Stewardship Prompts to Improve Antibiotic Selection for Pneumonia: The INSPIRE Randomized Clinical Trial.

Importance: Pneumonia is the most common infection requiring hospitalization and is a major reason for overuse of extended-spectrum antibiotics. Despite low risk of multidrug-resistant organism (MDRO) infection, clinical uncertainty often drives initial antibiotic selection. Strategies to limit empiric antibiotic overuse for patients with pneumonia are needed. Objective: To evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO infection risk estimates could reduce empiric extended-spectrum antibiotics for non-critically ill patients admitted with pneumonia. Design, Setting, and Participants: Cluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time MDRO risk-based CPOE prompts; n = 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in non-critically ill adults (≥18 years) hospitalized with pneumonia. There was an 18-month baseline period from April 1, 2017, to September 30, 2018, and a 15-month intervention period from April 1, 2019, to June 30, 2020. Intervention: CPOE prompts recommending standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics during the empiric period who have low estimated absolute risk (<10%) of MDRO pneumonia, coupled with feedback and education. Main Outcomes and Measures: The primary outcome was empiric (first 3 days of hospitalization) extended-spectrum antibiotic days of therapy. Secondary outcomes included empiric vancomycin and antipseudomonal days of therapy and safety outcomes included days to intensive care unit (ICU) transfer and hospital length of stay. Outcomes compared differences between baseline and intervention periods across strategies. Results: Among 59 hospitals with 96 451 (51 671 in the baseline period and 44 780 in the intervention period) adult patients admitted with pneumonia, the mean (SD) age of patients was 68.1 (17.0) years, 48.1% were men, and the median (IQR) Elixhauser comorbidity count was 4 (2-6). Compared with routine stewardship, the group using CPOE prompts had a 28.4% reduction in empiric extended-spectrum days of therapy (rate ratio, 0.72 [95% CI, 0.66-0.78]; P < .001). Safety outcomes of mean days to ICU transfer (6.5 vs 7.1 days) and hospital length of stay (6.8 vs 7.1 days) did not differ significantly between the routine and CPOE intervention groups. Conclusions and Relevance: Empiric extended-spectrum antibiotic use was significantly lower among adults admitted with pneumonia to non-ICU settings in hospitals using education, feedback, and CPOE prompts recommending standard-spectrum antibiotics for patients at low risk of MDRO infection, compared with routine stewardship practices. Hospital length of stay and days to ICU transfer were unchanged. Trial Registration: ClinicalTrials.gov Identifier: NCT03697070.

Stewardship Prompts to Improve Antibiotic Selection for Urinary Tract Infection: The INSPIRE Randomized Clinical Trial.

Importance: Urinary tract infection (UTI) is the second most common infection leading to hospitalization and is often associated with gram-negative multidrug-resistant organisms (MDROs). Clinicians overuse extended-spectrum antibiotics although most patients are at low risk for MDRO infection. Safe strategies to limit overuse of empiric antibiotics are needed. Objective: To evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO risk estimates could reduce use of empiric extended-spectrum antibiotics for treatment of UTI. Design, Setting, and Participants: Cluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time and risk-based CPOE prompts; 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in noncritically ill adults (≥18 years) hospitalized with UTI with an 18-month baseline (April 1, 2017-September 30, 2018) and 15-month intervention period (April 1, 2019-June 30, 2020). Interventions: CPOE prompts recommending empiric standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics who have low estimated absolute risk (<10%) of MDRO UTI, coupled with feedback and education. Main Outcomes and Measures: The primary outcome was empiric (first 3 days of hospitalization) extended-spectrum antibiotic days of therapy. Secondary outcomes included empiric vancomycin and antipseudomonal days of therapy. Safety outcomes included days to intensive care unit (ICU) transfer and hospital length of stay. Outcomes were assessed using generalized linear mixed-effect models to assess differences between the baseline and intervention periods. Results: Among 127 403 adult patients (71 991 baseline and 55 412 intervention period) admitted with UTI in 59 hospitals, the mean (SD) age was 69.4 (17.9) years, 30.5% were male, and the median Elixhauser Comorbidity Index count was 4 (IQR, 2-5). Compared with routine stewardship, the group using CPOE prompts had a 17.4% (95% CI, 11.2%-23.2%) reduction in empiric extended-spectrum days of therapy (rate ratio, 0.83 [95% CI, 0.77-0.89]; P < .001). The safety outcomes of mean days to ICU transfer (6.6 vs 7.0 days) and hospital length of stay (6.3 vs 6.5 days) did not differ significantly between the routine and intervention groups, respectively. Conclusions and Relevance: Compared with routine stewardship, CPOE prompts providing real-time recommendations for standard-spectrum antibiotics for patients with low MDRO risk coupled with feedback and education significantly reduced empiric extended-spectrum antibiotic use among noncritically ill adults admitted with UTI without changing hospital length of stay or days to ICU transfers. Trial Registration: ClinicalTrials.gov Identifier: NCT03697096.

Nasal Iodophor Antiseptic vs Nasal Mupirocin Antibiotic in the Setting of Chlorhexidine Bathing to Prevent Infections in Adult ICUs: A Randomized Clinical Trial.

Importance: Universal nasal mupirocin plus chlorhexidine gluconate (CHG) bathing in intensive care units (ICUs) prevents methicillin-resistant Staphylococcus aureus (MRSA) infections and all-cause bloodstream infections. Antibiotic resistance to mupirocin has raised questions about whether an antiseptic could be advantageous for ICU decolonization. Objective: To compare the effectiveness of iodophor vs mupirocin for universal ICU nasal decolonization in combination with CHG bathing. Design, Setting, and Participants: Two-group noninferiority, pragmatic, cluster-randomized trial conducted in US community hospitals, all of which used mupirocin-CHG for universal decolonization in ICUs at baseline. Adult ICU patients in 137 randomized hospitals during baseline (May 1, 2015-April 30, 2017) and intervention (November 1, 2017-April 30, 2019) were included. Intervention: Universal decolonization involving switching to iodophor-CHG (intervention) or continuing mupirocin-CHG (baseline). Main Outcomes and Measures: ICU-attributable S aureus clinical cultures (primary outcome), MRSA clinical cultures, and all-cause bloodstream infections were evaluated using proportional hazard models to assess differences from baseline to intervention periods between the strategies. Results were also compared with a 2009-2011 trial of mupirocin-CHG vs no decolonization in the same hospital network. The prespecified noninferiority margin for the primary outcome was 10%. Results: Among the 801 668 admissions in 233 ICUs, the participants' mean (SD) age was 63.4 (17.2) years, 46.3% were female, and the mean (SD) ICU length of stay was 4.8 (4.7) days. Hazard ratios (HRs) for S aureus clinical isolates in the intervention vs baseline periods were 1.17 for iodophor-CHG (raw rate: 5.0 vs 4.3/1000 ICU-attributable days) and 0.99 for mupirocin-CHG (raw rate: 4.1 vs 4.0/1000 ICU-attributable days) (HR difference in differences significantly lower by 18.4% [95% CI, 10.7%-26.6%] for mupirocin-CHG, P < .001). For MRSA clinical cultures, HRs were 1.13 for iodophor-CHG (raw rate: 2.3 vs 2.1/1000 ICU-attributable days) and 0.99 for mupirocin-CHG (raw rate: 2.0 vs 2.0/1000 ICU-attributable days) (HR difference in differences significantly lower by 14.1% [95% CI, 3.7%-25.5%] for mupirocin-CHG, P = .007). For all-pathogen bloodstream infections, HRs were 1.00 (2.7 vs 2.7/1000) for iodophor-CHG and 1.01 (2.6 vs 2.6/1000) for mupirocin-CHG (nonsignificant HR difference in differences, -0.9% [95% CI, -9.0% to 8.0%]; P = .84). Compared with the 2009-2011 trial, the 30-day relative reduction in hazards in the mupirocin-CHG group relative to no decolonization (2009-2011 trial) were as follows: S aureus clinical cultures (current trial: 48.1% [95% CI, 35.6%-60.1%]; 2009-2011 trial: 58.8% [95% CI, 47.5%-70.7%]) and bloodstream infection rates (current trial: 70.4% [95% CI, 62.9%-77.8%]; 2009-2011 trial: 60.1% [95% CI, 49.1%-70.7%]). Conclusions and Relevance: Nasal iodophor antiseptic did not meet criteria to be considered noninferior to nasal mupirocin antibiotic for the outcome of S aureus clinical cultures in adult ICU patients in the context of daily CHG bathing. In addition, the results were consistent with nasal iodophor being inferior to nasal mupirocin. Trial Registration: ClinicalTrials.gov Identifier: NCT03140423.

The Limited Utility of Ranking Hospitals Based on Their Colon Surgery Infection Rates.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) use colon surgical site infection (SSI) rates to rank hospitals and apply financial penalties. The CMS' risk-adjustment model omits potentially impactful variables that might disadvantage hospitals with complex surgical populations. METHODS: We analyzed adult patients who underwent colon surgery within facilities associated with HCA Healthcare from 2014 to 2016. SSIs were identified from National Health Safety Network (NHSN) reporting. We trained and validated 3 SSI prediction models, using (1) current CMS model variables, including hospital-specific random effects (HCA-adapted CMS model); (2) demographics and claims-based comorbidities (expanded-claims model); and (3) demographics, claims-based comorbidities, and NHSN variables (claims-plus-electronic health record [EHR] model). Discrimination, calibration, and resulting rankings were compared among all models and the current CMS model with published coefficient values. RESULTS: We identified 39 468 colon surgeries in 149 hospitals, resulting in 1216 (3.1%) SSIs. Compared to the HCA-adapted CMS model, the expanded-claims model had similar performance (c-statistic, 0.65 vs 0.67, respectively), while the claims-plus-EHR model was more accurate (c-statistic, 0.70; 95% confidence interval, .67-.73; P = .004). The sampling variation, due to the low surgical volume and small number of infections, contributed 74% of the total variation in observed SSI rates between hospitals. When CMS model rankings were compared to those from the expanded-claims and claims-plus-EHR models, 18 (15%) and 26 (22%) hospitals changed quartiles, respectively, and 10 (8.3%) and 12 (10%) hospitals changed into or out of the lowest-performing quartile, respectively. CONCLUSIONS: An expanded set of variables improved colon SSI risk predictions and quartile assignments, but low procedure volumes and SSI events remain a barrier to effectively comparing hospitals.

Vorinostat exhibits anticancer effects in triple-negative breast cancer cells by preventing nitric oxide-driven histone deacetylation.

Triple-negative breast cancers (TNBC) that produce nitric oxide (NO) are more aggressive, and the expression of the inducible form of nitric oxide synthase (NOS2) is a negative prognostic indicator. In these studies, we set out to investigate potential therapeutic strategies to counter the tumor-permissive properties of NO. We found that exposure to NO increased proliferation of TNBC cells and that treatment with the histone deacetylase inhibitor Vorinostat (SAHA) prevented this proliferation. When histone acetylation was measured in response to NO and/or SAHA, NO significantly decreased acetylation on histone 3 lysine 9 (H3K9ac) and SAHA increased H3K9ac. If NO and SAHA were sequentially administered to cells (in either order), an increase in acetylation was observed in all cases. Mechanistic studies suggest that the "deacetylase" activity of NO does not involve S-nitrosothiols or soluble guanylyl cyclase activation. The observed decrease in histone acetylation by NO required the interaction of NO with cellular iron pools and may be an overriding effect of NO-mediated increases in histone methylation at the same lysine residues. Our data revealed a novel pathway interaction of Vorinostat and provides new insight in therapeutic strategy for aggressive TNBCs.

Medical chart validation of inpatient diagnosis codes for transfusion-related acute lung injury 2013-2015.

INTRODUCTION: Transfusion-related acute lung injury (TRALI), an adverse event occurring during or within 6 hours of transfusion, is a leading cause of transfusion-associated fatalities reported to the US Food and Drug Administration. There is limited information on the validity of diagnosis codes for TRALI recorded in inpatient electronic medical records (EMRs). STUDY DESIGNS AND METHODS: We conducted a validation study to establish the positive predictive value (PPV) of TRALI International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes recorded within a large hospital system between 2013 and 2015. A physician with critical care expertise confirmed the TRALI diagnosis. As TRALI is likely underdiagnosed, we used the specific code (518.7), and codes for respiratory failure (518.82) in combination with transfusion reaction (999.80, 999.89, E934.7). RESULTS: Among almost four million inpatient stays, we identified 208 potential TRALI cases with ICD-9-CM codes and reviewed 195 medical records; 68 (35%) met clinical definitions for TRALI (26 [38%] definitive, 15 [22%] possible, 27 [40%] delayed). Overall, the PPV for all inpatient TRALI diagnoses was 35% (95% confidence interval (CI), 28-42). The PPV for the TRALI-specific code was 44% (95% CI, 35-54). CONCLUSION: We observed low PPVs (<50%) for TRALI ICD-9-CM diagnosis codes as validated by medical charts, which may relate to inconsistent code use, incomplete medical records, or other factors. Future studies using TRALI diagnosis codes in EMR databases may consider confirming diagnoses with medical records, assessing TRALI ICD, Tenth Revision, Clinical Modification codes, or exploring alternative ways for of accurately identifying TRALI in EMR databases. KEY POINTS: In 169 hospitals, we identified 208 potential TRALI cases, reviewed 195 charts, and confirmed 68 (35%) cases met TRALI clinical definitions. As many potential TRALI cases identified with diagnosis codes did not meet clinical definitions, medical record confirmation may be prudent.

Risk factors for suicide attempt in children, adolescents, and young adults hospitalized for mental health disorders.

BACKGROUND: Suicide is a leading cause of death among children, adolescents, and young adults (AYA), and mental health disorders are a major contributing factor. Yet, suicidal behaviors among children and AYA with mental health concerns remain understudied and age-specific risk factors are poorly understood. We examined the risk factors for suicide attempt in children and AYA with mental health disorders across three age groups: pre-adolescent children (aged ≤ 12), adolescents (aged 13-17), and young adults (aged 18-25). METHODS: A cross-sectional study of children and AYA hospitalized for a mental health disorder (n = 18,018) at a private hospital system with 141 facilities across the United States (year 2014). RESULTS: Suicide attempts six months prior to hospitalization were reported in 12.1% (n = 177) pre-adolescent children, 22% (n = 1476) adolescents, and 17.9% (n = 1766) young adults. Evidence of psychological trauma was present in 55.4% of pre-adolescent children, 51.2% of adolescents, and 44.5% of young adults. Predictors for suicide attempt observed across all three age groups included the following: female sex, depressive disorder, and being a victim of bullying. Risk factors for suicide attempt specific to pre-adolescent children included being uninsured and having an unsafe home or school environment. Among AYA, suicide attempt was associated with non-Hispanic white, family history of suicide, emotional traumas, and other traumatic experiences. Alcohol use disorder was also a significant predictor of suicide attempt in young adults. CONCLUSIONS: Suicide attempts among children and AYA admitted to a hospital with mental health concerns are highly prevalent. Socioeconomic stressors appeared to be an important contributing factor of suicidal behavior in pre-adolescent children but not in older AYA. Effective suicide prevention strategies targeting children and AYA would need to consider age-specific risk factors.

Chlorhexidine versus routine bathing to prevent multidrug-resistant organisms and all-cause bloodstream infections in general medical and surgical units (ABATE Infection trial): a cluster-randomised trial.

BACKGROUND: Universal skin and nasal decolonisation reduces multidrug-resistant pathogens and bloodstream infections in intensive care units. The effect of universal decolonisation on pathogens and infections in non-critical-care units is unknown. The aim of the ABATE Infection trial was to evaluate the use of chlorhexidine bathing in non-critical-care units, with an intervention similar to one that was found to reduce multidrug-resistant organisms and bacteraemia in intensive care units. METHODS: The ABATE Infection (active bathing to eliminate infection) trial was a cluster-randomised trial of 53 hospitals comparing routine bathing to decolonisation with universal chlorhexidine and targeted nasal mupirocin in non-critical-care units. The trial was done in hospitals affiliated with HCA Healthcare and consisted of a 12-month baseline period from March 1, 2013, to Feb 28, 2014, a 2-month phase-in period from April 1, 2014, to May 31, 2014, and a 21-month intervention period from June 1, 2014, to Feb 29, 2016. Hospitals were randomised and their participating non-critical-care units assigned to either routine care or daily chlorhexidine bathing for all patients plus mupirocin for known methicillin-resistant Staphylococcus aureus (MRSA) carriers. The primary outcome was MRSA or vancomycin-resistant enterococcus clinical cultures attributed to participating units, measured in the unadjusted, intention-to-treat population as the HR for the intervention period versus the baseline period in the decolonisation group versus the HR in the routine care group. Proportional hazards models assessed differences in outcome reductions across groups, accounting for clustering within hospitals. This trial is registered with ClinicalTrials.gov, number NCT02063867. FINDINGS: There were 189 081 patients in the baseline period and 339 902 patients (156 889 patients in the routine care group and 183 013 patients in the decolonisation group) in the intervention period across 194 non-critical-care units in 53 hospitals. For the primary outcome of unit-attributable MRSA-positive or VRE-positive clinical cultures (figure 2), the HR for the intervention period versus the baseline period was 0·79 (0·73-0·87) in the decolonisation group versus 0·87 (95% CI 0·79-0·95) in the routine care group. No difference was seen in the relative HRs (p=0·17). There were 25 (<1%) adverse events, all involving chlorhexidine, among 183 013 patients in units assigned to chlorhexidine, and none were reported for mupirocin. INTERPRETATION: Decolonisation with universal chlorhexidine bathing and targeted mupirocin for MRSA carriers did not significantly reduce multidrug-resistant organisms in non-critical-care patients. FUNDING: National Institutes of Health.

Variation in Identifying Sepsis and Organ Dysfunction Using Administrative Versus Electronic Clinical Data and Impact on Hospital Outcome Comparisons.

OBJECTIVES: Administrative claims data are commonly used for sepsis surveillance, research, and quality improvement. However, variations in diagnosis, documentation, and coding practices for sepsis and organ dysfunction may confound efforts to estimate sepsis rates, compare outcomes, and perform risk adjustment. We evaluated hospital variation in the sensitivity of claims data relative to clinical data from electronic health records and its impact on outcome comparisons. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 4.3 million adult encounters at 193 U.S. hospitals in 2013-2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sepsis was defined using electronic health record-derived clinical indicators of presumed infection (blood culture draws and antibiotic administrations) and concurrent organ dysfunction (vasopressors, mechanical ventilation, doubling in creatinine, doubling in bilirubin to ≥ 2.0 mg/dL, decrease in platelets to < 100 cells/µL, or lactate ≥ 2.0 mmol/L). We compared claims for sepsis prevalence and mortality rates between both methods. All estimates were reliability adjusted to account for random variation using hierarchical logistic regression modeling. The sensitivity of hospitals' claims data was low and variable: median 30% (range, 5-54%) for sepsis, 66% (range, 26-84%) for acute kidney injury, 39% (range, 16-60%) for thrombocytopenia, 36% (range, 29-44%) for hepatic injury, and 66% (range, 29-84%) for shock. Correlation between claims and clinical data was moderate for sepsis prevalence (Pearson coefficient, 0.64) and mortality (0.61). Among hospitals in the lowest sepsis mortality quartile by claims, 46% shifted to higher mortality quartiles using clinical data. Using implicit sepsis criteria based on infection and organ dysfunction codes also yielded major differences versus clinical data. CONCLUSIONS: Variation in the accuracy of claims data for identifying sepsis and organ dysfunction limits their use for comparing hospitals' sepsis rates and outcomes. Using objective clinical data may facilitate more meaningful hospital comparisons.

Evaluating the Risk Factors for Hospital-Onset Clostridium difficile Infections in a Large Healthcare System.

In this multicenter retrospective cohort study of over 1 million patients at 150 US hospitals, proton pump inhibitors increased the odds of a patient having hospital-onset Clostridium difficile infection as did third and fourth generation cephalosporins, carbapenems, and piperacillin/tazobactam. These findings support appropriate prescribing of acid-suppression therapy and high-risk antibiotics.

Nitric oxide reduces oxidative stress in cancer cells by forming dinitrosyliron complexes.

The chelatable iron pool (CIP) is a small but chemically significant fraction of total cellular iron. While this dynamic population of iron is limited, it is redox active and capable of generating reactive oxygen species (ROS) that can lead to oxidative stress which is associated with various pathologies. Nitric oxide (•NO), is a free radical signalling molecule that regulates numerous physiological and pathological conditions. We have previously shown that macrophages exposed to endogenously generated or exogenously administered nitric oxide (•NO) results in its interaction with CIP to form dinitrosyliron complexes with thiol containing ligands (DNICs). In this study we assessed the consequences of DNIC formation in cancer cells as •NO is known to be associated with numerous malignancies. Incubation of cancer cells with •NO led to a time and dose dependent increase in formation of DNICs. The formation of DNICs results in the sequestration of the CIP which is a major source of iron for redox reactions and reactive oxygen species (ROS) generation. Therefore, we set out to test the antioxidant effect of •NO by measuring the ability of DNICs to protect cells against oxidative stress. We observed that cancer cells treated with •NO were partially protected against H2O2 mediated cytotoxicity. This correlated to a concomitant decrease in the formation of oxidants when •NO was present during H2O2 treatment. Similar protective effects were achieved by treating cells with iron chelators in the presence of H2O2. Interestingly, •NO decreased the rate of cellular metabolism of H2O2 suggesting that a proportion of H2O2 is consumed via reactions with cellular iron. When the CIP was artificially increased by supplementation of cells with iron, a significant decrease in the cytoprotective effect of •NO was observed. Notably, •NO concentrations, at which cytoprotective and antioxidant effects were observed, correlated with concentration-dependent increases in DNIC formation. Collectively, these results demonstrate that •NO has antioxidant properties by its ability to sequester cellular iron. This could play a significant role in variety of diseases involving ROS mediated toxicity like cancer and neurodegenerative disorders where •NO has been shown to be an important etiologic factor.

Epigenetics: The third pillar of nitric oxide signaling.

Nitric oxide (NO), the endogenously produced free radical signaling molecule, is generally thought to function via its interactions with heme-containing proteins, such as soluble guanylyl cyclase (sGC), or by the formation of protein adducts containing nitrogen oxide functional groups (such as S-nitrosothiols, 3-nitrotyrosine, and dinitrosyliron complexes). These two types of interactions result in a multitude of down-stream effects that regulate numerous functions in physiology and disease. Of the numerous purported NO signaling mechanisms, epigenetic regulation has gained considerable interest in recent years. There is now abundant experimental evidence to establish NO as an endogenous epigenetic regulator of gene expression and cell phenotype. Nitric oxide has been shown to influence key aspects of epigenetic regulation that include histone posttranslational modifications, DNA methylation, and microRNA levels. Studies across disease states have observed NO-mediated regulation of epigenetic protein expression and enzymatic activity resulting in remodeling of the epigenetic landscape to ultimately influence gene expression. In addition to the well-established pathways of NO signaling, epigenetic mechanisms may provide much-needed explanations for poorly understood context-specific effects of NO. These findings provide more insight into the molecular mechanisms of NO signaling and increase our ability to dissect its functional role(s) in specific micro-environments in health and disease. This review will summarize the current state of NO signaling via epigenetic mechanisms (the "third pillar" of NO signaling).

Closing the Translation Gap: Toolkit-based Implementation of Universal Decolonization in Adult Intensive Care Units Reduces Central Line-associated Bloodstream Infections in 95 Community Hospitals.

BACKGROUND: Challenges exist in implementing evidence-based strategies, reaching high compliance, and achieving desired outcomes. The rapid adoption of a publicly available toolkit featuring routine universal decolonization of intensive care unit (ICU) patients may affect catheter-related bloodstream infections. METHODS: Implementation of universal decolonization-treatment of all ICU patients with chlorhexidine bathing and nasal mupirocin-used a prerelease version of a publicly available toolkit. Implementation in 136 adult ICUs in 95 acute care hospitals across the United States was supported by planning and deployment tactics coordinated by a central infection prevention team using toolkit resources, along with coaching calls and engagement of key stakeholders. Operational and process measures derived from a common electronic health record system provided real-time feedback about performance. Healthcare-associated central line-associated bloodstream infections (CLABSIs), using National Healthcare Safety Network surveillance definitions and comparing the preimplementation period of January 2011 through December 2012 to the postimplementation period of July 2013 through February 2014, were assessed via a Poisson generalized linear mixed model regression for CLABSI events. RESULTS: Implementation of universal decolonization was completed within 6 months. The estimated rate of CLABSI decreased by 23.5% (95% confidence interval, 9.8%-35.1%; P = .001). There was no evidence of a trend over time in either the pre- or postimplementation period. Adjusting for seasonality and number of beds did not materially affect these results. CONCLUSIONS: Dissemination of universal decolonization of ICU patients was accomplished quickly in a large community health system and was associated with declines in CLABSI consistent with published clinical trial findings.

Targeted versus universal decolonization to prevent ICU infection.

BACKGROUND: Both targeted decolonization and universal decolonization of patients in intensive care units (ICUs) are candidate strategies to prevent health care-associated infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: We conducted a pragmatic, cluster-randomized trial. Hospitals were randomly assigned to one of three strategies, with all adult ICUs in a given hospital assigned to the same strategy. Group 1 implemented MRSA screening and isolation; group 2, targeted decolonization (i.e., screening, isolation, and decolonization of MRSA carriers); and group 3, universal decolonization (i.e., no screening, and decolonization of all patients). Proportional-hazards models were used to assess differences in infection reductions across the study groups, with clustering according to hospital. RESULTS: A total of 43 hospitals (including 74 ICUs and 74,256 patients during the intervention period) underwent randomization. In the intervention period versus the baseline period, modeled hazard ratios for MRSA clinical isolates were 0.92 for screening and isolation (crude rate, 3.2 vs. 3.4 isolates per 1000 days), 0.75 for targeted decolonization (3.2 vs. 4.3 isolates per 1000 days), and 0.63 for universal decolonization (2.1 vs. 3.4 isolates per 1000 days) (P=0.01 for test of all groups being equal). In the intervention versus baseline periods, hazard ratios for bloodstream infection with any pathogen in the three groups were 0.99 (crude rate, 4.1 vs. 4.2 infections per 1000 days), 0.78 (3.7 vs. 4.8 infections per 1000 days), and 0.56 (3.6 vs. 6.1 infections per 1000 days), respectively (P<0.001 for test of all groups being equal). Universal decolonization resulted in a significantly greater reduction in the rate of all bloodstream infections than either targeted decolonization or screening and isolation. One bloodstream infection was prevented per 54 patients who underwent decolonization. The reductions in rates of MRSA bloodstream infection were similar to those of all bloodstream infections, but the difference was not significant. Adverse events, which occurred in 7 patients, were mild and related to chlorhexidine. CONCLUSIONS: In routine ICU practice, universal decolonization was more effective than targeted decolonization or screening and isolation in reducing rates of MRSA clinical isolates and bloodstream infection from any pathogen. (Funded by the Agency for Healthcare Research and the Centers for Disease Control and Prevention; REDUCE MRSA ClinicalTrials.gov number, NCT00980980).

Chlorhexidine and Mupirocin Susceptibility of Methicillin-Resistant Staphylococcus aureus Isolates in the REDUCE-MRSA Trial.

Whether targeted or universal decolonization strategies for the control of methicillin-resistant Staphylococcus aureus (MRSA) select for resistance to decolonizing agents is unresolved. The REDUCE-MRSA trial (ClinicalTrials registration no. NCT00980980) provided an opportunity to investigate this question. REDUCE-MRSA was a 3-arm, cluster-randomized trial of either screening and isolation without decolonization, targeted decolonization with chlorhexidine and mupirocin, or universal decolonization without screening to prevent MRSA infection in intensive-care unit (ICU) patients. Isolates from the baseline and intervention periods were collected and tested for susceptibility to chlorhexidine gluconate (CHG) by microtiter dilution; mupirocin susceptibility was tested by Etest. The presence of the qacA or qacB gene was determined by PCR and DNA sequence analysis. A total of 3,173 isolates were analyzed; 2 were nonsusceptible to CHG (MICs, 8 µg/ml), and 5/814 (0.6%) carried qacA or qacB At baseline, 7.1% of MRSA isolates expressed low-level mupirocin resistance, and 7.5% expressed high-level mupirocin resistance. In a mixed-effects generalized logistic regression model, the odds of mupirocin resistance among clinical MRSA isolates or MRSA isolates acquired in an ICU in intervention versus baseline periods did not differ across arms, although estimates were imprecise due to small numbers. Reduced susceptibility to chlorhexidine and carriage of qacA or qacB were rare among MRSA isolates in the REDUCE-MRSA trial. The odds of mupirocin resistance were no different in the intervention versus baseline periods across arms, but the confidence limits were broad, and the results should be interpreted with caution.

Association of a bundled intervention with surgical site infections among patients undergoing cardiac, hip, or knee surgery.

IMPORTANCE: Previous studies suggested that a bundled intervention was associated with lower rates of Staphylococcus aureus surgical site infections (SSIs) among patients having cardiac or orthopedic operations. OBJECTIVE: To evaluate whether the implementation of an evidence-based bundle is associated with a lower risk of S. aureus SSIs in patients undergoing cardiac operations or hip or knee arthroplasties. DESIGN, SETTING, AND PARTICIPANTS: Twenty hospitals in 9 US states participated in this pragmatic study; rates of SSIs were collected for a median of 39 months (range, 39-43) during the preintervention period (March 1, 2009, to intervention) and a median of 21 months (range, 14-22) during the intervention period (from intervention start through March 31, 2014). INTERVENTIONS: Patients whose preoperative nares screens were positive for methicillin-resistant S. aureus (MRSA) or methicillin-susceptible S. aureus (MSSA) were asked to apply mupirocin intranasally twice daily for up to 5 days and to bathe daily with chlorhexidine-gluconate (CHG) for up to 5 days before their operations. MRSA carriers received vancomycin and cefazolin or cefuroxime for perioperative prophylaxis; all others received cefazolin or cefuroxime. Patients who were MRSA-negative and MSSA-negative bathed with CHG the night before and morning of their operations. Patients were treated as MRSA-positive if screening results were unknown. MAIN OUTCOMES AND MEASURES: The primary outcome was complex (deep incisional or organ space) S. aureus SSIs. Monthly SSI counts were analyzed using Poisson regression analysis. RESULTS: After a 3-month phase-in period, bundle adherence was 83% (39% full adherence; 44% partial adherence). Overall, 101 complex S. aureus SSIs occurred after 28,218 operations during the preintervention period and 29 occurred after 14,316 operations during the intervention period (mean rate per 10,000 operations, 36 for preintervention period vs 21 for intervention period, difference, -15 [95% CI, -35 to -2]; rate ratio [RR], 0.58 [95% CI, 0.37 to 0.92]). The rates of complex S. aureus SSIs decreased for hip or knee arthroplasties (difference per 10,000 operations, -17 [95% CI, -39 to 0]; RR, 0.48 [95% CI, 0.29 to 0.80]) and for cardiac operations (difference per 10,000 operations, -6 [95% CI, -48 to 8]; RR, 0.86 [95% CI, 0.47 to 1.57]). CONCLUSIONS AND RELEVANCE: In this multicenter study, a bundle comprising S. aureus screening, decolonization, and targeted prophylaxis was associated with a modest, statistically significant decrease in complex S. aureus SSIs.

Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases.

Methylation of lysine residues on histone tails is an important epigenetic modification that is dynamically regulated through the combined effects of methyltransferases and demethylases. The Jumonji C domain Fe(II) α-ketoglutarate family of proteins performs the majority of histone demethylation. We demonstrate that nitric oxide ((•)NO) directly inhibits the activity of the demethylase KDM3A by forming a nitrosyliron complex in the catalytic pocket. Exposing cells to either chemical or cellular sources of (•)NO resulted in a significant increase in dimethyl Lys-9 on histone 3 (H3K9me2), the preferred substrate for KDM3A. G9a, the primary methyltransferase acting on H3K9me2, was down-regulated in response to (•)NO, and changes in methylation state could not be accounted for by methylation in general. Furthermore, cellular iron sequestration via dinitrosyliron complex formation correlated with increased methylation. The mRNA of several histone demethylases and methyltransferases was also differentially regulated in response to (•)NO. Taken together, these data reveal three novel and distinct mechanisms whereby (•)NO can affect histone methylation as follows: direct inhibition of Jumonji C demethylase activity, reduction in iron cofactor availability, and regulation of expression of methyl-modifying enzymes. This model of (•)NO as an epigenetic modulator provides a novel explanation for nonclassical gene regulation by (•)NO.

Nitric oxide suppresses tumor cell migration through N-Myc downstream-regulated gene-1 (NDRG1) expression: role of chelatable iron.

N-Myc downstream-regulated gene 1 (NDRG1) is a ubiquitous cellular protein that is up-regulated under a multitude of stress and growth-regulatory conditions. Although the exact cellular functions of this protein have not been elucidated, mutations in this gene or aberrant expression of this protein have been linked to both tumor suppressive and oncogenic phenotypes. Previous reports have demonstrated that NDRG1 is strongly up-regulated by chemical iron chelators and hypoxia, yet its regulation by the free radical nitric oxide ((•)NO) has never been demonstrated. Herein, we examine the chemical biology that confers NDRG1 responsiveness at the mRNA and protein levels to (•)NO. We demonstrate that the interaction of (•)NO with the chelatable iron pool (CIP) and the appearance of dinitrosyliron complexes (DNIC) are key determinants. Using HCC 1806 triple negative breast cancer cells, we find that NDRG1 is up-regulated by physiological (•)NO concentrations in a dose- and time-dependant manner. Tumor cell migration was suppressed by NDRG1 expression and we excluded the involvement of HIF-1α, sGC, N-Myc, and c-Myc as upstream regulatory targets of (•)NO. Augmenting the chelatable iron pool abolished (•)NO-mediated NDRG1 expression and the associated phenotypic effects. These data, in summary, reveal a link between (•)NO, chelatable iron, and regulation of NDRG1 expression and signaling in tumor cells.

Cluster randomized trials in comparative effectiveness research: randomizing hospitals to test methods for prevention of healthcare-associated infections.

BACKGROUND: The need for evidence about the effectiveness of therapeutics and other medical practices has triggered new interest in methods for comparative effectiveness research. OBJECTIVE: Describe an approach to comparative effectiveness research involving cluster randomized trials in networks of hospitals, health plans, or medical practices with centralized administrative and informatics capabilities. RESEARCH DESIGN: We discuss the example of an ongoing cluster randomized trial to prevent methicillin-resistant Staphylococcus aureus (MRSA) infection in intensive care units (ICUs). The trial randomizes 45 hospitals to: (a) screening cultures of ICU admissions, followed by Contact Precautions if MRSA-positive, (b) screening cultures of ICU admissions followed by decolonization if MRSA-positive, or (c) universal decolonization of ICU admissions without screening. SUBJECTS: All admissions to adult ICUs. MEASURES: The primary outcome is MRSA-positive clinical cultures occurring >or=2 days following ICU admission. Secondary outcomes include blood and urine infection caused by MRSA (and, separately, all pathogens), as well as the development of resistance to decolonizing agents. RESULTS: Recruitment of hospitals is complete. Data collection will end in Summer 2011. CONCLUSIONS: This trial takes advantage of existing personnel, procedures, infrastructure, and information systems in a large integrated hospital network to conduct a low-cost evaluation of prevention strategies under usual practice conditions. This approach is applicable to many comparative effectiveness topics in both inpatient and ambulatory settings.

In vivo circadian rhythms in gonadotropin-releasing hormone neurons.

Although it is generally accepted that the circadian clock provides a timing signal for the luteinizing hormone (LH) surge, mechanistic explanations of this phenomenon remain underexplored. It is known, for example, that circadian locomotor output cycles kaput (clock) mutant mice have severely dampened LH surges, but whether this phenotype derives from a loss of circadian rhythmicity in the suprachiasmatic nucleus (SCN) or altered circadian function in gonadotropin-releasing hormone (GnRH) neurons has not been resolved. GnRH neurons can be stimulated to cycle with a circadian period in vitro and disruption of that cycle disturbs secretion of the GnRH decapeptide. We show that both period-2 (PER2) and brain muscle Arnt-like-1 (BMAL1) proteins cycle with a circadian period in the GnRH population in vivo. PER2 and BMAL1 expression both oscillate with a 24-hour period, with PER2 peaking during the night and BMAL1 peaking during the day. The population, however, is not as homogeneous as other oscillatory tissues with only about 50% of the population sharing peak expression levels of BMAL1 at zeitgeber time 4 (ZT4) and PER2 at ZT16. Further, a light pulse that induced a phase delay in the activity rhythm of the GnRH-eGFP mice caused a similar delay in peak expression levels of BMAL1 and PER2. These studies provide direct evidence for a functional circadian clock in native GnRH neurons with a phase that closely follows that of the SCN.