What Is Left to Tackle in Inpatient Antimicrobial Stewardship Practice and Research.

Despite widespread uptake of antimicrobial stewardship in acute care hospitals, there is ongoing need for innovation and optimization of ASPs. This article discusses current antimicrobial stewardship practice challenges and ways to improve current antimicrobial stewardship workflows. Additionally, we propose new workflows that further engage front line clinicians in optimizing their own antibiotic decision making.

Infectious Diseases Consultation Associated With Reduced Mortality in Gram-Negative Bacteremia.

Gram-negative bacteremia (GN-BSI) can cause significant morbidity and mortality, but the benefit of infectious diseases consultation (IDC) is not well defined. A 24-site observational cohort study of unique hospitalized patients with 4861 GN-BSI episodes demonstrated a 40% decreased risk of 30-day mortality in patients with IDC compared to those without IDC.

Clinical, contextual and hospital-level factors associated with escalation and de-escalation of empiric Gram-negative antibiotics among US inpatients.

Background: Empiric Gram-negative antibiotics are frequently changed in response to new information. To inform antibiotic stewardship, we sought to identify predictors of antibiotic changes using information knowable before microbiological test results. Methods: We performed a retrospective cohort study. Survival-time models were used to evaluate clinical factors associated with antibiotic escalation and de-escalation (defined as an increase or decrease, respectively, in the spectrum or number of Gram-negative antibiotics within 5 days of initiation). Spectrum was categorized as narrow, broad, extended or protected. Tjur's D statistic was used to estimate the discriminatory power of groups of variables. Results: In 2019, 2 751 969 patients received empiric Gram-negative antibiotics at 920 study hospitals. Antibiotic escalation occurred in 6.5%, and 49.2% underwent de-escalation; 8.8% were changed to an equivalent regimen. Escalation was more likely when empiric antibiotics were narrow-spectrum (HR 19.0 relative to protected; 95% CI: 17.9-20.1), broad-spectrum (HR 10.3; 95% CI: 9.78-10.9) or extended-spectrum (HR 3.49; 95% CI: 3.30-3.69). Patients with sepsis present on admission (HR 1.94; 95% CI: 1.91-1.96) and urinary tract infection present on admission (HR 1.36; 95% CI: 1.35-1.38) were more likely to undergo antibiotic escalation than patients without these syndromes. De-escalation was more likely with combination therapy (HR 2.62 per additional agent; 95% CI: 2.61-2.63) or narrow-spectrum empiric antibiotics (HR 1.67 relative to protected; 95% CI: 1.65-1.69). Choice of empiric regimen accounted for 51% and 74% of the explained variation in antibiotic escalation and de-escalation, respectively. Conclusions: Empiric Gram-negative antibiotics are frequently de-escalated early in hospitalization, whereas escalation is infrequent. Changes are primarily driven by choice of empiric therapy and presence of infectious syndromes.

Evaluating the Follow-up of Post-discharge Positive Sterile Site Cultures and the Impact on Infection-Related Complications.

INTRODUCTION: Numerous patients have cultures pending at discharge which, if not addressed, may delay diagnosis and initiation of appropriate antimicrobials. The purpose of the study is to evaluate the appropriateness of discharge antimicrobial therapy and result documentation in patients with positive cultures finalized post-discharge. METHODS: This was a cross-sectional cohort study of patients admitted from July 1 to December 31, 2019 with positive sterile-site microbiologic cultures finalized post-discharge. Pertinent inclusion and exclusion factors were admission ≥ 48 h and non-sterile sites, respectively. The primary objective was to determine the frequency of discharged patients warranting antimicrobial changes based on finalized cultures. Secondary objectives included prevalence and timeliness of result documentation and rates of 30-day readmission, among intervention warranted versus not warranted. Chi-squared or Fisher's exact tests were used as appropriate. Binary multivariable logistic regression was completed for 30-day readmission stratified by infectious disease (ID) involvement due to the potential for effect modification. RESULTS: A total of 208 of 768 patients screened were included. Most patients were discharged from a surgical service (45.7%); deep tissue and blood were the most common culture sites (29.3%). Change in discharge antimicrobial was warranted in 36.5% of patients (n = 76). Result documentation was overall low (35.5%). Time to documentation was significantly shorter in patients warranting antimicrobial intervention (4 days vs. 9 days, P = 0.039), although rates of hospital readmission were higher in this group (32.9% vs. 22.7%, P = 0.109). Finally, in patients not being followed by ID, documentation of finalized results was associated with decreased odds of 30-day readmission (aOR 0.19; 95% CI 0.07-0.53). CONCLUSIONS: A significant number of patients with cultures finalized post-discharge warranted antimicrobial intervention. Acknowledgment of finalized culture results may decrease the risk of 30-day hospital readmission, particularly in patients not followed by ID. Quality improvement efforts should focus on methods to improve documentation and action on pending cultures to positively impact patient outcomes.

Is diagnostic stewardship possible in solid organ transplantation?

BACKGROUND: Diagnostic stewardship in solid organ transplant (SOT) recipients has the potential to help these vulnerable patients at risk for over-testing and overtreatment. METHODS: Herein, we review potential targets for diagnostic stewardship in SOT, such as Clostridioides difficile testing, urine cultures, molecular diagnostics, as well as novel areas of diagnostic stewardship. RESULTS: Bundled interventions focused on appropriate C. difficile testing can result in a significant decrease in testing and clinical diagnosis of C. difficile infection without any harms related to delay in diagnosis. In otherwise stable renal transplant recipients after the first month of transplant, screening urine cultures have not been shown to improve outcomes. Novel targets that require additional study in the SOT population include noninvasive fungal diagnostics and cytomegalovirus testing strategies CONCLUSIONS: Diagnostic stewardship is an innovative approach to improve diagnosis and limit unnecessary antimicrobial use. While there has been little direct exploration of diagnostic stewardship in the SOT population, there is great potential for benefit given frequent testing with diagnostics that have imperfect sensitivity and specificity, and sometimes great cost. Diagnostic stewardship in the SOT population is indeed possible but will require a multidisciplinary effort to ensure that appropriates tests and benefits are realized.

Real-world Antimicrobial Stewardship Experience in a Large Academic Medical Center: Using Statistical and Machine Learning Approaches to Identify Intervention "Hotspots" in an Antibiotic Audit and Feedback Program.

Background: Prospective audit with feedback (PAF) is an impactful strategy for antimicrobial stewardship program (ASP) activities. However, because PAF requires reviewing large numbers of antimicrobial orders on a case-by-case basis, PAF programs are highly resource intensive. The current study aimed to identify predictors of ASP intervention (ie, feedback) and to build models to identify orders that can be safely bypassed from review, to make PAF programs more efficient. Methods: We performed a retrospective cross-sectional study of inpatient antimicrobial orders reviewed by the University of Maryland Medical Center's PAF program between 2017 and 2019. We evaluated the relationship between antimicrobial and patient characteristics with ASP intervention using multivariable logistic regression models. Separately, we built prediction models for ASP intervention using statistical and machine learning approaches and evaluated performance on held-out data. Results: Across 17 503 PAF reviews, 4219 (24%) resulted in intervention. In adjusted analyses, a clinical pharmacist on the ordering unit or receipt of an infectious disease consult were associated with 17% and 56% lower intervention odds, respectively (adjusted odds ratios [aORs], 0.83 and 0.44; P ≤ .001 for both). Fluoroquinolones had the highest adjusted intervention odds (aOR, 3.22 [95% confidence interval, 2.63-3.96]). A machine learning classifier (C-statistic 0.76) reduced reviews by 49% while achieving 78% sensitivity. A "workflow simplified" regression model that restricted to antimicrobial class and clinical indication variables, 2 strong machine learning-identified predictors, reduced reviews by one-third while achieving 81% sensitivity. Conclusions: Prediction models substantially reduced PAF review caseloads while maintaining high sensitivities. Our results and approach may offer a blueprint for other ASPs.

Follow-up Blood Culture Practices for Gram-Negative Bloodstream Infections in Immunocompromised Hosts at a Large Academic Medical Center.

The role of follow-up blood cultures (FUBCs) in gram-negative bloodstream infections to improve clinical outcomes remains controversial, especially among immunocompromised patients. Among 139 patients, FUBCs were common (117, 84.2%); however, positive FUBCs were rare (3, 2.6%). Only presence of fever was associated with a positive FUBC.

Impact of Statewide Prevention and Reduction of Clostridioides difficile (SPARC), a Maryland public health-academic collaborative: an evaluation of a quality improvement intervention.

To evaluate changes in Clostridioides difficile incidence rates for Maryland hospitals that participated in the Statewide Prevention and Reduction of C. difficile (SPARC) collaborative. Pre-post, difference-in-difference analysis of non-randomised intervention using four quarters of preintervention and six quarters of postintervention National Healthcare Safety Network data for SPARC hospitals (April 2017 to March 2020) and 10 quarters for control hospitals (October 2017 to March 2020). Mixed-effects negative binomial models were used to assess changes over time. Process evaluation using hospital intervention implementation plans, assessments and interviews with staff at eight SPARC hospitals. Maryland, USA. All Maryland acute care hospitals; 12 intervention and 36 control hospitals. Participation in SPARC, a public health-academic collaborative made available to Maryland hospitals, with staggered enrolment between June 2018 and August 2019. Hospitals with higher C. difficile rates were recruited via email and phone. SPARC included assessments, feedback reports and ongoing technical assistance. Primary outcomes were C. difficile incidence rate measured as the quarterly number of C. difficile infections per 10 000 patient-days (outcome measure) and SPARC intervention hospitals' experiences participating in the collaborative (process measures). SPARC invited 13 hospitals to participate in the intervention, with 92% (n=12) participating. The 36 hospitals that did not participate served as control hospitals. SPARC hospitals were associated with 45% greater C. difficile reduction as compared with control hospitals (incidence rate ratio=0.55, 95% CI 0.35 to 0.88, p=0.012). Key SPARC activities, including access to trusted external experts, technical assistance, multidisciplinary collaboration, an accountability structure, peer-to-peer learning opportunities and educational resources, were associated with hospitals reporting positive experiences with SPARC. SPARC intervention hospitals experienced 45% greater reduction in C. difficile rates than control hospitals. A public health-academic collaborative might help reduce C. difficile and other hospital-acquired infections in individual hospitals and at state or regional levels.

Optimizing the Management of Uncomplicated Gram-Negative Bloodstream Infections: Consensus Guidance Using a Modified Delphi Process.

BACKGROUND: Guidance on the recommended durations of antibiotic therapy, the use of oral antibiotic therapy, and the need for repeat blood cultures remain incomplete for gram-negative bloodstream infections. We convened a panel of infectious diseases specialists to develop a consensus definition of uncomplicated gram-negative bloodstream infections to assist clinicians with management decisions. METHODS: Panelists, who were all blinded to the identity of other members of the panel, used a modified Delphi technique to develop a list of statements describing preferred management approaches for uncomplicated gram-negative bloodstream infections. Panelists provided level of agreement and feedback on consensus statements generated and refined them from the first round of open-ended questions through 3 subsequent rounds. RESULTS: Thirteen infectious diseases specialists (7 physicians and 6 pharmacists) from across the United States participated in the consensus process. A definition of uncomplicated gram-negative bloodstream infection was developed. Considerations cited by panelists in determining if a bloodstream infection was uncomplicated included host immune status, response to therapy, organism identified, source of the bacteremia, and source control measures. For patients meeting this definition, panelists largely agreed that a duration of therapy of ~7 days, transitioning to oral antibiotic therapy, and forgoing repeat blood cultures, was reasonable. CONCLUSIONS: In the absence of professional guidelines for the management of uncomplicated gram-negative bloodstream infections, the consensus statements developed by a panel of infectious diseases specialists can provide guidance to practitioners for a common clinical scenario.

HHV-6 Encephalitis After Chimeric Antigen Receptor T-cell Therapy (CAR-T): 2 Case Reports and a Brief Review of the Literature.

Human herpesvirus 6 (HHV-6) reactivation can occur in patients who are highly immunosuppressed, including those who have undergone hematopoietic stem cell transplantation (HSCT). HHV-6 encephalitis is a severe manifestation that is well described in the HSCT population. Chimeric antigen receptor T-cell (CAR-T) therapy is a novel cancer-directed immunotherapy that results in severe immunosuppression. Patients undergoing CAR-T therapy may be at risk for HHV-6 encephalitis, which can be difficult to distinguish from a common adverse effect of CAR-T therapy, neurotoxicity. Herein, we describe 2 patients diagnosed with HHV-6 encephalitis after CAR-T therapy and discuss the diagnostic approach and differential diagnosis for altered mental status after CAR-T therapy. Diagnosing HHV-6 encephalitis can be difficult in this patient population as altered mental status is common after CAR-T therapy and may be attributed to CAR-T-associated neurotoxicity.

Effectiveness and Safety of Biodegradable Calcium Sulfate Antibiotic Beads as Adjuvant Therapy in Vascular Graft Infections.

This is a retrospective cohort study evaluating the safety and effectiveness of biodegradable calcium sulfate antibiotic beads in vascular graft infections compared with standard of care. No differences in acute kidney injury or hypercalcemia were observed between the cohorts. Recurrence of infection did not occur in the 13-patient bead cohort compared with 14 patients who had recurrence in the 45-patient nonbead cohort with a number needed to treat of 4.0.

Change in hospital antibiotic use and acquisition of multidrug-resistant gram-negative organisms after the onset of coronavirus disease 2019.

Interrupted time series segmented regression was conducted to trend antibiotic use and multidrug-resistant gram-negative (MDRGN) acquisition relative to COVID-19 in an academic hospital. Total antibiotic use and antibiotic use related to pneumonia was higher in the period after the onset of COVID-19 compared to the similar calendar period in 2019. Furthermore, MDRGN acquisition increased 3% for every increase in positive COVID-19 tests per week.

Multicenter retrospective cohort study of the clinical significance of Staphylococcus lugdunensis isolated from a single blood culture set.

BACKGROUND: Staphylococcus lugdunensis is a coagulase negative Staphylococcus species and frequent human skin commensal with the potential for aggressive infection. Guidance surrounding S. lugdunensis bacteremia (SLB) from a single set of blood cultures is lacking. METHODS: A multicenter, retrospective cohort of patients with SLB from at least one blood culture set within the University of Maryland Medical System from 2015 to 2019 is presented. Objectives are to describe baseline characteristics, compare the clinical status and treatment course, and to evaluate the clinical outcomes among patients with SLB in single versus multiple sets. RESULTS: Thirty-six patients were included, 24 with one set of blood cultures positive for S lugdunensis and 12 with multiple sets. Baseline characteristics were similar between the groups, though patients with SLB in multiple sets were more commonly on hemodialysis (P = 0.029). Central lines were the most common source (17%). Most (97%) fulfilled systemic inflammatory response syndrome or Souvenir criteria, had an infectious focus on imaging, or had a second positive culture site. Most (78%) were treated as clinically significant. Patients with multiple positive sets were more commonly treated with antibiotics for >2 weeks (P = 0.02). CONCLUSIONS: SLB was rare and occurred more frequently as a single set of positive cultures. Patient characteristics and clinical courses were similar between single and multiple set groups. Given the potential severity of S. lugdunensis bacteremia it seems prudent to treat S. lugdunensis in a single blood culture as true bacteremia, pending larger studies and guidelines.

Diabetic Foot Infections: Local Prevalence of and Case-Control Study of Risk Factors for Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa.

We identified deep diabetic foot infections by culture and conducted a case-control study examining the risk factors for moderate to severe methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PsA) diabetic foot infections. Our MRSA prevalence was lower than literature values; PsA was higher. Gangrene may be predictive of Pseudomonas infection.

Agranulocytosis Following COVID-19 Recovery.

Clinicians have continued to report on the clinical behavior and characteristics of patients with coronavirus disease 2019 (COVID-19) as our knowledge of the virus continues to mature. Herein, we report the case of a 39-year-old male with multiple comorbidities who became critically ill with COVID-19 infection, requiring mechanical ventilation and vasopressors, and then developed agranulocytosis following clinical improvement and resolution of symptoms of COVID infection. The period of agranulocytosis coincided with the development of thrombocytosis, and following resolution of agranulocytosis, the platelet count also normalized, suggesting a possible related mechanism. Interestingly, the patient was treated with TBO-filgrastim 480 mcg daily with a rapid reconstitution of neutrophils. While the mechanism of agranulocytosis remains unknown, we report, to our knowledge, the first known case of agranulocytosis following COVID-19 infection and its successful treatment with granulocyte colony-stimulating factor.

Effect of urine reflex culturing on rates of cultures and infections in acute and long-term care.

BACKGROUND: Urine cultures are often positive in the absence of a urinary tract infection (UTI). Pyuria is generally considered necessary to diagnose a UTI. PROBLEM: Urine cultures are often positive in the absence of UTI leading to unnecessary antibiotics. METHODS: Quasi-experimental pre-post study of all patient urine cultures ordered in a VA acute care hospital, emergency department (ED), and two long-term care (LTC) facilities from August 2016 to August 2018. Urine cultures performed per 100 days were compared pre- (August 2016 to July 2017) versus post-intervention (August 2017 to August 2018) using interrupted time series negative binomial regression. INTERVENTION: We examined whether reflexing to urine culture only if a urinalysis (UA) found greater than 10 WBC/hpf decreased urine culturing. RESULTS: In acute-care, reflex culturing resulted in a 39% time series regression analysis adjusted decrease in the rate of cultures performed (pre-intervention, 3.6 cultures/100 days vs. Post-intervention, 1.8 cultures/100 days, p < 0.001). Pre-intervention, 29% (4/14) of Catheter-associated UTI (CAUTI) would not have been reported if reflex culturing was employed. In the ED, reflex culturing was associated with a 38% (p = 0.0015) regression analysis adjusted decrease in cultures, from 5.4/100 visits to 3.3/100 visits. In LTC, there was a small absolute, but regression analysis adjusted increase of 89% (p = 0.0018) in rates from (0.4/100 days to 0.5/100 days). CONCLUSION: In acute care and ED, urine reflex culturing decreased the number of urine cultures performed. A small absolute increase was seen between pre-post time periods in LTC. Reflex testing generally decreases cultures and may lead to more accurate diagnoses of CAUTI.

A Propensity Score Matched Study of the Positive Impact of Infectious Diseases Consultation on Antimicrobial Appropriateness in Hospitalized Patients with Antimicrobial Stewardship Oversight.

Hospital-based antibiotic stewardship (AS) programs provide oversight and guidance for appropriate antimicrobial use in acute care settings. Infectious disease expertise is beneficial in the care of hospitalized patients with infections. The impact of infectious diseases consultation (IDC) on antimicrobial appropriateness in a large tertiary hospital with an established AS program was investigated. This was a cross-sectional study from October 2017 to March 2019 at a large academic hospital with an AS-directed prospective audit and feedback process and multiple IDC services. Antimicrobial appropriateness was adjudicated by an AS team member after antimicrobial start. Antimicrobial appropriateness was compared among antimicrobial orders with and without IDC using propensity score matching and multivariable logistic regression. Analyses were stratified by primary services caring for the patients. There were 10,508 antimicrobial orders from 6,165 unique patient encounters. Overall appropriateness was 92%, with higher appropriateness among patients with IDC versus without IDC (94% versus 84%; P < 0.0001). After propensity score matching and adjustment for certain antibiotics, organisms, syndromes, and locations, IDC was associated with a greater antimicrobial appropriateness odds ratio (OR) of 2.4 (95% confidence interval [CI], 1.9 to 3.0). Stratification by primary service showed an OR of 2.9 (95% CI, 2.1 to 3.8) for surgical specialties and an OR of 1.6 (95% CI, 1.1 to 2.2) for medical specialties. Even with a high overall antimicrobial appropriateness, patients with IDC had greater odds of antimicrobial appropriateness than those without IDC, and this impact was greater in surgical specialties. Infectious diseases consultation can be synergistic with antimicrobial stewardship programs.

Dalbavancin Use in Vulnerable Patients Receiving Outpatient Parenteral Antibiotic Therapy for Invasive Gram-Positive Infections.

INTRODUCTION: Dalbavancin is approved for acute bacterial skin and skin structure infections (ABSSSIs) but offers a potential treatment option for complicated invasive gram-positive infections. Importantly, dalbavancin's real benefits may be in treating complicated infections in vulnerable patient populations, such as persons who inject drugs (PWID). METHODS: A multicenter retrospective analysis was performed from March 2014 to April 2017 to assess 30- and 90-day clinical cure and adverse drug events (ADEs) in adult patients who received ≥ 1 dose of dalbavancin for a non-ABSSSI indication. RESULTS: During the study period, 45 patients received dalbavancin, 28 for a non-ABSSSI indication. The predominant infections treated included osteomyelitis (46%), endovascular infection (25%) and uncomplicated bacteremia (14%). Half of the patients had positive Staphylococcus aureus in cultures, 29% methicillin resistant and 21% methicillin susceptible. Most patients were prescribed dalbavancin as sequential treatment with a median of 13.5 days of prior antibiotic therapy. The most common reason for choosing dalbavancin over standard therapy use was PWID (54%). Seven patients were lost to follow-up at day 30. Of the remaining evaluable patients, 30-day clinical cure was achieved in 15/21 (71%) patients. The most common reason for failure was lack of source control (4/6, 67%). At day 90, relapse occurred in two patients. Three patients had a potential dalbavancin-associated ADE: two patients with renal dysfunction and one patient with pruritus. CONCLUSIONS: This study demonstrates a possible role for dalbavancin in the treatment of non-ABSSSI invasive gram-positive infections in select vulnerable OPAT patients.