Microbiota or placebo after antimicrobial therapy for recurrent Clostridioides difficile at home: A clinical trial with novel home-based enrollment.

INTRODUCTION: Clostridiodes difficile infection is the leading cause of infectious diarrhea in the United States, with substantial morbidity and mortality. Recurrent infection is especially challenging, with each recurrence increasing the likelihood of a successive recurrence, leading to cycles of prolonged symptoms, frequent antimicrobial use, and decreased quality of life. Fecal microbiota transplantation to prevent recurrent infection is a promising intervention with a large effect size in observational studies, but with conflicting results from randomized controlled trials. We are conducting a Veterans Affairs-wide randomized controlled trial utilizing centralized case identification, with enrollment and fecal microbiota transplant administration occurring at the participant's home. This type of trial design significantly improves trial efficiency, greatly decreases trial cost, increases consistency of trial administration, and most importantly makes nationwide clinical trials in less-common diseases possible. METHODS: This is a randomized comparison of capsule-delivered fecal microbiota transplant for the prevention of recurrent Clostridiodes difficile infection, administered after successful initial treatment of recurrent C. difficile infection with standard therapy. The primary endpoint is the incidence of recurrent C. difficile infection or death. Cases are identified by searching the Veterans Affairs Corporate Data Warehouse, with central study coordinators then reaching out to potential participants. Individuals meeting inclusion criteria and interested in participation are scheduled for in-home consent, randomization, and capsule administration, followed by telephone follow-up for 6 months. To mitigate risks of COVID-19, enrollment via video visits has been implemented. RESULTS: A total of 102 participants have been enrolled through January 2021. Centralized case identification and in-home enrollment has facilitated enrollment from 34 unique states, with 38% being from rural or highly rural areas. DISCUSSION: Centralized case identification and in-home enrollment is a feasible and innovative method of conducting randomized controlled trials in the Veterans Affairs system, improving access to clinical research for populations who may have difficulty engaging with the traditional model of clinical trials where enrollment is based at large hospitals in major metropolitan areas.

Effect of 7 vs 14 Days of Antibiotic Therapy on Resolution of Symptoms Among Afebrile Men With Urinary Tract Infection: A Randomized Clinical Trial.

Importance: Determination of optimal treatment durations for common infectious diseases is an important strategy to preserve antibiotic effectiveness. Objective: To determine whether 7 days of treatment is noninferior to 14 days when using ciprofloxacin or trimethoprim/sulfamethoxazole to treat urinary tract infection (UTI) in afebrile men. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled noninferiority trial of afebrile men with presumed symptomatic UTI treated with ciprofloxacin or trimethoprim/sulfamethoxazole at 2 US Veterans Affairs medical centers (enrollment, April 2014 through December 2019; final follow-up, January 28, 2020). Of 1058 eligible men, 272 were randomized. Interventions: Participants continued the antibiotic prescribed by their treating clinician for 7 days of treatment and were randomized to receive continued antibiotic therapy (n = 136) or placebo (n = 136) for days 8 to 14 of treatment. Main Outcomes and Measures: The prespecified primary outcome was resolution of UTI symptoms by 14 days after completion of active antibiotic treatment. A noninferiority margin of 10% was selected. The as-treated population (participants who took ≥26 of 28 doses and missed no more than 2 consecutive doses) was used for the primary analysis, and a secondary analysis included all patients as randomized, regardless of treatment adherence. Secondary outcomes included recurrence of UTI symptoms and/or adverse events within 28 days of stopping study medication. Results: Among 272 patients (median [interquartile range] age, 69 [62-73] years) who were randomized, 100% completed the trial and 254 (93.4%) were included in the primary as-treated analysis. Symptom resolution occurred in 122/131 (93.1%) participants in the 7-day group vs 111/123 (90.2%) in the 14-day group (difference, 2.9% [1-sided 97.5% CI, -5.2% to ∞]), meeting the noninferiority criterion. In the secondary as-randomized analysis, symptom resolution occurred in 125/136 (91.9%) participants in the 7-day group vs 123/136 (90.4%) in the 14-day group (difference, 1.5% [1-sided 97.5% CI, -5.8% to ∞]) Recurrence of UTI symptoms occurred in 13/131 (9.9%) participants in the 7-day group vs 15/123 (12.9%) in the 14-day group (difference, -3.0% [95% CI, -10.8% to 6.2%]; P = .70). Adverse events occurred in 28/136 (20.6%) participants in the 7-day group vs 33/136 (24.3%) in the 14-day group. Conclusions and Relevance: Among afebrile men with suspected UTI, treatment with ciprofloxacin or trimethoprim/sulfamethoxazole for 7 days was noninferior to 14 days of treatment with regard to resolution of UTI symptoms by 14 days after antibiotic therapy. The findings support the use of a 7-day course of ciprofloxacin or trimethoprim/sulfamethoxazole as an alternative to a 14-day course for treatment of afebrile men with UTI. Trial Registration: ClinicalTrials.gov identifier: NCT01994538.

Cost-Effectiveness of Antibiotic Prophylaxis Strategies for Transrectal Prostate Biopsy in an Era of Increasing Antimicrobial Resistance.

OBJECTIVES: To determine the optimal antibiotic prophylaxis strategy for transrectal prostate biopsy (TRPB) as a function of the local antibiotic resistance profile. METHODS: We developed a decision-analytic model to assess the cost-effectiveness of four antibiotic prophylaxis strategies: ciprofloxacin alone, ceftriaxone alone, ciprofloxacin and ceftriaxone in combination, and directed prophylaxis selection based on susceptibility testing. We used a payer's perspective and estimated the health care costs and quality-adjusted life-years (QALYs) associated with each strategy for a cohort of 66-year-old men undergoing TRPB. Costs and benefits were discounted at 3% annually. Base-case resistance prevalence was 29% to ciprofloxacin and 7% to ceftriaxone, reflecting susceptibility patterns observed at the Minneapolis Veterans Affairs Health Care System. Resistance levels were varied in sensitivity analysis. RESULTS: In the base case, single-agent prophylaxis strategies were dominated. Directed prophylaxis strategy was the optimal strategy at a willingness-to-pay threshold of $50,000/QALY gained. Relative to the directed prophylaxis strategy, the incremental cost-effectiveness ratio of the combination strategy was $123,333/QALY gained over the lifetime time horizon. In sensitivity analysis, single-agent prophylaxis strategies were preferred only at extreme levels of resistance. CONCLUSIONS: Directed or combination prophylaxis strategies were optimal for a wide range of resistance levels. Facilities using single-agent antibiotic prophylaxis strategies before TRPB should re-evaluate their strategies unless extremely low levels of antimicrobial resistance are documented.

Urinary Tract Infection in Male Patients: Challenges in Management.

Urinary tract infections in male patients share many of the management principles as used in the management of female patients, including the need to accurately define the clinical syndrome, choose empirical therapy based on the severity of illness and the potential for antimicrobial resistance, and consider the need for source control in severely ill patients. The microbiology of the causative organisms is more unpredictable compared to female patients, and data to inform treatment decisions from clinical trials specific to male patients are relatively scarce.

Decreased antimicrobial prescribing rate following academic detailing of resident physicians in outpatient clinic.

Among 37 internal-medicine resident physicians assigned to our outpatient clinic at Minneapolis Veterans' Affairs Health Care System (MVAHCS) on July 1, 2017, we designed a pre- and postintervention observational study. Our results show that in-person academic detailing around outpatient antimicrobial selection was associated with a decrease in outpatient antimicrobial prescriptions in a group of high-prescribing resident physicians.

Comparative effectiveness of Clostridium difficile treatments: a systematic review.

BACKGROUND: Clostridium difficile infection is increasing in incidence and severity. The optimal treatment is unknown. PURPOSE: To determine whether, among adults with C. difficile infection, treatment with certain antibiotics compared with others results in differences in initial cure, recurrence, and harms. DATA SOURCES: MEDLINE, AMED, ClinicalTrials.gov, and Cochrane databases (search dates: inception through August 2011, limited to English-language reports); bibliography review. STUDY SELECTION: Randomized, controlled trials of adults with C. difficile infection, independent of outcomes, who were treated with medications available in the United States. Observational studies reporting strain were included. DATA EXTRACTION: Study design, inclusion and exclusion criteria, quality and strength of evidence as assessed by 2 reviewers, study definitions, and duration of treatment and follow-up. Outcomes included initial cure, recurrence, and treatment harms. DATA SYNTHESIS: 11 trials that included 1463 participants were identified. Three trials compared metronidazole with vancomycin; 8 compared metronidazole or vancomycin with another agent, combined agents, or placebo. Strain was analyzed in 1 trial and 2 cohort studies. No study comparing 2 antimicrobial agents demonstrated a statistically significant difference for initial cure; all comparisons were of low to moderate strength of evidence. Moderate-strength evidence from 1 study demonstrated that recurrence was decreased with fidaxomicin versus vancomycin (15% vs. 25%; difference, -10 percentage points [95% CI, -17 to -3 percentage points]; P=0.005). Subgroup analysis of a single study comparing metronidazole with vancomycin for patients who have severe C. difficile infection showed no difference by intention-to-treat analysis; this was rated as insufficient-strength evidence. Harms, when reported, did not differ between treatments in any study. LIMITATIONS: Definitions of diarrhea, C. difficile infection, initial cure, and relapse varied. Some studies reported insufficient detail to allow assessment of all randomly assigned participants or of harms. CONCLUSION: No antimicrobial agent is clearly superior for the initial cure of C. difficile infection. Recurrence is less frequent with fidaxomicin than with vancomycin. PRIMARY FUNDING SOURCE: U.S. Department of Health and Human Services.

Analysis of an Antibiotic Stewardship Program for Asymptomatic Bacteriuria in the Veterans Affairs Health Care System.

Importance: Antibiotic stewardship for asymptomatic bacteriuria (ASB) is an important quality improvement target. Understanding how to implement successful antibiotic stewardship interventions is limited. Objective: To evaluate the effectiveness of a quality improvement stewardship intervention on reducing unnecessary urine cultures and antibiotic use in patients with ASB. Design, Setting, and Participants: This interrupted time series quality improvement study was performed at the acute inpatient medical and long-term care units of 4 intervention sites and 4 comparison sites in the Veterans Affairs (VA) health care system from October 1, 2017, through April 30, 2020. Participants included the clinicians who order or collect urine cultures and who order, dispense, or administer antibiotics. Clinical outcomes were measured in all patients in a study unit during the study period. Data were analyzed from July 6, 2020, to May 24, 2021. Intervention: Case-based teaching on how to apply an evidence-based algorithm to distinguish urinary tract infection and ASB. The intervention was implemented through external facilitation by a centralized coordinating center, with a site champion at each intervention site serving as an internal facilitator. Main Outcomes and Measures: Urine culture orders and days of antibiotic therapy (DOT) and length of antibiotic therapy in days (LOT) associated with urine cultures, standardized by 1000 bed-days, were obtained from the VA's Corporate Data Warehouse. Results: Of 11 299 patients included, 10 703 (94.7%) were men, with a mean (SD) age of 72.6 (11.8) years. The decrease in urine cultures before and after the intervention was not significant in intervention sites per segmented regression analysis (-0.04 [95% CI, -0.17 to 0.09]; P = .56). However, difference-in-differences analysis comparing intervention with comparison sites found a significant reduction in the number of urine cultures ordered by 3.24 urine cultures per 1000 bed-days (P = .003). In the segmented regression analyses, the relative percentage decrease of DOT in the postintervention period at the intervention sites was 21.7% (P = .007), from 46.1 (95% CI, 28.8-63.4) to 37.0 (95% CI, 22.6-51.4) per 1000 bed-days. The relative percentage decrease of LOT in the postintervention period at the intervention sites was 21.0% (P = .001), from 36.7 (95% CI, 23.2-50.2) to 29.6 (95% CI, 18.2-41.0) per 1000 bed-days. Conclusions and Relevance: The findings of this quality improvement study suggest that an individualized intervention for antibiotic stewardship for ASB was associated with a decrease in urine cultures and antibiotic use when implemented at multiple sites via external and internal facilitation. The electronic health record database-derived outcome measures and centralized facilitation approach are both suitable for dissemination.

The Erosion of Public Trust and SARS-CoV-2 Vaccines- More Action Is Needed.

As states and health systems prepare to deliver severe acute respiratory syndrome coronavirus 2 vaccines to the American public, a confluence of factors has the potential to interfere with these efforts: misinformation about coronavirus disease 2019, vaccine hesitancy, and the erosion of the American public's trust in the vaccine regulatory process due to recent and ongoing events. Broad action is needed to address these issues, including improved and consistent communication by the Food and Drug Administration, restoration of the Centers for Disease Control as an independent and science-driven institution, and more aggressive policies to counteract misinformation, particularly on social media platforms.

Aspergillus Osteomyelitis Secondary to Chronic Necrotizing Pulmonary Aspergillosis in a Patient With Rheumatoid Arthritis.

Aspergillus spp. are ubiquitous molds that cause a wide range of clinical syndromes depending on the immune status of the host. Herein, we present a case of a patient with rheumatoid arthritis on long-term immunosuppressive medications, with a persistent dry cough and left-sided chest pain for over a year, who presented with acute sternal drainage. Computed tomography of the chest showed chronic pulmonary abnormalities, parasternal fluid, and bone destruction of the distal sternum and left sixth rib. The patient underwent debridement; sternal biopsy tissue showed septate hyphae with acute-angled branching, and Aspergillus fumigatus grew in culture. We suspected that the patient developed chronic necrotizing pulmonary aspergillosis (CNPA) that traversed tissue planes and caused chest wall osteomyelitis. The patient received voriconazole and surgical debridement, with clinical and radiological improvement. This case demonstrates the importance of considering CNPA as a diagnosis in patients with moderate degrees of immunosuppression and chronic respiratory symptoms, and Aspergillus spp. as an etiology of osteomyelitis in such patients.

Organizational readiness assessment in acute and long-term care has important implications for antibiotic stewardship for asymptomatic bacteriuria.

BACKGROUND: Prior to implementing an antibiotic stewardship intervention for asymptomatic bacteriuria (ASB), we assessed institutional barriers to change using the Organizational Readiness to Change Assessment. METHODS: Surveys were self-administered on paper in inpatient medicine and long-term care units at 4 Veterans Affairs facilities. Participants included providers, nurses, and pharmacists. The survey included 7 subscales: evidence (perceived strength of evidence) and six context subscales (favorability of organizational context). Responses were scored on a 5-point Likert-type scale. RESULTS: One hundred four surveys were completed (response rate = 69.3%). Overall, the evidence subscale had the highest score; the resources subscale (mean 2.8) was significantly lower than other subscales (P < .001). Scores for budget and staffing resources were lower than scores for training and facility resources (P < .001 for both). Pharmacists had lower scores than providers for the staff culture subscale (P = .04). The site with the lowest scores for resources (mean 2.4) also had lower scores for leadership and lower pharmacist effort devoted to stewardship. CONCLUSIONS: Although healthcare professionals endorsed the evidence about nontreatment of ASB, perceived barriers to antibiotic stewardship included inadequate resources and leadership support. These findings provide targets for tailoring the stewardship intervention to maximize success.

Teamwork and safety climate affect antimicrobial stewardship for asymptomatic bacteriuria.

OBJECTIVE: In preparation for a multisite antibiotic stewardship intervention, we assessed knowledge and attitudes toward management of asymptomatic bacteriuria (ASB) plus teamwork and safety climate among providers, nurses, and clinical nurse assistants (CNAs). DESIGN: Prospective surveys during January-June 2018. SETTING: All acute and long-term care units of 4 Veterans' Affairs facilities. METHODS: The survey instrument included 2 previously tested subcomponents: the Kicking CAUTI survey (ASB knowledge and attitudes) and the Safety Attitudes Questionnaire (SAQ). RESULTS: A total of 534 surveys were completed, with an overall response rate of 65%. Cognitive biases impacting management of ASB were identified. For example, providers presented with a case scenario of an asymptomatic patient with a positive urine culture were more likely to give antibiotics if the organism was resistant to antibiotics. Additionally, more than 80% of both nurses and CNAs indicated that foul smell is an appropriate indication for a urine culture. We found significant interprofessional differences in teamwork and safety climate (defined as attitudes about issues relevant to patient safety), with CNAs having highest scores and resident physicians having the lowest scores on self-reported perceptions of teamwork and safety climates (P < .001). Among providers, higher safety-climate scores were significantly associated with appropriate risk perceptions related to ASB, whereas social norms concerning ASB management were correlated with higher teamwork climate ratings. CONCLUSIONS: Our survey revealed substantial misunderstanding regarding management of ASB among providers, nurses, and CNAs. Educating and empowering these professionals to discourage unnecessary urine culturing and inappropriate antibiotic use will be key components of antibiotic stewardship efforts.

Antimicrobial urinary catheters: a systematic review.

Catheter-associated urinary tract infection (CAUTI) is a common occurrence, often clinically unapparent and with a benign course. However, in a small fraction of patients catheter-associated bacteriuria/funguria (CABF) produces overt clinical manifestations and adverse consequences, including (at the extreme end of the spectrum) urosepsis and death. Antimicrobial-coated catheters have been proposed as a method to prevent CAUTI and are in use worldwide, although their clinical efficacy is not well known. Randomized and quasi-randomized clinical trials have demonstrated that antimicrobial-coated catheters do decrease the incidence of CABF; however, evidence that such devices provide clinically meaningful benefit is lacking. Moreover, uncertainty exists as to which of the currently marketed catheters is most effective against CABF, since no published trial has directly compared different antimicrobial-coated catheters. We conducted a systematic review to summarize and evaluate existing evidence, and to address areas of uncertainty. We found consistent but variable evidence that antimicrobial-coated catheters prevent CABF during short-term catheterization; however, no study demonstrated a clinical benefit. Future efforts in this field should include randomized trials with clinically relevant end points, as well as research to develop improved mechanisms for bladder drainage, preferably without the risks and discomfort currently associated with urinary catheters.

Urinary tract infections.

Urinary tract infection (UTI), with its diverse clinical syndromes and affected host groups, remains one of the most common but widely misunderstood and challenging infectious diseases encountered in clinical practice. Antimicrobial resistance is a leading concern, with few oral options available to treat infections caused by Gram-negative organisms resistant to trimethoprim-sulfamethoxazole and fluoroquinolones, especially for patients with upper tract disease. Efforts should be made not to detect or treat asymptomatic bacteriuria and funguria; to ensure an appropriate duration of therapy for symptomatic infections; and to limit the use of broad-spectrum agents, especially fluoroquinolones, if narrower spectrum agents are available. Further research is needed regarding rapid diagnosis of UTI, accurate presumptive identification of patients with resistant pathogens, and development of new antimicrobials for drug-resistant UTI.

Conflicts of Interest Among Infectious Diseases Clinical Practice Guideline Authors and the Pharmaceutical Industry.

This cross-sectional study assesses the prevalence of conflicts of interest (COI) associated with guideline-recommended drugs among Infectious Diseases Society of America clinical practice guideline authors and compliance with the Council on Medical Specialty Societies and Institute of Medicine guidelines.

Resident Physician Knowledge of Urine Testing and Treatment Over Four Years.

We surveyed resident physicians at 2 academic medical centers regarding urinary testing and treatment as they progressed through training. Demographics and self-reported confidence were compared to overall knowledge using clinical vignette-based questions. Overall knowledge was 40% in 2011 and increased to 48%, 55%, and 63% in subsequent years (P<.001).Infect Control Hosp Epidemiol 2018;39:616-618.

Protocol to disseminate a hospital-site controlled intervention using audit and feedback to implement guidelines concerning inappropriate treatment of asymptomatic bacteriuria.

BACKGROUND: Antimicrobial stewardship to combat the spread of antibiotic-resistant bacteria has become a national priority. This project focuses on reducing inappropriate use of antimicrobials for asymptomatic bacteriuria (ASB), a very common condition that leads to antimicrobial overuse in acute and long-term care. We previously conducted a successful intervention, entitled "Kicking Catheter Associated Urinary Tract Infection (CAUTI): the No Knee-Jerk Antibiotics Campaign," to decrease guideline-discordant ordering of urine cultures and antibiotics for ASB. The current objective is to facilitate implementation of a scalable version of the Kicking CAUTI campaign across four geographically diverse Veterans Health Administration facilities while assessing what aspects of an antimicrobial stewardship intervention are essential to success and sustainability. METHODS: This project uses an interrupted time series design with four control sites. The two main intervention tools are (1) an evidence-based algorithm that distills the guidelines into a streamlined clinical pathway and (2) case-based audit and feedback to train clinicians to use the algorithm. Our conceptual framework for the development and implementation of this intervention draws on May's General Theory of Implementation. The intervention is directed at providers in acute and long-term care, and the goal is to reduce inappropriate screening for and treatment of ASB in all patients and residents, not just those with urinary catheters. The start-up for each facility consists of centrally-led phone calls with local site champions and baseline surveys. Case-based audit and feedback will begin at a given site after the start-up period and continue for 12 months, followed by a sustainability assessment. In addition to the clinical outcomes, we will explore the relationship between the dose of the intervention and clinical outcomes. DISCUSSION: This project moves from a proof-of-concept effectiveness study to implementation involving significantly more sites, and uses the General Theory of Implementation to embed the intervention into normal processes of care with usual care providers. Aspects of implementation that will be explored include dissemination, internal and external facilitation, and organizational partnerships. "Less is More" is the natural next step from our prior successful Kicking CAUTI intervention, and has the potential to improve patient care while advancing the science of implementation.