Real-world evaluation of early remdesivir in high-risk COVID-19 outpatients during Omicron including BQ.1/BQ.1.1/XBB.1.5.

BACKGROUND: A trial performed among unvaccinated, high-risk outpatients with COVID-19 during the delta period showed remdesivir reduced hospitalization. We used our real-world data platform to determine the effectiveness of remdesivir on reducing 28-day hospitalization among outpatients with mild-moderate COVID-19 during an Omicron period including BQ.1/BQ.1.1/XBB.1.5. METHODS: We did a propensity-matched, retrospective cohort study of non-hospitalized adults with SARS-CoV-2 infection between April 7, 2022, and February 7, 2023. Electronic healthcare record data from a large health system in Colorado were linked to statewide vaccination and mortality data. We included patients with a positive SARS-CoV-2 test or outpatient remdesivir administration. Exclusion criteria were other SARS-CoV-2 treatments or positive SARS-CoV-2 test more than seven days before remdesivir. The primary outcome was all-cause hospitalization up to day 28. Secondary outcomes included 28-day COVID-related hospitalization and 28-day all-cause mortality. RESULTS: Among 29,270 patients with SARS-CoV-2 infection, 1,252 remdesivir-treated patients were matched to 2,499 untreated patients. Remdesivir was associated with lower 28-day all-cause hospitalization (1.3% vs. 3.3%, adjusted hazard ratio (aHR) 0.39 [95% CI 0.23-0.67], p < 0.001) than no treatment. All-cause mortality at 28 days was numerically lower among remdesivir-treated patients (0.1% vs. 0.4%; aOR 0.32 [95% CI 0.03-1.40]). Similar benefit of RDV treatment on 28-day all-cause hospitalization was observed across Omicron periods, aOR (95% CI): BA.2/BA2.12.1 (0.77[0.19-2.41]), BA.4/5 (0.50[95% CI 0.50-1.01]), BQ.1/BQ.1.1/XBB.1.5 (0.21[95% CI 0.08-0.57]. CONCLUSION: Among outpatients with SARS-CoV-2 during recent Omicron surges, remdesivir was associated with lower hospitalization than no treatment, supporting current National Institutes of Health Guidelines.

Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients.

BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).

Are Clostridioides difficile infections being overdiagnosed in hematopoietic stem cell transplant recipients?

BACKGROUND: Because both diarrhea due to other causes and gastrointestinal colonization with toxigenic Clostridioides difficile are common in HSCT, there is a possibility of false-positive diagnoses of C difficile infections (CDI). METHODS: We estimated the probability of a patient being colonized by toxigenic C difficile by testing non-diarrheal surveillance stools from 223 HSCT recipients and the probability that a specimen submitted for C difficile testing was not CDI by determining the number of clinical tests that returned negative from this cohort. The number of expected false-positive CDI was estimated using these probabilities and compared with observed clinical test results. RESULTS: The expected false-positive and the observed numbers of positive clinical results were similar. The 20 patients diagnosed with CDI were also similar to 142 patients with diarrhea and C difficile-negative stools in number of stools on day of testing, associated symptoms, and the recorded number of days to formed stools. C difficile colonization was most commonly detected during the first week and CDI during the second. Retrospective analysis of 837 patients showed that 18 stools were submitted for each diagnosis of CDI. Ribotyping of the surveillance samples showed 17 ribotypes. CONCLUSIONS: Although several assumptions could impact the accuracy of our false-positive CDI estimates, it appears that many HSCT recipients diagnosed with CDI may actually represent colonized status and an alternative cause of diarrhea. Diagnostic stewardship, including limiting CDI diagnoses to patients with positive toxin and restricting stool submissions to patients with more severe symptoms, may decrease the number of false-positive diagnoses.

Antimicrobial Stewardship in a Hematological Malignancy Unit: Carbapenem Reduction and Decreased Vancomycin-Resistant Enterococcus Infection.

BACKGROUND: Antibiotic stewardship is challenging in hematological malignancy patients. METHODS: We performed a quasiexperimental implementation study of 2 antimicrobial stewardship interventions in a hematological malignancy unit: monthly antibiotic cycling for febrile neutropenia that included cefepime (± metronidazole) and piperacillin-tazobactam and a clinical prediction rule to guide anti-vancomycin-resistant Enterococcus faecium (VRE) therapy. We used interrupted time-series analysis to compare antibiotic use and logistic regression in order to adjust observed unit-level changes in resistant infections by background community rates. RESULTS: A total of 2434 admissions spanning 3 years pre- and 2 years postimplementation were included. Unadjusted carbapenem and daptomycin use decreased significantly. In interrupted time-series analysis, carbapenem use decreased by -230 days of therapy (DOT)/1000 patient-days (95% confidence interval [CI], -290 to -180; P < .001). Both VRE colonization (odds ratio [OR], 0.64; 95% CI, 0.51 to 0.81; P < .001) and infection (OR, 0.41; 95% CI, 0.2 to 0.9; P = .02) decreased after implementation. This shift may have had a greater effect on daptomycin prescribing (-160 DOT/1000 patient-days; 95% CI, -200 to -120; P < .001) than did the VRE clinical prediction score (-30 DOT/1000 patient-days; 95% CI, -50 to 0; P = .08). Also, 46.2% of Pseudomonas aeruginosa isolates were carbapenem-resistant preimplementation compared with 25.0% postimplementation (P = .32). Unit-level changes in methicillin-resistant Staphylococcus aureus and extended-spectrum beta lactamase (ESBL) incidence were explained by background community-level trends, while changes in AmpC ESBL and VRE appeared to be independent. The program was not associated with increased mortality. CONCLUSIONS: An antibiotic cycling-based strategy for febrile neutropenia effectively reduced carbapenem use, which may have resulted in decreased VRE colonization and infection and perhaps, in turn, decreased daptomycin prescribing.

Clostridioides difficile colonization and infection in patients admitted for a first autologous transplantation: Incidence, risk factors, and patient outcomes.

BACKGROUND: More data are needed regarding the incidence, risk factors, and outcomes for Clostridioides difficile infection (CDI) and colonization in patients undergoing an autologous hematopoietic stem cell transplantation (AHSCT). METHODS: We studied 472 consecutive patients admitted for a first AHSCT and conducted a prospective C difficile stool surveillance and ribotyping analysis in a subset of 94 patients. RESULTS: Clostridioides difficile infection was diagnosed in 7% of patients for an incidence of 3.4 CDI/1000 inpatient days, recurrent/reinfection CDI was rare. CDI was increased in patients who were colonized on admission, had required a recent pre-admission inpatient stay for fever and/or serious infection, or received empiric therapy with a carbapenem or extended-spectrum penicillin. CDI was associated with a longer length of stay and higher hospital costs. Twelve of 94 patients (13%) were found to have colonization on admission; CDI was diagnosed in 27% of these vs 1% in those with initial negative stools. Colonization in the hospital for those negative on admission was infrequent. C difficile ribotyping showed a predominance of 014/020. CONCLUSIONS: Clostridioides difficile infection is a significant infection in patients receiving a first AHSCT. The risk factors identified may be useful in designing preventive interventions.

Decrease in vancomycin-resistant Enterococcus colonization associated with a reduction in carbapenem use as empiric therapy for febrile neutropenia in patients with acute leukemia.

OBJECTIVE: To compare the effects of empiric carbapenems versus cycling cefepime and piperacillin/tazobactam on the rates of vancomycin-resistant Enterococcus (VRE) colonization, bloodstream infections, and outcomes of patients admitted with acute leukemia. DESIGN: Retrospective clinical study with VRE molecular strain typing and gastrointestinal microbiome comparison. SETTING: A regional referral center for acute leukemia. PATIENTS: 342 consecutive patients admitted with newly diagnosed acute leukemia. METHODS: In September 2015, we changed our empiric antibiotic of choice for neutropenic fever from a carbapenem to the cycling regimen. We studied 214 consecutive patients during the carbapenem period and 128 during the cycling period. Surveillance for VRE stool colonization was conducted weekly. Representative stool samples were analyzed for VRE MLST types and changes in the composition and diversity of the fecal microbiota. RESULTS: The change in empiric antibiotics was associated with a significant decrease in VRE colonization (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.27-0.66), a switch in the dominant VRE MLST types on the unit, and some modifications in the gastrointestinal microbiome. There were no differences in total gram-positive or gram-negative BSIs. During the carbapenem period, we observed higher absolute numbers of Candida spp and fewer ESBL BSIs, but these did not reach statistical significance. Patients during the carbapenem period had longer lengths of stay and durations of severe neutropenia and 10% higher hospital cost. CONCLUSIONS: Carbapenem-sparing empiric antibiotic regimens may have advantages related to VRE ecology, gastrointestinal dysbiosis, duration of neutropenia, cost and length of stay.

Clostridioides difficile colonization and infection in patients with newly diagnosed acute leukemia: Incidence, risk factors, and patient outcomes.

BACKGROUND: The frequency, risk factors, and outcomes for Clostridioides difficile infection (CDI) in patients with newly diagnosed acute leukemia (AL) admitted for induction therapy are unclear. METHODS: We studied 509 consecutive patients with AL admitted between 2006 and 2017 and conducted a prospective C difficile surveillance and ribotyping analysis in a subset of these. RESULTS: The incidence of CDI was 2.2/1,000 inpatient days during induction, and CDI was rare after discharge. CDI was highest in patients with acute myelogenous leukemia. A hospitalization shortly before admission and administration of a greater number of antibiotics increased the risk for CDI. No single class of antibiotics conveyed an increased risk. All cases were successfully treated, and CDI was not associated with an increase in length of stay, costs, or mortality. In a subgroup analysis, 16% of patients with acute myelogenous leukemia and 4% with other leukemia types were colonized on admission. Colonization was associated with a higher risk of CDI. Ribotyping of available isolates showed 27 different strain types with 014/020 and 027 being the most frequent. CONCLUSIONS: The number of antibiotics administered are a major risk factor for CDI in patients with AL. However, CDI appears to have minimal clinical impact in this population.

Epidemiology and Clinical Features of Invasive Fungal Infection in a US Health Care Network.

BACKGROUND: A better understanding of the epidemiology and clinical features of invasive fungal infection (IFI) is integral to improving outcomes. We describe a novel case-finding methodology, reporting incidence, clinical features, and outcomes of IFI in a large US health care network. METHODS: All available records in the Intermountain Healthcare Enterprise Data Warehouse from 2006 to 2015 were queried for clinical data associated with IFI. The resulting data were overlaid in 124 different combinations to identify high-probability IFI cases. The cohort was manually reviewed, and exclusions were applied. European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group definitions were adapted to categorize IFI in a broad patient population. Linear regression was used to model variation in incidence over time. RESULTS: A total of 3374 IFI episodes occurred in 3154 patients. The mean incidence was 27.2 cases/100 000 patients per year, and there was a mean annual increase of 0.24 cases/100 000 patients (P = .21). Candidiasis was the most common (55%). Dimorphic fungi, primarily Coccidioides spp., comprised 25.1% of cases, followed by Aspergillus spp. (8.9%). The median age was 55 years, and pediatric cases accounted for 13%; 26.1% of patients were on immunosuppression, 14.9% had autoimmunity or immunodeficiency, 13.3% had active malignancy, and 5.9% were transplant recipients. Lymphopenia preceded IFI in 22.1% of patients. Hospital admission occurred in 76.2%. The median length of stay was 16 days. All-cause mortality was 17.0% at 42 days and 28.8% at 1 year. Forty-two-day mortality was highest in Aspergillus spp. (27.5%), 20.5% for Candida, and lowest for dimorphic fungi (7.5%). CONCLUSIONS: In this population, IFI was not uncommon, affected a broad spectrum of patients, and was associated with high crude mortality.

The clinical and economic impact of cytomegalovirus infection in recipients of hematopoietic stem cell transplantation.

BACKGROUND: CMV infection (CMV-I) remains an important complication of hematopoietic stem cell transplantation (HSCT). METHODS: This was a retrospective, single-center cohort study in HSCT recipients. Primary outcomes were adjusted cost and all-cause mortality. Secondary analyses investigated CMV risk factors and the effect of serostatus. RESULTS: Overall, 690 transplant episodes were included (allogeneic [n = 310]; autologous [n = 380]). All received preemptive CMV antiviral therapy at first detectable DNAemia. CMV-I occurred in 34.8% of allogeneic and 2.1% of autologous transplants; median time to onset was 45 days. In allogeneic HSCT recipients, the primary risk factor for CMV-I was CMV donor/recipient (D/R) serostatus. In a Markov multi-state model for allogeneic HSCT recipients, the hazard ratio for CMV-I and relapse was 1.5 (95% CI 0.8-2.8) and for CMV-I and mortality 2.4 (95% CI 0.9-6.5). In a multivariable model for all patients, CMV-I was associated with increased total cost (coefficient = 0.21, estimated incremental daily cost USD $500; P = 0.02). Cost was attenuated in allogeneic HSCT recipients (coefficient = 0.13, USD $699 vs $613, or $24 892 per transplant episode; P = 0.23). CMV disease (CMV-D) complicated 29.6% of CMV-I events in allogeneic HSCT recipients, but was not associated with an incrementally increased adjusted risk of mortality compared with CMV-I alone. CMV-I (56.4%) and CMV-D (19.8%) were significantly overrepresented in D-/R+ serostatus HSCT recipients, and mortality was higher in R+ HSCT recipients. CONCLUSIONS: Despite early preemptive antiviral treatment, CMV-I impacts clinical outcomes and cost after HSCT, but the impact on cost is less pronounced in allogeneic HSCT recipients compared with autologous HSCT recipients.

Decrease in Vancomycin-Resistant Enterococcus Colonization After Extensive Renovation of a Unit Dedicated to the Treatment of Hematologic Malignancies and Hematopoietic Stem-Cell Transplantation.

OBJECTIVE While a direct relation between hospital construction and concomitant infection rates has been clearly established, few data are available regarding the environmental decontamination effects of renovation in which surfaces are replaced and regarding subsequent infection incidence. DESIGN Retrospective clinical study with vancomycin-resistant Enterococcus (VRE) molecular strain typing and environmental cultures. SETTING A regional referral center for acute leukemia and hematopoietic stem-cell transplantation. PATIENTS Overall, 536 consecutive hospital admissions for newly diagnosed acute leukemia or a first autologous or allogeneic stem-cell transplantation were reviewed. INTERVENTION During 2009-2010, our unit underwent complete remodeling including replacement of all surfaces. We assessed the effects of this construction on the incidence of hospital-acquired VRE colonization before, during, and after the renovation. RESULTS We observed a sharp decrease in VRE colonization rates (hazard ratio, <0.23; 95% confidence interval, 0.18-0.44; P<.0001) during the first year after the renovation, with a return to near baseline rates thereafter. The known risk factors for VRE colonization appeared to be stable over the study interval. Environmental cultures outside of patient rooms revealed several contaminated areas that are commonly touched by unit personnel. Multilocus sequence typing of VRE isolates that were cryopreserved over the study interval showed that dominant strains prior to construction disappeared and were replaced by other strains after the renovation. CONCLUSIONS Unit reconstruction interrupted endemic transmission of VRE, which resumed with novel strains upon reopening. Contamination of environmental surfaces and shared equipment may play an important role in endemic transmission of VRE. Infect Control Hosp Epidemiol 2017;38:1055-1061.

Prediction of Bloodstream Infection Due to Vancomycin-Resistant Enterococcus in Patients Undergoing Leukemia Induction or Hematopoietic Stem-Cell Transplantation.

BACKGROUND.: Bloodstream infection (BSI) to due vancomycin-resistant Enterococcus (VRE) is an important complication of hematologic malignancy. Determining when to use empiric anti-VRE antibiotic therapy in this population remains a clinical challenge. METHODS.: A single-center cohort representing 664 admissions for induction or hematopoietic stem-cell transplant (HSCT) from 2006 to 2014 was selected. We derived a prediction score using risk factors for VRE BSI and evaluated the model's predictive performance by calculating it for each of 16232 BSI at-risk inpatient days. RESULTS.: VRE BSI incidence was 6.5% of admissions (2.7 VRE BSI per 1000 BSI at-risk days). Adjusted 1-year mortality and length of stay were significantly higher in patients with VRE BSI. VRE colonization (adjusted odds ratio [aOR] = 8.4; 95% confidence interval [CI] = 3.4-20.6; P < .0001), renal insufficiency (aOR = 2.4; 95% CI = 1.0-5.8; P = .046), aminoglycoside use (aOR = 4.7; 95% CI = 2.2-9.8; P < .0001), and antianaerobic antibiotic use (aOR = 2.8; 95% CI = 1.3-5.8; P = .007) correlated most closely with VRE BSI. A prediction model with optimal performance included these factors plus gastrointestinal disturbance, severe neutropenia, and prior beta-lactam antibiotic use. The score effectively risk-stratified patients (area under the receiver operating curve = 0.84; 95% CI = 0.79-0.89). At a threshold of ≥5 points, per day probability of VRE BSI was increased nearly 4-fold. CONCLUSIONS.: This novel predictive score is based on risk factors reflecting a plausible pathophysiological model for VRE BSI in patients with hematological malignancy. Integrating VRE colonization status with risk factors for developing BSI is a promising method of guiding rational use of empiric anti-VRE antimicrobial therapy in patients with hematological malignancy. Validation of this novel predictive score is needed to confirm clinical utility.

Diagnosis and management of lung infections.

This article describes contemporary methods of diagnosis and current treatment regimens for most pulmonary infections. Modern techniques used to improve diagnostic yield in pulmonary infection include bronchoscopy, ultrasound- and electromagnetic-guided endoscopy, transthoracic needle biopsy, and samples obtained with thoracoscopy. The spectrum of bacterial, mycobacterial, fungal, and viral pathogens implicated in pulmonary disease is discussed. Treatment strategies and guideline recommendations for antimicrobial selection are described for community-acquired, health care-associated, hospital-acquired, and ventilator-associated pneumonia, and for the most common fungal, mycobacterial, and viral infections. The state-of-the art in topical and aerosolized anti-infective therapy and an algorithm for managing hemoptysis are also presented.

Chronic invasive sinus aspergillosis in immunocompetent hosts: a geographic comparison.

PURPOSE: To investigate potential differences in clinical presentation, histopathology, and outcomes of chronic invasive sinus aspergillosis (CISA) based on geographic region and species of Aspergillus isolated. MATERIALS AND METHODS: A retrospective analysis of published cases of CISA with a comparison of North American and worldwide cases comprised a systematic search of the English language literature. Thirty-four articles were identified detailing 15 North American and 76 global cases of CISA with cranio-cerebral extension in clinically immunocompetent patients. RESULTS: North American patients with CISA were older, had a more rapidly progressive course, and appeared to have higher rates of treatment failure and mortality. Anatomic distribution and presenting symptoms were similar between the two groups. North American cases were mostly due to A. fumigatus, while A. flavus was the predominant pathogen worldwide. While granulomatous inflammation was a rare observation in North American cases, it was seen in the majority of cases worldwide. CISA due to A. fumigatus was encountered in older adults, was associated with a chronic inflammatory response, an accelerated clinical course, and a trend toward treatment failure and higher mortality. Patients with A. flavus were younger, demonstrated granulomatous inflammation, and pursued an indolent, clinically responsive course. CONCLUSION: Observed differences in clinical presentation, histopathology, and outcome might involve a complex interplay between the human host, Aspergillus species, and local climatic conditions.