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Abstract: We evaluated the proportion of patients with trichomoniasis and chlamydial infections who received recommended versus nonrecommended antibiotic therapy after the updated 2021 Sexually Transmitted Infections Guideline. Of 712 patients, 473 (66%) received recommended therapy. Receipt of emergency department care was independently associated with recommended therapy (adjusted odds ratio, 2.1; 95% confidence interval, 1.5-2.9)., Competing Interests: Conflict of Interest and Sources of Funding: This study was funded by a research grant from the American Society of Health-System Pharmacists Research and Education Foundation. None of the investigators have conflict of interests to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Sexually Transmitted Diseases Association.)

Purpose: To evaluate judicious antibiotic prescribing of benzathine penicillin G (BPG) after implementation of an electronic health record-based medication shortage alert during a critical drug shortage., Methods: This was an institutional review board-approved retrospective cohort study of patients aged ≥3 months who received BPG between May 9, 2023, and February 28, 2024. The study included inpatient and outpatient visits after implementing a BPG medication shortage alert; patients with severe penicillin allergy, neurosyphilis, or congenital syphilis were excluded. Judicious BPG use was defined as use in patients diagnosed with primary, secondary, or latent syphilis or if they were prescribed a BPG alternative in response to the medication shortage alert; nonjudicious use included BPG for alternative diagnoses. Social determinants of health were assessed as exposure variables of interest. A separate cohort of syphilis patients receiving BPG or alternative therapy (i.e., doxycycline) was described., Results: A total of 453 patients were included. Most patients were non-Hispanic Black (n = 273, 60%) men (n = 272, 60%) with a median (interquartile range) age of 32 (22-44) years. Of these, 318 (70%) received judicious BPG, whereas 135 (30%) received nonjudicious BPG. The most nonjudicious diagnosis was streptococcal pharyngitis (n = 128, 95%). Variables associated with judicious use included age >32 years (adjusted odds ratio [adjOR], 2.273; 95% CI, 1.488-3.472), male sex (adjOR, 1.835; 95% CI, 1.206-2.792), and black race (adjOR, 1.847; 95% CI, 1.212-2.815). Among a cohort of 128 syphilis patients who received BPG (n = 64, 50%) or doxycycline (n = 64, 50%), those who received doxycycline were more likely be uninsured (35 [54.7%] vs 43 [67.2%]; P = .15) and receive outpatient treatment (3 [4.7%] vs 12 [18.7%]; P = .13)., Conclusion: Despite implementing an electronic health record drug shortage alert, 30% of BPG use was nonjudicious and mostly for pharyngitis., Competing Interests: The author(s) declares no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objective: To compare outcomes of ceftriaxone to AmpC-stable therapies in patients with bacteremia caused by low-risk AmpC harboring Enterobacterales., Methods: IRB-approved, retrospective cohort of hospitalized patients ≥18 years old with Serratia marcescens, Morganella morganii, or Providencia spp. bacteremia from 1/1/2017-2/28/2024. Patients were compared by definitive therapy with ceftriaxone vs AmpC-stable therapy (cefepime, carbapenem). The primary endpoint was 30-day all-cause mortality; secondary endpoints were clinical failure and development of ceftriaxone resistance., Results: 163 patients were included; 33.1 % received ceftriaxone, 66.9 % AmpC-stable therapies. 30-day all-cause mortality was 9.3 % ceftriaxone vs 10.1 % AmpC stable patients (P = 0.87); ceftriaxone definitive therapy was not associated with 30-day all-cause mortality (adjOR, 0.79; 95 %CI, 0.23-2.3). There were no differences in clinical failure (9.3 % vs 21.1 %, P = 0.059) or relapsing infection (5.6 % vs 9.3 %, P = 0.55) between ceftriaxone and AmpC-stable treated patients., Conclusions: Patients treated with definitive ceftriaxone for low-risk AmpC Enterobacterales bacteremia had similar outcomes to AmpC stable therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

AmpC β-lactamases are associated with development of ceftriaxone resistance despite initial in vitro susceptibility, but the risk of AmpC derepression is not equal among Enterobacterales. The purpose of this study was to evaluate the impact of an AmpC stewardship intervention on the definitive treatment of low- and no-risk Enterobacterales. This was an IRB-approved, single pre-test, post-test quasi-experiment at a 5-hospital system. An AmpC stewardship intervention was implemented in July 2022 and included prescriber education, the removal of microbiology comments indicating potential for ceftriaxone resistance on therapy, and the modification of a blood PCR comment for Serratia marcescens to recommend ceftriaxone. Adults ≥18 years pre-intervention (July 2021 to December 2021) and post-intervention (July 2022 to December 2022) who received ≥72 hours of inpatient definitive therapy and had non-urine cultures growing low- and no-risk organisms ( S. marcescens , Providencia spp., Citrobacter koseri , Citrobacter amalonaticus , or Morganella morganii ) were included. The primary endpoint was definitive treatment with ceftriaxone. A total of 224 patients were included; 115 (51%) in pre-intervention and 109 (49%) in post-intervention. Definitive ceftriaxone therapy was prescribed more frequently after intervention [6 (5%) vs 72 (66%), P < 0.001]. After adjustment for critical illness, patients in the post-group were more likely to receive definitive ceftriaxone (adjOR, 34.7; 95% CI, 13.9-86.6). The proportion of patients requiring retreatment was 18 (15%) and 11 (10%) for pre- and post-intervention patients ( P = 0.22), and ceftriaxone resistance within 30 days occurred in 5 (4%) and 2 (2%) patients in the pre- and post-group ( P = 0.45). An antimicrobial stewardship intervention was associated with increased ceftriaxone prescribing and similar patient outcomes for low- and no-risk AmpC Enterobacterales., Competing Interests: The authors declare no conflict of interest.

Background: Inability to access and afford discharge oral antimicrobials may delay discharges or result in therapeutic failure. "Test-claims" have the potential to identify such barriers. Objective: This study evaluated discharge antimicrobial access and patient outcomes after implementation of a standardized, inpatient pharmacist-initiated antimicrobial discharge medication cost inquiry (aDMCI) process. Methods: This was an Institutional Review Board (IRB)-approved, pilot retrospective cohort study that included adults admitted for ≥72 hours from November 1, 2018, to February 28, 2019, and discharged on oral antimicrobials. Patients with a cost inquiry (aDMCI group) were compared with those without (standard-of-care, SOC, group). Primary endpoint was discharge delay. Secondary endpoints included percentage of patients discharged on suboptimal antimicrobials and medication errors from aDMCI. Results: 84 patients were included: 43 in SOC and 41 in aDMCI. Seventy-five antimicrobial cost inquiries were evaluated among 41 patients. There were no discharge delays or medication errors associated with the standardized "test-claim" (aDMCI) workflow. Patients in the SOC group had a greater Charlson Comorbidity Index (4 [2-6] vs 2 [1-4], P = 0.004), were more likely to be immunosuppressed (24, 56% vs 12, 29%; P = 0.014), and had longer hospitalization (8 [5-15] vs 6 [5-9] days, P = 0.026). Primary access barriers were prior-authorization (8, 11%) and associated with linezolid and moxifloxacin cost inquiries. Most aDMCIs results were available in <24 hours (66, 88%). Conclusions: The aDMCI process is safe and offers an actionable transition of care tool that can identify barriers to accessing discharge medications while insulating patients from surprise out-of-pocket cost., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Introduction: Prior data have suggested that suboptimal antibiotic prescribing in the emergency department (ED) is common for uncomplicated lower respiratory tract infections (LRTI), urinary tract infections (UTI), and acute bacterial skin and skin structure infections (ABSSSI). The objective of this study was to measure the effect of indication-based antibiotic order sentences (AOS) on optimal antibiotic prescribing in the ED., Methods: This was an IRB-approved quasi-experiment of adults prescribed antibiotics in EDs for uncomplicated LRTI, UTI, or ABSSSI from January to June 2019 (pre-implementation) and September to December 2021 (post-implementation). AOS implementation occurred in July 2021. AOS are lean process, electronic discharge prescriptions retrievable by name or indication within the discharge order field. The primary outcome was optimal prescribing, defined as correct antibiotic selection, dose, and duration per local and national guidelines. Descriptive and bivariate statistics were performed; multivariable logistic regression was used to determine variables associated with optimal prescribing., Results: A total of 294 patients were included: 147 pre-group and 147 post-group. Overall optimal prescribing improved from 12 (8%) to 34 (23%) (P < 0.001). Individual components of optimal prescribing were optimal selection at 90 (61%) vs 117 (80%) (P < 0.001), optimal dose at 99 (67%) vs 115 (78%) (P = 0.036), and optimal duration at 38 (26%) vs 50 (34%) (P = 0.13) for pre- and post-group, respectively. AOS was independently associated with optimal prescribing after multivariable logistic regression analysis (adjOR, 3.6; 95%CI,1.7-7.2). A post-hoc analysis showed low uptake of AOS by ED prescribers., Conclusions: AOS are an efficient and promising strategy to enhance antimicrobial stewardship in the ED., Competing Interests: Declaration of Competing Interest None of the authors included on this manuscript have any significant or potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aminopenicillins (APs) achieve urinary concentrations that exceed typical minimum inhibitory concentrations for enterococcal lower urinary tract infection (UTI). The local clinical microbiology laboratory discontinued routine susceptibilities on enterococcal urine isolates, and reports that 'APs are predictably reliable for uncomplicated enterococcal UTI'. The objective of this study was to compare outcomes of APs with non-APs (NAPs) for enterococcal lower UTIs. This was an institutional-review-board-approved, retrospective cohort of adults hospitalized with symptomatic enterococcal lower UTIs from 2013 to 2021. The primary endpoint was composite clinical success at 14 days, defined as resolution of symptoms without new symptoms and no repeat culture growth of the index organism. A non-inferiority analysis was utilized with a 15% margin, and logistic regression evaluated characteristics associated with 14-day failure. In total, 178 subjects were included: 89 AP patients and 89 NAP patients. Vancomycin-resistant enterococci (VRE) were identified in 73 (82%) AP patients and 76 (85%) NAP patients (P=0.54); in total, 34 (38.2%) AP patients and 66 (74.2%) NAP patients had confirmed Enterococcus faecium (P<0.001). Amoxicillin (n=36, 40.5%) and ampicillin (n=36, 40.5%) were the most commonly used APs, and linezolid (n=41, 46%) and fosfomycin (n=30, 34%) were the most commonly used NAPs. Fourteen-day clinical success rates for APs and NAPs were 83.1% and 82.0%, respectively [1.1% difference, 97.5% confidence interval (CI) -0.117 to 0.139]. Among the E. faecium subgroup, 14-day clinical success was observed in 27/34 (79.4%) AP patients and 53/66 (80.3%) NAP patients (P=0.916). On logistic regression, APs were not associated with 14-day clinical failure (adjusted odds ratio 0.84, 95% CI 0.38-1.86). APs were non-inferior to NAPs for treating enterococcal lower UTIs, and may be considered irrespective of susceptibility results., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Objectives: Approximately 25% of patients with Clostridioides difficile infection (CDI) will experience recurrence, which is greater in immunocompromised patients. We report experience with an institutional guideline targeting high-risk immunocompromised patients. Methods: This was a retrospective cohort of consecutive patients with CDI who met institutional criteria for bezlotoxumab due to high risk for recurrent CDI between June 1, 2017, and November 30, 2018. The primary endpoint of recurrent CDI within 12 weeks was compared between patients who received the standard of care (SoC) plus or minus bezlotoxumab. Results: Twenty-three patients received bezlotoxumab infusion plus SoC and were compared to 30 SoC patients. 84% of patients were immunocompromised and 54.7% were transplant recipients. The primary endpoint occurred in 13% of bezlotoxumab patients compared to 23.3% of SoC patients. No serious adverse effects were identified. Conclusion: Bezlotoxumab was associated with a meaningful reduction in recurrent CDI in this cohort largely comprising immunocompromised and transplant patients. Larger studies are warranted to evaluate bezlotoxumab in this population.

Objective: To evaluate antibiotic prescribing in ambulatory oncology clinics and to identify opportunities to improve antibiotic use., Methods: Retrospective cohort of adult patients who received care at 4 ambulatory oncology clinics from May 2021 to December 2021. Patients were included if they actively followed with a hematologist-oncologist for a cancer diagnosis and received an antibiotic prescription for uncomplicated upper respiratory tract infection (URTI), lower respiratory tract infection (LRTI), urinary tract infection (UTI), or acute bacterial skin-skin structure infection (ABSSSI) at an oncology clinic. The primary outcome was receipt of optimal antibiotic therapy, defined as a composite of drug, dose, and duration according to local and national guidelines. Patient characteristics were described and compared; predictors of optimal antibiotic use were identified using multivariable logistic regression., Results: In total, 200 patients were included in this study: 72 (36%) received optimal antibiotics and 128 (64%) received suboptimal antibiotics. The proportions of patients receiving optimal therapy by indication were ABSSSI (52%), UTI (35%), URTI (27%), and LRTI (15%). The most common suboptimal prescribing components were dose (54%), selection (53%) and duration (23%). After adjusting for female sex and LRTI, ABSSSI (adjusted odds ratio, 2.28; 95% confidence interval, 1.19-4.37) was associated with optimal antibiotic therapy. Antibiotic-associated adverse drug events occurred in 7 patients; 6 occurred patients who received prolonged durations and 1 occurred in a patient who received an optimal duration ( P = .057)., Conclusions: Suboptimal antibiotic prescribing in ambulatory oncology clinics is common and mostly driven by antibiotic selection and dosing. Duration of therapy may also be an area for improvement as national oncology guidelines have not adopted short-course therapy., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2023.)

Cellular invasion is the gateway to metastasis, with cells moving from a primary tumor into neighboring regions of healthy tissue. Invasion assays provide a tractable experimental platform to quantitatively assess cellular movement in the presence of potential chemokines or inhibitors. Many such assays involve cellular movement from high cell densities to cell-free regions. To improve the physiological relevance of such assays, we developed an assay format to track cellular movement throughout a uniform density of cells. This assay format imparts diffusion-dominated environments along the channel, resulting in oxygen and nutrient gradients found in spheroids or poorly vascularized tumors. By incorporating oxygen- and pH-sensing films, we quantified spatial and temporal changes in the extracellular environment while simultaneously tracking the movement of a subset of cells engineered to express fluorescent proteins constitutively. Our results show the successful invasion into neighboring tissues likely arises from a small population with a highly invasive phenotype. These highly invasive cells continued to move throughout the 48 h experiment, suggesting they have stem-like or persister properties. Surprisingly, the distance these persister cells invaded was unaffected by the density of cells in the channel or the presence or absence of an oxygen gradient. While these datasets cannot determine if the invasive cells are inherent to the population or if diffusion-dominated environments promote them, they highlight the need for further study.

We compared optimal antibiotic prescribing before and after implementing an interpretive β-lactamase microbiology comment for Haemophilus influenzae and Moraxella catarrhalis in lower respiratory-tract infections. The postintervention group was associated with 5-fold increased odds of optimal de-escalation (adjusted odds ratio, 5.03; 95% confidence interval, 2.57-9.87)., (© The Author(s) 2023.)

Objective: The aim of the study is to evaluate the impact of inpatient substance use disorder (SUD) resources on outcomes of persons who inject stimulants and/or opioids (PWIDs) with infections., Methods: This retrospective cohort evaluated PWIDs hospitalized from July 1, 2020, to May 31, 2021, and prescribed an antimicrobial course. The patients were compared based on inpatient implementation of SUD resources, including consultation of addiction medicine/behavioral health, implementation of an opioid withdrawal treatment protocol, or continuation/initiation of medications for opioid use disorder. The primary outcome was a composite of antibiotic completion, no unplanned discharge, and no 30-day readmission. Notable secondary outcomes included length of stay and presence of stigmatizing language in the electronic medical record., Results: A total of 119 patients were analyzed-74 (62.2%) received SUD resources. The primary outcome was met by 43 patients with SUD resources implemented (58.1%) and 19 patients without resources (42.2%, P = 0.093). After adjustment for infection type, implementation of SUD resources (adjusted odds ratio, 2.593; 95% confidence interval, 1.162-5.789) was independently associated with primary outcome success. The patients who received SUD resources had a median length of stay of 7 days (4-13.3) compared with 4 days (2-6.5) in those without resources ( P < 0.001). Stigmatizing language was present in 98% of patient electronic medical records., Conclusions: Patient care provided to PWIDs with infections is optimized when SUD resources are implemented. This study further supports the necessity of improving SUD management when PWIDs are admitted to healthcare facilities., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)

Objective: To determine the impact of clinical decision support on guideline-concordant Clostridioides difficile infection (CDI) treatment., Design: Quasi-experimental study in >50 ambulatory clinics., Setting: Primary, specialty, and urgent-care clinics., Patients: Adult patients were eligible for inclusion if they were diagnosed with and treated for a first episode of symptomatic CDI at an ambulatory clinic between November 1, 2019, and November 30, 2020., Interventions: An outpatient best practice advisory (BPA) was implemented to notify prescribers that "vancomycin or fidaxomicin are preferred over metronidazole for C.difficile infection" when metronidazole was prescribed to a patient with CDI., Results: In total, 189 patients were included in the study: 92 before the BPA and 97 after the BPA. Their median age was 59 years; 31% were male; 75% were white; 30% had CDI-related comorbidities; 35% had healthcare exposure; 65% had antibiotic exposure; 44% had gastric acid suppression therapy within 90 days of CDI diagnosis. The BPA was accepted 23 of 26 times and was used to optimize the therapy of 16 patients in 6 months. Guideline-concordant therapy increased after implementation of the BPA (72% vs 91%; P = .001). Vancomycin prescribing increased and metronidazole prescribing decreased after the BPA. There was no difference in clinical response or unplanned encounter within 14 days after treatment initiation. Fewer patients after the BPA had CDI recurrence within 14-56 days of the initial episode (27% vs 7%; P < .001)., Conclusions: Clinical decision support increased prescribing of guideline-concordant CDI therapy in the outpatient setting. A targeted BPA is an effective stewardship intervention and may be especially useful in settings with limited antimicrobial stewardship resources.

Background: This study seeks to describe inpatient antimicrobial use (AU) utilizing the National Healthcare Safety Network-AU (NHSN-AU) framework among solid organ transplant recipients (SOTr) within 12 months after transplant., Methods: This cross-sectional study included SOTr ≥ 18 years of age who underwent transplantation from January 2015 to December 2016 at a Midwestern US transplant center. Inpatient AU was followed for 12 months post-transplant. Hospital days present up to 12 months post-transplant, AU variables, and Clostridioides difficile infection (CDI) occurrences were analyzed., Results: The cohort of 530 SOTr included 225 kidney (42.5%), 171 liver (32.3%), 45 lung (8.5%), 40 heart (7.5%), 39 multivisceral (7.4%), seven small bowel (1.3%), and three pancreas (0.6%) transplants. Total days of therapy (DOT) were 22 782 among the cohort, with a median of 5 days [interquartile range [IQR], 1-12]. Lung and liver transplants had the most total DOT (6571 vs. 5569 days), while lungs and small bowels had the highest median DOT (13 [IQR, 2-56] vs. 12 [IQR, 2-31]). The facility-wide DOT/1000 days were lowest in pancreas and highest in lung transplants (5.3 vs. 428.1). Small bowel transplants received the most resistant-Gram-positive infection and hospital-onset infection agents for facility-wide DOT/1000 days present. Pancreas and kidney transplants accounted for the most high-risk CDI agents. CDI occurred in 34 patients, with kidney and liver transplants experiencing 13 each., Conclusion: This study represents one of the first reports of AU in SOTr utilizing the NHSN-AU framework. More studies are needed for further peer-to-peer comparison of AU in this complex patient population., (© 2022 Wiley Periodicals LLC.)

Importance: Although prescribers face numerous patient-centered challenges during transitions of care (TOC) at hospital discharge, prolonged duration of antimicrobial therapy for common infections remains problematic, and resources are needed for antimicrobial stewardship throughout this period., Objective: To evaluate a pharmacist-driven intervention designed to improve selection and duration of oral antimicrobial therapy prescribed at hospital discharge for common infections., Design, Setting, and Participants: This quality improvement study used a nonrandomized stepped-wedge design with 3 study phases from September 1, 2018, to August 31, 2019. Seventeen distinct medicine, surgery, and specialty units from a health system in Southeast Michigan participated, including 1 academic tertiary hospital and 4 community hospitals. Hospitalized adults who had urinary, respiratory, skin and/or soft tissue, and intra-abdominal infections and were prescribed antimicrobials at discharge were included in the analysis. Data were analyzed from February 18, 2020, to February 28, 2022., Interventions: Clinical pharmacists engaged in a new standard of care for antimicrobial stewardship practices during TOC by identifying patients to be discharged with a prescription for oral antimicrobials and collaborating with primary teams to prescribe optimal therapy. Academic and community hospitals used both antimicrobial stewardship and clinical pharmacists in a multidisciplinary rounding model to discuss, document, and facilitate order entry of the antimicrobial prescription at discharge., Main Outcomes and Measures: The primary end point was frequency of optimized antimicrobial prescription at discharge. Health system guidelines developed from national guidelines and best practices for short-course therapies were used to evaluate optimal therapy., Results: A total of 800 patients prescribed oral antimicrobials at hospital discharge were included in the analysis (441 women [55.1%]; mean [SD] age, 66.8 [17.3] years): 400 in the preintervention period and 400 in the postintervention period. The most common diagnoses were pneumonia (264 [33.0%]), upper respiratory tract infection and/or acute exacerbation of chronic obstructive pulmonary disease (214 [26.8%]), and urinary tract infection (203 [25.4%]). Patients in the postintervention group were more likely to have an optimal antimicrobial prescription (time-adjusted generalized estimating equation odds ratio, 5.63 [95% CI, 3.69-8.60]). The absolute increase in optimal prescribing in the postintervention group was consistent in both academic (37.4% [95% CI, 27.5%-46.7%]) and community (43.2% [95% CI, 32.4%-52.8%]) TOC models. There were no differences in clinical resolution or mortality. Fewer severe antimicrobial-related adverse effects (time-adjusted generalized estimating equation odds ratio, 0.40 [95% CI, 0.18-0.88]) were identified in the postintervention (13 [3.2%]) compared with the preintervention (36 [9.0%]) groups., Conclusions and Relevance: The findings of this quality improvement study suggest that targeted antimicrobial stewardship interventions during TOC were associated with increased optimal, guideline-concordant antimicrobial prescriptions at discharge.

Background: Case reports and pharmacokinetic data suggest off-label echinocandin dosing may be needed to reach adequate serum concentrations in obese patients. Few outcome studies exist evaluating this population., Objectives: Of this study were to (1) determine the association of body mass index (BMI) with clinical outcomes of candidemia patients on standard doses of anidulafungin and (2) characterize fungal infections by body weight., Methods: A retrospective cohort was conducted to evaluate hospitalized patients treated for candidemia with anidulafungin at Food and Drug Administration-labeled dosing for at least 72 hours from January 1, 2014, through January 31, 2018. Candidemia was diagnosed by blood culture or T2 magnetic resonance (T2MR). Patients were compared according to BMI category., Results: One hundred seventy-three patients were included. Candida albicans and Candida glabrata were identified in 58 (33%) and 57 (33%) patients, respectively. Mortality was comparable according to BMI category: 4 (36.4%) underweight, 8 (25.8%) normal weight, 16 (32.0%) overweight, 20 (33.9%) obese, and 7 (31.8%) morbidly obese, P = .976. Variables associated with mortality included: severe sepsis (adjusted odds ratio [OR] = 5.1, 95% CI: 1.7-14.8) and liver disease (adjusted OR = 3.2, 95% CI: 1.1-9.4). Variables that were protective of mortality included: line removal (adjusted OR = 0.05, 95% CI: 0.02-0.2) and receipt of anidulafungin for at least 5 days (adjusted OR = 0.35, 95% CI: 0.15-0.8)., Conclusion: There was no difference detected in mortality among patients with candidemia across BMI category. Larger studies are needed to confirm whether standard doses of anidulafungin are sufficient for candidemia in obese patients.

Resource-intensive interventions and education are susceptible to a lack of long-term sustainability and regression to the mean. The respiratory culture nudge changed reporting to "Commensal Respiratory Flora only: No S. aureus /MRSA or P. aeruginosa. " This study demonstrated sustained reduction in broad-spectrum antibiotic duration and long-term sustainability 3 years after implementation., (© The Author(s) 2022.)

Diagnostic stewardship interventions can decrease unnecessary antimicrobial therapy and microbiology laboratory resources and costs. This retrospective cross-sectional study evaluated factors associated with inappropriate initial cerebrospinal fluid (CSF) testing in patients with suspected community-acquired meningitis or encephalitis. In 250 patients, 202 (80.8%) and 48 (19.2%) were suspected meningitis and encephalitis, respectively. 207 (82.8%) patients had inappropriate and 43 (17.2%) appropriate testing. Any inappropriate CSF test was greatest in the immunocompromised (IC) group (n = 54, 91.5%), followed by non-IC (n = 109, 80.1%) and HIV (n = 44, 80%). Ordering performed on the general ward was associated with inappropriate CSF test orders (adjOR 2.81, 95% CI [1.08-7.34]). Laboratory fee costs associated with excessive testing was close to $300,000 per year. A stepwise algorithm defining empiric and add on tests according to CSF parameters and patient characteristics could improve CSF test ordering in patients with suspected meningitis or encephalitis., Competing Interests: Declaration of competing interest The authors report no conflicts of interest relevant to this article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Motivation: COVID-19 has several distinct clinical phases: a viral replication phase, an inflammatory phase and in some patients, a hyper-inflammatory phase. High mortality is associated with patients developing cytokine storm syndrome. Treatment of hyper-inflammation in these patients using existing approved therapies with proven safety profiles could address the immediate need to reduce mortality., Results: We analyzed the changes in the gene expression, pathways and putative mechanisms induced by SARS-CoV2 in NHBE, and A549 cells, as well as COVID-19 lung versus their respective controls. We used these changes to identify FDA approved drugs that could be repurposed to help COVID-19 patients with severe symptoms related to hyper-inflammation. We identified methylprednisolone (MP) as a potential leading therapy. The results were then confirmed in five independent validation datasets including Vero E6 cells, lung and intestinal organoids, as well as additional patient lung sample versus their respective controls. Finally, the efficacy of MP was validated in an independent clinical study. Thirty-day all-cause mortality occurred at a significantly lower rate in the MP-treated group compared to control group (29.6% versus 16.6%, P = 0.027). Clinical results confirmed the in silico prediction that MP could improve outcomes in severe cases of COVID-19. A low number needed to treat (NNT = 5) suggests MP may be more efficacious than dexamethasone or hydrocortisone., Availability and Implementation: iPathwayGuide is available at https://advaitabio.com/ipathwayguide/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The purpose of this study was to evaluate the safety of administering high-dose daptomycin (HDD; > 6 mg/kg actual body weight) as a 2-minute intravenous (IV) push (IVP) compared to traditional 30-minute IV piggyback (IVPB) infusion., Methods: Retrospective cohort study comparing patients receiving HDD as an IVP or IVPB infusion. The primary outcome was the proportion of patients with a documented infusion-related reaction (IRR) to daptomycin., Results: Three hundred patients were included in the final analysis, 200 patients received IVP, and 100 patients received IVPB representing a total of 1697 administrations. Median (IQR) daptomycin dose was IVP 700 mg (550-900) and IVPB 700 mg (600-900), with mg/kg doses of 8.2 (7.9-10) and 8.3 (8-10), respectively. After adjudication, IRR occurred in 1% of subjects in each treatment group., Conclusions: This study provides data in more than 1100 administrations of HDD administered via IVP. Infusion-related reactions were documented in 1% of patients regardless of infusion method, suggesting comparable safety to traditional infusion methods. This practice may be useful during fluid shortage and in the outpatient setting., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Davis has served as a consultant for Spero Therapeutics and Tetraphase Pharmaceuticals. All other authors report no conflict of interest., (© The Author(s) 2019.)

Aging is associated with heart and vascular dysfunction that contributes to cardiovascular disease (CVD) risk. Clinical data support a sexual dimorphism in the time course of aging-associated CVD. However, the mechanisms driving sex differences in cardiovascular aging and whether they can be modeled in mice have not been explored. Mineralocorticoid receptors (MRs) regulate blood pressure, and we previously demonstrated in male mice that MR expression increases in aging mouse vessels and smooth muscle cell-specific MR deletion (SMC-MR-KO) protects from cardiovascular aging. This study characterizes sex differences in murine cardiovascular aging and the associated sex-specific role of SMC-MR. Aortic stiffness, measured by pulse wave velocity, increased from 3 to 12 mo of age in males but not until 18 mo in females. The timing of the rise in aortic stiffening correlated with the timing of increased aortic MR expression, and aortic stiffness did not increase with age in SMC-MR-KO mice of both sexes. Vascular fibrosis increased at 12 mo in males and later at 18 mo in females; however, fibrosis was attenuated by SMC-MR-KO in males only. In resistance vessels, angiotensin type 1 receptor (AT 1 R)-mediated vasoconstriction also increased at 12 mo in males and 18 mo in females. ANG II-induced vasoconstriction was decreased in SMC-MR-KO specifically in males in association with decreased AT 1 R expression. Cardiac systolic function declined in males and females by 18 mo of age, which was prevented by SMC-MR-KO specifically in females. Cardiac perivascular fibrosis increased with age in both sexes accompanied by sex-specific changes in the expression levels of MR-regulated profibrotic genes. NEW & NOTEWORTHY These data demonstrate that the delayed and steeper decline in cardiovascular function observed in aging females can be modeled in aging mice. Moreover, the mechanisms driving vascular and cardiac aging phenotypes are distinct between males and females. Mineralocorticoid receptors in smooth muscle cells play a significant role in cardiovascular aging in both sexes; however, they do so by distinct mechanisms. Overall, these findings suggest that sex-specific therapies may be necessary to retard the aging process and improve cardiovascular disease outcomes in the aging population.

Background: Antistaphylococcal β-lactams antibiotics are the preferred treatment for methicillin-sensitive Staphylococcus aureus (MSSA) infections. Patient-reported β-lactam allergies may complicate antibiotic decision-making and delay optimal therapy, with potential implications on patient outcomes., Objective: To determine the impact of reported β-lactam allergies on the receipt of optimal therapy and outcomes for MSSA bloodstream infections (BSI)., Methods: Retrospective, matched cohort of MSSA BSI patients with and without a reported β-lactam allergy. The primary end point was receipt of optimal therapy, defined as an antistaphylococcal β-lactam., Results: Two hundred twelve patients were included: 53 with reported β-lactam allergy and 159 without β-lactam allergy. Commonly reported β-lactam allergies were 26 (49%) immune-mediated reaction and 8 (15%) intolerance, with 19 (36%) having no documented reaction. Optimal antibiotics were given to 135 patients without a β-lactam allergy and 37 patients with a reported β-lactam allergy (85% vs 70%, P = .015). Among reported β-lactam allergy patients, those without a documented reaction were less likely to receive optimal therapy (47% vs 79 %, P = .042). Reported β-lactam allergy was not associated with clinical response ( P = .61) or MSSA-related mortality ( P = .83). When adjusting for immunosuppression, variables independently associated with optimal therapy were β-lactam allergy (adjusted odds ratio [adjOR], 0.3; 95% confidence interval [CI], 0.1-0.6) and infectious diseases consultation (adjOR, 6.1; 95%CI, 2.7-13.9). Optimal antibiotic use was associated with decreased all-cause 90-day mortality (adjOR, 0.23; 95%CI, 0.09-0.54)., Conclusions: Patients with reported β-lactam allergies, particularly those without a documented reaction, were less likely to receive optimal antibiotics for MSSA BSI. Patient outcomes may be improved with enhanced quality of allergy history and routine infectious disease consultation.

Background: There is no proven antiviral or immunomodulatory therapy for coronavirus disease 2019 (COVID-19). The disease progression associated with the proinflammatory host response prompted us to examine the role of early corticosteroid therapy in patients with moderate to severe COVID-19., Methods: We conducted a single pretest, single posttest quasi-experiment in a multicenter health system in Michigan from 12 March to 27 March 2020. Adult patients with confirmed moderate to severe COVID were included. A protocol was implemented on 20 March 2020 using early, short-course, methylprednisolone 0.5 to 1 mg/kg/day divided in 2 intravenous doses for 3 days. Outcomes of standard of care (SOC) and early corticosteroid groups were evaluated, with a primary composite endpoint of escalation of care from ward to intensive care unit (ICU), new requirement for mechanical ventilation, and mortality. All patients had at least 14 days of follow-up., Results: We analyzed 213 eligible subjects, 81 (38%) and 132 (62%) in SOC and early corticosteroid groups, respectively. The composite endpoint occurred at a significantly lower rate in the early corticosteroid group (34.9% vs 54.3%, P = .005). This treatment effect was observed within each individual component of the composite endpoint. Significant reduction in median hospital length of stay was also observed in the early corticosteroid group (5 vs 8 days, P < .001). Multivariate regression analysis demonstrated an independent reduction in the composite endpoint at 14-days controlling for other factors (adjusted odds ratio: 0.41; 95% confidence interval, .22 - .77)., Conclusions: An early short course of methylprednisolone in patients with moderate to severe COVID-19 reduced escalation of care and improved clinical outcomes., Clinical Trials Registration: NCT04374071., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: Prescribing metrics, cost, and surrogate markers are often used to describe the value of antimicrobial stewardship (AMS) programs. However, process measures are only indirectly related to clinical outcomes and may not represent the total effect of an intervention. We determined the global impact of a multifaceted AMS initiative for hospitalized adults with common infections., Design: Single center, quasi-experimental study., Methods: Hospitalized adults with urinary, skin, and respiratory tract infections discharged from family medicine and internal medicine wards before (January 2017-June 2017) and after (January 2018-June 2018) an AMS initiative on a family medicine ward were included. A series of AMS-focused initiatives comprised the development and dissemination of: handheld prescribing tools, AMS positive feedback cases, and academic modules. We compared the effect on an ordinal end point consisting of clinical resolution, adverse drug events, and antimicrobial optimization between the preintervention and postintervention periods., Results: In total, 256 subjects were included before and after an AMS intervention. Excessive durations of therapy were reduced from 40.3% to 22% (P < .001). Patients without an optimized antimicrobial course were more likely to experience clinical failure (OR, 2.35; 95% CI, 1.17-4.72). The likelihood of a better global outcome was greater in the family medicine intervention arm (62.0%, 95% CI, 59.6-67.1) than in the preintervention family medicine arm., Conclusion: Collaborative, targeted feedback with prescribing metrics, AMS cases, and education improved global outcomes for hospitalized adults on a family medicine ward.

Background: Outpatient parenteral antimicrobial therapy (OPAT) is a widely used, safe, and cost-effective treatment. Most public and private insurance providers require prior authorization (PA) for OPAT, yet the impact of the inpatient PA process is not known. Our aim was to characterize discharge barriers and PA delays associated with high-priced OPAT antibiotics., Methods: This was an institutional review board-approved study of adult patients discharged with daptomycin, ceftaroline, ertapenem, and novel beta-lactam-beta-lactamase inhibitor combinations from January 2017 to December 2017. Patients with an OPAT PA delay were compared with patients without a delay. The primary endpoint was total direct hospital costs from the start of treatment., Results: Two-hundred patients were included: 141 (71%) no OPAT delay vs 59 (30%) OPAT delay. More patients with a PA delay were discharged to a subacute care facility compared with an outpatient setting: 37 (63%) vs 52 (37%), P = .001. Discharge delays and median total direct hospital costs were higher for patients with OPAT delays: 31 (53%) vs 21 (15%), P < .001 and $19 576 (interquartile range [IQR], 10 056-37 038) vs $7770 (IQR, 3031-13 974), P < .001. In multiple variable regression, discharge to a subacute care facility was associated with an increased odds of discharge delay, age >64 years was associated with a decreased odds of discharge delay., Conclusions: OPAT with high-priced antibiotics requires significant care coordination. PA delays are common and contribute to discharge delays. OPAT transitions of care represent an opportunity to improve patient care and address access barriers., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Optimal antimicrobial therapy for Enterococcus faecium bloodstream infection (EFBSI) in the solid organ transplant (SOT) population is not well defined. The purpose of this study was to describe the pharmacotherapy and outcomes of EFBSI in SOT patients. This was a single-center retrospective cohort of SOT patients with EFBSI from 2013 to 2019. Susceptibility testing was performed with Vitek ® 2 or Etest. Estimates of optimal DAP pharmacokinetic/pharmacodynamic exposures (dose <10 mg/kg, fAUC/MIC >27.4) were made from previously established literature and equations. Fifty-one unique cases were included in the analysis. The median age was 61 years and liver (64%), intestinal (19%), and kidney (12%) were the most common organs transplanted. Most patients had indwelling central lines (75%) at the time of bacteremia; intra-abdominal abscesses/fluid collections were present in 44% of patients and 8% had endocarditis. Nineteen (37%) patients had polymicrobial infections. The most common definitive antimicrobial regimens were as follows: DAP plus beta-lactam (46%), DAP monotherapy (18%), and LZD (25%). Of the 33 patients that received DAP, 21% of E faecium isolates developed DAP resistance. 30-day mortality was 25% overall but higher in patients who received an initial DAP dose <10 mg/kg (43% vs 13%). Vancomycin-resistance, severity of illness, neutropenia, and source control were also associated with mortality. Inadequate DAP dosing for EFBSI may be associated with mortality in the SOT population. Larger, controlled analyses are necessary to determine the impact of optimized pharmacodynamics in this population., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Oxygen is a transcriptional regulator responsible for tissue homeostasis and maintenance. Studies relating cellular phenotype with oxygen tension often use hypoxia chambers, which expose cells to a single, static oxygen tension. Despite their ease of use, these chambers are unable to replicate the oxygen gradients found in healthy and diseased tissues. Microfabricated devices capable of imposing an oxygen gradient across tissue-like structures are a promising tool for these studies, as they can provide a high density of information in a single experimental setup. We describe the fabrication and characterization of a modular device, which leverages the gas-permeability of silicone to impose gradients of oxygen across cell-containing regions, assembled by layering sheets of laser cut acrylic and silicone rubber. The silicone also acts as a barrier, separating the flowing gases from the cell culture medium, preventing evaporation or bubble formation in experiments that require prolonged periods of incubation. The acrylic components provide a rigid framework to provide a sterile culture environment. Using oxygen-sensing films, we show the device can support gradients of different ranges and steepness by simply changing the composition of the gases flowing through the silicone components of the BLOCC. Using a cell-based reporter assay, we demonstrate that cellular responses to hypoxia are proportional to oxygen tension., Competing Interests: Conflicts of interest There are no conflicts to declare.

Arterial stiffness progressively increases with aging and is an independent predictor of cardiovascular disease (CVD) risk. Evidence supports that there are sex differences in the time course of aging-related arterial stiffness and the associated CVD risk, which increases disproportionately in postmenopausal women. The association between arterial stiffness and mortality is almost twofold higher in women versus men. The differential clinical characteristics of the development of arterial stiffness between men and women indicate the involvement of sex-specific mechanisms. This review summarizes the current literature on sex differences in vascular stiffness induced by aging, obesity, hypertension, and sex-specific risk factors as well as the impact of hormonal status, diet, and exercise on vascular stiffness in males and females. An understanding of the mechanisms driving sex differences in vascular stiffness has the potential to identify novel sex-specific therapies to lessen CVD risk, the leading cause of death in males and females. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc., (© 2019 The British Pharmacological Society.)

T2 Magnetic Resonance Candida Panel (T2MR) detects Candida directly in blood. Rapid turnaround time and high negative predictive value make it a useful diagnostic test to support antifungal discontinuation. This retrospective quasi-experiment compared empiric anidulafungin days of therapy (DOTs) in intensive care unit (ICU) patients with suspected candidemia that had negative blood cultures and negative 1,3-β-D-glucan (BDG) versus negative blood cultures and negative T2MR. In 206 ICU patients, median anidulafungin DOTs were 2 (1, 5) compared to 1 (1, 2), respectively (P < 0.001); T2MR was associated with early discontinuation, AdjOR 3.0 95% CI (1.7-5.6), P < 0.001. Proven candidemia after discontinuation of anidulafungin occurred in 3% of BDG and 2% of T2MR patients at a median of 8 and 21 days, respectively. T2MR testing supports safe, early discontinuation of empiric antifungal therapy in ICU patients with suspected candidemia. Prospective studies to better define the role of T2MR in antifungal stewardship are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Hypoxia is a common feature in solid tumors. Clinical samples show a positive correlation between the expression of the hypoxia-inducible factor HIF-1α and estrogen receptor alpha (ERα) and a negative correlation between HIF-1α and hormone sensitivity. Results from monolayer cultures are in contention with clinical observations, showing that ER (+) cell lines no longer express ERα under hypoxic conditions (1% O 2 ). Here, we compared the impact of hypoxia on the ERα signaling pathway for T47D cells in a 2D and 3D culture format. In the 2D format, the cells were cultured as monolayers. In the 3D format, paper-based scaffolds supported cells suspended in a collagen matrix. Using ELISA, Western blot, and immunofluorescence measurements, we show that hypoxia differentially regulates ERα protein levels in a culture environment-dependent manner. In the 2D format, the protein levels are significantly decreased in hypoxia. In the 3D format, the protein levels are maintained in hypoxia. Hypoxia reduced ERα transcriptional activation in both culture formats. These results highlight the importance of considering tissue dimensionality for in vitro studies. They also show that ERα protein levels in hypoxia are not an accurate indicator of ERα transcriptional activity, and confirm that a positive stain for ERα in a clinical sample may not necessarily indicate hormone sensitivity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to improve antimicrobial management and outcomes of critically ill patients with community-acquired pneumonia (CAP) through implementation of a pharmacist-driven bundle for ordering evidence-based diagnostic tests in a medical intensive care unit (MICU)., Methods: An inpatient collaborative practice agreement (CPA) was established for MICU pharmacists to order criteria-driven diagnostic testing for CAP from November 2017-March 2018. Adults admitted to the MICU and started on empiric antibiotics for CAP were included. The intervention arm was compared with a standard of care (SOC) group from November 2016-March 2017., Results: Ninety-one patients were included in each group. There was no difference in the median antibiotic duration between SOC and CPA, at 7 days (interquartile range [IQR], 6-10) versus 7 days (IQR, 6-8), respectively. The overall use of evidence-based diagnostic tests increased in the CPA group. Patients in the CPA group had more frequent pathogen identification (SOC and CPA, respectively: 31 [34%] versus 46 [51%], p = 0.035) and antimicrobial deescalation (24 [26%] versus 53 [58%], p < 0.001). There was no significant difference in length of intensive care unit stay, at 4 days for SOC (IQR, 2-10) versus 6 days for CPA (IQR, 3-10), and no significant difference in inpatient all-cause mortality (13 [14%] versus 7 [8%]), retreatment 14 [15%] versus 11 [12%]), or 30-day readmission 16 ([18%] versus 13 [14%]) for SOC and CPA, respectively. The CPA was the only variable that was independently associated with antimicrobial deescalation (odds ratio, 4.030; 95% confidence interval, 2.101-7.731) in a multiple logistic regression., Conclusion: Implementation of a pharmacy-driven pneumonia diagnostic stewardship bundle improved the use of evidence-based diagnostics and increased the frequency of pathogen identification. This intervention was associated with increased antimicrobial deescalation without a negative impact on patient safety outcomes., (© American Society of Health-System Pharmacists 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cellular movement is essential in the formation and maintenance of healthy tissues as well as in disease progression such as tumor metastasis. In this work, we describe a paper-based Transwell assay capable of quantifying cellular invasion through an extracellular matrix. The paper-based Transwell assays generate similar datasets, with equivalent reproducibility, to commercially available Transwell assays. With different culture configurations, we quantify invasion: upon addition of an exogenous factor or in the presence of medium obtained from other cell types, in an indirect or direct co-culture format whose medium composition is dynamically changing, and in a single-zone or parallel (96-zone) format.

Background: Systematic and behavioral interventions are needed to improve antibiotic use for common conditions like pneumonia., Methods: Single pretest, post-test quasi-experiment in a 4-hospital health system in metropolitan Detroit, Michigan. Hospitalized patients treated with anti-methicillin-resistant Staphylococcus aureus and antipseudomonal antibiotics for respiratory infections from August 1, 2015, through January 31, 2016, and August 1, 2016, through January 31, 2017, were eligible for inclusion. Beginning in May 2016, respiratory cultures with no dominant organism growth and no Pseudomonas sp. or Staphylococcus aureus were reported by the clinical microbiology laboratory as "commensal respiratory flora only: No S. aureus /MRSA [methicillin-resistant Staphylococcus aureus ] or P. [ Pseudomonas ] aeruginosa. " Before intervention, these were reported as "commensal respiratory flora." The primary end point was de-escalation or discontinuation of anti-methicillin-resistant Staphylococcus aureus or antipseudomonal therapy. Secondary clinical and safety outcomes included nephrotoxicity and in-hospital, all-cause mortality., Results: Two hundred ten patients were included in the study. De-escalation/discontinuation was more commonly performed in the intervention group (39% vs 73%, P < .001). After adjusting for APACHE II and Charlson Comorbidity Index, the intervention comment was associated with a 5.5-fold increased odds of de-escalation (adjusted odds ratio, 5.5; 95% confidence interval, 2.8-10.7). Acute kidney injury was reduced in the intervention phase (31% vs 14%, P = .003). No difference in all-cause mortality was detected between the groups (30% vs 18%, P = .052)., Conclusion: A simple, behavioral nudge in microbiology reporting increased de-escalation and discontinuation of unnecessary broad-spectrum antibiotics. This highlights the importance of clear, persuasive communication of diagnostic testing in improving antibiotic prescribing behaviors.

Antimicrobial management of viral pneumonia has proven to be a challenge in hospitalized immunocompromised patients. A host of factors contribute to the dilemma, such as diagnostic uncertainty, lack of organism identification, and clinical status of the patient. Respiratory virus panel (RVP) use was compared between 131 immunocompromised patients who received send-out (n = 56) vs in-house (n = 75) testing. Antimicrobial optimization interventions consisted of antiviral addition/discontinuation, antibiotic discontinuation/de-escalation, or modification of immunosuppressive regimen. After implementation of an in-house test with audit and feedback, turnaround time of the RVP was reduced from 46.7 to 5.5 hours (P < .001) and time to intervention was reduced from 52.1 to 13.9 hours (P < .001), yet the frequency of antimicrobial optimization interventions was unchanged (30.7% vs 35.7%). Differences were not observed in duration of empiric antibiotic therapy or length of stay. The overall discontinuation rate for patients tested with a RVP was low (4.6%), and those with positive RVP (n = 43) had antibiotics stopped in 14% of cases. Bacterial pneumonia coinfection was confirmed in 2 patients. Further systematic efforts should be taken to reduce antibiotic use in viral pneumonia and identify the major barriers in the immunocompromised population., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Paper-based cultures are an emerging platform for preparing 3D tissue-like structures. Chemical gradients can be imposed upon these cultures, generating microenvironments similar to those found in poorly vascularized tumors. There is increasing evidence that the tumor microenvironment is responsible for promoting drug resistance and increased invasiveness. Acidosis, or the acidification of the extracellular space, is particularly important in promoting these aggressive cancer phenotypes. To better understand how cells respond to acidosis there is a need for 3D culture platforms that not only model relevant disease states but also contain sensors capable of quantifying small molecules in the extracellular environment. In this work, we describe pH-sensing optodes that are capable of generating high spatial and temporal resolution maps of pH gradients in paper-based cultures. This sensor was fabricated by suspending microparticles containing pH-sensitive (fluorescein) and pH-insensitive (diphenylanthracene) dyes in a polyurethane hydrogel, which was then coated onto a transparent film. The pH-sensing films have a fast response time, are reversible, stable in long-term culture environments, have minimal photobleaching, and are not cytotoxic. These films have a pK a of 7.61 ± 0.04 and are sensitive in the pH range corresponding to normal and tumorigenic tissues. With these optodes, we measured the spatiotemporal evolution of pH gradients in paper-based tumor models.

As antimicrobial stewardship increasingly receives worldwide attention for improving patient care by optimizing antimicrobial therapy, programs are evaluating new tools that may augment antimicrobial stewardship activities. Biomarkers are objective, accurate, and reproducible measures that provide information about medical conditions. A systematic literature search using PubMed/MEDLINE databases was performed to evaluate the use of novel biomarkers as additions to the antimicrobial stewardship armamentarium. Procalcitonin may help clinicians discriminate between bacterial and viral infections, help with antimicrobial discontinuation decisions, and predict mortality. β-d-glucan, Candida albicans germ tube antibody, and galactomannan are useful in suspected fungal infections and may reduce inappropriate antifungal use. Adrenomedullin and soluble triggering receptor on myeloid cells-1 may be useful for mortality prediction and the determination of a need for empiric antibacterials. Although studies evaluating these biomarkers are promising, these biomarkers are not without limitations and should be used in combination with clinical signs, symptoms, or other biomarkers. For successful implementation of biomarker use, stewardship programs should consider the populations most likely to benefit, without using them indiscriminately in all patients. Antimicrobial stewardship programs should facilitate education of clinicians through institutional guidelines to ensure the appropriate use and interpretation of these biomarkers., (© 2017 Pharmacotherapy Publications, Inc.)

Cellular invasion is the gateway to metastasis, which is the leading cause of cancer-related deaths. Invasion is driven by a number of chemical and mechanical stresses that arise in the tumor microenvironment. In vitro assays are needed for the systematic study of cancer progress. To be truly predictive, these assays must generate tissue-like environments that can be experimentally controlled and manipulated. While two-dimensional (2D) monolayer cultures are easily assembled and evaluated, they lack the extracellular components needed to assess invasion. Three-dimensional (3D) cultures are better suited for invasion studies because they generate cellular phenotypes that are more representative of those found in vivo. This feature article provides an overview of four invasion platforms. We focus on paper-based cultures, an emerging 3D culture platform capable of generating tissue-like structures and quantifying cellular invasion. Paper-based cultures are as easily assembled and analyzed as monolayers, but provide an experimentally powerful platform capable of supporting: co-cultures and representative extracellular environments; experimentally controlled gradients; readouts capable of quantifying, discerning, and separating cells based on their invasiveness. With a series of examples we highlight the potential of paper-based cultures, and discuss how they stack up against other invasion platforms.

Introduction: Anti-staphylococcal penicillins are generally accepted as first-line therapy for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, but their use may be limited by interstitial nephritis and acute kidney injury. Alternatives include first-generation cephalosporins including cefazolin., Methods: We conducted a retrospective cohort study to compare adverse effects and clinical outcomes among patients with MSSA bacteremia treated with cefazolin or nafcillin. The primary endpoint was acute kidney injury (AKI), defined as a 0.3 mg/dL or 50% increase from baseline., Results: Incidence of AKI was 27/82 (33%) versus 9/68 (13%) (p = 0.007) in the nafcillin and cefazolin arms, respectively. After adjusting for endocarditis and intensive care unit admission in multivariate logistic regression, nafcillin was an independent predictor of AKI [adj odds ratio (OR) = 2.74; 95% (CI) 1.1-6.6]. Patients who experienced AKI were more likely to have a prolonged intensive care unit stay., Conclusion: Risk of nephrotoxicity is increased with nafcillin compared with cefazolin. Cefazolin should considered as a safer alternative to nafcillin for select patients with MSSA bacteremia.

Purpose: The process of developing objective and measurable postgraduate year 1 (PGY1) residency graduation requirements and a progress tracking system is described., Summary: The PGY1 residency accreditation standard requires that programs establish criteria that must be met by residents for successful completion of the program (i.e., graduation requirements), which should presumably be aligned with helping residents to achieve the purpose of residency training. In addition, programs must track a resident's progress toward fulfillment of residency goals and objectives. Defining graduation requirements and establishing the process for tracking residents' progress are left up to the discretion of the residency program. To help standardize resident performance assessments, leaders of an academic medical center-based PGY1 residency program developed graduation requirement criteria that are objective, measurable, and linked back to residency goals and objectives. A system for tracking resident progress relative to quarterly progress targets was instituted. Leaders also developed a focused, on-the-spot skills assessment termed "the Thunderdome," which was designed for objective evaluation of direct patient care skills. Quarterly data on residents' progress are used to update and customize each resident's training plan. Implementation of this system allowed seamless linkage of the training plan, the progress tracking system, and the specified graduation requirement criteria., Conclusion: PGY1 residency requirements that are objective, that are measurable, and that attempt to identify what skills the resident must demonstrate in order to graduate from the program were developed for use in our residency program. A system for tracking the residents' progress by comparing residents' performance to predetermined quarterly benchmarks was developed., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Background: Use of alternative antimicrobials to vancomycin is a potential strategy to reduce acute kidney injury (AKI) in high-risk patients, but current data do not support widespread adoption of this practice., Objective: To determine the efficacy of early switch to a nonnephrotoxic alternative for prevention of AKI in high-risk patients who receive vancomycin., Methods: This was an IRB-approved, prospective randomized controlled trial in a single, tertiary care academic medical center. Patients initially prescribed vancomycin between October 2011 to April 2013 with at least 2 risk factors for AKI were included. Treatment randomization was stratified by indication for therapy. Patients were randomized to continuation of dose-optimized vancomycin or early switch to an alternative antimicrobial agent. The primary end point was nephrotoxicity by consensus guideline definition adjudicated by blinded review; the secondary end point was AKI network-defined AKI., Results: A total of 103 patients were randomized; 100 were included in the modified intent-to-treat population, 51 in the vancomycin group and 49 in the alternative group. The incidence of nephrotoxicity was 6.1% in the alternative therapy arm and 9.8% in the vancomycin group ( P = 0.72). The incidence of AKI was 32.7% in the alternative therapy group and 31.4% in the vancomycin group ( P = 0.89)., Conclusions: No significant difference in nephrotoxicity or AKI was detected among patients treated with alternative antimicrobials compared with vancomycin. The use of alternative antimicrobial therapy instead of vancomycin solely for the purpose of preventing AKI in high-risk patients does not appear to be warranted.

Objectives: There are few convenient intravenous options for long-term outpatient treatment of osteoarticular infection (OAI) and limited effectiveness and safety data exist for this off-label use of ceftaroline. The objective of this study was to describe the long-term effectiveness and safety of ceftaroline for the treatment of OAI., Methods: This was a matched retrospective cohort study of patients receiving ceftaroline- or vancomycin-based therapy for OAI in the outpatient setting. Patients were matched according to infection subtype, anatomical site and microbiology. The primary endpoint was 180 day infection-related readmission (IRR). Secondary endpoints included all-cause readmission, time-to-IRR and adverse event incidence., Results: The final matched cohort consisted of 50 ceftaroline-treated patients and 50 vancomycin-treated patients. The IRR incidence was 22% for ceftaroline patients and 30% for vancomycin patients; OR = 0.66 (95% CI = 0.27-1.62; P = 0.362). There was no significant difference between groups in all-cause readmission or time-to-IRR. Attributable adverse event incidences were 24% and 18% for ceftaroline and vancomycin, respectively. Rash (10%) and nausea (6%) were the most common ceftaroline adverse events, while acute kidney injury (6%) and rash (4%) were the most common vancomycin adverse events., Conclusions: Attributable readmission and adverse events were common among patients treated with outpatient intravenous antimicrobials for OAI. This study found no appreciable difference in effectiveness or tolerability between ceftaroline- or vancomycin-treated patients. Although further research will be important to delineate the role of ceftaroline in the management of OAI, data derived from this study may aid clinicians in determining therapy when limited options exist., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: The purpose of this study was to determine the incidence of and risk factors for surgical site infections in microvascular reconstruction for patients with head and neck cancer., Methods: One hundred seventeen patients with head and neck cancer undergoing microvascular reconstruction received postoperative surgical infection prophylaxis and were followed for 30 days. Surgical infection prophylaxis was categorized by empiric spectrum of activity. Risk factors for surgical site infection development and cumulative incidence of surgical site infections were characterized., Results: Thirty-seven patients developed surgical site infection (cumulative surgical site infection incidence of 31.6%). Risk factors identified in logistic regression include alcohol use (odds ratio [OR] = 2.704; 95% confidence interval [CI] = 1.029-7.106), increased surgical duration (OR = 1.403; 95% CI = 1.185-1.661), American Society of Anesthesiologists (ASA) class IV (OR = 3.075; 95% CI = 1.000-9.459), and lack of postoperative gram-negative coverage (OR = 15.139; 95% CI = 3.083-74.347)., Conclusion: Alcohol use, longer surgical duration, and lack of gram-negative postoperative prophylactic coverage are modifiable risk factors for surgical site infection development. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1454, 2016., (© 2016 Wiley Periodicals, Inc.)

Doxorubicin and nogalamycin are antitumor antibiotics that interact with DNA via intercalation and threading mechanisms, respectively. Because the importance of water, particularly its impact on entropy changes, has been established in other biological processes, we investigated the role of water in these two drug-DNA binding events. We used the osmotic stress method to calculate the number of water molecules exchanged (Δnwater), and isothermal titration calorimetry to measure Kbinding, ΔH, and ΔS for two synthetic DNAs, poly(dA·dT) and poly(dG·dC), and calf thymus DNA (CT DNA). For nogalamycin, Δnwater<0 for CT DNA and poly(dG·dC). For doxorubicin, Δnwater>0 for CT DNA and Δnwater<0 for poly(dG·dC). For poly(dA·dT), Δnwater~0 with both drugs. Net enthalpy changes were always negative, but net entropy changes depended on the drug. The effect of water exchange on the overall sign of entropy change appears to be smaller than other contributions., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Extended-spectrum β-lactamase (ESBL) enzymes cause resistance to common β-lactam antibiotics and are associated with poor outcomes. Management of ESBL urinary tract infections (UTIs) is challenging given the limited treatment options available outside the hospital setting. In this study, the primary endpoint of UTI-related 30-day hospital re-admission or emergency department/clinic revisit rates was compared for fosfomycin and ertapenem outpatient ESBL UTI treatments. A retrospective cohort study was performed on patients with ESBL UTIs treated with outpatient fosfomycin or ertapenem from January 2010 to February 2015. Inclusion criteria were age ≥18 years, outpatient treatment with fosfomycin or ertapenem for symptomatic ESBL UTI, and positive urine cultures with microbiologically proven ESBL-producing bacteria. A non-inferiority margin of 0.15 was selected to detect a difference in the primary endpoint. Patient and infection characteristics were compared. A sensitivity analysis with propensity score matching was performed. In total, 178 patients were included (89 fosfomycin-treated and 89 ertapenem-treated). Ertapenem-treated patients received longer outpatient antibiotic treatment (10 days vs. 6 days; P <0.001). ESBL isolates identified were 149 Escherichia coli (83.7%), 26 Klebsiella spp. (14.6%) and 3 other (1.7%). Common dosage regimens were oral dose of 3 g fosfomycin every 72 h (62%), oral dose of 3 g fosfomycin every 48 h (23%) and intravenous dose of 1 g ertapenem daily (76%). The thirty-day re-admission/revisit rates for fosfomycin and ertapenem were 14.6% vs. 13.5% (1.1% difference; 97.5% CI, -0.11 to 0.13). Fosfomycin was non-inferior to ertapenem for treating outpatient ESBL UTIs and should be considered as appropriate step-down therapy for these infections., (Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Paper-based scaffolds are an attractive material for generating 3D tissue-like cultures because paper is readily available and does not require specialized equipment to pattern, cut, or use. By controlling the exchange of fresh culture medium with the paper-based scaffolds, we can engineer diffusion-dominated environments similar to those found in spheroids or solid tumors. Oxygen tension directly regulates cellular phenotype and invasiveness through hypoxia-inducible transcription factors and also has chemotactic properties. To date, gradients of oxygen generated in the paper-based cultures have relied on cellular response-based readouts. In this work, we prepared a luminescent thin film capable of quantifying oxygen tensions in apposed cell-containing paper-based scaffolds. The oxygen sensors, which are polystyrene films containing a Pd(II) tetrakis(pentafluorophenyl)porphyrin dye, are photostable, stable in culture conditions, and not cytotoxic. They have a linear response for oxygen tensions ranging from 0 to 160 mmHg O2, and a Stern-Volmer constant (K sv) of 0.239 ± 0.003 mmHg O2 (-1). We used these oxygen-sensing films to measure the spatial and temporal changes in oxygen tension for paper-based cultures containing a breast cancer line that was engineered to constitutively express a fluorescent protein. By acquiring images of the oxygen-sensing film and the fluorescently labeled cells, we were able to approximate the oxygen consumption rates of the cells in our cultures.