related toxicity with acyclovir or valacyclovir. No conclusive data exist concerning the best technique and duration of surveillance for CMV infection in patients for whom active surveillance for late-onset CMV should be performed, i.e., those reaching the end of prophylaxis. Only large randomised controlled trials, with long follow-up periods, will provide definitive conclusions regarding the comparative prophylactic roles of the major antiviral agents in this population, and how their use fits with a strategy of active surveillance and pre-emptive therapy.

Antifungal Prophylaxis in Solid-Organ Transplant Recipients: Considerations for Clinical Trial Design

There are several key issues regarding clinical trial design for antifungal prophylaxis in organ transplant recipients. The existing and emerging data on the epidemiology and risk factors for invasive mycoses in organ transplant recipients formed the basis for discerning the subgroups that may be targeted for prophylaxis, the unique end points to be considered, and the attributes of currently available drugs that may be suitable candidates for antifungal prophylaxis. Epidemiological characteristics of invasive mycoses in organ transplant recipients have evolved sufficiently to warrant thoughtful reconsideration of the subsets of patients and the fungal pathogens to be targeted for antifungal prophylactic trials in the current era. Safety and tolerability of antifungal agents and outcome stratified by severity of illness are important end points given the potential for drug interactions with immunosuppressive agents and the fact that a beneficial effect of prophylaxis on outcome has been difficult to document in organ transplant recipients. Clinical trial design for antifungal prophylaxis must carefully consider the unique issues pertaining to the selection of patients most likely to benefit, as well as the tolerability and drug interactions of antifungal agents in organ transplant recipients.