Development and implementation of "handshake rounds": An antibiotic stewardship intervention for hospitalized adult patients with hematologic malignancies.

Objective: To design and implement "handshake rounds" as an antibiotic stewardship intervention to reduce inpatient intravenous (IV) antibiotic use in patients with hematologic malignancies. Design: Quasi-experimental analysis of antibiotic use (AU) and secondary outcomes before and and after handshake rounds were implemented. Setting: Quaternary-care, academic medical center. Patients: Hospitalized adults with hematologic malignancies receiving IV antibiotics. Methods: We performed a retrospective review of a preintervention cohort prior to the intervention. A multidisciplinary team developed criteria for de-escalation of antibiotics, logistics of handshake rounds, and outcome metrics. Eligible patients were discussed during scheduled handshake rounds between a hematology-oncology pharmacist and transplant-infectious diseases (TID) physician. Prospective data were collected over 30 days in the postintervention cohort. Due to small sample size, 2:1 matching was used to compare pre- to and postintervention AU. Total AU in days of therapy per 1,000 patient days (DOT/1,000 PD) was reported. Mean AU per patient was analyzed using Wilcoxon rank-sum test. A descriptive analysis of secondary outcomes of pre- and postintervention cohorts was performed. Results: Total AU was substantially lower after the intervention, with 517 DOT/1,000 PD compared to 865 DOT/1,000 PD before the intervention. There was no statistically significant difference in the mean AU per patient between the 2 cohorts. There was a lower rate of 30-day mortality in the postintervention cohort and rates of ICU admissions were similar. Conclusions: Conducting handshake rounds is a safe and effective way to implement an antibiotic stewardship intervention among high-risk patient population such as those with hematologic malignancies.

Evaluation of healthcare-associated infection rates in patients with hematologic malignancies and stem cell transplantation during the coronavirus disease 2019 (COVID-19) pandemic.

Objective: To evaluate whether rates of healthcare-associated infections (HAIs) changed during the coronavirus disease 2019 (COVID-19) pandemic in malignant hematology and stem cell transplant patients. Design: A retrospective, cohort study. Patients: The study included malignant hematology and stem cell transplant patients admitted between March 1, 2019, through July 31, 2019, and March 1, 2020, through July 31, 2020. Methods: Rates of catheter-associated urinary tract infections (CAUTIs), central-line-associated bloodstream infections (CLABSIs), central-line-associated mucosal barrier injury infections (CLAMBIs), and Clostridioides difficile infections (CDIs) during the pandemic were compared to those in a control cohort. Secondary outcomes included the rate of non-COVID-19 respiratory viruses. Results: The rate of CAUTIs per 1,000 hospital days was 0.435 before the pandemic and 0.532 during the pandemic (incidence rate ratio [IRR], 1.224; 95% confidence interval [CI], 0.0314-47.72; P = .899). The rate of CLABSIs was 0.435 before the pandemic and 1.064 during the pandemic (IRR, 2.447; 95% CI, 0.186-72.18; P = .516). The rate of CLAMBIs was 2.61 before the pandemic and 1.064 during the pandemic (IRR 0.408, 95% CI 0.057-1.927; P = .284). The rate of CDIs was 2.61 before the pandemic and 1.579 during the pandemic (IRR, 0.612; 95% CI, 0.125-2.457; P = .512). Non-COVID-19 respiratory virus cases decreased significantly from 12 (30.8%) to 2 cases (8.3%) (P = 0.014). Conclusions: There was no significant difference in HAIs among inpatient malignant hematology and stem cell transplant patients during the COVID-19 pandemic compared to those of a control cohort. Rates of infection were low among both cohorts. Rates of community-acquired respiratory viruses decreased significantly during the pandemic among this population.

Bloodstream Infections in Hematologic Malignancy Patients With Fever and Neutropenia: Are Empirical Antibiotic Therapies in the United States Still Effective?

Background: Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant. Methods: In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation. Results: Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with variability across centers. Cefepime and piperacillin-tazobactam were the most commonly prescribed empirical antibiotics for FN, at 62% and 23%, respectively; a GP-directed agent was empirically included in nearly half of all FN episodes within the first 24 hours. Susceptibility to fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems was 49%, 84%, 88%, and 96%, respectively, among GN isolates. Critical illness (CrI), defined as a new requirement for mechanical ventilation, vasopressor, or death within 30 days, occurred in 15% and did not correlate with fluoroquinolone prophylaxis, organism type, initial antibiotics, or adequacy of coverage. Only severity of illness at presentation, signified by a Pitt bacteremia score ≥2, predicted for critical illness within 30 days. Mortality was 4% by day 7 and 10% overall. Conclusions: In accordance with US guidelines, cefepime or piperacillin-tazobactam remain effective agents or empirical treatment for high-risk cancer patients with FN who are stable at presentation, maintaining high GN pathogen susceptibility and yielding excellent outcomes.

Safety and value of pretransplant antibiotic allergy delabeling in a quaternary transplant center.

BACKGROUND: Self-reported antibiotic allergies, also known as antibiotic allergy labels, are common and may lead to worse patient outcomes. Within immunocompromized patients, antibiotic allergy labels can lead to inappropriate use of antimicrobials and may limit options for prophylactic and therapeutic options in the posttransplant period. While antibiotic allergy delabeling is considered an important aspect of antibiotic stewardship protocols, evidence and awareness of its application in transplant recipients is limited. METHODS: We describe our experience with an antibiotic allergy delabeling intervention in the pretransplant evaluation period and its impact on posttransplant antimicrobial utilization. This was a retrospective analysis of patients with an antibiotic allergy label who underwent evaluation for solid organ or stem cell transplantation between 2015 and 2020. Patients included in this analysis were those who completed pretransplant antibiotic allergy delabeling through our Drug Allergy Clinic and were retained in care for 6 months after transplant. RESULTS: Twenty-six of 27 patients underwent pretransplant antibiotic allergy delabeling and safely received the delabeled antibiotic posttransplant. There were no reported side effects to the delabeled antibiotic within 6 months posttransplant. Specific examination of sulfonamide (sulfa)-antibiotic delabeling showed cost savings of $254 to $2910 per patient in the posttransplant period compared to the use of alternative antibiotics for prophylaxis protocol. CONCLUSION: Antibiotic allergy delabeling prior to transplant is safe, is of high value, and should be considered in the pretransplant evaluation period. More resources are needed for the development of delabeling guidelines and support for broad implementation of pretransplant antibiotic allergy delabeling programs.

Coinfections in Patients With Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Study.

BACKGROUND: The frequency of coinfections and their association with outcomes have not been adequately studied among patients with cancer and coronavirus disease 2019 (COVID-19), a high-risk group for coinfection. METHODS: We included adult (≥18 years) patients with active or prior hematologic or invasive solid malignancies and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, using data from the COVID-19 and Cancer Consortium (CCC19, NCT04354701). We captured coinfections within ±2 weeks from diagnosis of COVID-19, identified factors cross-sectionally associated with risk of coinfection, and quantified the association of coinfections with 30-day mortality. RESULTS: Among 8765 patients (hospitalized or not; median age, 65 years; 47.4% male), 16.6% developed coinfections: 12.1% bacterial, 2.1% viral, 0.9% fungal. An additional 6.4% only had clinical diagnosis of a coinfection. The adjusted risk of any coinfection was positively associated with age >50 years, male sex, cardiovascular, pulmonary, and renal comorbidities, diabetes, hematologic malignancy, multiple malignancies, Eastern Cooperative Oncology Group Performance Status, progressing cancer, recent cytotoxic chemotherapy, and baseline corticosteroids; the adjusted risk of superinfection was positively associated with tocilizumab administration. Among hospitalized patients, high neutrophil count and C-reactive protein were positively associated with bacterial coinfection risk, and high or low neutrophil count with fungal coinfection risk. Adjusted mortality rates were significantly higher among patients with bacterial (odds ratio [OR], 1.61; 95% CI, 1.33-1.95) and fungal (OR, 2.20; 95% CI, 1.28-3.76) coinfections. CONCLUSIONS: Viral and fungal coinfections are infrequent among patients with cancer and COVID-19, with the latter associated with very high mortality rates. Clinical and laboratory parameters can be used to guide early empiric antimicrobial therapy, which may improve clinical outcomes.

Herpes simplex virus-infected squamous cell carcinoma: a case report.

BACKGROUND: Herpes simplex virus (HSV)-1 is a highly prevalent, non-oncogenic virus that has higher morbidity in immunocompromised hosts. Its most common clinical manifestation is superficial ulceration of the integument or mucus membranes. CASE PRESENTATION: A 65-year-old woman with a history of acute myelogenous leukemia treated with allogenic peripheral blood stem cell transplant presented for resection of an ulcerated buccal squamous cell carcinoma. We report a case of HSV-1-infected malignant cells discovered on histopathological examination of the carcinoma specimen ultimately treated with valacyclovir. CONCLUSIONS: HSV-1 is not considered an oncogenic virus itself but may increase risk of malignant progression. Cancer cells are vulnerable to superimposed viral infections, including HSV-1, which likely led to the findings in this case.

Antimicrobial de-escalation in patients with high-risk febrile neutropenia: Attitudes and practices of adult hospital care providers.

In a survey of adult hospital providers regarding antibiotic use in the treatment of febrile neutropenia, clinical fellows, and pharmacists showed higher comfort levels with early antimicrobial de-escalation compared to hematology-oncology and transplant infectious diseases physicians. These frontline team members are ideal partners to champion antimicrobial stewardship interventions in febrile neutropenia.

Hematopoietic Cell Transplantation, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient's own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results in immune-mediated cellular injury of several organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the management of GVHD in adult patients with malignant disease.

Early viral reactivation despite excellent immune reconstitution following haploidentical Bone marrow transplant with post-transplant cytoxan for sickle cell disease.

BACKGROUND: Haploidentical bone marrow transplant (haplo-BMT) offers near universal donor availability as a curative modality for individuals with severe sickle cell disease (SCD). However, the required intense immunodepletion is associated with increased infectious complications. A paucity of data exists on immune reconstitution following haplo-BMT for SCD. METHODS: A multi-institution learning collaborative was developed in the context of a phase II clinical trial of a non-myeloablative, related haplo-BMT with post-transplant cyclophosphamide for SCD. We report results from a cohort of 23 patients for whom immune reconstitution data up to one year were available. RESULTS: Median age was 14.8 years. Out of 23, 18 participants received pre-conditioning with azathioprine, hydroxyurea, and hypertransfusions. 70% (16/23) of participants had multiple indications for haplo-BMT. We observed excellent immune reconstitution of CD4, CD8, CD19, and CD56 cellular subsets by 6 months post transplant. Engraftment rate and event-free survival in this cohort were 100% and 96%, respectively. 70% (16/23) of patients had at least one viral reactivation or infection, including CMV 35% (8/23), HHV-6 22% (5/23), and polyoma virus 17% (4/23), with no cases of post-transplant lymphoproliferative disease. CONCLUSION: Further prospective studies are needed to better characterize immune reconstitution and the immunologic basis for increased viral reactivation following haplo-BMT with post-transplant cyclophosphamide for SCD.

Work-up for Fever During Neutropenia for Both the Stem Cell Transplant Recipient and the Hematologic Malignancy Patient.

Fever is a common complication in patients with underlying neutropenia and is associated with significant mortality in neutropenic patients with acute myelogenous leukemia or hematopoietic cell transplant. Fever may be the only sign of infection and requires further clinical assessment, including a history, a physical examination, and additional laboratory and radiographic testing. National and international guidelines recommend initiation of empiric antimicrobial therapy in patients with fever during neutropenia. Stepwise escalation of antibacterial therapy, followed by antifungal therapy for patients with persistent fever, generally is recommended. Consideration should also be given to de-escalation of antimicrobial therapy in the appropriate clinical settings.

Defining Incidence and Risk Factors for Catheter-Associated Bloodstream Infections in an Outpatient Adult Hematopoietic Cell Transplantation Program.

Allogeneic hematopoietic cell transplantation (HCT) patients are at an increased risk of developing central line-associated bloodstream infections (CLABSIs) due to prolonged periods of myelosuppression, immunosuppression, and indwelling catheter days. CLABSIs are among the most serious complications in HCT recipients and can lead to prolonged hospitalizations, intensive care unit admissions, lengthy antimicrobial therapies, and increased mortality. There is a lack of data regarding the incidence and risk factors associated with the development of CLABSIs in the HCT population undergoing outpatient transplantation. This was a single-center, retrospective analysis of adult patients who underwent allogeneic HCT between July 2012 and July 2016 in an outpatient transplant unit at a tertiary academic medical center. The primary outcome was the cumulative incidence of CLABSIs from the date of central line placement through the first 100 days post-transplantation. Secondary outcomes included risk factors for CLABSI, number of hospitalizations due to CLABSI, mortality rate at 6 months post-transplantation, and the cumulative incidence, speciation, and presence of multidrug resistance in identified microorganisms. Three hundred fifty-nine patients underwent allogeneic HCT at Vanderbilt University Medical Center and 352 were included for analysis. The cumulative incidence of CLABSIs was 9%, with the majority occurring within the first 30 days post HCT (67%). The use of a matched unrelated donor (MUD) and/or haploidentical donor (odds ratio, 3.993; 95% confidence interval [CI], 1.329 to 12.001; P = .0136) and use of an ablative conditioning regimen (odds ratio, 2.394; 95% CI, 1.052 to 5.446; P = .0374) were independently associated with development of a CLABSI on multivariate analysis. The most common organism implicated in CLABSI was Staphylococcus epidermidis (34%). Patients who developed a CLABSI had an almost 5 times higher risk of mortality at 6 months post-transplantation compared with patients who did not develop a CLABSI (hazard ratio, 4.932; 95% CI, 2.463 to 9.878; P < .001). There is a low incidence of CLABSIs in patients undergoing HCT in the outpatient setting. Patients who underwent HCT using a MUD or haploidentical donor and received ablative conditioning were at higher risk for developing CLABSIs. Overall mortality at 6 months post-transplantation was higher in patients who developed a CLABSI. Additional prospective studies are needed to confirm these observations.

Systematic review of infectious events with the Bruton tyrosine kinase inhibitor ibrutinib in the treatment of hematologic malignancies.

OBJECTIVE: Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) in B lymphocytes as well as other kinases including interleukin-2-inducible T-cell kinase (ITK) in CD4+ Th2 regulatory T cells. Increased infections have been observed in patients taking ibrutinib. The overall incidence has not been systematically evaluated. METHODS: The published literature and conference abstracts of prospective clinical trials using ibrutinib in hematologic malignancies were identified and reviewed using PubMed, Google Scholar, and HemOnc.org per PRISMA guidelines. Infectious events with a focus on pneumonia were collated per the Common Terminology Criteria for Adverse Events Version 4.03 grading. RESULTS: Infectious complications are common, occurring in 56% of patients taking single-agent ibrutinib and 52% of those on combination therapy. Approximately one in 5 patients developed pneumonia, which was the major contributor to a 2% rate of death from infections. Many of the cases of pneumonia were due to opportunistic pathogens. CONCLUSIONS: Ibrutinib use requires prudent consideration of the impacts on host immunity. We identified a high rate of serious adverse infectious events within prospective clinical trials. Data suggest a role of both BTK and ITK inhibition for the increased events. There was considerable variability in the reporting of adverse events between trials, journals, and conference reports.

Prevention and Treatment of Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.

Infectious diseases are important causes of morbidity and mortality in patients with cancer. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This portion of the guidelines highlights the sections on antifungal and antiviral prophylaxis. Antifungal and antiviral prophylaxis recommendations have expanded over the past few years. New agents for the treatment of fungal infections and incorporation of therapeutic drug monitoring are presented. Antiviral prophylaxis for hepatitis B and management considerations for hepatitis C and HIV have been further developed.

BK polyomavirus reactivation after reduced-intensity double umbilical cord blood cell transplantation.

Serial serum samples from 27 patients who underwent double umbilical cord blood transplantation (dUCBT) were analyzed for BK polyomavirus (BKPyV) DNA by real-time PCR and BKPyV-specific immune globulin by ELISA. Clinical data were collected on all patients. All pre-transplant sera had detectable anti-BKPyV IgG. Fifteen patients (56%) had detectable serum BKPyV DNA (median 8.9 × 10(4) copies/ml; range 4.1 × 10(3)-7.9 × 10(6) copies/ml) a median of 40 days (range, 27-733 days) after dUCBT, with highest viral loads on Day 100 assessment. The cumulative probability of developing BKPyV viremia by Day 100 was 0.52 (95% CI, 0.33-0.71). Six of 15 patients with BKPyV viremia experienced hemorrhagic cystitis by Day 100. By Day 100, there was a trend towards higher BKPyV viral loads in sera of patients with hemorrhagic cystitis than in those BKPyV viremic patients without hemorrhagic cystitis (p = 0.06). BKPyV viremia was associated with significantly higher anti-BKPyV IgM values at 6 months post-dUCBT (P = 0.003). BKPyV viremia occurs early after dUBCT and is associated with a detectable humoral immune response by 6 months post-dUBCT.

BK virus disease after allogeneic stem cell transplantation: a cohort analysis.

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.

Mycobacterial infections in a large Virginia hospital, 2001-2009.

BACKGROUND: In areas where both tuberculosis (TB) and nontuberculous mycobacteria (NTM) are prevalent, descriptive studies of the clinical features of individual mycobacteria are needed to inform clinical triage. METHODS: We queried the University of Virginia Clinical Data Repository for all mycobacterial infections from 2001-2009. RESULTS: Of 494 mycobacterial infections in 467 patients there were 22 species. Patients with pulmonary Tb were more likely to be reported as immigrants (p < 0.001) and less likely to have a predisposing risk factor for NTM (pre-existing lung disease or host predisposition; p = 0.002). Review of chest CT scans revealed that TB infection was more likely to exhibit cavities and pleural effusion than NTM infection (p < 0.05). Among NTM infections M. kansasii, M. xenopi, and M. fortuitum were more likely than MAC to have cavities. There were at least 83 patients that met criteria for NTM lung disease and these were caused by 9 species. M. abscessus infection was associated with cystic fibrosis and M. xenopi infection was associated with male gender. CONCLUSIONS: In our center mycobacterial infections were common and of diverse species. Immigrant status, cavities, and effusion were associated with TB vs. NTM.

Selected neurotrophins, neuropeptides, and cytokines: developmental trajectory and concentrations in neonatal blood of children with autism or Down syndrome.

Using a double-antibody immunoaffinity assay (Luminex) and ELISA technology, we measured concentrations of certain neurotrophins, neuropeptides, and cytokines in pooled samples (one to three subjects per sample) eluted from archived neonatal blood of children with later-diagnosed autism, Down syndrome, very preterm birth, or term control infants. We also measured analytes in blood from healthy adult controls. Case or control status for infant subjects was ascertained by retrospective review of service agency medical records. We observed inhibitory substances in eluates from archived bloodspots, especially marked for measurement of BDNF. Concentrations in control subjects differed by age: BDNF rose markedly with age, while NT-3 and NT-4/5 concentrations were lower in adults than in newborn infants. IL-8 concentrations were higher in newborn infants, preterm and term, than in adults. Considered by diagnostic group, total protein was higher in Down syndrome than in either autism or control subjects. In infants with Down syndrome, concentrations of IL-8 levels were higher than in controls, whether or not corrected for total protein; NT-3 and CGRP were lower and VIP higher. In samples from autistic subjects, NT-3 levels were significantly lower than controls and an increase in VIP approached statistical significance. Concentrations of NT-4/5 and CGRP were correlated in infants with autism but not in Down syndrome or controls. Some of these results differ from earlier findings using a single-antibody recycling immunoaffinity chromatography (RIC) system. We discuss interrelationships of VIP, NT-3 and IL-8 and their potential relevance to features of the neuropathology of autism or Down syndrome.

Neonatal cytokines and cerebral palsy in very preterm infants.

To examine the relationship of cytokines in blood of very preterm neonates with later diagnosis of spastic cerebral palsy (CP) compared with infants of similar gestational age without CP, we measured concentrations of inflammatory cytokines and other substances in archived neonatal blood by recycling immunoaffinity chromatography. Subjects were surviving children born before 32 wk gestational age (GA) to women without preeclampsia, 64 with later diagnoses of CP and 107 control children. The initial analyses were augmented by measurement of 11 cytokines by a bead-based flow analytic system (Luminex) in an additional 37 children with CP and 34 control children from the same cohort. Concentrations of examined substances did not differ by presence of indicators of infection in mother, infant, or placenta. On ANOVA, concentrations of a number of cytokines were significantly related to neonatal ultrasound abnormalities (periventricular leukomalacia, ventricular enlargement, or moderate or severe germinal matrix hemorrhage). None of the substances measured either by immunoaffinity chromatography or flow analytic methods, including IL-1, -6, and -8 and tumor necrosis factor-alpha, was related to later diagnosis of CP or its subtypes. Inflammatory cytokines in neonatal blood of very premature infants did not distinguish those with later diagnoses of CP from control children.