Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models. METHODS: Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression. RESULTS: Common adverse effects included rash (31.7% Grades 1-2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1-2), diarrhoea (37% Gr 1-2), and hypertension (17% Gr 1-2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D. CONCLUSIONS: The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02833883.

Factors That Affect Legionella Positivity in Healthcare Building Water Systems from a Large, National Environmental Surveillance Initiative.

Legionella growth in healthcare building water systems can result in legionellosis, making water management programs (WMPs) important for patient safety. However, knowledge is limited on Legionella prevalence in healthcare buildings. A dataset of quarterly water testing in Veterans Health Administration (VHA) healthcare buildings was used to examine national environmental Legionella prevalence from 2015 to 2018. Bayesian hierarchical logistic regression modeling assessed factors influencing Legionella positivity. The master dataset included 201,146 water samples from 814 buildings at 168 VHA campuses. Overall Legionella positivity over the 4 years decreased from 7.2 to 5.1%, with the odds of a Legionella-positive sample being 0.94 (0.90-0.97) times the odds of a positive sample in the previous quarter for the 16 quarters of the 4 year period. Positivity varied considerably more at the medical center campus level compared to regional levels or to the building level where controls are typically applied. We found higher odds of Legionella detection in older buildings (OR 0.92 [0.86-0.98] for each more recent decade of construction), in taller buildings (OR 1.20 [1.13-1.27] for each additional floor), in hot water samples (O.R. 1.21 [1.16-1.27]), and in samples with lower residual biocide concentrations. This comprehensive healthcare building review showed reduced Legionella detection in the VHA healthcare system over time. Insights into factors associated with Legionella positivity provide information for healthcare systems implementing WMPs and for organizations setting standards and regulations.

Single Dose of an mRNA Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) Vaccine Is Associated With Lower Nasopharyngeal Viral Load Among Nursing Home Residents With Asymptomatic Coronavirus Disease 2019 (COVID-19).

In nursing home residents with asymptomatic COVID-19 diagnosed through twice-weekly surveillance testing, single-dose BNT162b2 vaccination (Pfizer-BioNTech) was associated with -2.4 mean log10 lower nasopharyngeal viral load than detected in absence of vaccination (P = .004). Since viral load is linked to transmission, single-dose mRNA SARS-CoV-2 vaccination may help control outbreaks.

Sustained Reductions in Overall and Unnecessary Antibiotic Prescribing at Primary Care Clinics in a Veterans Affairs Healthcare System Following a Multifaceted Stewardship Intervention.

BACKGROUND: Most antibiotic prescribing is in outpatient settings. However, antibiotic stewardship has focused overwhelmingly on hospitalized patients. In a few studies, behavioral interventions decreased unnecessary outpatient prescribing against acute respiratory infections, but data are conflicting on sustained benefits after intervention discontinuation. METHODS: We conducted a prospective, observational study in 7 primary care clinics, in which an intervention comprised of clinician education, peer comparisons, and computer decision support order sets was directed against all antibiotic prescribing. After 6 months, peer comparisons were discontinued. Antibiotic prescribing was compared in the baseline (January-June 2016), intervention (January-June 2017), and postintervention (January-June 2018) periods. RESULTS: Mean antibiotic prescriptions significantly decreased from 76.9 (baseline) to 49.5 (intervention) and 56.3 (postintervention) per 1000 visits (35.6% and 26.8% reductions, respectively; P values < .001). The rate of unnecessary antibiotic prescribing (ie, antibiotic not indicated) decreased from 58.8% (baseline) to 37.8% (intervention) and 44.3% (postintervention) (35.7% and 24.7% decreases, respectively; P = .001 and P = .01). Overall, 19.9% (27/136), 36.6% (66/180), and 34.9% (67/192) of antibiotics were prescribed optimally (ie, antibiotics were indicated, and a guideline-concordant agent was prescribed for guideline-concordant duration) during the baseline, intervention, and postintervention periods, respectively (baseline vs intervention and postintervention, P = .001 and P = .003, respectively). Differences between intervention and postintervention periods in overall, unnecessary, or optimal antibiotic prescribing were not significant. CONCLUSIONS: A multifaceted outpatient stewardship intervention achieved reductions in overall, unnecessary, and suboptimal antibiotic prescription rates, which were sustained for a year after components of the intervention were discontinued. There is opportunity for further improvement, as inappropriate and suboptimal prescribing remained common.

Decreased Overall and Inappropriate Antibiotic Prescribing in a Veterans Affairs Hospital Emergency Department following a Peer Comparison-Based Stewardship Intervention.

Antibiotic prescribing is very common in emergency departments (EDs). Optimal stewardship intervention strategies in EDs are not well defined. We conducted a prospective, observational cohort study in a Veterans Affairs ED in which clinician education and monthly e-mail-based peer comparisons were directed against all oral antibiotic prescribing for discharged patients. Oral antibiotic prescriptions were compared in baseline (June 2016 to December 2017) and intervention (January to June 2018) periods using an interrupted time series regression model. Prescribing appropriateness was compared during January to June 2017 and the intervention period. During the intervention period, antibiotic prescriptions decreased monthly by 10.4 prescriptions per 1,000 ED visits (P = 0.07 [95% confidence interval {CI}, -21.7 to 1.0]). The relative decrease in the trend of antibiotic prescriptions during the intervention period compared to baseline was 9.9 prescriptions per 1,000 ED visits per month (P = 0.07 [95% CI, -20.9 to 1.0]). The intervention was associated with a significant decrease and increase in amoxicillin-clavulanate and cephalexin prescriptions, respectively (P < 0.001, P = 0.004). Decreasing trends in ciprofloxacin prescriptions during the baseline period were maintained during the intervention. Unnecessary antibiotic prescribing (i.e., antibiotic not indicated) decreased from 55.6% to 38.7% during the intervention (30.4% decrease, P = 0.003). Optimal antibiotic prescribing (i.e., antibiotics were indicated, and a guideline-concordant agent was prescribed for guideline-concordant duration) increased by 36% (21.6% to 29.3%, P = 0.12). A peer comparison-based stewardship intervention directed at ED clinicians was associated with reductions in overall and unnecessary oral antibiotic prescribing. There is potential to further improve antibiotic use as suboptimal prescribing remained common.

Antibiotic Consumption and Stewardship at a Hospital outside of an Early Coronavirus Disease 2019 Epicenter.

There are scant data on the impact of coronavirus disease 2019 (COVID-19) on hospital antibiotic consumption, and no data from outside epicenters. At our nonepicenter hospital, antibiotic days of therapy (DOT) and bed days of care (BDOC) were reduced by 151.5/month and 285/month, respectively, for March to June 2020 compared to 2018-2019 (P = 0.001 and P < 0.001). DOT per 1,000 BDOC was increased (8.1/month; P = 0.001). COVID-19 will impact antibiotic consumption, stewardship, and resistance in ways that will likely differ temporally and by region.

Bacterial and Fungal Etiology of Sepsis in Children in the United States: Reconsidering Empiric Therapy.

OBJECTIVES: Timely empiric antimicrobial therapy is associated with improved outcomes in pediatric sepsis, but minimal data exist to guide empiric therapy. We sought to describe the prevalence of four pathogens that are not part of routine empiric coverage (e.g., Staphylococcus aureus, Pseudomonas aeruginosa, Clostridium difficile, and fungal infections) in pediatric sepsis patients in a contemporary nationally representative sample. DESIGN: This was a retrospective cohort study using administrative data. SETTING: We used the Nationwide Readmissions Database from 2014, which is a nationally representative dataset that contains data from nearly half of all discharges from nonfederal hospitals in the United States. PATIENTS: Discharges of patients who were less than 19 years old at discharge and were not neonatal with a discharge diagnosis of sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 19,113 pediatric admissions with sepsis (6,300 [33%] previously healthy and 12,813 [67%] with a chronic disease), 31% received mechanical ventilation, 19% had shock, and 588 (3.1%) died during their hospitalization. Among all admissions, 8,204 (42.9%) had a bacterial or fungal pathogen identified. S. aureus was the most common pathogen identified in previously healthy patients (n = 593, 9.4%) and those with any chronic disease (n = 1,430, 11.1%). Methicillin-resistant S. aureus, P. aeruginosa, C. difficile, and fungal infections all had high prevalence in specific chronic diseases associated with frequent contact with the healthcare system, early surgery, indwelling devices, or immunosuppression. CONCLUSIONS: In this nationally representative administrative database, the most common identified pathogen was S. aureus in previously healthy and chronically ill children. In addition, a high proportion of children with sepsis and select chronic diseases had infections with methicillin-resistant S. aureus, fungal infections, Pseudomonas infections, and C. difficile. Clinicians caring for pediatric patients should consider coverage of these organisms when administering empiric antimicrobials for sepsis.

Controversies in Perioperative Antimicrobial Prophylaxis.

Although clinical guidelines for antibiotic prophylaxis across a wide array of surgical procedures have been proposed by multidisciplinary groups of physicians and pharmacists, clinicians often deviate from recommendations. This is particularly true when recommendations are based on weak data or expert opinion. The goal of this review is to highlight certain common but controversial topics in perioperative prophylaxis and to focus on the data that does exist for the recommendations being made.

Improved Antibiotic Prescribing within a Veterans Affairs Primary Care System through a Multifaceted Intervention Centered on Peer Comparison of Overall Antibiotic Prescribing Rates.

Reducing inappropriate outpatient antibiotic use is an important national goal. Limited data exist on targeted education and peer comparison of overall antibiotic prescribing rates as an antimicrobial stewardship strategy. Primary care professionals (PCPs) from all seven clinics within our health care system were offered an education session, followed by monthly e-mails with their antibiotic prescribing rate, peer prescribing rates, and a system target. A pre-post analysis was conducted to compare prescribing rates during the intervention period (January to June 2017) to a seasonal baseline (January to June 2016) using a regression model. A random sample of prescriptions was reviewed for adherence to consensus guidelines. Educational sessions were attended by 68.5% (50/73) of PCPs. From the baseline to the intervention period, the mean rate of monthly antibiotic prescriptions declined from 76.9 to 49.5 per 1,000 office visits (35.6% reduction [P < 0.001]). Among reviewed cases, unnecessary antibiotic prescribing declined (58.8% [80/136] versus 38.9% [70/180]; 33.9% reduction [P = 0.0006]), and the rate of optimally prescribed antibiotics increased (19.9% [27/136] versus 30% [54/180]; 50.8% increase [P = 0.05]). If an antibiotic was indicated, there were no significant differences in prescribing of guideline-discordant agents (21.4% [12/56] versus 19.1% [21/110] [P = 0.8]) or guideline-concordant agents for a guideline-discordant duration (38.6% [17/44] versus 39.3% [35/89] [P = 1]). There were significant reductions in azithromycin and fluoroquinolone prescriptions (50.9% and 59.4% [P values of <0.001], respectively), but most prescriptions for these agents in the intervention period remained inappropriate. Initial education followed by monthly peer comparison of overall antibiotic prescribing rates reduced total and unnecessary antibiotic prescribing in primary care clinics.

Prevalence of Inappropriate Antibiotic Prescribing in Primary Care Clinics within a Veterans Affairs Health Care System.

Data are needed from outpatient settings to better inform antimicrobial stewardship. In this study, a random sample of outpatient antibiotic prescriptions by primary care providers (PCPs) at our health care system was reviewed and compared to consensus guidelines. Over 12 months, 3,880 acute antibiotic prescriptions were written by 76 PCPs caring for 40,734 patients (median panel, 600 patients; range, 33 to 1,547). PCPs ordered a median of 84 antibiotic prescriptions per 1,000 patients per year. Azithromycin (25.8%), amoxicillin-clavulanate (13.3%), doxycycline (12.4%), amoxicillin (11%), fluoroquinolones (11%), and trimethoprim-sulfamethoxazole (10.6%) were prescribed most commonly. Medical records corresponding to 300 prescriptions from 59 PCPs were analyzed in depth. The most common indications for these prescriptions were acute respiratory tract infection (28.3%), urinary tract infection (23%), skin and soft tissue infection (15.7%), and chronic obstructive pulmonary disease (COPD) exacerbation (6.3%). In 5.7% of cases, no reason for the prescription was listed. No antibiotic was indicated in 49.7% of cases. In 12.3% of cases, an antibiotic was indicated, but the prescribed agent was guideline discordant. In another 14% of cases, a guideline-concordant antibiotic was given for a guideline-discordant duration. Therefore, 76% of reviewed prescriptions were inappropriate. Ciprofloxacin and azithromycin were most likely to be prescribed inappropriately. A non-face-to-face encounter prompted 34% of prescriptions. The condition for which an antibiotic was prescribed was not listed in primary or secondary diagnosis codes in 54.5% of clinic visits. In conclusion, there is an enormous opportunity to reduce inappropriate outpatient antibiotic prescriptions.

Synergy, Salary, and Satisfaction: Benefits of Training in Critical Care Medicine and Infectious Diseases Gleaned From a National Pilot Survey of Dually Trained Physicians.

BACKGROUND: An increasing number of physicians are seeking dual training in critical care medicine (CCM) and infectious diseases (ID). Understanding experiences and perceptions of CCM-ID physicians could inform career choices and programmatic innovation. METHODS: All physicians trained and/or certified in both CCM and ID to date in the United States were sent a Web-based questionnaire in 2015. Responses enabled a cross-sectional analysis of physician demographics and training and practice characteristics and satisfaction. RESULTS: Of 202 CCM-ID physicians, 196 were alive and reachable. The response rate was 79%. Forty-six percent trained and 34% practice in the northeastern United States. Only 40% received dual training at the same institution. Eighty-three percent identified as either an intensivist with ID expertise (44%) or as equally an intensivist and ID physician (38%). Median salary was $265 000 (interquartile range [IQR], $215 000-$350 000). Practice settings were split between academic (45%) and community settings (42%). Two-thirds are clinicians but 62% conduct some research and 26% practice outpatient ID. Top reasons to dually specialize included clinical synergy (70%), procedural activity (50%), and less interest in pulmonology (49%). Although 38% cited less proficiency with bronchoscopy as a disadvantage, 87% seldom need pulmonary consultation in the intensive care unit. Median career satisfaction was 4 (IQR, 4-5) out of 5, and 76% would dually train again. CONCLUSIONS: CCM-ID graduates prefer the acute care setting, predominantly CCM or a combination of CCM and ID. They find combination training and practice to be synergistic and satisfying, but most have had to seek CCM and ID training independently at separate institutions. Given these findings, avenues for combined training in CCM-ID should be considered.

The role of water in healthcare-associated infections.

PURPOSE OF REVIEW: The aim is to discuss the epidemiology of infections that arise from contaminated water in healthcare settings, including Legionnaires' disease, other Gram-negative pathogens, nontuberculous mycobacteria, and fungi. RECENT FINDINGS: Legionella can colonize a hospital water system and infect patients despite use of preventive disinfectants. Evidence-based measures are available for secondary prevention. Vulnerable patients can develop healthcare-associated infections with waterborne organisms that are transmitted by colonization of plumbing systems, including sinks and their fixtures. Room humidifiers and decorative fountains have been implicated in serious outbreaks, and pose unwarranted risks in healthcare settings. SUMMARY: Design of hospital plumbing must be purposeful and thoughtful to avoid the features that foster growth and dissemination of Legionella and other pathogens. Exposure of patients who have central venous catheters and other invasive devices to tap water poses a risk for infection with waterborne pathogens. Healthcare facilities must conduct aggressive clinical surveillance for Legionnaires' disease and other waterborne infections in order to detect and remediate an outbreak promptly. Hand hygiene is the most important measure to prevent transmission of other Gram-negative waterborne pathogens in the healthcare setting.

Sharp decline in rates of community respiratory viral detection among patients at the National Institutes of Health Clinical Center during the coronavirus disease 2019 (COVID-19) pandemic.

OBJECTIVES: To analyze the frequency and rates of community respiratory virus infections detected in patients at the National Institutes of Health Clinical Center (NIHCC) between January 2015 and March 2021, comparing the trends before and during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: We conducted a retrospective study comparing frequency and rates of community respiratory viruses detected in NIHCC patients between January 2015 and March 2021. Test results from nasopharyngeal swabs and washes, bronchoalveolar lavages, and bronchial washes were included in this study. Results from viral-challenge studies and repeated positives were excluded. A quantitative data analysis was completed using cross tabulations. Comparisons were performed using mixed models, applying the Dunnett correction for multiplicity. RESULTS: Frequency of all respiratory pathogens declined from an annual range of 0.88%-1.97% between January 2015 and March 2020 to 0.29% between April 2020 and March 2021. Individual viral pathogens declined sharply in frequency during the same period, with no cases of influenza A/B orparainfluenza and 1 case of respiratory syncytial virus (RSV). Rhino/enterovirusdetection continued, but with a substantially lower frequency of 4.27% between April 2020 and March 2021, compared with an annual range of 8.65%-18.28% between January 2015 and March 2020. CONCLUSIONS: The decrease in viral respiratory infections detected in NIHCC patients during the pandemic was likely due to the layered COVID-19 prevention and mitigation measures implemented in the community and the hospital. Hospitals should consider continuing the use of nonpharmaceutical interventions in the future to prevent nosocomial transmission of respiratory viruses during times of high community viral load.

Management of Unique Pneumonias Seen in the Intensive Care Unit.

Infection of the lower respiratory tract is a potentially severe or life-threatening illness. Taking the right steps to recognize, identify, and treat pneumonia is critical to improving patient outcomes. An awareness of the diversity of potential infectious causes, the local endemic flora and resistance patterns, as well as testing strategies to differentiate causes of pneumonia is essential to providing the best patient outcomes. Understanding surveillance definitions allow intensivists to become partners in reducing hospital-associated infections and improving quality of care.

Detection of Vancomycin-Resistant Enterococcus faecium Endocarditis After Clearance of Vancomycin-Sensitive Enterococcus faecium Bacteremia.

Vancomycin-resistant enterococcal (VRE) bacteremia is associated with higher mortality rates and longer hospitalizations than vancomycin-sensitive enterococcal (VSE) bacteremia. A 67-year-old man with a right psoas abscess and pacemaker-associated tricuspid valve endocarditis in September 2020 grew VSE Enterococcus faecium from blood cultures that cleared after administration of intravenous vancomycin and gentamicin. Subsequently, he underwent tricuspid valve repair, pacemaker removal, and partial lead extraction. Valve and postoperative blood cultures grew VRE E. faecium, which cleared after administration of intravenous daptomycin. One VSE and two VRE isolates were collected and sequenced. All isolates belonged to E. faecium multilocus sequence type ST17 and were closely related, having <20 mutations in pairwise genome comparisons. Vancomycin resistance was due to the acquisition of a plasmid-encoded VanA operon. None of the isolates encoded the virulence factors asa1, gelE, cylA, or hyl; all encoded a homologue of efaAfm. VSE E. faecium, but not VRE E. faecium isolates, encoded a glucose transporter gene mutation. Two VRE E. faecium isolates formed more robust biofilms than the VSE E. faecium isolate (p < 0.001). The VRE E. faecium isolates, which generated larger biofilms than the VSE E. faecium isolate, could have remained protected in the heart valve and only caused bacteremia when disrupted during cardiac surgery. This study demonstrates that bacteria detected in the bloodstream of patients with endocarditis may not fully represent the organisms adherent to the cardiac valves or indwelling devices.

Working with State and Provincial Apiary Programs to Manage Honey Bee (Apis mellifera) Health.

Honey bee (Apis mellifera) health and hive transport are regulated by local apiary programs composed of apiary inspectors. Inspectors monitor and ensure the health of honey bees through field visits to apiaries where they inspect, identify, diagnose, and provide recommendations for the treatment of honey bee health issues. Laws and regulations pertaining to beekeeping and honey bee health are present in most states, territories, and provinces. Veterinarians are encouraged to establish a relationship with their local apiary inspector to further support beekeepers and the management of healthy honey bee colonies.