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Highlights • Prophylaxis with brincidofovir 100 mg twice weekly did not decrease clinically significant cytomegalovirus (CMV) infection (CMV disease or CMV DNAemia requiring preemptive therapy) through post-hematopoietic cell transplantation (HCT) week 24 compared with placebo. • Brincidofovir demonstrated anti-CMV activity, with decreased overall occurrence of CMV DNAemia and need for preemptive therapy through post-HCT week 24. • Brincidofovir was associated with increased gastrointestinal toxicity, which could not be differentiated from acute gastrointestinal GVHD in this blinded study with a safety management plan. ABSTRACT Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio,.95 [95% confidence interval,.64 to 1.41]; P =.805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P <.001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity. [ABSTRACT FROM AUTHOR]

Objective While infection burden is high among patients with systemic lupus erythematosus (SLE), there is uncertainty about whether infection rates differ by immunosuppressive drug regimens. We undertook this study to compare infection rates among SLE patients newly initiating immunosuppressive therapy with mycophenolate mofetil (MMF), azathioprine (AZA), or cyclophosphamide (CYC). Methods Within the Medicaid Analytic eXtract database (2000-2010; 29 most populated US states), we identified adults with SLE starting MMF, AZA, or CYC treatment. We estimated propensity scores for receipt of MMF versus AZA and MMF versus CYC based on sociodemographic, comorbidity, and medication use information. After 1:1 propensity score matching, we estimated incidence rates of serious infections up to 6 and 12 months after drug initiation and used Cox regression to estimate hazard ratios (HRs) of first infection and death, with 95% confidence intervals (95% CIs). We performed primary intent-to-treat (ITT) and secondary as-treated analyses. Results We studied 1,350 propensity score-matched pairs of MMF and AZA initiators and 674 propensity score-matched pairs of MMF and CYC initiators. In 6-month ITT analyses, the incidence rate per 100 person-years for first serious hospitalized infection was 14.6 in MMF users and 15.2 in AZA users (HR of MMF versus AZA 0.99 [95% CI 0.74-1.32]). Comparing MMF to CYC, the incidence rate per 100 person-years for first serious infection was 24.1 in MMF users and 24.6 in CYC users (HR 0.95 [95% CI 0.69-1.32]). There were no differences in mortality in either comparison. As-treated analyses yielded similar results. Conclusion In a nationwide longitudinal study of Medicaid SLE patients at high risk of infection, rates of serious infection and mortality did not differ among new users of MMF, AZA, or CYC. [ABSTRACT FROM AUTHOR]

Little data are available regarding the safety and immunologic response to pandemic H1N1 influenza vaccine in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). We measured serum antibody titers against A/California/7/2009 H1N1 using a hemagglutination inhibition assay in 82 allogeneic HSCT recipients who received the 2009 H1N1 vaccine between November 2009 and January 2010 after it became available at our institution. The median time between HSCT and vaccination was 19 months (range, 2.5-94 months), and the median time from vaccination to specimen collection was 56 days (range, 14-140 days). Seroprotective antibody titers (hemagglutination inhibition titer ≥1:40) against 2009 H1N1 influenza A virus were detected in 51% of patients. The presence of chronic graft-versus-host disease and type of conditioning regimen did not affect the rate of detection of seroprotective titers after vaccination. Patients were more likely to have a seroprotective titer the farther away from HSCT they were (adjusted odds ratio, 1.79 per year; 95% confidence interval, 1.12-2.85). Rituximab administration in the year before vaccination was associated with a lack of seroprotective titer (adjusted odds ratio, 0.11; 95% confidence interval, 0.01-0.97). The vaccine was safe and well tolerated. Strategies are needed to improve the influenza vaccine response in this population, especially those receiving immunotherapy. [Copyright &y& Elsevier]

Background. Alemtuzumab is an emerging therapy for refractory lymphoproliferative disorders. The associated long-term risks of infection remain poorly defined. Methods. From July 2001 through December 2003, all patients who received alemtuzumab for the treatment of lymphoproliferative disorders at 1 institution underwent a retrospective evaluation to document infectious complications until death or end of follow-up in October 2004. Alemtuzumab recipients who underwent allogeneic hematopoietic stem cell transplantation were compared with a concurrent cohort who also underwent allogeneic hematopoietic stem cell transplantation but did not receive alemtuzumab. Results. Twenty-seven patients were identified (21 with chronic lymphocytic leukemia and 6 with plasma cell disorders). The overall mortality was 37%, with 7 of 10 deaths being related to infection. Significant opportunistic infections occurred in 9 patients (43%) with chronic lymphocytic leukemia, including cytomegalovirus, progressive multifocal leukoencephalopathy, adenovirus, toxoplasmosis, and acanthamaebiasis. Thirty nonopportunistic infections in 22 patients (82%) were also identified. The 3 deaths related to nonopportunistic infections all involved Enterococcus species bacteremia. When compared with a concurrent chronic lymphocytic leukemia cohort that underwent allogeneic hematopoietic stem cell transplantation, alemtuzumab recipients had an incidence of cytomegalovirus reactivation of 66.7% (6 of 9 patients), compared with 37% in the non-alemtuzumab group (10 of 27 patients; P = .15), and an incidence of post-transplant opportunistic infections (excluding herpesviruses) of 44.4% (compared with 29.6% in the non-alemtuzumab group; P = .41). Conclusions. Despite the use of herpesvirus and Pneumocystis pneumonia prophylaxis, serious infectious complications occur in patients receiving alemtuzumab for lymphoproliferative disorders. Infectious complications are more varied and diverse in patients receiving alemtuzumab than has been reported in trials to date. [ABSTRACT FROM AUTHOR]

Abstract: Sirolimus is increasingly used in transplantation for prevention and treatment of graft-versus-host disease and organ rejection. Voriconazole is contraindicated when used concomitantly with sirolimus because of a substantial increase in sirolimus drug exposure with unadjusted dosing, but voriconazole is also considered the best initial treatment of invasive aspergillosis and other fungal infections. Patients who received voriconazole and sirolimus concomitantly were identified by a review of the medical records of all allogeneic hematopoietic stem cell recipients at our institution from September 1, 2002, to June 1, 2005. Data including baseline characteristics, indications for both drugs, and potential adverse effects were evaluated. Eleven patients received voriconazole and sirolimus concomitantly for a median of 33 days (range, 3-100 days). In 8 patients whose sirolimus dose was initially reduced by 90%, trough sirolimus levels were similar to those obtained before the administration of voriconazole; no obvious significant toxicity from either drug was observed during coadministration. Serious adverse events were observed in 2 patients in whom sirolimus dosing was not adjusted during voriconazole administration. Sirolimus and voriconazole may be safely coadministered if there is an empiric initial 90% sirolimus dose reduction combined with systematic monitoring of trough levels. [Copyright &y& Elsevier]

The close linkage of infection with the nature and intensity of the transplant immunosuppressive program has led to the concept of the therapeutic prescription. This has two components: an immunosuppressive one to prevent or treat rejection and graft-versus-host disease and an antimicrobial one to make it safe. This review provides a conceptual framework to approach the risk and risk periods for infection in solid organ and hematopoietic stem cell transplant recipients as well as an approach to antimicrobial use in this population. [ABSTRACT FROM AUTHOR]

There are no parenteral antihelminthic drugs licensed for use in humans. We report the successful treatment of disseminated strongyloidiasis with a parenteral veterinary formulation of ivermectin in a patient presenting with severe malabsorption and paralytic ileus. To our knowledge, ivermectin levels are reported for the first time in this situation. [ABSTRACT FROM AUTHOR]

Abstract: Hematopoietic stem cell transplantation (HSCT) recipients are at risk for varicella-zoster virus (VZV) reactivation. Vaccination may help restore VZV immunity; however, the available live attenuated VZV vaccine (Zostavax) is contraindicated in immunocompromised hosts. We report our experience with using a single dose of VZV vaccine in 110 adult autologous and allogeneic HSCT recipients who were about 2 years after transplantation, free of graft-versus-host disease, and not receiving immunosuppression. One hundred eight vaccine recipients (98.2%) had no clinically apparent adverse events with a median follow-up period of 9.5 months (interquartile range, 6 to 16; range, 2 to 28). Two vaccine recipients (1.8%) developed a skin rash (one zoster-like rash with associated pain, one varicella-like) within 42 days post-vaccination that resolved with antiviral therapy. We could not confirm if these rashes were due to vaccine (Oka) or wild-type VZV. No other possible cases of VZV reactivation have occurred with about 1178 months of follow-up. Live attenuated zoster vaccine appears generally safe in this population when vaccinated as noted; the overall vaccination risk needs to be weighed against the risk of wild-type VZV disease in this high-risk population. [Copyright &y& Elsevier]

Background PIV infections are an important cause of morbidity and mortality in HCT recipients. DAS181, a sialidase fusion protein, has demonstrated activity in pre-clinical and clinical studies. Methods Adult immunocompromised patients (IC), including HCT recipients, diagnosed with PIV LRTI on chest imaging and required SO ≥ 2L/min were randomized 2:1 (stratified by mechanical ventilation [MV] at baseline) to nebulized DAS181 (4.5 mg in 3.5mL/day) or matching placebo for up to 10 consecutive days. The primary endpoint was the proportion of patients reaching clinical stability survival (CSS, defined as alive, resolution of SO requirement, and normalization of vital signs) by Day 45. An exploratory end point of proportion to return to room air (RTRA) was analyzed. Results Out of the 110 patients randomized, 64 HCT recipients received study drug (43 DAS181 and 21 placebo). Median age was 53 years (range, 19-77), half were male (50%), white (84%), and had received an allogeneic HCT (86%). A post-hoc analysis of the HCT recipients on SO showed that day 45 CSS was achieved by 46.5% of DAS181-treated patients compared to 33.3% of placebo (p = 0.23). In addition, when compared to placebo, HCT recipients on SO who received DAS181 within 1 year from transplant were more likely to achieve CSS at day 45 (48.4% vs. 12.5%; p = 0.071), were more likely to RTRA at day 28 and day 45 (53.3% vs. 12.5%; p = 0.04 and 60% vs. 25%; p = 0.086, respectively), more likely to be discharged from the hospital by day 45 (64.5% vs. 12.5%; p = 0.011), and had a trend for lower mortality at day 45 (25.8% vs. 62.5%, p = 0.064). The rate of adverse events was similar in both treatment groups. Conclusion DAS181 was well tolerated and a post-hoc analysis in HCT recipients with PIV LRTI on SO within 1 year of transplant, DAS181 was effective (RTRA) and showed a trend towards lower mortality by day 45. DAS181 was granted Breakthrough Therapy Designation for the treatment of PIV LRTI in IC patients and a phase 3 trial is being planned. [ABSTRACT FROM AUTHOR]

Presents a case report of a man with neurosyphilis that presented features of herpes simplex encephalitis. Results of laboratory and physical examinations; Diagnosis and therapy; Classical findings in herpes encephalitis.

Background Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19). Methods Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020–April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients. Results Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was −0.69 (95% confidence interval [CI], −1.25 to −.14) log10 copies/mL for IC patients and −0.31 (95% CI, −.42 to −.20) log10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%). Conclusions IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695. [ABSTRACT FROM AUTHOR]

We describe 3 cases of invasive fungal disease in the setting of transplantation-associated immunosuppression, developing months to years after clinically resolved penetrating soft-tissue injuries with wood fragments. Invasive fungal disease resulting from remote inoculation is a distinct syndrome in immunocompromised patients presenting with soft-tissue abnormalities in areas of prior trauma. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial," by T. J. Walsh and colleagues in the 2007 issue.

Background: Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients. Methods: We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran’s Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates. Results: Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27–0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36–1.87) or overall mortality (RR 0.95, 95% CI 0.46–1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing. Conclusions: Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals. [ABSTRACT FROM AUTHOR]

Background Methicillin-susceptible Staphylococcus aureus (MSSA) is a common cause of bloodstream infection (BSI) in patients with febrile neutropenia, but treatment practices vary, and guidelines are not clear on the optimal regimen. Methods We conducted a multicenter retrospective cohort study of MSSA BSI in febrile neutropenia. We divided patients into 3 treatment groups: (1) broad-spectrum beta-lactams (ie, piperacillin-tazobactam, cefepime, meropenem); (2) narrow-spectrum beta-lactams (ie, cefazolin, oxacillin, nafcillin); and (3) combination beta-lactams (ie, both narrow- and broad-spectrum). We used multivariable logistic regression to compare 60-day mortality and bacteremia recurrence while adjusting for potential confounders. Results We identified 889 patients with MSSA BSI, 128 of whom had neutropenia at the time of the index culture: median age 56 (interquartile range, 43–65) years and 76 (59%) male. Of those, 56 (44%) received broad-spectrum beta-lactams, 30 (23%) received narrow-spectrum beta-lactams, and 42 (33%) received combination therapy. After adjusting for covariates, including disease severity, combination therapy was associated with a significantly higher odds for 60-day all-cause mortality compared with broad spectrum beta-lactams (adjusted odds ratio [aOR], 3.39; 95% confidence interval [CI], 1.29–8.89; P  = .013) and compared with narrow spectrum beta-lactams, although the latter was not statistically significant (aOR, 3.30; 95% CI,.80–13.61; P  = .071). Conclusions Use of combination beta-lactam therapy in patients with MSSA BSI and febrile neutropenia is associated with a higher mortality compared with treatment with broad-spectrum beta-lactam after adjusting for potential confounders. Patients in this study who transitioned to narrow-spectrum beta-lactam antibiotics did not have worse clinical outcomes compared with those who continued broad-spectrum beta-lactam therapy. [ABSTRACT FROM AUTHOR]

Recombinant herpes zoster (HZ) vaccines may be an alternative to the live-attenuated HZ vaccine for immunocompromised individuals. This was a phase 1/2, randomized, observer-blind, placebo-controlled study in adults with multiple myeloma, non-Hodgkin lymphoma (B- or T-cell), Hodgkin lymphoma, or acute myeloid leukemia who had undergone autologous hematopoietic stem-cell transplant 50 to 70 days earlier. Subjects (N = 121) were randomized 1:1:1:1 to receive (at months 0, 1, 3) three doses of 50 μg varicella-zoster virus glycoprotein E (gE) adjuvanted with AS01B, 3 doses of gE adjuvanted with AS01E, 1 dose of saline followed by 2 doses of gE/AS01B, or 3 doses of saline. One month after the last dose (6 months after transplant), frequencies of CD4+ T cells expressing ⩾2 activation markers after induction with gE and anti-gE antibody concentrations were higher with all gE/AS01 regimens than with saline. Both responses persisted up to 1 year in subjects vaccinated with gE/AS01. Immune responses were higher in the gE/AS01B 3-dose group than in the gE/AS01B 2-dose group but not higher than in the gE/AS01E 3-dose group. One serious adverse event (pneumonia) was considered vaccine related. Both formulations and both schedules were immunogenic and well tolerated in this population. This study was registered at www.clinicaltrials.gov as #NCT00920218. (Blood. 2014;124(19):2921 -2929) [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) provides effective treatment for hematologic malignancies and immune disorders. Monitoring of posttransplant complications is critical, yet current diagnostic options are limited. Here, we show that cellfree DNA (cfDNA) in blood is a versatile analyte for monitoring of the most important complications that occur after HCT: graft-versus-host disease (GVHD), a frequent immune complication of HCT, infection, relapse of underlying disease, and graft failure. We demonstrate that these therapeutic complications are informed from a single assay, low-coverage bisulfite sequencing of cfDNA, followed by disease-specific bioinformatic analyses. To inform GVHD, we profile cfDNA methylation marks to trace the cfDNA tissues-oforigin and to quantify tissue-specific injury. To inform infection, we implement metagenomic cfDNA profiling. To inform cancer relapse, we implement analyses of tumor-specific genomic aberrations. Finally, to detect graft failure, we quantify the proportion of donor- and recipient-specific cfDNA. We applied this assay to 170 plasma samples collected from 27 HCT recipients at predetermined timepoints before and after allogeneic HCT. We found that the abundance of solid-organ-derived cfDNA in the blood at 1 mo after HCT is predictive of acute GVHD (area under the curve, 0.88). Metagenomic profiling of cfDNA revealed the frequent occurrence of viral reactivation in this patient population. The fraction of donor-specific cfDNA was indicative of relapse and remission, and the fraction of tumor-specific cfDNA was informative of cancer relapse. This proof-of-principle study shows that cfDNA has the potential to improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT. [ABSTRACT FROM AUTHOR]

Clarithromycin (CYP inhibitor) can be used instead of azithromycin for nontuberculous mycobacteria therapy in patients requiring CYP substrates to mitigate rifampin's CYP induction. We found no differences in adverse events (10/13 vs 14/17; P  = .73), drug intolerability (1/5 vs 4/11; P  = 1), or 90-day mortality (0/13 vs 1/17; P  = 1) in patients receiving clarithromycin vs azithromycin. [ABSTRACT FROM AUTHOR]

Background Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies. [ABSTRACT FROM AUTHOR]

Background Omadacycline is an aminomethylcycline antimicrobial approved by the US Food and Drug Administration in 2018 for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It has in vitro activity against nontuberculous mycobacteria, including Mycobacterium abscessus complex, but clinical data for this indication are lacking. Methods Omadacycline use was reviewed at an 804-bed academic medical center. Patients were included if they received omadacycline for culture-proven M abscessus disease in 2019. Results Four patients received omadacycline for the treatment of culture-positive M abscessus disease in 2019. Two patients had cutaneous disease, 1 had pulmonary disease, and 1 had osteomyelitis and bacteremia. The patients received omadacycline for a median duration of 166 days (range, 104–227) along with a combination of other antimicrobial agents. Omadacycline-containing regimens were associated with a clinical cure in 3 of 4 patients, with 1 patient improving on ongoing treatment. Omadacycline's tolerability was acceptable for patients with M abscessus disease, with 1 patient discontinuing therapy in month 6 due to nausea. Conclusions Omadacycline is a novel oral option for the treatment of M abscessus disease, for which safe and effective options are needed. Although this case series is promising, further data are required to determine omadacycline's definitive role in the treatment of M abscessus disease. [ABSTRACT FROM AUTHOR]

We report a case of fulminant Acanthamoeba castellanii encephalitis in a patient with chronic lymphocytic leukemia treated with ibrutinib. The unusually rapid neurologic decline and fatal outcome observed are probably related to alterations in immunologic function associated with inhibition of Bruton tyrosine kinase. [ABSTRACT FROM AUTHOR]

Background: Human Herpes Virus 8 (HHV8) can cause Kaposi’s Sarcoma (KS) in immunosuppressed individuals. However, little is known about the association between chemotherapy or hematopoietic stem cell transplantation (HSCT), circulating HHV8 DNA levels, and clinical KS in HIV-1-infected individuals with various malignancies. Therefore, we examined the associations between various malignancies, systemic cancer chemotherapy, T cell phenotypes, and circulating HHV8 DNA in 29 HIV-1-infected participants with concomitant KS or other cancer diagnoses. Methods: We quantified HHV8 plasma viral loads and cell-associated HHV8 DNA and determined the relationship between circulating HHV8 DNA and lymphocyte counts, and markers of early and late lymphocyte activation, proliferation and exhaustion. Results: There were no significant differences in plasma HHV8 DNA levels between baseline and post-chemotherapy time points or with the presence or absence of clinical KS. However, in two participants circulating HHV8 DNA increased following treatment for KS or HSCT for lymphoma,. We observed an approximately 2-log10 reduction in plasma HHV8 DNA in an individual with KS and multicentric Castleman disease following rituximab monotherapy. Although individuals with clinical KS had lower mean CD4+ T cell counts and percentages as expected, there were no significant associations with these factors and plasma HHV8 levels. We identified increased proportions of CD8+ and CD4+ T cells expressing CD69 (P = 0.01 & P = 0.04 respectively), and increased CD57 expression on CD4+ T cells (P = 0.003) in participants with detectable HHV8. Conclusion: These results suggest there is a complex relationship between circulating HHV8 DNA and tissue-based disease in HIV-1 and HHV8 co-infected individuals with various malignancies. [ABSTRACT FROM AUTHOR]

Infection is a major complication of hematopoietic cell transplantation. Prolonged neutropenia and graft-versus-host disease are the 2 major complications with an associated risk for infection, and these complications differ according to the graft source. A phase 3, multicenter, randomized trial (Blood and Marrow Transplant Clinical Trials Network [BMT CTN] 0201) of transplantation of bone marrow (BM) versus peripheral blood stem cells (PBSC) from unrelated donors showed no significant differences in 2-year survival between these graft sources. In an effort to provide data regarding whether BM or PBSC could be used as a preferential graft source for transplantation, we report a detailed analysis of the infectious complications for 2 years after transplantation from the BMT CTN 0201 trial. A total of 499 patients in this study had full audits of infection data. A total of 1347 infection episodes of moderate or greater severity were documented in 384 (77%) patients; 201 of 249 (81%) of the evaluable patients had received a BM graft and 183 of 250 (73%) had received a PBSC graft. Of 1347 infection episodes, 373 were severe and 123 were life-threatening and/or fatal; 710 (53%) of these episodes occurred on the BM arm and 637 (47%) on the PBSC arm, resulting in a 2-year cumulative incidence 84.7% (95% confidence interval [CI], 79.6 to 89.8) for BM versus 79.7% (95% CI, 73.9 to 85.5) for PBSC, P = .013. The majority of these episodes, 810 (60%), were due to bacteria, with a 2-year cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively ( P = .003). The cumulative incidence of bloodstream bacterial infections during the first 100 days was 44.8% (95% CI, 38.5 to 51.1) for BM versus 35.0% (95% CI, 28.9 to 41.1) for PBSC ( P = .027). The total infection density (number of infection events/100 patient days at risk) was .67 for BM and .60 for PBSC. The overall infection density for bacterial infections was .4 in both arms; for viral infections, it was .2 in both arms; and for fungal/parasitic infections, it was .04 and .05 for BM and PBSC, respectively. The cumulative incidence of infection before engraftment was 47.9% (95% CI, 41.5 to 53.9) for BM versus 32.8% (95% CI, 27.1 to 38.7) for PBSC ( P = .002), possibly related to quicker neutrophil engraftment using PBSC. Infections remain frequent after unrelated donor hematopoietic cell transplantation, particularly after BM grafts. [ABSTRACT FROM AUTHOR]

Background. Invasive fusariosis remains an aggressive, albeit infrequent infection in immunocompromised patients. Methods. We identified all cases of invasive fusariosis between January 2002 and December 2014. We recorded patient characteristics including clinical presentation, treatment, and outcomes at 6 and 12 weeks after diagnosis, as well as species identification and antifungal drug susceptibilities. Results. Fifteen patients were diagnosed with proven (12, 80%) or probable (3, 20%) fusariosis. Median age was 60 years (range, 26-78), and 10 patients were male. Underlying conditions included hematological malignancies (13, 87%), juvenile idiopathic arthritis (1, 7%), and third-degree burns (1, 7%). Five patients underwent hematopoietic stem-cell transplantation before diagnosis. Six patients (40%) received systemic glucocorticoids, and 11 patients (73%) had prolonged neutropenia at the time of diagnosis. Clinical presentations included the following: skin/ soft tissue infection (8, 53%), febrile neutropenia (4, 27%), respiratory tract infection (2, 13%), and septic arthritis (1, 7%). Twelve patients were treated with voriconazole: 6 (40%) with voriconazole alone, 4 (27%) with voriconazole and terbinafine, and 2 (13%) with voriconazole, terbinafine, and amphotericin. One patient (7%) was treated with terbinafine alone, and another with micafungin alone. Four patients underwent surgical debridement (4, 27%). Susceptibility testing was performed on 9 isolates; 8 demonstrated voriconazole minimum inhibitory concentrations ≥4 μg/mL. The cumulative probability of survival was 66.7% and 53.3% at 6 and 12 weeks after diagnosis. Conclusions. Mortality associated with invasive fusariosis remains high. Cumulative mortality at our center was lower than previous reports despite elevated voriconazole minimum inhibitory concentrations. Combination therapy should be studied systematically for fusariosis. [ABSTRACT FROM AUTHOR]

Objective To examine the epidemiology of serious infections, a significant cause of morbidity and mortality in systemic lupus erythematosus (SLE), in a nationwide cohort of SLE and lupus nephritis (LN) patients. Methods Using the Medicaid Analytic eXtract database for the years 2000-2006, we identified patients ages 18-64 years who had SLE and the subset who had LN. We ascertained cases of serious hospitalized infections using validated algorithms, and we determined 30-day mortality rates. Poisson regression was used to calculate infection incidence rates and multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) for the first infection, adjusted for sociodemographic variables, medication use, and an SLE-specific risk adjustment index. Results We identified 33,565 patients with SLE, 7,113 of whom had LN. There were 9,078 serious infections in 5,078 SLE patients and 3,494 infections in 1,825 LN patients. The infection incidence rate per 100 person-years was 10.8 in the SLE cohort and 23.9 in the LN subcohort. In adjusted models for the SLE cohort, we observed increased risks of infection in men as compared to women (HR 1.33 [95% confidence interval (95% CI) 1.20-1.47]), in blacks as compared to whites (HR 1.14 [95% CI 1.06-1.21]), and in users of glucocorticoids (HR 1.51 [95% CI 1.43-1.61]) and immunosuppressive drugs (HR 1.11 [95% CI 1.03-1.20]) as compared to never users. Hydroxychloroquine users had a reduced risk of infection as compared to never users (HR 0.73 [95% CI 0.68-0.77]). The 30-day mortality rate per 1,000 person-years among those hospitalized with infections was 21.4 in the SLE cohort and 38.6 in the LN subcohort. Conclusion In this diverse, nationwide cohort of SLE patients, we observed a substantial burden of serious infections with many subsequent deaths, particularly among those with LN. [ABSTRACT FROM AUTHOR]

Abstract: The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT. BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of .47/1000 patient-days (95% confidence interval [CI], .37 to .59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio [aHR] 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials. [Copyright &y& Elsevier]

Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem cell transplantation (HSCT); its most severe manifestation is the syndrome of posttransplantation acute limbic encephalitis (HHV-6-PALE). The epidemiology, risk factors, and characteristics of HHV-6-PALE after unrelated cord-blood transplantation (UCBT) are not well characterized. We analyzed 1344 patients undergoing allogeneic HSCT between March 2003 and March 2010 to identify risk factors and characteristics of HHV-6-PALE. The cohort included 1243 adult-donor HSCT and 101 UCBT recipients. All patients diagnosed with HHV-6-PALE had HHV-6 DNA in cerebrospinal fluid (CSF) specimens in addition to symptoms and studies indicating limbic encephalitis. Nineteen cases (1.4%) of HHV-6-PALE were identified during this study: 10 after UCBT (9.9%) and 9 after adult-donor HSCT (0.7%), for an incidence rate of 1.2 cases/1000 patient-days compared to 0.08 cases/1000 patient-days (P < .001), respectively. Risk factors for HHV-6-PALE on multivariable Cox modeling were UCBT (adjusted hazard ratio [aHR], 20.0; 95% confidence interval [CI], 7.3-55.0; P < .001), time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (aHR, 7.5; 95% CI, 2.8-19.8; P < .001), and adult-mismatched donor (aHR, 4.3; 95% CI, 1.1-17.3; P = .04). Death from HHV-6-PALE occurred in 50% of affected patients undergoing UCBT and no recipients of adult-donor cells. Patients receiving UCBT have increased risk for HHV-6-PALE and greater morbidity from this disease. [ABSTRACT FROM AUTHOR]

Sirolimus is used in allogeneic hematopoietic stem cell transplants (HSCTs) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this population for invasive fungal disease (IFD) prophylaxis and treatment. As posaconazole strongly inhibits CYP3A4, concurrent administration of sirolimus, a CYP3A4 substrate, and posaconazole has been reported to increase sirolimus drug exposure substantially. Coadministration of posaconazole and sirolimus is contraindicated by the manufacturer of posaconazole. We identified 15 patients who underwent HSCTs at our institution receiving a steady-state dose of sirolimus who subsequently started posaconazole therapy from January 2006 to March 2009. We recorded baseline characteristics, drug administration details, and potential adverse effects related to either drug. All patients underwent HSCTs for treatment of hematologic malignancy. All patients were initially prescribed sirolimus for GVHD prophylaxis and continued therapy after developing GVHD. Twelve patients (80%) received posaconazole for IFD prophylaxis in the setting of GVHD and 3 (20%) for IFD treatment. Patients received sirolimus and posaconazole concurrently for a median of 78 days (interquartile range [IQR] 25-177; range, 6-503). The median daily dose of sirolimus (2 mg/day) before initiation of posaconazole was reduced 50% to a median daily dose of 1 mg/day at steady state. Six patients experienced sirolimus trough levels greater than 12 ng/mL during coadministration, but only 1 patient experienced an adverse event potentially associated with sirolimus exposure during the first month of coadministration. This patient''s sirolimus dose was empirically reduced by only 30% on posaconazole initiation. Concurrent sirolimus and posaconazole use seems to be well tolerated with a 33% to 50% empiric sirolimus dose reduction and close monitoring of serum sirolimus trough levels at the time of posaconazole initiation. [Copyright &y& Elsevier]

Parainfluenza virus (PIV) can cause significant morbidity after allogeneic stem cell transplantation (SCT). We report the first use of inhaled DAS181 for PIV in an allogeneic SCT recipient. Symptoms, oxygenation, and pulmonary function tests improved. Nasopharyngeal samples showed a reduction in viral load. DAS181 should be systematically evaluated for severe PIV infection. [ABSTRACT FROM AUTHOR]

We investigated the prevalence of xenotropic murine leukemia virus-related virus (XMRV) among 293 participants seen at academic hospitals in Boston, Massachusetts. Participants were recruited from the following 5 groups of patients: chronic fatigue syndrome (n=32), human immunodeficiency virus infection (n=43), rheumatoid arthritis (n=97), hematopoietic stem-cell or solid organ transplant (n=26), or a general cohort of patients presenting for medical care (n=95). XMRV DNA was not detected in any participant samples. We found no association between XMRV and patients with chronic fatigue syndrome or chronic immunomodulatory conditions. [ABSTRACT FROM AUTHOR]

Background. Diagnosis of invasive fungal disease (IFD) is challenging, and it remains a significant cause of morbidity and mortality in immunocompromised patients. The (1r3)-b-D-glucan (BG) assay may be a useful adjunct, but its diagnostic performance is not well characterized. Methods. We retrospectively assessed the diagnostic indices of the BG assay in patients at risk of IFD who had a compatible clinical syndrome for the diagnosis of IFD a week after initial BG testing and at the end of the hospitalization associated with the first BG value. Patients with IFD were classified according to current European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria, independent of BG results. Results. A total of 1308 BG assays were performed for 871 patients. One hundred twelve proven or probable IFD cases were diagnosed within 1 week after initial testing, and 116 cases were diagnosed by the end of hospitalization. Sensitivity of an initial BG level ⩾80 pg/mL for IFD at 1 week was 0.64 (95% confidence interval [CI], 0.55-0.73), specificity was 0.84 (95% CI, 0.81-0.86), the positive likelihood ratio was 3.93 (95% CI, 2.94-5.26), and the negative likelihood ratio was 0.43 (95% CI, 0.31-0.59). Albumin, intravenous immunoglobulin, and hemodialysis were associated with elevated BG levels in patients without IFD (odds ratio, 4.78; 95% CI, 2.59- 8.80). After excluding patients with these factors, specificity and the positive likelihood ratio of an initial BG level ⩾80 pg/mL increased slightly. Empirical systemic antifungal treatment did not reduce overall BG sensitivity. Sensitivity was slightly lower among patients with hematologic malignancy or stem cell transplantation. Consideration of BG results would have increased the diagnostic certainty to probable in 54% of possible IFD cases. Conclusions. BG level appears to be a fair diagnostic adjunct for IFD in patients with appropriate pretest probability and a suggestive clinical syndrome, especially when checked serially in patients not receiving factors associated with an elevated BG level in the absence of IFD. [ABSTRACT FROM AUTHOR]

Reactivation of resolved hepatitis B virus (HBV) infection has been reported in allogeneic hematopoetic stem cell transplantation (HSCT) recipients, but its epidemiology is not well characterized. We performed a retrospective assessment of the timing and risk factors of HBV reactivation among patients with resolved HBV infection undergoing allogeneic HSCT between January 2000 and March 2008. HBV reactivation was defined as development of positive hepatitis B surface antigen after transplant. Among the 61 patients with resolved HBV infection before transplant (hepatitis B core antibody-positive, hepatitis B surface antigen-negative), 12 (19.7%) developed HBV reactivation. The cumulative probability of HBV reactivation 1, 2, and 4 years after transplant was 9.0%, 21.7%, and 42.9%, respectively. In a time-dependent Cox model, the adjusted hazard ratio (HR) of HBV reactivation for patients with pretransplant hepatitis B surface antibody levels <10 milli-international units per milliliter (mIU/mL) was 4.56 (95% confidence interval [CI] 1.23-16.9) compared to those with levels ≥10 mIU/mL; the adjusted HR among patients who developed extensive chronic graft-versus-host disease (cGVHD) was 7.21 (95% CI 1.25-41.5) compared to those who did not. HBV reactivation is a common late complication among allogeneic HSCT recipients with pretransplant resolved infection. Screening for HBV reactivation should be considered for at-risk HSCT recipients. In this cohort, HBV reactivation often developed in patients with cGVHD. Liver biopsy was useful in those patients with both to delineate the contribution of each to liver dysfunction. [Copyright &y& Elsevier]

Background. Human babesiosis is a tickborne malaria-like illness that generally resolves without complication after administration of atovaquone and azithromycin or clindamycin and quinine. Although patients experiencing babesiosis that is unresponsive to standard antimicrobial therapy have been described, the pathogenesis, clinical course, and optimal treatment regimen of such cases remain uncertain. Methods. We compared the immunologic status, clinical course, and treatment of 14 case patients who ex- perienced morbidity or death after persistence of Babesia microti infection, despite repeated courses of antibabesial treatment, with those of 46 control subjects whose infection resolved after a single course of standard therapy. This retrospective case-control study was performed in southern New England, New York, and Wisconsin. Results. All case patients were immunosuppressed at the time of acute babesiosis, compared with <10% of the control subjects. Most case patients experienced B cell lymphoma and were asplenic or had received rituximab before babesial illness. The case patients were more likely than control subjects to experience complications, and 3 died. Resolution of persistent infection occurred in 11 patients after 2-10 courses of therapy, including admin- istration of a final antimicrobial regimen for at least 2 weeks after babesia were no longer seen on blood smear. Conclusions. Immunocompromised people who are infected by B. microti are at risk of persistent relapsing illness. Such patients generally require antibabesial treatment for ⩾6 weeks to achieve cure, including 2 weeks after parasites are no longer detected on blood smear. [ABSTRACT FROM AUTHOR]

Background Trimethoprim-sulfamethoxazole (TMP-SMX) use for PJP prophylaxis has been associated with a variety of adverse reactions including myelosuppression, hypersensitivity reactions, acute kidney injury, and hyperkalemia. Atovaquone is used as an alternative drug, but it has several disadvantages, such as breakthrough PJP risk, dysgeusia, and higher cost compared with TMP-SMX. Indications for atovaquone prophylaxis at our institutions include severe cytopenias, hypersensitivity, renal impairment, or hyperkalemia. We evaluated atovaquone use and compliance with institutional PJP prophylaxis guidelines. Methods This was a retrospective study of inpatient atovaquone prescribing for PJP prophylaxis at Brigham and Women's Hospital and Dana-Farber Cancer Institute from 7/1/18 to 9/30/18. We included adult patients who received ≥1 dose of atovaquone and ≥3 months of PJP prophylaxis with any agent. The primary endpoint of this study was the proportion of patients who could have been safely switched to TMP-SMX 3 months after atovaquone initiation. Other endpoints included the incidence of breakthrough PJP, reasons for TMP-SMX avoidance, and estimated cost savings. Results Two-hundred and eighteen patients were evaluated and 164 were included. Most common indications for atovaquone prophylaxis were bone marrow transplant (44.5%), solid-organ transplant (30.5%) and use of immunosuppressive agents (21.9%). Atovaquone was started in 145 patients (88.4%) according to institutional guidance. Three months after initiation, 89 patients (45.7%) could have been safely switched to TMP-SMX. Failure to timely change to TMP-SMX was associated with 1,615 additional patient-days of atovaquone therapy and $103,683 in excess costs within 3 months of initiation. Major reasons for TMP-SMX avoidance were thrombocytopenia (51.3%), neutropenia (35.4%), renal impairment (31.7%), allergy history (26.8%), and hyperkalemia (19.5%). No breakthrough PJP infections were observed while patients were on atovaquone. Conclusion Institutional-guideline compliance was high during atovaquone initiation. However, after 3 months, many patients who could have been safely transitioned to TMP-SMX continued to receive atovaquone. This resulted in excess costs and potentially sub-optimal therapy. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background IA remains a leading cause of morbidity and mortality in immunocompromised children, and our understanding regarding epidemiology and outcomes of IA are limited and based on adult studies. Methods We conducted a retrospective evaluation of cases of proven or probable IA according to the 2008 EORTC/MSG criteria cared for at Boston Children's Hospital from 2007 to 2019. We collected data including demographics, clinical characteristics, diagnosis modality, antifungal treatment, and survival. Survival curves over one year were estimated using the Kaplan–Meier method and univariate and multivariate Cox modeling was used to evaluate for risk factors for mortality. Results 67 patient cases were identified, 20 (30%) with proven IA and 47 (70%) with probable IA. The mean age at diagnosis was 11.9 years (6 months–28 years). Underlying conditions included hematopoietic-cell transplantation (HCT) in 45%, cancer in 21%, and solid-organ transplantation in 18%. Pulmonary IA was the most common (70.1%) presentation. Diagnostic modalities included positive microbiology alone (18%), fungal PCR alone (1.5%), galactomannan alone (28%), and multiple modalities for the remaining cases (52.5%). 44.8% of patients were neutropenic at diagnosis and 78.5% of patients with malignancies were receiving chemotherapy. Immunosuppressive drugs included glucocorticoids in 34.3%, calcineurin inhibitors in 31.3%, and IMDH inhibitors in 25.3%. Voriconazole was the most common treatment used (72%). Twenty-two (33%) deaths occurred in the cohort attributable to IA (6 of which underwent autopsies and 4 had histopathological confirmation) Most deaths occurred in the BMT patients (15 patients, 45% of deaths). The 6 week mortality was 18% while the 12 week mortality was 25.4%. No antifungal or immunosuppressive regimen had a statistically significant impact on mortality. Conclusion We demonstrate in our >10-year retrospective cohort analysis of immunocompromised hosts that IA is associated with 49% all-cause mortality with particular impact on the BMT population. No protective nor harmful association was also noted with a particular antifungal or immunosuppressive regimen. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Patients with hematologic malignancies (HM) are at risk of invasive fungal disease (IFD). Identification of those patients at the highest risk for IFD would help optimize prophylactic or preemptive treatment decisions in this population. We previously found that among patients with myeloid malignancies who develop invasive aspergillosis, 15% had a mutation in the gene GATA2. Here, we report the incidence of IFD in a cohort of patients with HM related to a pathogenic sequence variant of GATA2. Methods We identified 6343 patients cared for at Dana-Farber/Brigham and Women's Cancer Center between January 2014 and August 2018 who underwent a next-generation sequencing assay of 95 genes recurrently mutated in hematologic malignancy. Those found to have a pathogenic GATA2 sequence variant were selected for retrospective chart review with respect to serious infectious complications including IFD. Results We identified 54 patients with a pathogenic GATA2 variant. 5 had a germline mutation related to familial GATA2 deficiency. The other 49 had a HM, mostly (41/49) acute myeloid leukemia or myelodysplastic syndrome. The frequency of the variant GATA2 allele in this group ranged from 2.5 to 92.0% of sequencing reads. 14 patients were excluded due to lack of sufficient follow-up, often related to treatment at another institution. Of the remaining 35 patients, 13 (37%) had proven/probable invasive fungal infection (IFI). Fourteen others had syndromes consistent with possible IFD. In total, 16 of these 35 patients (46%) received antifungal therapy for proven, probable or possible IFD. Four of the patients not treated with antifungals were diagnosed with a serious infection including 2 cases of Staphylococcus aureus bacteremia, and one case of disseminated Mycobacterium avium complex. Conclusion We identified a high incidence of IFD among patients with HM related to a pathogenic sequence variant of GATA2. The wide range of variant allele frequency observed raises the possibility that either inherited or acquired GATA2 dysfunction could incur predisposition to infection. These data suggest that personalized genetic diagnostics of patients with HM may be useful for assessment of infectious risk. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Antimicrobial resistance (AMR) poses an increasing challenge to the treatment of the nosocomial pathogen Pseudomonas aeruginosa , with the majority of highly resistant infections caused by relatively few high-risk clones. We investigated the role of clonal complex 298 (CC298: ST298 and ST446) in multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections at Northwestern Memorial Hospital (NMH). Methods We determined the AMR of 40 whole-genome sequenced CC298 isolates, including 30 from patients at NMH in Chicago (2000–2017), 7 from hospital environments (e.g. sinks) in Chicago (2017–2018), and 3 from patients at Brigham and Women's Hospital (BWH) in Boston (2015–2016). We used phylogenetics to assess the population structure of these isolates and 38 additional publicly available CC298 genomes. We interrogated the genomes of NMH CC298 isolates to uncover drivers of AMR. Results NMH CC298 isolates showed high rates of AMR, with 76.7% (23/30) MDR and 46.7% (14/30) XDR. Phylogenetic analysis revealed that 21/23 MDR (13/14 XDR) isolates from NMH formed a subclade of ST298, termed ST298*, as of yet not seen elsewhere. A time-scaled phylogeny of ST298* indicates a last common ancestor in 1980 (mean 1980.8, 95% HPD interval 1973.3–1987.4), with XDR ST298* isolates seen between 2001 and 2017. Many ST298* isolates, including all XDR isolates, harbored a large plasmid with an AMR class 1 integron. This plasmid is part of a family of large Pseudomonas genus plasmids. By comparing a plasmid-cured strain to its parent, we show that the plasmid imparts resistance to gentamicin and piperacillin–tazobactam. In the parental strain we detect T83I GyrA and S87L ParC substitutions known to cause fluoroquinolone resistance, showing that mutational resistance also contributes to the high AMR of ST298*. Publicly available genomes and previous reports indicate that CC298 has caused infections worldwide with multiple instances of significant AMR. Conclusion The repeated isolation of XDR ST298* P. aeruginosa at NMH over 16 years raises concern for the ability of this strain to persist in the healthcare environment. With this local epidemic and additional reports of MDR CC298 isolates around the world, we argue that CC298 should be considered a high-risk clone. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Rhinosinusitis, malignant otitis externa, and skull base osteomyelitis represent a spectrum of cranial invasive fungal disease (IFD). These syndromes have distinct characteristics, yet they may progress to involve similar structures, resulting in inflammation and invasion of the adjacent internal carotid artery (ICA). Invasive fungal carotiditis can have devastating consequences, including cerebral infarction, subarachnoid hemorrhage, and death. Methods We retrospectively studied all patients diagnosed with cranial IFD and carotid involvement at our institution from 2003 to 2018. We also searched Medline/PubMed for reports of Aspergillus or Mucorales cranial infections with ICA involvement. All cases with mycologic evidence of cranial IFD and radiographic or pathologic evidence of ICA involvement were included. Results We identified 78 cases of invasive fungal carotiditis between 1958 and 2018, including 4 cases at our own institution. Forty-one were caused by Aspergillus and 37 by Mucorales species. Presenting symptoms included vision changes (73%), cranial nerve palsy (69%), and headache (42%). Carotid events included occlusion, aneurysm formation, and vessel rupture. Cerebral infarcts occurred in 50% of cases. Mortality at 6 weeks, 12 weeks, and 2 years was 27%, 41%, and 71% respectively. The median time from symptom onset to death was 150 days for cases due to Aspergillus and 51 days for cases due to Mucorales species. Conclusions Invasive fungal carotiditis is a rare but morbid manifestation of cranial IFD. Early suspicion of IFD and administration of antifungal treatment, vascular imaging, and endovascular interventions should be considered to reduce the high mortality of this disease. [ABSTRACT FROM AUTHOR]

We describe a patient with a history of allogeneic hematopoietic stem cell transplantation complicated by chronic graft-versus-host disease who developed painful meningo-radiculitis and myositis due to Lyme borreliosis. To our knowledge, this is the first report of such an infection occurring after allogeneic hematopoietic stem cell transplantation in the United States. [ABSTRACT FROM AUTHOR]