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.

Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America.

Asymptomatic bacteriuria (ASB) is a common finding in many populations, including healthy women and persons with underlying urologic abnormalities. The 2005 guideline from the Infectious Diseases Society of America recommended that ASB should be screened for and treated only in pregnant women or in an individual prior to undergoing invasive urologic procedures. Treatment was not recommended for healthy women; older women or men; or persons with diabetes, indwelling catheters, or spinal cord injury. The guideline did not address children and some adult populations, including patients with neutropenia, solid organ transplants, and nonurologic surgery. In the years since the publication of the guideline, further information relevant to ASB has become available. In addition, antimicrobial treatment of ASB has been recognized as an important contributor to inappropriate antimicrobial use, which promotes emergence of antimicrobial resistance. The current guideline updates the recommendations of the 2005 guideline, includes new recommendations for populations not previously addressed, and, where relevant, addresses the interpretation of nonlocalizing clinical symptoms in populations with a high prevalence of ASB.

Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America.

Asymptomatic bacteriuria (ASB) is a common finding in many populations, including healthy women and persons with underlying urologic abnormalities. The 2005 guideline from the Infectious Diseases Society of America recommended that ASB should be screened for and treated only in pregnant women or in an individual prior to undergoing invasive urologic procedures. Treatment was not recommended for healthy women; older women or men; or persons with diabetes, indwelling catheters, or spinal cord injury. The guideline did not address children and some adult populations, including patients with neutropenia, solid organ transplants, and nonurologic surgery. In the years since the publication of the guideline, further information relevant to ASB has become available. In addition, antimicrobial treatment of ASB has been recognized as an important contributor to inappropriate antimicrobial use, which promotes emergence of antimicrobial resistance. The current guideline updates the recommendations of the 2005 guideline, includes new recommendations for populations not previously addressed, and, where relevant, addresses the interpretation of nonlocalizing clinical symptoms in populations with a high prevalence of ASB.

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.

Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review.

BACKGROUND: The role of fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI) is not well-known. PURPOSE: To assess the efficacy, comparative effectiveness, and harms of FMT for CDI. DATA SOURCES: MEDLINE (1980 to January 2015), Cochrane Library, and ClinicalTrials.gov, followed by hand-searching references from systematic reviews and identified studies. STUDY SELECTION: Any study of FMT to treat adult patients with CDI; case reports were only used to report harms. DATA EXTRACTION: Data were extracted by 1 author and verified by another; 2 authors independently assessed risk of bias and strength of evidence. DATA SYNTHESIS: Two randomized, controlled trials (RCTs); 28 case-series studies; and 5 case reports were included. Two RCTs and 21 case-series studies (516 patients receiving FMT) reported using FMT for patients with recurrent CDI. A high proportion of treated patients had symptom resolution; however, the role of previous antimicrobials is unclear. One RCT comparing FMT with 2 control groups (n = 43) reported resolution of symptoms in 81%, 31%, and 23% of the FMT, vancomycin, or vancomycin-plus-bowel lavage groups, respectively (P < 0.001 for both control groups vs. FMT). An RCT comparing FMT route (n = 20) reported no difference between groups (60% in the nasogastric tube group and 80% in the colonoscopy group; P = 0.63). Across all studies for recurrent CDI, symptom resolution was seen in 85% of cases. In 7 case-series studies of patients with refractory CDI, symptom resolution ranged from 0% to 100%. Among 7 patients treated with FMT for initial CDI, results were mixed. LIMITATION: Most studies were uncontrolled case-series studies; only 2 RCTs were available for analysis. CONCLUSION: Fecal microbiota transplantation may have a substantial effect with few short-term adverse events for recurrent CDI. Evidence is insufficient on FMT for refractory or initial CDI treatment and on whether effects vary by donor, preparation, or delivery method. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

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.

Clinical decision support menu for reducing unnecessary urine cultures.

A clinical decision support menu requiring selection of urine culture (UC) indication within outpatient and inpatient settings of a large integrated health care system significantly reduced UC sample collection. Clear documentation of selected UC indication in most post-intervention cases affirms its potential as an effective diagnostic stewardship strategy.

Rifampin for Prosthetic Joint Infections: Lessons Learned Over 20 Years at a VA Medical Center.

Background: The Minneapolis Veterans Affairs Health Care System uses debridement and implant retention (DAIR) combined with oral rifampin and a second antibiotic to treat orthopedic implant infections. However, the success rate of this approach in a veteran population is unknown. Methods: We performed a retrospective analysis of patients who underwent DAIR with a rifampin-containing regimen for an orthopedic implant infection over the past 20 years at the Minneapolis Veterans Affairs Health Care System. The primary outcome was treatment success among participants who were treated with curative intent, defined as planned device retention without ongoing antibiotic use. Secondary outcomes were treatment harms and therapy duration. Treatment success was defined as the absence of recurrent infection or further measures to suppress infection within 1 year of completing antimicrobial therapy. Results: A total of 78 patients (88% male) were included (median age, 65.5 years), with 50 treated with curative intent (primary analysis group). Forty-one participants (82%) in the curative intent group experienced treatment success. The success rate was higher among participants whose implant was < 2 months old vs those whose implant was ≥ 2 months old (93% vs 65%, respectively; P = .02). The 28 participants treated without curative intent had more comorbidities, higher rates of chronic infection, and older implants than those treated with curative intent. Conclusions: Veterans with orthopedic implant infections can be successfully treated with DAIR combined with a rifampin-containing antimicrobial regimen. Success is highest for patients with a recent implant. Debridement and implant retention using regimens that include rifampin is an evidence-based strategy for managing patients with infected prosthetic hardware. Here we report that this approach is feasible in a veteran population, especially with recently implanted prosthetic material.

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.

Engaging patients in antimicrobial stewardship: co-designed educational tool to improve periprocedural care through de-implementation of guideline-discordant antimicrobial use.

Effective de-implementation models often include replacement of an ineffective practice with an alternative. We co-developed patient education materials as a replacement strategy for inappropriate post-procedural antibiotics in cardiac device procedures. Lessons learned and developed materials may be used to promote infection prevention in other periprocedural settings.

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.

Timing of Patient Management Decisions Relative to Echocardiography in Staphylococcus aureus Bacteremia: A Single-Center Retrospective Analysis.

Background: In patients with Staphylococcus aureus bacteremia (SAB), endocarditis evaluation includes transthoracic echocardiography (TTE) and, in patients at increased risk of endocarditis, subsequent transesophageal echocardiography (TEE). Whether performing TTE before TEE influences clinicians' decision making has not been well studied in patients deemed to warrant TEE. Methods: In this retrospective case series, we studied clinician behavior at a large Veterans Affairs medical center regarding the care of adult patients diagnosed with SAB who completed both TTE and TEE (n = 206 episodes of SAB). The timing of key patient management decisions was compared to the timing of the patient's TTE and TEE. It was inferred whether each management decision could have been informed by TTE alone versus TTE plus subsequent TEE. Management decisions included the following: documentation of antibiotic treatment duration, initiation of synergistic antibiotics, consultation of relevant specialists, ordering of relevant imaging studies, and performance of valve surgery or cardiac device explanation. Results: The primary outcome (any of the above 5 management decisions taking place) occurred after completion of TTE but before TEE in 13 SAB episodes (6.3%). The primary outcome occurred after completion of both TTE and TEE in 178 SAB episodes (86.4%). Documentation of antibiotic treatment duration accounted for the large majority of observed management decisions. Conclusions: Among patients with SAB who are deemed to warrant TEE for endocarditis evaluation, TTE results alone rarely prompt clinical management decisions.

Identification of novel factors associated with inappropriate treatment of asymptomatic bacteriuria in acute and long-term care.

BACKGROUND: Chart reviews often fall short of determining what drove antibiotic treatment of asymptomatic bacteriuria (ASB). To overcome this shortcoming, we searched providers' free-text for documentation of their decision-making and for misleading signs and symptoms that may trigger unnecessary treatment of ASB. METHODS: We reviewed a random sample of 10 positive urine cultures per month, per facility, from patients in acute or long-term care wards at 8 Veterans Affairs facilities. Cultures were classified as urinary tract infection (UTI) or ASB, and as treated or untreated. Charts were searched for 13 potentially misleading symptoms, and free-text documentation of providers' decision-making was classified into 5 categories. We used generalized estimating equations logistic regression to identify factors associated with ASB treatment. RESULTS: One hundred fifty-eight (27.5%) of 575 ASB cases were inappropriately treated with antibiotics. Significant factors associated with inappropriate treatment included: abdominal pain, falls, decreased urine output, urine characteristics, abnormal vital signs, laboratory values, and voiding issues. Providers prescribed an average of 1.4 antimicrobials to patients with ASB, with cephalosporins (41%) and fluoroquinolones (21%) being the most common classes prescribed. CONCLUSIONS: Chart reviews of providers' decision-making highlighted new factors associated with inappropriate ASB treatment. These findings can help design antibiotic stewardship interventions for ASB.

Promoting de-implementation of inappropriate antimicrobial use in cardiac device procedures by expanding audit and feedback: protocol for hybrid III type effectiveness/implementation quasi-experimental study.

BACKGROUND: Despite a strong evidence base and clinical guidelines specifically recommending against prolonged post-procedural antimicrobial use, studies indicate that the practice is common following cardiac device procedures. Formative evaluations conducted by the study team suggest that inappropriate antimicrobial use may be driven by information silos that drive provider belief that antimicrobials are not harmful, in part due to lack of complete feedback about all types of clinical outcomes. De-implementation is recognized as an important area of research that can lead to reductions in unnecessary, wasteful, or harmful practices, such as excess antimicrobial use following cardiac device procedures; however, investigations into strategies that lead to successful de-implementation are limited. The overarching hypothesis to be tested in this trial is that a bundle of implementation strategies that includes audit and feedback about direct patient harms caused by inappropriate prescribing can lead to successful de-implementation of guideline-discordant care. METHODS: We propose a hybrid type III effectiveness-implementation stepped-wedge intervention trial at three high-volume, high-complexity VA medical centers. The main study intervention (an informatics-based, real-time audit-and-feedback tool) was developed based on learning/unlearning theory and formative evaluations and guided by the integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) Framework. Elements of the bundled and multifaceted implementation strategy to promote appropriate prescribing will include audit-and-feedback reports that include information about antibiotic harms, stakeholder engagement, patient and provider education, identification of local champions, and blended facilitation. The primary study outcome is adoption of evidence-based practice (de-implementation of inappropriate antimicrobial use). Clinical outcomes (cardiac device infections, acute kidney injuries and Clostridioides difficile infections) are secondary. Qualitative interviews will assess relevant implementation outcomes (acceptability, adoption, fidelity, feasibility). DISCUSSION: De-implementation theory suggests that factors that may have a particularly strong influence on de-implementation include strength of the underlying evidence, the complexity of the intervention, and patient and provider anxiety and fear about changing an established practice. This study will assess whether a multifaceted intervention mapped to identified de-implementation barriers leads to measurable improvements in provision of guideline-concordant antimicrobial use. Findings will improve understanding about factors that impact successful or unsuccessful de-implementation of harmful or wasteful healthcare practices. TRIAL REGISTRATION: ClinicalTrials.gov NCT05020418.