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Background: Despite high negative predictive values (NPVs) seen with methicillin-resistant Staphylococcus aureus (MRSA) nares polymerase chain reaction (PCR) assays, utilization of both respiratory sample Gram stain and MRSA nares PCR in patients with pneumonia may contribute to overuse of laboratory resources. The purpose of this study was to evaluate if a Gram stain demonstrating no Gram-positive organisms from a respiratory sample is sufficient to allow for de-escalation of vancomycin therapy. Methods: This single center study retrospectively identified intensive care unit (ICU) patients started on vancomycin for presumed pneumonia at University of Wisconsin (UW) Health in Madison, WI between August 2022 and March 2023. Patients with respiratory sample demonstrating no Gram-positives on Gram stain met inclusion criteria if the sample was ordered within 24 h of vancomycin initiation. The primary outcome was NPV of respiratory sample Gram stain demonstrating no Gram-positive organisms with respect to MRSA detection of the respiratory culture. Secondary outcomes included the NPV of combined MRSA nares PCR plus respiratory sample Gram stain, and difference in time to event in patients that had both a respiratory sample and MRSA nares PCR ordered. Results: A total of 370 patients were screened for study eligibility; of which 99 patients met inclusion criteria. NPV of respiratory sample Gram stain was 99% for MRSA culture. The combined NPV of respiratory sample Gram stain plus MRSA nares PCR was 98.9% for MRSA culture (n = 88). Respiratory sample was ordered 2.3 h faster compared to MRSA nares PCR (4.3 vs 6.6 h, P = .036). Respiratory sample Gram stain resulted 4.5 h faster compared to MRSA nares PCR (10.7 vs 15.2 h, P = .002). Conclusion: Respiratory sample Gram stains demonstrating no Gram-positive organisms may be used to de-escalate vancomycin and deprioritize the use of MRSA nares PCR.

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SF001 is a next-generation polyene antifungal drug in development, designed to have increased specificity to fungal ergosterol, which is absent in humans, and decreased binding to cholesterol. SF001 demonstrates long-acting, potent, broad-spectrum fungicidal activity. The goal of the current study was to determine the pharmacodynamic index and target of SF001 in an immunocompromised mouse model of invasive pulmonary aspergillosis against six Aspergillus fumigatus isolates. Minimum inhibitory concentration (MIC) values ranged from 0.5 to 2.0 mg/L. Plasma and epithelial lining fluid (ELF) pharmacokinetics were performed following single intraperitoneal doses of 1, 4, 16, and 64 mg/kg. Treatment efficacy was assessed with each of the six fungal isolates using daily doses of SF001 ranging from 0.25 to 64 mg/kg/day over a 96-h treatment duration. Efficacy was assessed by A. fumigatus quantitative PCR of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24-h exposure-response relationships for both plasma and ELF area under the concentration/MIC and Cmax/MIC ratios were strong and relatively similar [coefficient of determination (R2) = 0.74-0.75). Exposure-response relationships included a median plasma 24-h Cmax/MIC target for stasis and 1-log kill endpoint of 0.5 and 0.6, respectively. The present studies demonstrated in vitro and in vivo SF001 potency against A. fumigatus. These results have potential relevance for SF001 clinical dose selection and evaluation of susceptibility breakpoints.

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PURPOSE: The fluoroquinolone restriction for the prevention of Clostridioides difficile infection (FIRST) trial is a multisite clinical study in which sites carry out a preauthorization process via electronic health record-based best-practice alert (BPA) to optimize the use of fluoroquinolone antibiotics in acute care settings. Our research team worked closely with clinical implementation coordinators to facilitate the dissemination and implementation of this evidence-based intervention. Clinical implementation coordinators within the antibiotic stewardship team (AST) played a pivotal role in the implementation process; however, considerable research is needed to further understand their role. In this study, we aimed to (1) describe the roles and responsibilities of clinical implementation coordinators within ASTs and (2) identify facilitators and barriers coordinators experienced within the implementation process. METHODS: We conducted a directed content analysis of semistructured interviews, implementation diaries, and check-in meetings utilizing the conceptual framework of middle managers' roles in innovation implementation in healthcare from Urquhart et al. RESULTS: Clinical implementation coordinators performed a variety of roles vital to the implementation's success, including gathering and compiling information for BPA design, preparing staff, organizing meetings, connecting relevant stakeholders, evaluating clinical efficacy, and participating in the innovation as clinicians. Coordinators identified organizational staffing models and COVID-19 interruptions as the main barriers. Facilitators included AST empowerment, positive relationships with staff and oversight/governance committees, and using diverse implementation strategies. CONCLUSION: When implementing healthcare innovations, clinical implementation coordinators facilitated the implementation process through their roles and responsibilities and acted as strategic partners in improving the adoption and sustainability of a fluoroquinolone preauthorization protocol.

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This cohort study examines the rates of neutropenic fever­associated admissions and outpatient antibiotic use among patients with cancer receiving chemotherapy before and during the COVID-19 pandemic.

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This study evaluated the performance and clinical utility of performing intravascular catheter tip cultures (CTC). A retrospective chart review was conducted over a 2.5 year period on all patients who demonstrated growth of at least one organism on CTC. There were a total of 391 CTC performed. 88 (23%) grew at least one organism, while 303 (77%) had no growth. Of the positive CTC, 81 (92%) had blood cultures (BC) collected within 14 days, whereas 7 (8%) did not. Of the positive CTC with BC, 67 (83%) were BC-positive, whereas 14 (17%) were negative. For cases with growth on both CTC and BC, the organisms identified were concordant for 46 (69%) cases and discordant for 21 (31%). Of the concordant cases, 43 (93%) were clinically considered to be bacterial bloodstream infections that were secondary to a catheter infection. For all of the positive CTC cases total, there was no change in the antibiotics or management, with the exceptions of 2 out of 88 (2%) cases. Catheters were removed and cultured for an average of 38.6 h (range: -98 to 288 h) after positive BC results were available. Most CTC are negative, and for the CTC that are positive, most are concordant with BC results. CTC results are generally only available several days after positive BC results are known. The CTC results did not alter the antibiotic therapy or management, with the exceptions of rare cases. As such, this study concludes that CTC do not contribute diagnostic or therapeutic value. Therefore, current guidelines by the Infectious Diseases Society of America on catheter-related bloodstream infection diagnosis should be revised to exclude CTC collection. IMPORTANCE In patients with intravascular catheters who are febrile or have positive blood cultures and no other obvious sources of infection, catheter tip cultures are often obtained to evaluate potential catheter-related bloodstream infections. However, previous studies reported that the management of catheter-related bloodstream infection cases is entirely based on blood culture growth and susceptibilities and that catheter tip cultures have low diagnostic positive predictive value. Our study represents the largest contemporary evaluation that includes chart reviews on all positive catheter tip culture cases. We found that positive cultures led to no changes in antibiotics or management, except for in two cases. Furthermore, 92% of positive catheter tip cultures were associated with blood culture collections, and catheter cultures were generally available only several days after the blood culture results were known. Thus, our study supports the claim that positive catheter tip cultures add limited diagnostic and therapeutic value in suspected catheter-related bloodstream infections.

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The rise in infections caused by antibiotic-resistant bacteria is outpacing the development of new antibiotics. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a group of clinically important bacteria that have developed resistance to multiple antibiotics and are commonly referred to as multidrug resistant (MDR). The medical and research communities have recognized that, without new antimicrobials, infections by MDR bacteria will soon become a leading cause of morbidity and death. Therefore, there is an ever-growing need to expedite the development of novel antimicrobials to combat these infections. Toward this end, we set out to refine an existing mouse model of pulmonary Pseudomonas aeruginosa infection to generate a robust preclinical tool that can be used to rapidly and accurately predict novel antimicrobial efficacy. This refinement was achieved by characterizing the virulence of a panel of genetically diverse MDR P. aeruginosa strains in this model, by both 50% lethal dose (LD50) analysis and natural history studies. Further, we defined two antibiotic regimens (aztreonam and amikacin) that can be used as comparators during the future evaluation of novel antimicrobials, and we confirmed that the model can effectively differentiate between successful and unsuccessful treatments, as predicted by in vitro inhibitory data. This validated model represents an important tool in our arsenal to develop new therapies to combat MDR P. aeruginosa strains, with the ability to provide rapid preclinical evaluation of novel antimicrobials and support data from clinical studies during the investigational drug development process. IMPORTANCE The prevalence of antibiotic resistance among bacterial pathogens is a growing problem that necessitates the development of new antibiotics. Preclinical animal models are important tools to facilitate and speed the development of novel antimicrobials. Successful outcomes in animal models not only justify progression of new drugs into human clinical trials but also can support FDA decisions if clinical trial sizes are small due to a small population of infections with specific drug-resistant strains. However, in both cases the preclinical animal model needs to be well characterized and provide robust and reproducible data. Toward this goal, we have refined an existing mouse model to better predict the efficacy of novel antibiotics. This improved model provides an important tool to better predict the clinical success of new antibiotics.

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We reviewed the electronic health records of 1,419 inpatients with anterior nares (AN) and oropharynx (OP) MRSA PCR tests. Concordance was 96.5%. In discordant cases, AN negative-OP positive results increased detection of probable MRSA pneumonia by only 0.3%. A dual testing approach has limited utility in detecting MRSA pneumonia and increases resource utilization.

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OBJECTIVE: To identify significant factors that help predict whether health care personnel (HCP) will test positive for severe acute respiratory coronavirus 2 (SARS-CoV-2). PATIENTS AND METHODS: We conducted a prospective cohort study among 7015 symptomatic HCP from March 25, 2020, through November 11, 2020. We analyzed the associations between health care role, contact history, symptoms, and a positive nasopharyngeal swab SARS-CoV-2 polymerase chain reaction test results, using univariate and multivariable modelling. RESULTS: Of the symptomatic HCP, 624 (8.9%) were positive over the study period. On multivariable analysis, having a health care role other than physician or advanced practice provider, contact with family or community member with known or suspected coronavirus disease 2019 (COVID-19), and seven individual symptoms (cough, anosmia, ageusia, fever, myalgia, chills, and headache) were significantly associated with higher adjusted odds ratios for testing positive for SARS-CoV-2. For each increase in symptom number, the odds of testing positive nearly doubled (odds ratio, 1.93; 95% CI, 1.82 to 2.07, P<.001). CONCLUSION: Symptomatic HCP have higher adjusted odds of testing positive for SARS-CoV-2 based on three distinct factors: (1) nonphysician/advanced practice provider role, (2) contact with a family or community member with suspected or known COVID-19, and (3) specific symptoms and symptom number. Differences among health care roles, which persisted after controlling for contacts, may reflect the influence of social determinants. Contacts with COVID-19-positive patients and/or HCP were not associated with higher odds of testing positive, supporting current infection control efforts. Targeted symptom and contact questionnaires may streamline symptomatic HCP testing for COVID-19.

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PURPOSE: Small community hospitals often lack the human, financial, and technological resources necessary to implement and maintain successful antimicrobial stewardship programs now required by national regulatory and accrediting bodies. Creative solutions are needed to address this problem. SUMMARY: A 3-stage, quasi-experimental study including patients receiving antibiotics for pneumonia, skin and soft tissue infections, and urinary tract infections at a community hospital in Wisconsin from June 2013 to December 2015 was conducted. Remote telehealth prospective audit and feedback, guideline and order set management, and staff education targeting pharmacists, nurses, and physicians were provided during the 7-month intervention phase; these services were then removed for the postintervention period. Antimicrobial utilization (days of therapy [DOT] per 1,000 patient-days), hospital length of stay, and readmission and 30-day mortality rates were assessed to determine the impact of telehealth services on these outcomes. During the preintervention (baseline), intervention, and postintervention periods, 1,037 patients received antibiotics for the targeted infectious disease conditions. Patient demographics and rates of infectious disease conditions were similar among the different periods. Telehealth antimicrobial stewardship reduced broad-spectrum antibiotic use, including use of imipenem (from 83 to 31 DOT, P < 0.001), levofloxacin (from 123 to 99 DOT, P < 0.001), and vancomycin (from 104 to 85 DOT, P < 0.001), compared to utilization during the baseline period; mean (SD) length of stay also decreased (from 4.6 [2.8] days to 4.2 [2.6] days, P = 0.02). After nonrenewal of telehealth stewardship, vancomycin and piperacillin/tazobactam usage returned to or exceeded baseline levels. CONCLUSION: The partnership between an academic medical center and a small community hospital improved antimicrobial utilization and clinical outcomes. Successful telehealth antimicrobial stewardship models should be explored further as a means to provide optimal patient care.

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INTRODUCTION: Clostridioides difficile infection (CDI) is one of the most common healthcare-associated infections in the USA, having high incidence in intensive care units (ICU). Antibiotic use increases risk of CDI, with fluoroquinolones (FQs) particularly implicated. In healthcare settings, antibiotic stewardship (AS) and infection control interventions are effective in CDI control, but there is little evidence regarding the most effective AS interventions. Preprescription authorisation (PPA) restricting FQs is a potentially promising AS intervention to reduce CDI. The FQ Restriction for the Prevention of CDI (FIRST) trial will evaluate the effectiveness of an FQ PPA intervention in reducing CDI rates in adult ICUs compared with preintervention care, and evaluate implementation effectiveness using a human-factors and systems engineering model. METHODS AND ANALYSIS: This is a multisite, stepped-wedge, cluster, effectiveness-implementation clinical trial. The trial will take place in 12 adult medical-surgical ICUs with ≥10 beds, using Epic as electronic health record (EHR) and pre-existing AS programmes. Sites will receive facilitated implementation support over the 15-month trial period, succeeded by 9 months of follow-up. The intervention comprises a clinical decision support system for FQ PPA, integrated into the site EHRs. Each ICU will be considered a single site and all ICU admissions included in the analysis. Clinical data will be extracted from EHRs throughout the trial and compared with the corresponding pretrial period, which will constitute the baseline for statistical analysis. Outcomes will include ICU-onset CDI rates, FQ days of therapy (DOT), alternative antibiotic DOT, average length of stay and hospital mortality. The study team will also collect implementation data to assess implementation effectiveness using the Systems Engineering Initiative for Patient Safety model. ETHICS AND DISSEMINATION: The trial was approved by the Institutional Review Board at the University of Wisconsin-Madison (2018-0852-CP015). Results will be made available to participating sites, funders, infectious disease societies, critical care societies and other researchers. TRIAL REGISTRATION NUMBER: NCT03848689.

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BACKGROUND: Healthcare personnel (HCP) are at increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We posit that current infection control guidelines generally protect HCP from SARS-CoV-2 infection in a healthcare setting. METHODS: In this retrospective case series, we used viral genomics to investigate the likely source of SARS-CoV-2 infection in HCP at a major academic medical institution in the Upper Midwest of the United States between 25 March and 27 December 2020. We obtained limited epidemiological data through informal interviews and review of the electronic health record and combined this information with healthcare-associated viral sequences and viral sequences collected in the broader community to infer the most likely source of infection in HCP. RESULTS: We investigated SARS-CoV-2 infection clusters involving 95 HCP and 137 possible patient contact sequences. The majority of HCP infections could not be linked to a patient or coworker (55 of 95 [57.9%]) and were genetically similar to viruses circulating concurrently in the community. We found that 10.5% of HCP infections (10 of 95) could be traced to a coworker. Strikingly, only 4.2% (4 of 95) could be traced to a patient source. CONCLUSIONS: Infections among HCP add further strain to the healthcare system and put patients, HCP, and communities at risk. We found no evidence for healthcare-associated transmission in the majority of HCP infections evaluated. Although we cannot rule out the possibility of cryptic healthcare-associated transmission, it appears that HCP most commonly become infected with SARS-CoV-2 via community exposure. This emphasizes the ongoing importance of mask wearing, physical distancing, robust testing programs, and rapid distribution of vaccines.

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The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled "Advancing Animal Models for Antibacterial Drug Development" on 5 March 2020. The workshop mainly focused on models of pneumonia caused by Pseudomonas aeruginosa and Acinetobacter baumannii The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.

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BACKGROUND: Multiple factors have led to an extremely high volume of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) testing. Concerns exist about sensitivity and false-negative SARS-CoV-2 RT-PCR testing results. We describe a retrospective observational study examining the utility of repeat nasopharyngeal (NP) SARS-CoV-2 RT-PCR testing at an academic center in a low-prevalence setting. METHODS: All patients within our health system with >1 NP SARS-CoV-2 RT-PCR test result were included. SARS-CoV-2 RT-PCR testing was performed according to 1 of 4 validated assays. Key clinical and demographic data were collected, including whether the patient was inpatient or outpatient at time of the test and whether the test was performed as part of a person under investigation (PUI) for possible coronavirus disease 2019 or for asymptomatic screening. RESULTS: A total of 660 patients had >1 NP SARS-CoV-2 PCR test performed. The initial test was negative in 638. There were only 6 negative-to-positive conversions (0.9%). All 6 were outpatients undergoing a PUI workup 5-17 days after an initial negative result. In >260 inpatients with repeat testing, we found no instances of negative-to-positive conversion including those undergoing PUI or asymptomatic evaluation. CONCLUSIONS: In a low-prevalence area, repeat inpatient testing after an initial negative result, using a highly analytically sensitive SARS-CoV-2 RT-PCR, failed to demonstrate negative-to-positive conversion. The clinical sensitivity of NP RT-PCR testing may be higher than previously believed. These results have helped shape diagnostic stewardship guidelines, in particular guidance to decrease repeated testing in the inpatient setting to optimize test utilization and preserve resources.

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MRX-8 is a novel polymyxin analogue in development for the treatment of infections caused by Gram-negative pathogens, including those resistant to other antibiotic classes. In the present study, we examined the pharmacodynamic activity of MRX-8 against a variety of common Gram-negative pathogens in the neutropenic mouse thigh and lung models. Additionally, we examined polymyxin B (PMB) as a comparator. Plasma pharmacokinetics of MRX-8 and PMB were linear over a broad dosing range of 0.156 to 10 mg/kg of body weight and had similar AUC0-∞ (area under the drug concentration-time curve from 0 h to infinity) exposures of MRX-8, 0.22 to 12.64 mg · h/liter, and PMB, 0.12 to 13.22 mg · h/liter. Dose fractionation was performed for MRX-8 using a single Escherichia coli isolate, and the results demonstrated that both Cmax (maximum concentration of drug in serum)/MIC and AUC/MIC ratios were strongly associated with efficacy. In the thigh model, dose-ranging studies included strains of E. coli (n = 3), Pseudomonas aeruginosa (n = 2), Klebsiella pneumoniae (n = 3), and Acinetobacter baumannii (n = 1). Both MRX-8 and PMB exhibited increased effects with increasing doses. MRX-8 and PMB free AUC/MIC exposures for net stasis were similar for E. coli and K. pneumoniae at 20 to 30. Notably, for P. aeruginosa and A. baumannii, the free AUC/MIC ratio for stasis was numerically much smaller for MRX-8 at 6 to 8 than for PMB at 16 to 37. In the lung model, MRX-8 was also more effective than PMB when dosed to achieve similar free-drug AUC exposures over the study period. MRX-8 is a promising novel polymyxin analogue with in vivo activity against many different clinically relevant species in both the mouse thigh and lung models.

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OBJECTIVE: We conducted a quality improvement initiative to restrict fluoroquinolone prescribing on two inpatient units housing high-risk patients and applied a human factors approach to understanding the barriers and facilitators to success of this intervention by front-line providers. METHODS: This was a mixed-methods, quasi-experimental study. This study was conducted on two inpatient units at a tertiary care academic medical center: the medical-surgical intensive care and abdominal solid organ transplant units. Unit-level data were collected retrospectively for 24 months pre- and post- fluoroquinolone restriction intervention, implemented in July 2016, for all admissions to the study units. Our restriction intervention required antimicrobial stewardship pre-approval for fluoroquinolone prescribing. We explored barriers and facilitators to optimal fluoroquinolone prescribing using semi-structured interviews attending, fellow and resident physicians, advanced practice providers and pharmacists on these units. RESULTS: Hospital-onset C. difficile infection did not decrease significantly, but fluoroquinolone use declined significantly from 111.6 to 19.8 days of therapy per 1000 patient-days without negatively impacting length of stay, readmissions or mortality. Third generation cephalosporin and aminoglycoside use increased post-restriction. Providers identified our institution's strong antimicrobial stewardship program and pharmacy involvement in antimicrobial decision making as key facilitators of fluoroquinolone optimization and patient complexity, lack of provider education and organizational culture as barriers to optimal prescribing. CONCLUSIONS: Fluoroquinolones can be safely restricted even among high-risk patients without negatively impacting length of stay, readmissions or mortality. Our study provides a framework for successful antimicrobial stewardship interventions informed by perceptions of front line providers.

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