Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients.

BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).

Concordance Between Initial Presumptive and Final Adjudicated Diagnoses of Infection Among Patients Meeting Sepsis-3 Criteria in the Emergency Department.

BACKGROUND: Guidelines emphasize rapid antibiotic treatment for sepsis, but infection presence is often uncertain at initial presentation. We investigated the incidence and drivers of false-positive presumptive infection diagnosis among emergency department (ED) patients meeting Sepsis-3 criteria. METHODS: For a retrospective cohort of patients hospitalized after meeting Sepsis-3 criteria (acute organ failure and suspected infection including blood cultures drawn and intravenous antimicrobials administered) in 1 of 4 EDs from 2013 to 2017, trained reviewers first identified the ED-diagnosed source of infection and adjudicated the presence and source of infection on final assessment. Reviewers subsequently adjudicated final infection probability for a randomly selected 10% subset of subjects. Risk factors for false-positive infection diagnosis and its association with 30-day mortality were evaluated using multivariable regression. RESULTS: Of 8267 patients meeting Sepsis-3 criteria in the ED, 699 (8.5%) did not have an infection on final adjudication and 1488 (18.0%) patients with confirmed infections had a different source of infection diagnosed in the ED versus final adjudication (ie, initial/final source diagnosis discordance). Among the subset of patients whose final infection probability was adjudicated (n = 812), 79 (9.7%) had only "possible" infection and 77 (9.5%) were not infected. Factors associated with false-positive infection diagnosis included hypothermia, altered mental status, comorbidity burden, and an "unknown infection source" diagnosis in the ED (odds ratio: 6.39; 95% confidence interval: 5.14-7.94). False-positive infection diagnosis was not associated with 30-day mortality. CONCLUSIONS: In this large multihospital study, <20% of ED patients meeting Sepsis-3 criteria had no infection or only possible infection on retrospective adjudication.

A Pragmatic, Stepped-Wedge, Cluster-controlled Clinical Trial of Real-Time Pneumonia Clinical Decision Support.

Rationale: Care of emergency department (ED) patients with pneumonia can be challenging. Clinical decision support may decrease unnecessary variation and improve care. Objectives: To report patient outcomes and processes of care after deployment of electronic pneumonia clinical decision support (ePNa): a comprehensive, open loop, real-time clinical decision support embedded within the electronic health record. Methods: We conducted a pragmatic, stepped-wedge, cluster-controlled trial with deployment at 2-month intervals in 16 community hospitals. ePNa extracts real-time and historical data to guide diagnosis, risk stratification, microbiological studies, site of care, and antibiotic therapy. We included all adult ED patients with pneumonia over the course of 3 years identified by International Classification of Diseases, 10th Revision discharge coding confirmed by chest imaging. Measurements and Main Results: The median age of the 6,848 patients was 67 years (interquartile range, 50-79), and 48% were female; 64.8% were hospital admitted. Unadjusted mortality was 8.6% before and 4.8% after deployment. A mixed effects logistic regression model adjusting for severity of illness with hospital cluster as the random effect showed an adjusted odds ratio of 0.62 (0.49-0.79; P < 0.001) for 30-day all-cause mortality after deployment. Lower mortality was consistent across hospital clusters. ePNa-concordant antibiotic prescribing increased from 83.5% to 90.2% (P < 0.001). The mean time from ED admission to first antibiotic was 159.4 (156.9-161.9) minutes at baseline and 150.9 (144.1-157.8) minutes after deployment (P < 0.001). Outpatient disposition from the ED increased from 29.2% to 46.9%, whereas 7-day secondary hospital admission was unchanged (5.2% vs. 6.1%). ePNa was used by ED clinicians in 67% of eligible patients. Conclusions: ePNa deployment was associated with improved processes of care and lower mortality. Clinical trial registered with www.clinicaltrials.gov (NCT03358342).

Epidemiology, Clinical Features, and Outcomes of Coccidioidomycosis, Utah, 2006-2015.

On the basis of a 1957 geographic Coccidioides seropositivity survey, 3 counties in southwestern Utah, USA, were considered coccidioidomycosis-endemic, but there has been a paucity of information on the disease burden in Utah since. We report findings from a recent clinical and epidemiologic study of coccidioidomycosis in Utah. To describe clinical characteristics, we identified all coccidioidomycosis cases in an integrated health system in the state during 2006-2015. For epidemiologic analysis, we used cases reported to the Utah Department of Health during 2009-2015. Mean state incidence was 1.83 cases/100,000 population/year. Washington County, in southwestern Utah, had the highest incidence, 17.2 cases/100,000 population/year. In a generalized linear model with time as a fixed effect, mean annual temperature, population, and new construction were associated with regional variations in incidence. Using these variables in a spatiotemporal model, we estimated the adjusted regional variation by county to predict areas where Coccidioides infections might increase.

Antimicrobial Stewardship in a Hematological Malignancy Unit: Carbapenem Reduction and Decreased Vancomycin-Resistant Enterococcus Infection.

BACKGROUND: Antibiotic stewardship is challenging in hematological malignancy patients. METHODS: We performed a quasiexperimental implementation study of 2 antimicrobial stewardship interventions in a hematological malignancy unit: monthly antibiotic cycling for febrile neutropenia that included cefepime (± metronidazole) and piperacillin-tazobactam and a clinical prediction rule to guide anti-vancomycin-resistant Enterococcus faecium (VRE) therapy. We used interrupted time-series analysis to compare antibiotic use and logistic regression in order to adjust observed unit-level changes in resistant infections by background community rates. RESULTS: A total of 2434 admissions spanning 3 years pre- and 2 years postimplementation were included. Unadjusted carbapenem and daptomycin use decreased significantly. In interrupted time-series analysis, carbapenem use decreased by -230 days of therapy (DOT)/1000 patient-days (95% confidence interval [CI], -290 to -180; P < .001). Both VRE colonization (odds ratio [OR], 0.64; 95% CI, 0.51 to 0.81; P < .001) and infection (OR, 0.41; 95% CI, 0.2 to 0.9; P = .02) decreased after implementation. This shift may have had a greater effect on daptomycin prescribing (-160 DOT/1000 patient-days; 95% CI, -200 to -120; P < .001) than did the VRE clinical prediction score (-30 DOT/1000 patient-days; 95% CI, -50 to 0; P = .08). Also, 46.2% of Pseudomonas aeruginosa isolates were carbapenem-resistant preimplementation compared with 25.0% postimplementation (P = .32). Unit-level changes in methicillin-resistant Staphylococcus aureus and extended-spectrum beta lactamase (ESBL) incidence were explained by background community-level trends, while changes in AmpC ESBL and VRE appeared to be independent. The program was not associated with increased mortality. CONCLUSIONS: An antibiotic cycling-based strategy for febrile neutropenia effectively reduced carbapenem use, which may have resulted in decreased VRE colonization and infection and perhaps, in turn, decreased daptomycin prescribing.

Antibiotic Exposure and Risk for Hospital-Associated Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) is a health care-associated infection associated with significant morbidity and cost, with highly varied risk across populations. More effective, risk-based prevention strategies are needed. Here, we investigate risk factors for hospital-associated CDI in a large integrated health system. In a retrospective cohort of all adult admissions to 21 Intermountain Healthcare hospitals from 2006 to 2012, we identified all symptomatic (i) hospital-onset and (ii) health care-facility-associated, community-onset CDI. We then evaluated the risk associated with antibiotic exposure, including that of specific agents, using multivariable logistic regression. A total of 2,356 cases of CDI among 506,068 admissions were identified (incidence, 46.6 per 10,000). Prior antibiotic use was the dominant risk factor, where for every antibiotic day of therapy prior to the index admission, the odds of subsequent CDI increased by 12.8% (95% confidence interval [CI], 12.2 to 13.4%; P < 0.0001). This was a much stronger association than was inpatient antibiotic exposure (odds ratio [OR], 1.007 [95% CI, 1.005 to 1.009]; P < 0.0001). The highest-risk antibiotics included second-generation and later cephalosporins (especially oral), carbapenems, fluoroquinolones, and clindamycin, while doxycycline and daptomycin were associated with a lower CDI risk. We concluded that cumulative antibiotic exposure prior to admission is the greatest contributor to the risk of subsequent CDI. Most classes of antibiotics carry some risk, which varies by drug and route. This information may be useful for antimicrobial stewardship efforts.

Strategies for prediction of drug-resistant pathogens and empiric antibiotic selection in community-acquired pneumonia.

PURPOSE OF REVIEW: Although most patients with community-acquired pneumonia (CAP) are appropriately treated with narrow-spectrum antibiotics, predicting which patients require coverage of drug-resistant pathogens (DRP) remains a challenge. The 2019 American Thoracic Society/Infectious Diseases Society of America CAP guidelines endorse using locally validated prediction models for DRP. Here we review risk factors for DRP and provide a summary of available risk prediction models. RECENT FINDINGS: Both inadequate initial empiric spectrum as well as unnecessary broad-spectrum antibiotic use are associated with poor outcomes in CAP. Multiple prediction models for DRP-based patient-level risk factors have been published, with some variation in included predictor variables and test performance characteristics. Seven models have been robustly externally validated, and implementation data have been published for two of these models. All models demonstrated better performance than the healthcare-associated pneumonia criteria, with most favoring sensitivity over specificity. We also report validation of the novel, risk factor-based treatment algorithm proposed in the American Thoracic Society/Infectious Diseases Society of America guidelines which strongly favors specificity over sensitivity, especially in nonsevere pneumonia. SUMMARY: Using patient-level risk factors to guide the decision whether to prescribe broad-spectrum antibiotics is a rational approach to treatment. Several viable candidate prediction models are available. Hospitals should evaluate the local performance of existing scores before implementing in routine clinical practice.

Are Clostridioides difficile infections being overdiagnosed in hematopoietic stem cell transplant recipients?

BACKGROUND: Because both diarrhea due to other causes and gastrointestinal colonization with toxigenic Clostridioides difficile are common in HSCT, there is a possibility of false-positive diagnoses of C difficile infections (CDI). METHODS: We estimated the probability of a patient being colonized by toxigenic C difficile by testing non-diarrheal surveillance stools from 223 HSCT recipients and the probability that a specimen submitted for C difficile testing was not CDI by determining the number of clinical tests that returned negative from this cohort. The number of expected false-positive CDI was estimated using these probabilities and compared with observed clinical test results. RESULTS: The expected false-positive and the observed numbers of positive clinical results were similar. The 20 patients diagnosed with CDI were also similar to 142 patients with diarrhea and C difficile-negative stools in number of stools on day of testing, associated symptoms, and the recorded number of days to formed stools. C difficile colonization was most commonly detected during the first week and CDI during the second. Retrospective analysis of 837 patients showed that 18 stools were submitted for each diagnosis of CDI. Ribotyping of the surveillance samples showed 17 ribotypes. CONCLUSIONS: Although several assumptions could impact the accuracy of our false-positive CDI estimates, it appears that many HSCT recipients diagnosed with CDI may actually represent colonized status and an alternative cause of diarrhea. Diagnostic stewardship, including limiting CDI diagnoses to patients with positive toxin and restricting stool submissions to patients with more severe symptoms, may decrease the number of false-positive diagnoses.

Repurposing an Old Drug for a New Epidemic: Ursodeoxycholic Acid to Prevent Recurrent Clostridioides difficile Infection.

Recurrent Clostridioides difficile infection (rCDI) may be mediated in part by secondary bile acids. Here we report salvage therapy with ursodeoxycholic acid (UDCA) to prevent rCDI in 16 high-risk patients. Patients on UDCA had a low observed recurrence rate (12.5%). Controlled trials are needed to confirm these observations.

Broad-spectrum antibiotic use and poor outcomes in community-onset pneumonia: a cohort study.

QUESTION: Is broad-spectrum antibiotic use associated with poor outcomes in community-onset pneumonia after adjusting for confounders? METHODS: We performed a retrospective, observational cohort study of 1995 adults with pneumonia admitted from four US hospital emergency departments. We used multivariable regressions to investigate the effect of broad-spectrum antibiotics on 30-day mortality, length of stay, cost and Clostridioides difficile infection (CDI). To address indication bias, we developed a propensity score using multilevel (individual provider) generalised linear mixed models to perform inverse-probability of treatment weighting (IPTW) to estimate the average treatment effect in the treated. We also manually reviewed a sample of mortality cases for antibiotic-associated adverse events. RESULTS: 39.7% of patients received broad-spectrum antibiotics, but drug-resistant pathogens were recovered in only 3%. Broad-spectrum antibiotics were associated with increased mortality in both the unweighted multivariable model (OR 3.8, 95% CI 2.5-5.9; p<0.001) and IPTW analysis (OR 4.6, 95% CI 2.9-7.5; p<0.001). Broad-spectrum antibiotic use by either analysis was also associated with longer hospital stay, greater cost and increased CDI. Healthcare-associated pneumonia was not associated with mortality independent of broad-spectrum antibiotic use. In manual review we identified antibiotic-associated events in 17.5% of mortality cases. CONCLUSION: Broad-spectrum antibiotics appear to be associated with increased mortality and other poor outcomes in community-onset pneumonia.

Clostridioides difficile colonization and infection in patients admitted for a first autologous transplantation: Incidence, risk factors, and patient outcomes.

BACKGROUND: More data are needed regarding the incidence, risk factors, and outcomes for Clostridioides difficile infection (CDI) and colonization in patients undergoing an autologous hematopoietic stem cell transplantation (AHSCT). METHODS: We studied 472 consecutive patients admitted for a first AHSCT and conducted a prospective C difficile stool surveillance and ribotyping analysis in a subset of 94 patients. RESULTS: Clostridioides difficile infection was diagnosed in 7% of patients for an incidence of 3.4 CDI/1000 inpatient days, recurrent/reinfection CDI was rare. CDI was increased in patients who were colonized on admission, had required a recent pre-admission inpatient stay for fever and/or serious infection, or received empiric therapy with a carbapenem or extended-spectrum penicillin. CDI was associated with a longer length of stay and higher hospital costs. Twelve of 94 patients (13%) were found to have colonization on admission; CDI was diagnosed in 27% of these vs 1% in those with initial negative stools. Colonization in the hospital for those negative on admission was infrequent. C difficile ribotyping showed a predominance of 014/020. CONCLUSIONS: Clostridioides difficile infection is a significant infection in patients receiving a first AHSCT. The risk factors identified may be useful in designing preventive interventions.

The clinical and economic impact of cytomegalovirus infection in recipients of hematopoietic stem cell transplantation.

BACKGROUND: CMV infection (CMV-I) remains an important complication of hematopoietic stem cell transplantation (HSCT). METHODS: This was a retrospective, single-center cohort study in HSCT recipients. Primary outcomes were adjusted cost and all-cause mortality. Secondary analyses investigated CMV risk factors and the effect of serostatus. RESULTS: Overall, 690 transplant episodes were included (allogeneic [n = 310]; autologous [n = 380]). All received preemptive CMV antiviral therapy at first detectable DNAemia. CMV-I occurred in 34.8% of allogeneic and 2.1% of autologous transplants; median time to onset was 45 days. In allogeneic HSCT recipients, the primary risk factor for CMV-I was CMV donor/recipient (D/R) serostatus. In a Markov multi-state model for allogeneic HSCT recipients, the hazard ratio for CMV-I and relapse was 1.5 (95% CI 0.8-2.8) and for CMV-I and mortality 2.4 (95% CI 0.9-6.5). In a multivariable model for all patients, CMV-I was associated with increased total cost (coefficient = 0.21, estimated incremental daily cost USD $500; P = 0.02). Cost was attenuated in allogeneic HSCT recipients (coefficient = 0.13, USD $699 vs $613, or $24 892 per transplant episode; P = 0.23). CMV disease (CMV-D) complicated 29.6% of CMV-I events in allogeneic HSCT recipients, but was not associated with an incrementally increased adjusted risk of mortality compared with CMV-I alone. CMV-I (56.4%) and CMV-D (19.8%) were significantly overrepresented in D-/R+ serostatus HSCT recipients, and mortality was higher in R+ HSCT recipients. CONCLUSIONS: Despite early preemptive antiviral treatment, CMV-I impacts clinical outcomes and cost after HSCT, but the impact on cost is less pronounced in allogeneic HSCT recipients compared with autologous HSCT recipients.

Prediction of Bloodstream Infection Due to Vancomycin-Resistant Enterococcus in Patients Undergoing Leukemia Induction or Hematopoietic Stem-Cell Transplantation.

BACKGROUND.: Bloodstream infection (BSI) to due vancomycin-resistant Enterococcus (VRE) is an important complication of hematologic malignancy. Determining when to use empiric anti-VRE antibiotic therapy in this population remains a clinical challenge. METHODS.: A single-center cohort representing 664 admissions for induction or hematopoietic stem-cell transplant (HSCT) from 2006 to 2014 was selected. We derived a prediction score using risk factors for VRE BSI and evaluated the model's predictive performance by calculating it for each of 16232 BSI at-risk inpatient days. RESULTS.: VRE BSI incidence was 6.5% of admissions (2.7 VRE BSI per 1000 BSI at-risk days). Adjusted 1-year mortality and length of stay were significantly higher in patients with VRE BSI. VRE colonization (adjusted odds ratio [aOR] = 8.4; 95% confidence interval [CI] = 3.4-20.6; P < .0001), renal insufficiency (aOR = 2.4; 95% CI = 1.0-5.8; P = .046), aminoglycoside use (aOR = 4.7; 95% CI = 2.2-9.8; P < .0001), and antianaerobic antibiotic use (aOR = 2.8; 95% CI = 1.3-5.8; P = .007) correlated most closely with VRE BSI. A prediction model with optimal performance included these factors plus gastrointestinal disturbance, severe neutropenia, and prior beta-lactam antibiotic use. The score effectively risk-stratified patients (area under the receiver operating curve = 0.84; 95% CI = 0.79-0.89). At a threshold of ≥5 points, per day probability of VRE BSI was increased nearly 4-fold. CONCLUSIONS.: This novel predictive score is based on risk factors reflecting a plausible pathophysiological model for VRE BSI in patients with hematological malignancy. Integrating VRE colonization status with risk factors for developing BSI is a promising method of guiding rational use of empiric anti-VRE antimicrobial therapy in patients with hematological malignancy. Validation of this novel predictive score is needed to confirm clinical utility.

Derivation and Multicenter Validation of the Drug Resistance in Pneumonia Clinical Prediction Score.

The health care-associated pneumonia (HCAP) criteria have a limited ability to predict pneumonia caused by drug-resistant bacteria and favor the overutilization of broad-spectrum antibiotics. We aimed to derive and validate a clinical prediction score with an improved ability to predict the risk of pneumonia due to drug-resistant pathogens compared to that of HCAP criteria. A derivation cohort of 200 microbiologically confirmed pneumonia cases in 2011 and 2012 was identified retrospectively. Risk factors for pneumonia due to drug-resistant pathogens were evaluated by logistic regression, and a novel prediction score (the drug resistance in pneumonia [DRIP] score) was derived. The score was then validated in a prospective, observational cohort of 200 microbiologically confirmed cases of pneumonia at four U.S. centers in 2013 and 2014. The DRIP score (area under the receiver operator curve [AUROC], 0.88 [95% confidence interval {CI}, 0.82 to 0.93]) performed significantly better (P = 0.02) than the HCAP criteria (AUROC, 0.72 [95% CI, 0.64 to 0.79]). At a threshold of ≥4 points, the DRIP score demonstrated a sensitivity of 0.82 (95% CI, 0.67 to 0.88), a specificity of 0.81 (95% CI, 0.73 to 0.87), a positive predictive value (PPV) of 0.68 (95% CI, 0.56 to 0.78), and a negative predictive value (NPV) of 0.90 (95% CI, 0.81 to 0.93). By comparison, the performance of HCAP criteria was less favorable: sensitivity was 0.79 (95% CI, 0.67 to 0.88), specificity was 0.65 (95% CI, 0.56 to 0.73), PPV was 0.53 (95% CI, 0.42 to 0.63), and NPV was 0.86 (95% CI, 0.77 to 0.92). The overall accuracy of the HCAP criteria was 69.5% (95% CI, 62.5 to 75.7%), whereas that of the DRIP score was 81.5% (95% CI, 74.2 to 85.6%) (P = 0.005). Unnecessary extended-spectrum antibiotics were recommended 46% less frequently by applying the DRIP score (25/200, 12.5%) than by use of HCAP criteria (47/200, 23.5%) (P = 0.004), without increasing the rate at which inadequate treatment recommendations were made. The DRIP score was more predictive of the risk of pneumonia due to drug-resistant pathogens than HCAP criteria and may have the potential to decrease antibiotic overutilization in patients with pneumonia. Validation in larger cohorts of patients with pneumonia due to all causes is necessary.

Empiric antibiotic selection and risk prediction of drug-resistant pathogens in community-onset pneumonia.

PURPOSE OF REVEIW: Empiric antibiotic selection in community-onset pneumonia is complicated by uncertainty regarding risk of drug-resistant pathogens (DRPs). The healthcare-associated pneumonia (HCAP) criteria have limited predictive value and lead to unnecessary antibiotic use. Better methods of predicting risk of DRP and selecting empiric antibiotics are needed. Here we give an update on risk factors for DRP, available risk prediction models, and treatment strategy in patients with pneumonia. RECENT FINDINGS: Evidence supporting factors that contribute to risk of DRP has improved since the advent of HCAP. Many of these risk factors have been reproducibly identified in heterogeneous populations. Newer methods of predicting DRP based on these factors demonstrate better performance than HCAP. Recent innovations include the potential to discriminate between risk for methicillin-resistant Staphylococcus aureus and other DRP, and use of severity as a modifier of treatment threshold. However, there is wide variation in included predictor variables, and at proposed thresholds most scores still favor overtreatment. SUMMARY: Until reliable molecular diagnostics are available, additional development and validation of decision support models integrating local resistance rates, estimated DRP risk, severity, and threshold for anti-DRP antibiotics are needed. Once optimized models are identified, implementation studies will be needed to confirm safety and efficacy.

The impact of 2011 ACGME duty hour restrictions on internal medicine resident workload and education.

The Accreditation Council for Graduate Medical Education (ACGME) implemented work hour restrictions for physicians in training in 2003 that were revised July 1, 2011. Current published data are insufficient to assess whether such work hour restrictions will have long-term impact on residents' education. We searched computer-generated reports of hospital in-patient census, continuity clinic census, in-training exam scores and first-year resident attendance at educational conferences for the academic years 2010-2011 (August 1, 2010-May 31, 2011) and 2011-2013 (August 1, 2011-May 31, 2013). During the first year of the study period, the residents' inpatient internal medicine services admitted 1,754 patients; during this same period for academic years 2011-2012 and 2012-2013, the teaching services admitted 1,539 and 1,428 patients respectively, yielding a decrease of 16.4%. Monthly, these services cared for a mean of 27.1 (27.1/175.4 [15.4%]) fewer patients and 9.7 (9.7/34.4 [28.2%]) fewer patients per intern than in the previous year. No statistical difference was observed regarding continuity clinic attendance and in-training exam scores. Residents in the years following work hours restrictions attended more educational conferences. Implementation of 2011 ACGME work hour regulations resulted in fewer patients seen by first-year residents in hospital, but did not affect in-training exam scores. Whether these findings will translate into differences in patient outcomes, and quality of care remains to be seen.

Real-World Effectiveness of Intravenous and Oral Antibiotic Stepdown Strategies for Gram-Negative Complicated Urinary Tract Infection With Bacteremia.

Background: Robust data are lacking regarding the optimal route, duration, and antibiotic choice for gram-negative bloodstream infection from a complicated urinary tract infection source (GN-BSI/cUTI). Methods: In this multicenter observational cohort study, we simulated a 4-arm registry trial using a causal inference method to compare effectiveness of the following regimens for GN-BSI/cUTI: complete course of an intravenous ß-lactam (IVBL) or oral stepdown therapy within 7 days using fluoroquinolones (FQs), trimethoprim-sulfamethoxazole (TMP-SMX), or high-bioavailability ß-lactams (HBBLs). Adults treated between January 2016 and December 2022 for Escherichia coli or Klebsiella species GN-BSI/cUTI were included. Propensity weighting was used to balance characteristics between groups. The 60-day recurrence was compared using a multinomial Cox proportional hazards model with probability of treatment weighting. Results: Of 2571 patients screened, 759 (30%) were included. Characteristics were similar between groups. Compared with IVBLs, we did not observe a difference in effectiveness for FQs (adjusted hazard ratio, 1.09 [95% confidence interval, .49-2.43]) or TMP-SMX (1.44 [.54-3.87]), and the effectiveness of TMP-SMX/FQ appeared to be optimal at durations of >10 days. HBBLs were associated with nearly 4-fold higher risk of recurrence (adjusted hazard ratio, 3.83 [95% confidence interval, 1.76-8.33]), which was not mitigated by longer treatment durations. Most HBBLs (67%) were not optimally dosed for bacteremia. Results were robust to multiple sensitivity analyses. Conclusions: These real-world data suggest that oral stepdown therapy with FQs or TMP-SMX have similar effectiveness as IVBLs. HBBLs were associated with higher recurrence rates, but dosing was suboptimal. Further data are needed to define optimal dosing and duration to mitigate treatment failures.

Oral ß-Lactams, Fluoroquinolones, or Trimethoprim-Sulfamethoxazole for Definitive Treatment of Uncomplicated Escherichia coli or Klebsiella Species Bacteremia From a Urinary Tract Source.

Background: Fluoroquinolones (FQs) are effective for oral step-down therapy for gram-negative bloodstream infections but are associated with unfavorable toxic effects. Robust data are lacking for trimethoprim-sulfamethoxazole (TMP-SMX) and high-bioavailability ß-lactams (HBBLs). Methods: In this multicenter observational cohort study, we simulated a 3-arm registry trial using causal inference methods to compare the effectiveness of FQs, TMP-SMX, or HBBLs for gram-negative bloodstream infections oral step-down therapy. The study included adults treated between January 2016 and December 2022 for uncomplicated Escherichia coli or Klebsiella species bacteremia of urinary tract origin who were who were transitioned to an oral regimen after ≤4 days of effective intravenous antibiotics. Propensity weighting was used to balance characteristics between groups. 60-day recurrence was compared using a multinomial Cox proportional hazards model with probability of treatment weighting. Results: Of 2571 patients screened, 648 (25%) were included. Their median age (interquartile range) was 67 (45-78) years, and only 103 (16%) were male. Characteristics were well balanced between groups. Compared with FQs, TMP-SMX had similar effectiveness (adjusted hazard ratio, 0.91 [95% confidence interval, .30-2.78]), and HBBLs had a higher risk of recurrence (2.19 [.95-5.01]), although this difference was not statistically significant. Most HBBLs (70%) were not optimally dosed for bacteremia. A total antibiotic duration ≤8 days was associated with a higher recurrence rate in select patients with risk factors for failure. Conclusions: FQs and TMP-SMX had similar effectiveness in this real-world data set. HBBLs were associated with higher recurrence rates but suboptimal dosing may have contributed. Further studies are needed to define optimal BL dosing and duration to mitigate treatment failures.

Real-world use of nirmatrelvir-ritonavir in COVID-19 outpatients during BQ.1, BQ.1.1., and XBB.1.5 predominant omicron variants in three U.S. health systems: a retrospective cohort study.

Background: Ritonavir-boosted Nirmatrelvir (NMV-r), a protease inhibitor with in vitro activity against SARS-CoV-2, can reduce risk of progression to severe COVID-19 among high-risk individuals infected with earlier variants, but less is known about its effectiveness against omicron variants BQ.1/BQ.1.1/XBB.1.5. We sought to evaluate effectiveness of NMV-r in BQ.1/BQ.1.1/XBB.1.5 omicron variants by comparing hospitalisation rates to NMV-r treated patients during a previous omicron phase and to contemporaneous untreated patients. Methods: We conducted a retrospective observational cohort study of non-hospitalised adult patients with SARS-CoV-2 infection using real-world data from three health systems in Colorado and Utah, and compared hospitalisation rates in NMV-r-treated patients in a BA.2/BA.2.12.1/BA.4/BA.5 variant-predominant (first) phase (April 3, 2022-November 12, 2022), with a BQ.1/BQ.1.1/XBB.1.5 variant-predominant (second) phase (November 13, 2022-March 7, 2023). In the primary analysis, we used Firth logistic regression with a two-segment (phase) linear time model, and pre-specified non-inferiority bounds for the mean change between segments. In a pre-specified secondary analysis, we inferred NMV-r effectiveness in a cohort of treated and untreated patients infected during the second phase. For both analyses, the primary outcome was 28-day all-cause hospitalisation. Subgroup analyses assessed treatment effect heterogeneity. Findings: In the primary analysis, 28-day all-cause hospitalisation rates in NMV-r treated patients in the second phase (n = 12,061) were non-inferior compared to the first phase (n = 25,075) (198 [1.6%] vs. 345 [1.4%], adjusted odds ratio (aOR): 0.76 [95% CI 0.54-1.06]), with consistent results among secondary endpoints and key subgroups. Secondary cohort analyses revealed additional evidence for NMV-r effectiveness, with reduced 28-day hospitalisation rates among treated patients compared to untreated patients during a BQ.1/BQ.1.1/XBB.1.5 predominant phase (198/12,061 [1.6%] vs. 376/10,031 [3.7%], aOR 0.34 [95% CI 0.30-0.38), findings robust to additional sensitivity analyses. Interpretation: Real-world evidence from major US healthcare systems suggests ongoing NMV-r effectiveness in preventing hospitalisation during a BQ.1/BQ.1.1/XBB.1.5-predominant phase in the U.S, supporting its continued use in similar patient populations. Funding: U.S. National Institutes of Health.