Antimicrobial Stewardship in the ICU.

Increasing rates of infection and multidrug-resistant pathogens, along with a high use of antimicrobial therapy, make the intensive care unit (ICU) an ideal setting for implementing and supporting antimicrobial stewardship efforts. Overuse of antimicrobial agents is common in the ICU, as practitioners are challenged daily with achieving early, appropriate empiric antimicrobial therapy to improve patient outcomes. While early antimicrobial stewardship programs focused on the financial implications of antimicrobial overuse, current goals of stewardship programs align closely with those of critical care providers-to optimize patient outcomes, reduce development of resistance, and minimize adverse outcomes associated with antibiotic overuse and misuse such as acute kidney injury and Clostridioides difficile-associated disease. Significant opportunities exist in the ICU for critical care clinicians to support stewardship practices at the bedside, including thoughtful and restrained initiation of antimicrobial therapy, use of biomarkers in addition to rapid diagnostics, Staphylococcus aureus screening, and traditional microbiologic culture and susceptibilities to guide antibiotic de-escalation, and use of the shortest duration of therapy that is clinically appropriate. Integration of critical care practitioners into the initiatives of antimicrobial stewardship programs is key to their success. This review summarizes key components of antimicrobial stewardship programs and mechanisms for critical care practitioners to share the responsibility for antimicrobial stewardship.

Effectiveness of fidaxomicin versus oral vancomycin in the treatment of recurrent clostridioides difficile.

WHAT IS KNOWN AND OBJECTIVE: The 2017 IDSA/SHEA Clinical Practice Guidelines for Clostridioides difficile infection (CDI) recommend treating recurrent episodes with fidaxomicin or oral vancomycin, but there is little evidence to support one strategy over another, particularly beyond the first recurrence. The aim of this study was to compare clinical outcomes in patients with recurrent CDI treated with vancomycin vs. fidaxomicin. METHODS: This retrospective study evaluated inpatients with recurrent CDI treated with vancomycin or fidaxomicin between 1 January 2013 and 1 May 2019. The primary outcome was CDI recurrence. Secondary outcomes included re-infection, treatment failure, infection-related length of stay (IRLOS) and in-hospital all-cause mortality (IHACM). The Wilcoxon rank-sum test, Pearson's chi-square test or Fisher's exact test was utilized, as appropriate. A multivariable logistic regression (MLR) model was used to estimate the adjusted odds ratio and 95% confidence interval assessing recurrence while adjusting for confounding variables. A survival analysis was also conducted. RESULTS: 135 patients met the inclusion criteria (35 fidaxomicin vs. 100 vancomycin). There was no difference in CDI recurrence [7 (20%) fidaxomicin vs. 11 (11%) vancomycin, p = 0.18]; this persisted in the MLR model (OR: 0.85 [95% CI 0.27-2.7]) and survival analysis (p = 0.1954). Additionally, there was no difference in re-infection rate (p = 0.73), treatment failure (p = 0.13), IRLOS (p = 0.19) or IHACM (p = 0.65). WHAT IS NEW AND CONCLUSION: This represents the first analysis of CDI recurrence that included patients with >2 prior episodes of CDI. The study found no difference in additional recurrences when patients were treated with oral vancomycin vs fidaxomicin for recurrent CDI. However, the current study is limited by the small sample size available for inclusion. Prospective randomized studies with larger sample sizes are needed to confirm this study's conclusions.

Standardizing clinical culture specimen collection in Ethiopia: a training-of-trainers.

BACKGROUND: Proper specimen collection is central to improving patient care by ensuring optimal yield of diagnostic tests, guiding appropriate management, and targeting treatment. The purpose of this article is to describe the development and implementation of a training-of-trainers educational program designed to improve clinical culture specimen collection among healthcare personnel (HCP) in Ethiopia. METHODS: A Clinical Specimen Collection training package was created consisting of a Trainer's Manual, Reference Manual, Assessment Tools, Step-by-Step Instruction Guides (i.e., job aides), and Core Module PowerPoint Slides. RESULTS: A two-day course was used in training 16 master trainers and 47 facility-based trainers responsible for cascading trainings on clinical specimen collection to HCP at the pre-service, in-service, or national-levels. The Clinical Specimen Collection Package is offered online via The Ohio State University's CANVAS online platform. CONCLUSIONS: The training-of-trainers approach may be an effective model for development of enhanced specimen collection practices in low-resource countries.

Clinical Impact of an Antibiotic Time Out Initiative at an Academic Medical Center.

Background: Various strategies aimed at limiting inappropriate antimicrobial use including antibiotic time out (ATO) have been proposed to combat the development of antimicrobial resistance, yet there are limited studies that have assessed the impact of ATO on clinical outcomes. Methods: This single-center retrospective study reviewed the effect of a passive ATO strategy by comparing 100 adult patients with an ATO matched by infection type to 100 antibiotic-treated adult patients lacking an ATO note. Results: No difference in clinical outcomes was observed, however, ATO did result in improved optimization of antibiotic selection and duration, and reduction of piperacillin/tazobactam and vancomycin use. Conclusion: Further studies are warranted to evaluate the impact of ATO on clinical outcomes of a larger homogenous population with specified infectious diagnoses and clinical characteristics.

Prediction of Antibiotic Susceptibility for Urinary Tract Infection in a Hospital Setting.

Empiric antibiotic prescribing can be supported by guidelines and/or local antibiograms, but these have limitations. We sought to use data from a comprehensive electronic health record to use statistical learning to develop predictive models for individual antibiotics that incorporate patient- and hospital-specific factors. This paper reports on the development and validation of these models with a large retrospective cohort. This was a retrospective cohort study including hospitalized patients with positive urine cultures in the first 48 h of hospitalization at a 1,500-bed tertiary-care hospital over a 4.5-year period. All first urine cultures with susceptibilities were included. Statistical learning techniques, including penalized logistic regression, were used to create predictive models for cefazolin, ceftriaxone, ciprofloxacin, cefepime, and piperacillin-tazobactam. These were validated on a held-out cohort. The final data set used for analysis included 6,366 patients. Final model covariates included demographics, comorbidity score, recent antibiotic use, recent antimicrobial resistance, and antibiotic allergies. Models had acceptable to good discrimination in the training data set and acceptable performance in the validation data set, with a point estimate for area under the receiver operating characteristic curve (AUC) that ranged from 0.65 for ceftriaxone to 0.69 for cefazolin. All models had excellent calibration. We used electronic health record data to create predictive models to estimate antibiotic susceptibilities for urinary tract infections in hospitalized patients. Our models had acceptable performance in a held-out validation cohort.

Efficacy of combination therapy versus monotherapy in the treatment of Stenotrophomonas maltophilia pneumonia.

BACKGROUND: Stenotrophomonas maltophilia is intrinsically resistant to several antibiotics, making it potentially challenging to treat. Studies have demonstrated treatment failures and resistance development with monotherapy (MT); however, clinical data are limited with combination therapy (CT). OBJECTIVES: To compare clinical outcomes with CT versus MT for S. maltophilia pneumonia. METHODS: This was a retrospective cohort study of patients admitted between November 2011 and October 2017 with S. maltophilia pneumonia who received at least 48 h of effective therapy. The primary outcome was clinical response after 7 days of effective therapy with CT versus MT. Secondary outcomes included development of a non-susceptible isolate, 30 day microbiological cure, infection recurrence, infection-related mortality and all-cause mortality. The Wilcoxon rank sum test, the Pearson χ2 test and Fisher's exact test were utilized for univariate analyses. A multivariable logistic regression model was used to assess clinical response while adjusting for confounding variables. RESULTS: Of 252 patients with S. maltophilia pneumonia included, 38 received CT and 214 received MT. There was no difference in 7 day clinical response with CT versus MT (47.4% versus 39.7%, P = 0.38), even after controlling for immune status, APACHE II score and polymicrobial pneumonia (adjusted OR 1.51, 95% CI 0.63-3.65). Thirty day microbiological cure (P = 0.44), recurrence (P = 0.53), infection-related mortality (P = 0.19) and isolation of a non-susceptible isolate during or after therapy (P = 1.00 each) were also similar between both groups; however, 30 day all-cause mortality was greater with CT (P = 0.03). CONCLUSIONS: CT had similar rates of clinical efficacy and resistance development compared with MT for S. maltophilia pneumonia.

Methicillin-resistant Staphylococcus aureus in Ohio EMS Providers: A Statewide Cross-sectional Study.

The objective was to determine the nasal carriage prevalence of methicillin-resistant Staphylococcus aureus (MRSA) among emergency medical service (EMS) personnel and the associated risk factors. A cross-sectional study was conducted among Ohio EMS personnel randomly sampled from 84 urban and rural agencies. Surveys assessing demographics, occupational history, health, cohabitation status, and hygiene practice were collected with nasal swabs from those who enrolled. Survey weight adjusted analysis was performed (1) to estimate MRSA nasal carriage prevalence of Ohio EMS providers, and (2) to identify variables associated with MRSA. MRSA was detected in 4.6% (13/280) EMS personnel sampled. After employing a survey-weighted analysis the following risk factors associated with MRSA carriage were identified: those who did not practice frequent hand hygiene after glove use (OR, 10.51; 95% CI, 2.54-43.45; P = 0.0012), living with someone with a recent staphylococcal infection (OR, 9.02; 95% CI, 1.03-78.98; P = 0.0470), and individuals with low frequency of hand washing (< 8 times per shift) (OR, 4.20; 95% CI 1.02-17.27; P = 0.0468). An additional risk factor identified through the logistic regression analysis on the study population was EMS workers with an open wound or skin infection (OR, 6.75; 95% CI, 1.25-36.36; P = 0.0262). However, this was not significant in the survey-weighted analysis. The high prevalence of MRSA in Ohio EMS personnel is both an occupational hazard and patient safety concern. Implementing methods to reinforce CDC guidelines for proper hygiene could decrease MRSA found in the EMS setting. Previous literature suggests that a reduction in MRSA colonization can lead to decreases in transmission and improved health for both patients and personnel.

Molecular and clinical characteristics of hospital and community onset methicillin-resistant Staphylococcus aureus strains associated with bloodstream infections.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are classified epidemiologically as health care-associated hospital onset (HAHO)-, health care-associated community onset (HACO)-, or community-associated (CA)-MRSA. Clinical and molecular differences between HAHO- and HACO-MRSA BSI are not well known. Thus, we evaluated clinical and molecular characteristics of MRSA BSI to determine if distinct features are associated with HAHO- or HACO-MRSA strains. Molecular genotyping and medical record reviews were conducted on 282 MRSA BSI isolates from January 2007 to December 2009. MRSA classifications were 38% HAHO-, 54% HACO-, and 8% CA-MRSA. Comparing patients with HAHO-MRSA to those with HACO-MRSA, HAHO-MRSA patients had significantly higher rates of malignancy, surgery, recent invasive devices, and mortality and longer hospital stays. Patients with HACO-MRSA were more likely to have a history of renal failure, hemodialysis, residence in a long-term-care facility, long-term invasive devices, and higher rate of MRSA relapse. Distinct MRSA molecular strain differences also were seen between HAHO-MRSA (60% staphylococcal cassette chromosome mec type II [SCCmec II], 30% SCCmec III, and 9% SCCmec IV) and HACO-MRSA (47% SCCmec II, 35% SCCmec III, and 16% SCCmec IV) (P < 0.001). In summary, our study reveals significant clinical and molecular differences between patients with HAHO- and HACO-MRSA BSI. In order to decrease rates of MRSA infection, preventive efforts need to be directed toward patients in the community with health care-associated risk factors in addition to inpatient infection control.

Impact of a Cost Visibility Tool in the Electronic Medical Record on Antibiotic Prescribing in an Academic Medical Center.

BACKGROUND: Studies evaluating the impact of passive cost visibility tools on antibiotic prescribing are lacking. OBJECTIVE: The objective of this study was to evaluate whether the implementation of a passive antibiotic cost visibility tool would impact antibiotic prescribing and decrease antibiotic spending. METHODS: An efficiency and effectiveness initiative (EEI) was implemented in October 2012. To support the EEI, an antibiotic cost visibility tool was created in June 2013 displaying the relative cost of antibiotics. Using an observational study of interrupted time series design, 3 time frames were studied: pre EEI, post EEI, and post cost visibility tool implementation. The primary outcome was antibiotic cost per 1,000 patient days. Secondary outcomes included case mix index (CMI)-adjusted antibiotic cost per 1,000 patient days and utilization of the cost visibility tool. RESULTS: Initiation of the EEI was associated with a $4,675 decrease in antibiotic cost per 1,000 patient days (P = .003), and costs continued to decrease in the months following EEI (P = .009). After implementation of the cost visibility tool, costs remained stable (P = .844). Despite CMI increasing over time, adjustment for CMI had no impact on the directionality or statistical significance of the results. CONCLUSION: Our study demonstrated a significant and sustained decrease in antibiotic cost per 1,000 patient days when focused medication cost reduction efforts were implemented, but passive cost visibility tool implementation was not associated with additional cost reduction. Antibiotic cost visibility tools may be of most benefit when prior medication cost reduction efforts are lacking or when an active intervention is incorporated.

Nephrotoxicity Risk Factors and Intravenous Vancomycin Dosing in the Immediate Postoperative Period Following Antibiotic-Impregnated Cement Spacer Placement.

BACKGROUND: Several case reports have documented acute kidney injury (AKI) attributable to antibiotic-impregnated cement (AIC) spacers. OBJECTIVES: To identify AKI risk factors among patients who underwent AIC placement and determine whether vancomycin-AIC placement affects systemic vancomycin dosing. METHODS: Phase 1 was a case-control study to identify AKI risk factors among patients who underwent AIC placement. Cases experienced AKI; controls had unchanged renal function. Phase 2 was a retrospective cohort study. Patients who received ≥72 hours of intravenous (IV) vancomycin were divided into 2 groups according to whether they underwent vancomycin-AIC placement. Primary outcome was number of vancomycin dosing changes. RESULTS: Phase 1: Among 26 cases and 74 controls AKI risk factors on univariate and multivariable analysis included exposure to angiotensin-converting-enzyme (ACE) inhibitor exposure within 7 days of AIC placement (42% vs 20%, P = 0.03) and piperacillin-tazobactam within 7 days following AIC placement (31% vs 12%, P = 0.03). Phase 2: Among 53 patients who underwent vancomycin-AIC placement and 104 who underwent another surgery type, vancomycin was adjusted more frequently in patients who underwent vancomycin-AIC placement (28% vs 15%, P = 0.06). CONCLUSIONS: Among patients who undergo AIC placement with vancomycin and/or tobramycin, exposure to ACE inhibitors and piperacillin-tazobactam are associated with increased risk of AKI in the immediate postoperative period. No empirical adjustments to IV vancomycin dosing are necessary in patients undergoing vancomycin-AIC placement.

Anticoagulating New-Onset Atrial Fibrillation After COVID-19: A Single-Center Experience.

Anticoagulation (AC) strategy in new-onset atrial fibrillation (NOAF) secondary to other illnesses has not been broadly studied, and society-level guidance does not provide a strong recommendation regarding outpatient continuation upon discharge. Our study focused specifically on patients experiencing NOAF secondary to COVID-19. It sought to understand whether our facility's rounding prescribers were continuing patients on AC at discharge, the presence of arrhythmia at one-year follow-up, and to observe the risk of adverse outcomes in light of this unique precipitant. A retrospective cohort analysis and chart review were conducted of 231 consecutive inpatients during the initial 19 months of the COVID-19 pandemic. Eighteen patients experiencing NOAF with an average calculated CHA2DS2-VASc score of four were included in the cohort. Four patients (22%) died during hospitalization and 14 patients were discharged. Twelve of fourteen patients (86%) were discharged on AC, and eight remained adherent at follow-up. Two discharged patients died of unknown causes prior to follow-up. At follow-up, which occurred at a median of 1.2 years, 25% of the surviving cohort remained in atrial fibrillation (AF). No major bleeding events were recorded during the studied period. This retrospective analysis of a small sample of patients admitted to a single medical center for COVID-19 and experiencing NOAF demonstrates that local prescribers are continuing AC at discharge, that the rate of recurrence of AF is similar to onset in non-COVID illness at one year, and that risk of death approximated that of COVID-19 itself rather than NOAF.

Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms.

BACKGROUND: Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections. METHODS: The OVERCOME (Colistin Monotherapy versus Combination Therapy) trial was an international, randomized, double-blind, placebo-controlled trial. We randomly assigned participants to receive colistin (5 mg/kg once followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI caused by XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality, and secondary outcomes included clinical failure and microbiologic cure. RESULTS: Between 2012 and 2020, a total of 464 participants were randomly assigned to treatment, and 423 eligible patients comprised the modified intention-to-treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43 vs. 37%; P=0.17), clinical failure (65 vs. 58%; difference, 6.8 percentage points; 95% confidence interval [CI], -3.1 to 16.6), microbiologic cure (65 vs. 60%; difference, 4.8 percentage points; 95% CI, -5.6 to 15.2), or adverse events (acute kidney injury, 52 vs. 49% [P=0.55]; hypersensitivity reaction, 1 vs. 3% [P=0.22]; and neurotoxicity, 5 vs. 2% [P=0.29]) between patients receiving monotherapy and combination therapy, respectively. CONCLUSIONS: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens. (Funded by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases protocol 10-0065; ClinicalTrials.gov number, NCT01597973.).

Is the "low-hanging fruit" worth picking for antimicrobial stewardship programs?

A new antimicrobial stewardship program can be overwhelmed at the breadth of interventions and education required to conduct a successful program. The expression "low-hanging fruit," in reference to stewardship, refers to selecting the most obtainable targets rather than confronting more complicated management issues. These targets include intravenous-to-oral conversions, batching of intravenous antimicrobials, therapeutic substitutions, and formulary restriction. These strategies require fewer resources and less effort than other stewardship activities; however, they are applicable to a variety of healthcare settings, including limited-resource hospitals, and have demonstrated significant financial savings. Our stewardship program found that staged and systematic interventions that focus on obvious areas of need, that is, low hanging fruit, provided early successes in our expanded program with a substantial cumulative cost savings of $832,590.

Rapid and reproducible surveillance for ventilator-associated pneumonia.

BACKGROUND: The complexity and subjectivity of ventilator-associated pneumonia (VAP) surveillance limit its value in assessing and comparing quality of care for ventilated patients. A simpler, more quantitative VAP definition may increase utility. METHODS: We streamlined the Centers for Disease Control and Prevention definition of VAP to increase objectivity and efficiency. Qualitative criteria were replaced with quantitative criteria, and changes in ventilator settings were used to screen patients for worsening oxygenation. We retrospectively compared surveillance time, reproducibility, and outcomes for streamlined versus conventional surveillance among medical and surgical patients on mechanical ventilation in 3 university hospitals. RESULTS: Application of the streamlined definition was faster (mean 3.5 minutes vs 39.0 minutes per patient) and more objective (interrater reliability κ 0.79 vs 0.45) than the conventional definition. On multivariate analysis, the streamlined definition predicted increases in ventilator days (6.5 days [95% CI, 4.1-10.0] vs 6.4 days [95% CI, 4.7-8.6]), intensive care days (5.6 days [95% CI, 3.2-8.9] vs 6.2 days [95% CI, 4.6-8.2]), and hospital mortality (odds ratio [OR] 0.84 [95% CI, 0.31-2.29] vs OR 0.69 [95% CI, 0.30-1.55]) as effectively as conventional surveillance. The conventional definition was a marginally superior predictor of increased hospital days (5.2 days [95% CI, 3.4-7.6] vs 2.1 days [95% CI, -0.5-5.6]). CONCLUSIONS: A streamlined version of the VAP definition was faster, more objective, and predicted patients' outcomes almost as effectively as the conventional definition. VAP surveillance using the streamlined method may facilitate more objective and efficient quality assessment for ventilated patients.

Methicillin-resistant Staphylococcus aureus sequence type 239-III, Ohio, USA, 2007-2009.

Methicillin-resistant Staphylococcus aureus (MRSA) is a human pathogen that has diverse molecular heterogeneity. Most MRSA strains in the United States are pulsed-field gel electrophoresis USA100 sequence type (ST) 5 and USA300 ST8. Infections with MRSA ST239-III are common and found during health care-associated outbreaks. However, this strain has been rarely reported in the United States. As part of a study supported by the Prevention Epicenter Program of the Centers for Disease Control and Prevention (Atlanta, GA, USA), which evaluated transmission of MRSA among hospitals in Ohio, molecular typing identified 78 (6%) of 1,286 patients with MRSA ST239-III infections. Ninety-five percent (74/78) of these infections were health care associated, and 65% (51/78) of patients had histories of invasive device use. The crude case-fatality rate was 22% (17/78). Identification of these strains, which belong to a virulent clonal group, emphasizes the need for molecular surveillance.

Objective surveillance definitions for ventilator-associated pneumonia.

OBJECTIVES: The subjectivity and complexity of surveillance definitions for ventilator-associated pneumonia preclude meaningful internal or external benchmarking and therefore hamper quality improvement initiatives for ventilated patients. We explored the feasibility of creating objective surveillance definitions for ventilator-associated pneumonia. DESIGN: We identified clinical signs suitable for inclusion in objective definitions, proposed candidate definitions incorporating these objective signs, and then applied these definitions to retrospective clinical data to measure their frequencies and associations with adverse outcomes using multivariate regression models for cases and matched controls. SETTING: Medical and surgical intensive care units in eight U.S. hospitals (four tertiary centers, three community hospitals, and one Veterans Affairs institution). PATIENTS: Eight thousand seven hundred thirty-five consecutive episodes of mechanical ventilation for adult patients. INTERVENTIONS: We evaluated 32 different candidate definitions composed of different combinations of the following signs: three thresholds for respiratory deterioration defined by sustained increases in daily minimum positive end-expiratory pressure or FIO2 after either 2 or 3 days of stable or decreasing ventilator settings, abnormal temperature, abnormal white blood cell count, purulent pulmonary secretions defined by neutrophils on Gram stain, and positive cultures for pathogenic organisms. MEASUREMENTS AND MAIN RESULTS: Ventilator-associated pneumonia incidence, attributable ventilator days, hospital days, and hospital mortality. All candidate definitions were significantly associated with increased ventilator days and hospital days, but only definitions requiring objective evidence of respiratory deterioration were significantly associated with increased hospital mortality. Significant odds ratios for hospital mortality ranged from 1.9 (95% confidence interval 1.2-2.9) to 6.1 (95% confidence interval 2.2-17). Requiring additional clinical signs beyond respiratory deterioration alone decreased event rates, had little impact on attributable lengths of stay, and diminished sensitivity and positive predictive values for hospital mortality. CONCLUSIONS: Objective surveillance definitions that include quantitative evidence of respiratory deterioration after a period of stability strongly predict increased length of stay and hospital mortality. These definitions merit further evaluation of their utility for hospital quality and safety improvement programs.

Case-case-control study of risk factors for carbapenem-resistant Enterobacterales infections among hospitalized patients.

Objective: To identify important risk factors for carbapenem-resistant Enterobacterales (CRE) infections among hospitalized patients. Design: We utilized a case-case-control design that compared patients with CRE infections to patients with carbapenem-susceptible Enterobacterales (CSE) infections and randomly selected controls during the period from January 2011 through December 2016. Setting: The study population was selected from patients at a large metropolitan tertiary-care and instructional medical center. Patients: Cases of CRE were defined as initial admission of adults diagnosed with a bacterial infection of an Enterobacterales species resistant clinically or through sensitivity testing to carbapenems 48 hours or more after admission. Cases of CSE were selected from the same patient population as the CRE cases within a 30-day window for admission, with diagnostic pathogens identified as susceptible to carbapenems. Controls were defined as adult patients admitted to any service within a 30-day window from a CRE case for >48 hours who did not meet either of the above case definitions during that admission. Results: Antibiotic exposure within 90 days prior to admission and length of hospital stay were both associated with increased odds of CRE and CSE infections compared to controls. Patients with CRE infections had >18 times greater odds of prior antibiotic exposure compared to patients with CSE infections. Conclusions: Antibiotic exposure and increased length of hospital stay may result in increased patient risk of developing an infection resistant to carbapenems and other ß-lactams.

Predictors of respiratory bacterial co-infection in hospitalized COVID-19 patients.

The primary objectives were to determine the prevalence of and identify variables associated with respiratory bacterial co-infection in COVID-19 inpatients. Secondary outcomes included length of stay and in-hospital mortality. Eighty-two (11.2%) of 735 COVID-19 inpatients had respiratory bacterial co-infection. Fifty-seven patients met inclusion criteria and were matched to three patients lacking co-infection (N = 228 patients). Patients with co-infection were more likely to receive antibiotics [57 (100%) vs 130 (76%), P < 0.0001] and for a longer duration [19 (13-33) vs 8 (4-13) days, P < 0.0001]. The multi-variable logistic regression model revealed risk factors of respiratory bacterial co-infection to be admission from SNF/LTAC/NH (AOR 6.8, 95% CI 2.6-18.2), severe COVID-19 (AOR 3.03, 95% CI 0.78-11.9), and leukocytosis (AOR 3.03, 95% CI 0.99-1.16). Although respiratory bacterial co-infection is rare in COVID-19 inpatients, antibiotic use is common. Early recognition of respiratory bacterial coinfection predictors in COVID-19 inpatients may improve empiric antibiotic prescribing.

Market withdrawal of new molecular entities approved in the United States from 1980 to 2009.

PURPOSE: Economic factors, market dynamics, and safety issues are largely responsible for decisions to withdraw pharmaceutical products from the market. In this study, new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) were examined in the USA from 1980 to 2009. METHODS: Data were obtained from the FDA, Micromedex, Medline, and Lexis-Nexis. Descriptive analyses were used to classify product discontinuations by therapeutic category, time frame for discontinuation, and reason for withdrawal. RESULTS: There were 740 NMEs approved by the FDA during the study period. As of 1 December 2010, the number of drugs discontinued was 118 (15.9%). Discontinuations were the highest for antiparasitic products, insecticides, and repellents (6, 33.3% of approvals), systemic hormonal preparations excluding sex hormones and insulins (5, 33.3%), musculo-skeletal system (11, 32.4%), diagnostic agents (16, 28.1%), and anti-infectives for systemic use (27, 25.2%). Safety was the primary reason for withdrawing 26 drugs (3.5% of approvals). CONCLUSIONS: Approximately one in seven approved NMEs were discontinued from the market in the period of 1980-2009. Less than one-quarter (22%) of the total withdrawals were attributed to safety reasons. An ongoing evaluation of new drugs throughout their product life cycle is important to determine their efficacy, safety, and value to society.

Synovial Fluid-Induced Aggregation Occurs across Staphylococcus aureus Clinical Isolates and is Mechanistically Independent of Attached Biofilm Formation.

Rapid synovial fluid-induced aggregation of Staphylococcus aureus is currently being investigated as an important factor in the establishment of periprosthetic joint infections (PJIs). Pathogenic advantages of aggregate formation have been well documented in vitro, including recalcitrance to antibiotics and protection from host immune defenses. The objective of the present work was to determine the strain dependency of synovial fluid-induced aggregation by measuring the degree of aggregation of 21 clinical S. aureus isolates cultured from either PJI or bloodstream infections using imaging and flow cytometry. Furthermore, by measuring attached bacterial biomass using a conventional crystal violet assay, we assessed whether there is a correlation between the aggregative phenotype and surface-associated biofilm formation. While all of the isolates were stimulated to aggregate upon exposure to bovine synovial fluid (BSF) and human serum (HS), the extent of aggregation was highly variable between individual strains. Interestingly, the PJI isolates aggregated significantly more upon BSF exposure than those isolated from bloodstream infections. While we were able to stimulate biofilm formation with all of the isolates in growth medium, supplementation with either synovial fluid or human serum inhibited bacterial surface attachment over a 24 h incubation. Surprisingly, there was no correlation between the degree of synovial fluid-induced aggregation and quantity of surface-associated biofilm as measured by a conventional biofilm assay without host fluid supplementation. Taken together, our findings suggest that synovial fluid-induced aggregation appears to be widespread among S. aureus strains and mechanistically independent of biofilm formation. IMPORTANCE Bacterial infections of hip and knee implants are rare but devastating complications of orthopedic surgery. Despite a widespread appreciation of the considerable financial, physical, and emotional burden associated with the development of a prosthetic joint infection, the establishment of bacteria in the synovial joint remains poorly understood. It has been shown that immediately upon exposure to synovial fluid, the viscous fluid in the joint, Staphylococcus aureus rapidly forms aggregates which are resistant to antibiotics and host immune cell clearance. The bacterial virulence associated with aggregate formation is likely a step in the establishment of prosthetic joint infection, and as such, it has the potential to be a potent target of prevention. We hope that this work contributes to the future development of therapeutics targeting synovial fluid-induced aggregation to better prevent and treat these infections.