Mendoza, Maria A.

AbstractBackgroundThe incidence of mycobacterial infections in patients with hematologic malignancies and hematopoietic stem cell transplant (HSCT) recipients is increasing, contributing to significant mortality and morbidity. This review explores the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of nontuberculous mycobacteria (NTM) in this population.MethodsA literature search was performed using PubMed with keywords and MeSH terms pertaining to the topics of nontuberculous mycobacteria, hematologic malignancies, hematopoietic stem cell transplant, cellular therapies, chimeric antigen therapies, epidemiology, diagnosis, and treatment. Additionally, we examined the reference lists of the included articles to identify other pertinent studies.ResultsDiagnosing mycobacterial disease among patients with hematologic disease and treatment‐associated immunosuppressive conditions is challenging due to the lack of distinctive clinical, radiographic, and laboratory markers, as well as the atypical manifestations compared to immunocompetent patients. Treatment involves using a combination of antibiotics for extended durations, coupled with strategies to achieve source control and reduce immunosuppression when feasible. This is complicated by the absence of clear data correlating in‐vitro drug susceptibility and clinical outcome for many antimicrobials use to treat NTM, adverse drug‐drug interactions, and the frequent challenges related to poor medication tolerability and toxicities.ConclusionThe rising incidence and corresponding clinical challenges of mycobacterial infections in this unique patient population necessitate a heightened awareness and familiarity of NTM disease by clinicians to achieve timely diagnosis and favorable treatment outcomes. image

Abstract Background Powassan virus (POWV) is an emerging arthropod-borne flavivirus, transmitted by Ixodes spp. ticks, which has been associated with neuroinvasive disease and poor outcomes. Methods A retrospective study was conducted at Mayo Clinic from 2013 to 2022. We included clinical and epidemiologic data of probable and confirmed neuroinvasive POWV cases. Results Sixteen patients with neuroinvasive POWV were identified; their median age was 63.2 years, and 62.5% were male. Six patients presented with rhombencephalitis, 4 with isolated meningitis, 3 with meningoencephalitis, 2 with meningoencephalomyelitis, and 1 with opsoclonus myoclonus syndrome. A median time of 18 days was observed between symptom onset and diagnosis. Cerebrospinal fluid analysis showed lymphocytic pleocytosis with elevated protein and normal glucose in the majority of patients. Death occurred within 90 days in 3 patients (18.8%), and residual neurologic deficits were seen in 8 survivors (72.7%). Conclusions To our knowledge, this is the largest case series of patients with neuroinvasive POWV infection. We highlight the importance of a high clinical suspicion among patients who live in or travel to high-risk areas during the spring to fall months. Our data show high morbidity and mortality rates among patients with neuroinvasive disease.

The literature regarding Clostridioides difficile infection (CDI) in left ventricular assist devices (LVADs) patients is limited. Therefore, we aimed to characterize the clinical course, risk factors, management, and outcomes of LVAD patients who developed CDI. Adult patients who underwent LVAD placement during 2010–2022 and developed CDI were included. To determine risk factors and outcomes, we matched CDI patients with LVAD patients who did not develop CDI. Each CDI case was matched with up to two control subjects by age, sex, and time from LVAD implantation. Forty-seven of 393 LVAD patients (12.0%) developed CDI. The median time from LVAD implantation to CDI was 147 days (interquartile range 22.5–647.0). The most common CDI treatment was oral vancomycin (n = 26, 55.3%). Thirteen patients (27.7%) required treatment extension because of a lack of clinical response. Three patients (6.4%) developed recurrent CDI. When 42 cases were matched to 79 control subjects, antibiotic exposure within 90 days was significantly associated with CDI (adjusted odds ratio 5.77; 95% confidence interval, 1.87–17.74; p = 0.002). Moreover, CDI was associated with 1 year mortality (adjusted hazard ratio 2.62; 95% confidence interval, 1.18–5.82; p = 0.018). This infection occurs most often within the first year after LVAD implantation and was associated with 1 year mortality. Antibiotic exposure is an important risk for CDI.

AbstractBackgroundCurrent guidelines recommend immunomodulators, tocilizumab or baricitinib, for the management of severe coronavirus disease‐2019 (COVID‐19) in patients with increasing oxygen requirements. Given their immunosuppressive effects, there is a concern for higher rates of infection among transplant recipients.MethodsA retrospective cohort study of transplant patients with severe COVID‐19 between April 2020 and January 2022 was performed at the Mayo Clinic. The primary outcome was incidence of secondary infections after COVID‐19 diagnosis. Secondary outcomes were 90‐day mortality, ventilatory days, and thromboembolic events.ResultsA total of 191 hospitalized transplant patients were studied, including 77 (40.3%) patients who received an immunomodulator. Overall, 89% were solid organ transplant recipients, with kidney as the most common transplanted organ (50.3%). The majority (89.0%) required oxygen supplementation on admission, and 39.8% of these patients required mechanical ventilation during the hospital course. There was no significant difference in the incidence of secondary infections between those who received or did not receive an immunomodulator (p = .984). Likewise, there was no difference in 90‐day mortality between patients who received or did not receive an immunomodulator (p = .134). However, higher mortality was observed among patients that developed a secondary infection (p < .001).ConclusionThe use of immunomodulators in transplant patients with severe COVID‐19 was not significantly associated with an increased risk of secondary infections. Secondary infections were associated with higher risk of all‐cause mortality. Future studies of larger cohorts are needed to explore the effect of immunomodulators on survival among transplant patients with COVID‐19. image

Abstract Background Hospital-Acquired Pneumonia (HAP), defined as pneumonia that occurs 48 hours or more after hospital admission, is considered a part of the health care-associated infections (HAIs). HAIs are one of the top ten causes of death in the United States. Correct diagnosis of HAIs is key to reducing its impact, however, the diagnosis of HAP is challenging because clinical findings are nonspecific and there is no combination of signs, symptoms, and laboratory or imaging results that can predict this diagnosis with a good sensitivity or specificity. This study aims to clarify the prioritization of clinical elements considered in the diagnosis of HAP by physicians at our center. Methods This is a cross-sectional study at a large, tertiary care academic center in Miami, Florida. The target population included hospitalists, internal medicine residents, critical care and infectious disease fellows. REDCap was used to administer the survey and collect data. A rank individual analysis was conducted to assess for the most significant diagnostic criteria overall. Kruskal-Wallis analysis was conducted to assess for significance of the individual diagnostic criteria. Results At the end of the survey period, 130 people responded (45.8% of sent surveys). Overall Kruskal-Wallis rank sum test of the systemic factors showed significant differences between the diagnostic criteria chosen. The presence of a new or worsening infiltrate on imaging was selected as most important. After that, fever, a positive respiratory culture, worsening hypoxia and new cough and shortness of breath were in the second tier of important criteria (Figure 1). The median number of factors needed to have HAP in the differential diagnosis and start empiric treatment was 3, while the needed number to secure the diagnosis of HAP was 4. In an immunocompromised patient, the median number of factors needed was 2 (Figure 2). Color red, represents selection 1 - meaning, the larger the tab, it means that specific factor was highly considered as the first factor in the diagnosis of HAP. Color green represents second most selected factor Color blue represents third most selected factor Upper box: median number of factors needed to secure the diagnosis of HAP Mid box: median number of factors needed to include HAP as the differential diagnosis in an immunocompromised patient Lower box: media number of factors needed to have HAP in the differential and start empirical treatment Conclusion In this study, we observed that the most highly considered criteria for the diagnosis of HAP are new or worsening infiltrate on imaging, new or worsening hypoxia, and respiratory cultures with growth of a classical respiratory pathogen. Most of these criteria are part of the IDSA guidelines on the evaluation and treatment of HAP. Future directions include developing a decision support tool for diagnosing HAP. Disclosures All Authors: No reported disclosures.

Abstract Background The incidence of end-stage heart failure necessitating advanced cardiac therapy continues to increase in the United states. Implantable left ventricular assist devices (LVADs) represent an important modality that is utilized both as a bridge to heart transplant or as destination therapy. LVAD-associated infections, ranging from driveline exit site or pocket infections to endovascular infections, are a major complication with high mortality. Antibiotic prophylaxis at time of LVAD implantation is therefore an important strategy to mitigate infections. However, a clear surgical infection prophylaxis regimen and associated outcomes have not been reported. Methods We performed a single center, retrospective cohort study evaluating the impact of antimicrobial prophylaxis on risk of infection in patients who underwent LVAD implantation between February 2007 and June 2019 at Mayo Clinic. LVAD-specific and related infections were defined according to the International Society of Heart Lung Transplantation criteria. Single drug prophylaxis (SDP) included cefazolin only, vancomycin only, or cefazolin and vancomycin; multidrug (MDP) regimen includes either of the SDP regimens plus another antibiotic. We compared incidence of infection within 90-day and within one-year of implantation, as well as risk of C. difficile infections between the SDP and MDP cohorts. Results We reviewed 403 patients who received LVAD implantation (Table 1), 402 of had information on surgical prophylaxis. 307 (76%) patients received SDP and 95 patients (24%) received MDP. 14 patients developed an infection within 1 year of implantation (Table 2). There was no difference in the incidence of infections between SDP and MDP arms both at 90 days and 1-year post-implantation (p=0.11). The median time of infection since LVAD implantation was similar between SDP and MDP (p=0.37) arms. Incidence of C. difficile infection was not different between groups (p=0.10) (Table 3). Conclusion There was no significant difference in incidence or time to first infection, within 90-day and 1-year of implantation, between single- and multidrug antibiotic surgical prophylaxis regimens administered at the time of LVAD implantation. Future prospective trials are needed to develop a clear LVAD antibiotic prophylaxis protocol. Disclosures John C. O'Horo, Sr., MD, MPH, Bates college: Advisor/Consultant|MITRE corporation: Grant/Research Support|nferenec, Inc: Grant/Research Support.

Abstract Background Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV) infected people worldwide. Patients with HIV who have latent TB are 20-30 times more likely to develop active TB. Integrated antiretroviral therapy (ART) early in the treatment for tuberculosis is recommended due to improved morbidity and mortality, however, there can be serious drug interactions. Rifamycins are potent inducers of the CYP3A4 isoform, which can cause sub-therapeutic concentrations of anti-retroviral drugs, among these, rifabutin (RBN) is a less potent inducer of CYP3A4. Pharmacokinetic (PK) studies done on healthy adults showed that rifampin decreased dolutegravir (DTG) concentrations by more than 50 % whereas RBN decreased it by 30%. RBN has been preferred given that its favorable pharmacokinetic and toxicity profile. Currently there are no studies examining the use of RBN and DTG in co-infected persons. This is a case series of 4 co-infected patients receiving both agents who underwent PK analysis. Methods Retrospective analysis of patients in the respiratory care unit (RCU) at Jackson Memorial Hospital in Miami. We included adult patients, admitted to the RCU, with a concomitant diagnosis of HIV and active TB disease who received DTG and RBN, and for which DTG and RBN plasma concentrations were measured for therapeutic drug monitoring (TDM). A non-compartmental analysis was performed and the area under the concentration-time curve (AUC) was calculated for DTG and RBN. Results We report 4 patients (Figure 1) that met criteria and underwent PK analysis. All patients with TB who were treated with RBN had low concentrations of DTG, requiring higher doses of DTG (Table 1 & 2). After adjustments based on PK analysis, there was evidence of a favorable response to treatment in 2 patients, with a less than robust in the 2 others. Adequate suppression of viral load could not be determined for 3 of the patients because of the short observation time. Figure 1:Timelines of patients describing admission and HIV and tuberculosis treatment providedDTG, dolutegravir. RFB, rifabutin. VL, viral load. AFB, Acid fast bacilli. LAD, lymphadenopathy. TAF, Tenofovir alafenamide. FTC, Emtricitabine. TDF, Tenofovir Disoproxil Fumarate. INH, Isoniazid. PYZ, Pyrazinamide. BID, twice a day. QD, daily. IRIS, Immune reconstitution inflammatory syndrome. GU, genitourinary. TB, tuberculosis.Table 1:Patients’ pharmacokinetics of DTGAUCX-Y, area under the concentration-time curve from time X to Y hours; AUC0-tau, area under the concentration-time curve from time zero to the end of the dosing interval; DTG, dolutegravir; TDM, therapeutic drug monitoring. a) AUC0-6 was calculated.Table 2:Patients’ pharmacokinetics of RBNAUCX-Y, area under the concentration-time curve from time X to Y hours; AUC0-tau, area under the concentration-time curve from time zero to the end of the dosing interval; RBN, Rifabutin; TDM, therapeutic drug monitoring. a) All RBN doses given every 24 hours, b) RBN value was trace and AUC was not calculated. Conclusion All patients with HIV and TB who were treated with RBN had low concentrations of DTG. This case series demonstrates that for optimal concomitant use of rifabutin and dolutegravir it is highly recommended to use TDM. Prospective clinical studies are needed to further determine the PK interactions between RBN and DTG and virologic response to treatment. Disclosures All Authors: No reported disclosures.

Abstract Background Immunomodulators have been shown to improve the outcomes of patients with severe COVID-19. However, it is not known if tocilizumab or baricitinib use would be beneficial in transplant patients who are already receiving immunomodulating agents. Moreover, augmented immunomodulation may increase risk of opportunistic infection. There are few studies analyzing the outcomes and complications of these medications in this population. Methods This is a detailed review of the medical records of all transplant patients who received tocilizumab or baricitinib for COVID-19 indication at our multi-state transplant center from April 2020 to March 2022. Results A total of 57 transplant patients received tocilizumab (n=48) or baricitinib (n=9) for management of COVID-19. Baseline characteristics are in Table 1. 60% had received at least one dose of COVID-19 vaccine. At diagnosis, all patients were lymphopenic (median 0.4 x109 cells/L) with high CRP (median 76.8mg/L) and elevated IL-6 levels (median 145.5pg/ml.). The majority had reduction in transplant immunosuppression (75%) and received remdesivir (86%) and dexamethasone (90%). Majority were admitted to the ICU (68%), including 40% who required invasive mechanical ventilation (Table 2). Almost a third developed bacterial or fungal superinfection. Bacterial infections include respiratory cultures with Klebsiella spp, MRSA, P. aeruginosa, Enterobacter spp and Stenotrophomonas. Blood cultures were positive for Klebsiella spp, MDR P. aeruginosa, E faecalis. Fungal infections include three patients with Aspergillus spp infections who received antifungals. No statistical difference was seen in mortality between patients with infections and not infections group. No statistical difference was seen between type of transplants for infection or mortality. Mortality at 90 days was 46%. Conclusion Transplant patients who received tocilizumab or baricitinib for severe or critical COVID-19 have poor outcome. This case series found high rates of mortality and opportunistic superinfections after tocilizumab and baricitinib use compared to the current literature. Future directions include a matched case-control study to compare the outcomes in this population. Disclosures Raymund R. Razonable, MD, Gilead: Grant/Research Support|Glaxo Smith Kline: Advisor/Consultant|Novartis: DSMB|Regeneron: Grant/Research Support|Roche: Grant/Research Support.

Abstract Background Invasive Mold Infections (IMI) cause significant morbidity and mortality, particularly in patients with hematologic malignancies (HM) and hematopoietic stem cell transplant (HSCT) recipients. Although the risk has significantly decreased with the use of triazole agents as primary prophylaxis, breakthrough infections still occur. Risk factors for IMI have been well-described. Limited data exist on factors predicting mortality. Methods We identified cases using the Cancer registry and Microbiology data at Mayo Clinic Minnesota from 11/19/2011–8/6/2021 and Mayo Clinic Arizona and Florida from 09/13/2017–11/19/2021. We conducted a retrospective review to identify cases of proven/probable IMI per EORTC/MSG criteria. Patients who received at least 7 days of anti-mold prophylaxis were considered having breakthrough infection (Br-IMI). Survival function was estimated using the Kaplan-Meier method. We evaluated predictors of mortality using Cox regression analysis. Results 401 cases of IMI were included (80.2% aspergillosis, 10.2% fusariosis, 8.4% mucormycosis, 1.2% scedosporiosis). 189 patients had proven/probable and 212 had possible disease. 12-week mortality for the entire cohort was 33%. There were 87 cases of Br-IMI (21.6%) on mold-active prophylaxis (posaconazole n=54, voriconazole n=26, isavuconazole n=5, itraconazole n=1, liposomal amphotericin B n=1). A comparison between patients not receiving prophylaxis and those with Br-IMI is shown in Table 1. Higher proportion of patients with Br-IMI had prolonged neutropenia/lymphopenia and graft-versus-host disease involving the gastrointestinal tract or lungs. Positive Aspergillus galactomannan (index ≥ 1.0) was seen more in patients who were not on mold-active prophylaxis. Mortality was 31.5% in patients not receiving prophylaxis and 41.3% with Br-IMI (Figure 1). In multivariate analysis, age, prolonged neutropenia, active HM, Br-IMI and HSCT were associated with increased mortality (Table 2). Conclusion In this cohort, the rate of Br-IMI was significant despite the use of primary prophylaxis (mainly posaconazole). Mortality was higher in patients with Br-IMI compared to those not receiving mold-active prophylaxis. Therefore, clinicians should remain alert to the possibility of Br-IMI. Disclosures Paschalis Vergidis, MD, AbbVie: DSMB|Cidara: Grant/Research Support|Scynexis: Grant/Research Support.

Background: Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV)-infected people worldwide. Currently there are no studies examining the use of Rifabutin (RBN) and Dolutegravir (DTG) in co-infected persons. This is a case series of 4 co-infected patients receiving both agents who underwent Pharmacokinetic (PK) analysis. Methods and Results: This is a retrospective chart review study of four patients diagnosed with both HIV and TB, receiving RBN and DTG and undergoing therapeutic drug monitoring. All 4 cases had lower than expected DTG concentrations at least once, including those on the current recommended dose of DTG with RBN, and even those receiving higher doses. Conclusions: Given the frequency of low DTG and RBN concentrations, therapeutic drug monitoring (TDM) for these drugs is advisable. Prospective clinical studies are needed to further determine the PK interactions between RBN and DTG, and virologic response to treatment.