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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]

Background Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase. Methods In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16. Results 352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80–42.74]; P  < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02–16.88]; P  = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs. Conclusions Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE). [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]

Invasive aspergillosis (IA) remains a common cause of mortality in pediatric immunocompromised populations. Much of our knowledge of IA stems from adult literature. We conducted a retrospective evaluation of cases of proven or probable IA, defined according to the 2019 EORTC/MSG criteria, in patients with underlying immunocompromising conditions at Boston Children's Hospital from January 1, 2007 to January 1, 2019. We estimated survival curves over 12 weeks using the Kaplan-Meier method for all-cause mortality, and we used univariate Cox proportional hazards modeling to evaluate for mortality risk factors. We identified 59 cases, 29% with proven and 71% with probable IA. Pulmonary IA was the most common presentation (78%). The median age at diagnosis was 11 years (range, 0.5–28). Hematopoietic cell transplantation (HCT) was the most frequent predisposing underlying condition (41%). Among affected patients, 44.8% were neutropenic and 59.3% were lymphopenic at diagnosis. The 12-week all-cause mortality rate was 25.4%; HCT recipients comprised the majority of deaths (9/15) with a hazard ratio of 2.47 [95% CI, 0.87–6.95]. No patients with congenital immunodeficiencies (n = 8) died within 12 weeks of IA diagnosis. Other risk factors that were significantly associated with mortality included mechanical ventilation at diagnosis, intensive care unit stay, and lymphopenia; treatment with an Aspergillus -active azole was associated with decreased mortality. In conclusion, our study found that in pediatric immunocompromised hosts, IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the HCT population. Lay abstract This study explores the epidemiology, outcomes and predictors of mortality of invasive aspergillosis (IA) at a high-volume pediatric center for immunocompromised hosts. Much of our understanding of pediatric IA is extrapolated from the adult literature. Our study found that IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the hematopoietic cell transplantation study cohort. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice. For primary treatment failure, a change in antifungal therapy should be made: (i) when mycological susceptibility testing identifies an organism from a confirmed site of infection, which is resistant to the antifungal given for primary therapy, or a resistance mutation is identified by molecular testing; (ii) at, or after, 8 days of primary antifungal treatment if there is increasing serum galactomannan, or galactomannan positivity in serum, or bronchoalveolar lavage fluid when the antigen was previously undetectable, or there is sudden clinical deterioration, or a new clearly distinct site of infection is detected; and (iii) at, or after, 15 days of primary antifungal treatment if the patient is clinically stable but with ≥2 serum galactomannan measurements persistently elevated compared with baseline or increasing, or if the original lesions on CT or other imaging, show progression by >25% in size in the context of no apparent change in immune status. [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]

This post hoc analysis of international phase III isavuconazole trials identified 50 patients (90% immunocompromised or diabetic) with invasive fungal sinusitis (88% mucormycetes, Aspergillus) who received isavuconazole as primary (n = 33) or salvage (n = 17) therapy for a median of 82 days (range, 2–882). Overall survival was 82% at day 42 and 70% at day 84. [ABSTRACT FROM AUTHOR]

Background There are no antiviral therapies for parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV. Methods Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment. Results A total of 111 patients were randomized to DAS181 (n = 74) or placebo (n = 37). CSS was achieved by 45.0% DAS181-treated patients in the SO stratum compared with 31.0% for placebo (P =.15), whereas patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with placebo (34.5%) at day 28 (P =.17). In a post hoc analysis of solid organ transplant, hematopoietic cell transplantation within 1 year, or chemotherapy within 1 year, more SO stratum patients achieved RTRA on DAS181 (51.8%) compared with placebo (15.8%) by day 28 (P =.012). Conclusions The primary endpoint was not met, but post hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation. Clinical Trials Registration. NCT01644877. [ABSTRACT FROM AUTHOR]

Background Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI). Methods Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality. Results From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (−1.12 vs −1.09 log10 copies/mL; treatment difference −0.02 log10 copies/mL, 95% confidence interval: −.62,.57; P =.94), median supplemental oxygen-free days (26 vs 28 days, P =.84), incident respiratory failure (10.3 vs 10.7%, P =.98), or all-cause mortality (0 vs 7.1%, P =.19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients. Conclusions Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo. Clinical Trials Registration www.clinicaltrials.gov , NCT02254421; EudraCT, #2014-002475-29 [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]

Background Antimicrobial resistance (AMR) is a major challenge in the treatment of infections caused by Pseudomonas aeruginosa. Highly drug-resistant infections are disproportionally caused by a small subset of globally distributed P. aeruginosa sequence types (STs), termed "high-risk clones." We noted that clonal complex (CC) 446 (which includes STs 298 and 446) isolates were repeatedly cultured at 1 medical center and asked whether this lineage might constitute an emerging high-risk clone. Methods We searched P. aeruginosa genomes from collections available from several institutions and from a public database for the presence of CC446 isolates. We determined antibacterial susceptibility using microbroth dilution and examined genome sequences to characterize the population structure of CC446 and investigate the genetic basis of AMR. Results CC446 was globally distributed over 5 continents. CC446 isolates demonstrated high rates of AMR, with 51.9% (28/54) being multidrug-resistant (MDR) and 53.6% of these (15/28) being extensively drug-resistant (XDR). Phylogenetic analysis revealed that most MDR/XDR isolates belonged to a subclade of ST298 (designated ST298*) of which 100% (21/21) were MDR and 61.9% (13/21) were XDR. XDR ST298* was identified repeatedly and consistently at a single academic medical center from 2001 through 2017. These isolates harbored a large plasmid that carries a novel antibiotic resistance integron. Conclusions CC446 isolates are globally distributed with multiple occurrences of high AMR. The subclade ST298* is responsible for a prolonged epidemic (≥16 years) of XDR infections at an academic medical center. These findings indicate that CC446 is an emerging high-risk clone deserving further surveillance. [ABSTRACT FROM AUTHOR]

The incidence of invasive fungal diseases (IFDs) with central nervous system (CNS) involvement is increasing due to the rising numbers of immunocompromised individuals, such as patients receiving chemotherapy, transplantation procedures, or immune-modulating therapies. CNS IFDs cause significant morbidity and mortality, and treatments are complicated by difficulties in identifying fungal pathogens and delivering antifungal agents to the CNS. Isavuconazole is a novel triazole with broad-spectrum activity that has shown good blood–brain barrier penetration in animal models. We present a retrospective analysis of isavuconazole in the treatment of patients with CNS IFDs and who either participated in the phase III VITAL or SECURE clinical trials, or were included in a named-patient program. A total of 36 patients were identified, including 27 patients from the clinical trials. Of these patients, 47.2% had hematologic malignancies, while 13.9% had no identifiable underlying conditions. Mucorales, Aspergillus species, and Cryptococcus species accounted for 30.6%, 22.2%, and 13.9% of infections, respectively. The overall survival rate was 80.6% at day 42 and 69.4% at day 84, and at the end of treatment, a complete or partial clinical response was achieved in 58.3% of patients. Isavuconazole exhibited clinical activity in a variety of CNS IFDs. [ABSTRACT FROM AUTHOR]

Background In a phase 3 trial, letermovir reduced clinically significant cytomegalovirus infections (CS-CMVi) and all-cause mortality at week 24 versus placebo in CMV-seropositive allogeneic hematopoietic cell transplantation (HCT) recipients. This post hoc analysis of phase 3 data further investigated the effects of letermovir on all-cause mortality. Methods Kaplan-Meier survival curves were generated by treatment group for all-cause mortality. Observations were censored at trial discontinuation for reasons other than death or at trial completion. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox modeling, adjusting for risk factors associated with mortality. Results Of 495 patients with no detectable CMV DNA at randomization, 437 had vital-status data available through week 48 post-HCT at trial completion (101 deaths, 20.4%). Following letermovir prophylaxis, the HR for all-cause mortality was 0.58 (95% CI, 0.35–0.98; P =.04) at week 24 and 0.74 (95% CI, 0.49–1.11; P =.14) at week 48 post-HCT versus placebo. Incidence of all-cause mortality through week 48 post-HCT in the letermovir group was similar in patients with or without CS-CMVi (15.8 vs 19.4%; P =.71). However, in the placebo group, all-cause mortality at week 48 post-HCT was higher in patients with versus those without CS-CMVi (31.0% vs 18.2%; P =.02). The HR for all-cause mortality in patients with CS-CMVi was 0.45 (95% CI, 0.21–1.00; P =.05) at week 48 for letermovir versus placebo. Conclusions Letermovir may reduce mortality by preventing or delaying CS-CMVi in HCT recipients. Clinical Trials Registration clinicaltrials.gov, NCT02137772. [ABSTRACT FROM AUTHOR]

Background: Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin's risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up.Methods: We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs.Results: A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04-2.24).Conclusions: Both micafungin and comparator PAFs were associated with HCC mortality rates of <0.2 per 1000 person-years. Given the very low event rates, any potential risk for HCC should not play a role in clinical decisions regarding treatment with micafungin or other PAFs investigated in this study. [ABSTRACT FROM AUTHOR]

There were no cases of tuberculosis in a cohort of 2531 patients who underwent hematopoietic cell transplantation from 2010 to 2015 after 7323 person-years of follow up (95% confidence interval [CI], 0.0–0.05 cases/100 person-years), including 29 (1.15%) patients with untreated latent tuberculosis after 89 person-years of follow-up (95% CI, 0.0–4.06 cases/100 person-years). [ABSTRACT FROM AUTHOR]

Background Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains. Methods Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs). Results From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57–75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses. Conclusions Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified. Clinical Trials Registration NCT01611974. [ABSTRACT FROM AUTHOR]

Viral infections have been reported with dasatinib use, but its cytomegalovirus risk after hematopoietic-cell transplantation (HCT) is not known. We found that post-HCT dasatinib use increased the risk of cytomegalovirus reactivation (adjusted hazard ratio, 7.65; 95% confidence interval, 1.84–31.7), controlling for acute graft-versus-host disease, in 109 patients with Philadelphia-chromosome-positive malignancies. [ABSTRACT FROM AUTHOR]

Background: Systemic chemotherapies for various malignancies have been shown to significantly, yet transiently, decrease numbers of CD4+ T lymphocytes, a major reservoir for human immunodeficiency virus type 1 (HIV-1) infection. However, little is known about the impact of cytoreductive chemotherapy on HIV-1 reservoir dynamics, persistence, and immune responses.Methods: We investigated the changes in peripheral CD4+ T-cell-associated HIV-1 DNA and RNA levels, lymphocyte activation, viral population structure, and virus-specific immune responses in a longitudinal cohort of 15 HIV-1-infected individuals receiving systemic chemotherapy or subsequent autologous stem cell transplantation for treatment of hematological malignancies and solid tumors.Results: Despite a transient reduction in CD4+ T cells capable of harboring HIV-1, a 1.7- and 3.3-fold increase in mean CD4+ T-cell-associated HIV-1 RNA and DNA, respectively, were observed months following completion of chemotherapy in individuals on antiretroviral therapy. We also observed changes in CD4+ T-cell population diversity and clonal viral sequence expansion during CD4+ T-cell reconstitution following chemotherapy cessation. Finally, HIV-1 DNA was preferentially, and in some cases exclusively, detected in cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-responsive CD4+ T cells following chemotherapy.Conclusions: Expansion of HIV-infected CMV/EBV-specific CD4 + T cells may contribute to maintenance of the HIV DNA reservoir following chemotherapy. [ABSTRACT FROM AUTHOR]

Background. Osteoradionecrosis of the jaw (ORN) is an infrequent yet potentially devastating complication of radiation therapy to the head and neck region.Treatment options include antimicrobial therapy, local sequestrectomy, resection, and the use of hyperbaric oxygen (HBO). Published data on ORN are difficult to compare because of the lack of a universally accepted classification and staging system, and the literature on the use of HBO to either prevent or successfully manage ORN is controversial and inconclusive. Therefore, we aimed to establish a standard approach for using HBO at our institution. Materials and Methods. A literature search was conducted of articles published in the English language between January 1980 and January 2016. Retrieved articles were evaluated by two independent reviewers. Isolated case reports, abstracts, case series, review articles, and cohort studies without a control group were excluded; summary data were extracted from the remaining studies. A panel of experts from Head and Neck Oncology and Oral Medicine from the Dana-Farber Cancer Institute and Brigham and Women's Hospital reviewed the summary data and established multidisciplinary guidelines on the use of HBO for the prevention and management of ORN. Results. Seven studies were evaluated and reviewed by the multidisciplinary panel. There was no consistent evidence in support of HBO for either the prevention or management of ORN. Conclusion. Based on the available evidence and expert opinion, routine use of HBO for the prevention or management of ORN is not recommended and is rarely used at our institution. [ABSTRACT FROM AUTHOR]

Background: Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice.Methods: MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis.Results: There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators.Conclusion: For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications. [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]

In this assessment of volatile Aspergillus metabolites in the breath of 64 patients with suspected fungal pneumonia, a secondary metabolite signature of α-trans-bergamotene, β-trans-bergamotene, a β-vatirenene–like sesquiterpene, or trans-geranylacetone identified patients with invasive aspergillosis with 94% sensitivity and 93% specificity.Background. Invasive aspergillosis (IA) remains a leading cause of mortality in immunocompromised patients, in part due to the difficulty of diagnosing this infection.Methods. Using thermal desorption-gas chromatography/mass spectrometry, we characterized the in vitro volatile metabolite profile of Aspergillus fumigatus, the most common cause of IA, and other pathogenic aspergilli. We prospectively collected breath samples from patients with suspected invasive fungal pneumonia from 2011 to 2013, and assessed whether we could discriminate patients with proven or probable IA from patients without aspergillosis, as determined by European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions, by direct detection of fungal volatile metabolites in these breath samples.Results. The monoterpenes camphene, α- and β-pinene, and limonene, and the sesquiterpene compounds α- and β-trans-bergamotene were distinctive volatile metabolites of A. fumigatus in vitro, distinguishing it from other pathogenic aspergilli. Of 64 patients with suspected invasive fungal pneumonia based on host risk factors, clinical symptoms, and radiologic findings, 34 were diagnosed with IA, whereas 30 were ultimately diagnosed with other causes of pneumonia, including other invasive mycoses. Detection of α-trans-bergamotene, β-trans-bergamotene, a β-vatirenene–like sesquiterpene, or trans-geranylacetone identified IA patients with 94% sensitivity (95% confidence interval [CI], 81%–98%) and 93% specificity (95% CI, 79%–98%).Conclusions. In patients with suspected fungal pneumonia, an Aspergillus secondary metabolite signature in breath can identify individuals with IA. These results provide proof-of-concept that direct detection of exogenous fungal metabolites in breath can be used as a novel, noninvasive, pathogen-specific approach to identifying the precise microbial cause of pneumonia. [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]

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 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]

Face transplantation was performed in a highly sensitized recipient with positive preoperative crossmatch and subsequent antibody-mediated rejection. The recipient was a 45-year-old female with extensive conventional reconstructions after chemical burns over the majority of the body. Residual quality of life and facial functions were poor. Levels of circulating anti-human leukocyte antigen (HLA) antibodies were high, and panel reactive antibody score was 98%. A potential donor was identified; however, with positive T and B cell flow crossmatches. The transplant team proceeded with face transplantation from this donor, under tailored immune suppression and with available salvage options. The operation was successful. Plasmapheresis and induction immune suppression (i.e., thymoglobulin followed by mycophenolate mofetil, tacrolimus, and steroids) were provided. Five days later, there was significant facial swelling, rising anti-HLA antibody titers, and unprecedented evidence of C4d deposits on skin. High doses of steroids and thymoglobulin were provided; however, rejection increased such that by day 19 it was diagnosed grade III in the BANFF scale. After stopping thymoglobulin because of serum sickness, combination therapy of plasmapheresis, eculizumab, bortezomib, and alemtuzumab was provided. HLA antibody levels decreased while swelling and redness improved. At 3 months, there were no longer signs of rejection on biopsy. [ABSTRACT FROM AUTHOR]