Quantitative SARS-CoV-2 RT-PCR and Bronchoalveolar Cytokine Concentrations Redefine the COVID-19 Phenotypes in Critically Ill Patients.

RATIONALE: Recent studies suggest that both hypo- and hyperinflammatory acute respiratory distress syndrome (ARDS) phenotypes characterize severe COVID-19-related pneumonia. The role of lung Severe Acute Respiratory Syndrome - Coronavirus 2 (SARS-CoV-2) viral load in contributing to these phenotypes remains unknown. OBJECTIVES: To redefine COVID-19 ARDS phenotypes when considering quantitative SARS-CoV-2 RT-PCR in the bronchoalveolar lavage of intubated patients. To compare the relevance of deep respiratory samples versus plasma in linking the immune response and the quantitative viral loads. METHODS: Eligible subjects were adults diagnosed with COVID-19 ARDS who required mechanical ventilation and underwent bronchoscopy. We recorded the immune response in the bronchoalveolar lavage and plasma and the quantitative SARS-CoV-2 RT-PCR in the bronchoalveolar lavage. Hierarchical clustering on principal components was applied separately on the 2 compartments' datasets. Baseline characteristics were compared between clusters. MEASUREMENTS AND RESULTS: Twenty subjects were enrolled between August 2020 and March 2021. Subjects underwent bronchoscopy on average 3.6 days after intubation. All subjects were treated with dexamethasone prior to bronchoscopy, 11 of 20 (55.6%) received remdesivir and 1 of 20 (5%) received tocilizumab. Adding viral load information to the classic 2-cluster model of ARDS revealed a new cluster characterized by hypoinflammatory responses and high viral load in 23.1% of the cohort. Hyperinflammatory ARDS was noted in 15.4% of subjects. Bronchoalveolar lavage clusters were more stable compared to plasma. CONCLUSIONS: We identified a unique group of critically ill subjects with COVID-19 ARDS who exhibit hypoinflammatory responses but high viral loads in the lower airways. These clusters may warrant different treatment approaches to improve clinical outcomes.

Comparison of Empiric Antibiotic Treatment Regimens for Hospitalized, Non-severe Community-acquired Pneumonia: A Retrospective, Multicenter Cohort Study.

PURPOSE: Consensus guidelines for hospitalized, non-severe community-acquired pneumonia (CAP) recommend empiric macrolide + ß-lactam or respiratory fluoroquinolone monotherapy in patients with no risk factors for resistant organisms. In patients with allergies or contraindications, doxycycline + ß-lactam is a recommended alternative. The purpose of this study was to compare differences in outcomes among guideline-recommended regimens in this population. METHODS: This retrospective, multicenter cohort study included patients ≥18 years of age with CAP who received respiratory fluoroquinolone monotherapy, empiric macrolide + ß-lactam, or doxycycline + ß-lactam. Major exclusion criteria included patients with immunocompromising conditions, requiring vasopressors or invasive mechanical ventilation within 48 hours of admission, and receiving less than 2 days of total antibiotic therapy. The primary outcome was in-hospital mortality. Secondary outcomes included clinical failure, 14- and 30-day hospital readmission, and hospital length of stay. Safety outcomes included incidence of new Clostridioides difficile infection and aortic aneurysm ruptures. FINDINGS: Of 4685 included patients, 1722 patients received empiric respiratory fluoroquinolone monotherapy, 159 received empiric doxycycline + ß-lactam, and 2804 received empiric macrolide + ß-lactam. Incidence of in-hospital mortality was not observed to be significantly different among empiric regimens (doxycycline + ß-lactam group: 1.9% vs macrolide + ß-lactam: 1.9% vs respiratory fluoroquinolone monotherapy: 1.5%, P = 0.588). No secondary outcomes were observed to differ significantly among groups. IMPLICATIONS: We observed no differences in clinical or safety outcomes among three guideline-recommended empiric CAP regimens. Empiric doxycycline + ß-lactam may be a safe empiric regimen for hospitalized CAP patients with non-severe CAP, although additional research is needed to corroborate these observations with larger samples.

Effect of Early Administration of Vasopressin on New-Onset Arrhythmia Development in Patients With Septic Shock: A Retrospective, Observational Cohort Study.

Background: Adjunctive vasopressin use in septic shock reduces catecholamine requirements and is associated with a lower incidence of new-onset arrhythmias (NOAs). The association of vasopressin timing on NOA development is ill-described. Objective: To determine whether early administration of vasopressin was associated with a lower incidence of NOA in septic shock patients. Methods: A retrospective analysis of intensive care unit (ICU) patients at a large, academic medical center. Septic shock patients who required vasopressin and norepinephrine were eligible for inclusion. Patients were excluded for receipt of other vasoactive agents, history of cardiac arrhythmias, or outside hospital admission. Early vasopressin was defined as receipt within 6 hours of septic shock onset. The primary outcome was incidence of NOA. Results: In total, 436 patients, 220 (50.4%) in the early and 216 (49.6%) in the late vasopressin group, were included. Early vasopressin was not associated with a lower incidence of NOA compared with late vasopressin (9% vs 7%, median absolute difference [95% confidence interval, CI]: -2.1 [-7.2, 3.0], P = 0.41). Early vasopressin patients were observed to have shorter shock duration (2 vs 4 days, median absolute difference [95% CI]: 2 [1, 2], P < 0.001), and ICU length of stay (6 vs 7 days, median absolute difference [95% CI]: 1 [0, 2], P = 0.02). Conclusions and Relevance: Early vasopressin use was not associated with a lower incidence of NOA. Additional studies are needed to elucidate the effect of vasopressin timing on NOA and other clinical outcomes.

Is Zero Ventilator-Associated Pneumonia Achievable? Updated Practical Approaches to Ventilator-Associated Pneumonia Prevention.

Ventilator-associated pneumonia (VAP) remains a significant clinical entity with reported incidence rates of 7% to 15%. Given the considerable adverse consequences associated with this infection, VAP prevention became a core measure required in most US hospitals. Many institutions took pride in implementing effective VAP prevention bundles that combined at least head of bed elevation, hand hygiene, chlorhexidine oral care, and subglottic drainage. Spontaneous breathing and awakening trials have also consistently been shown to shorten the duration of mechanical ventilation and secondarily reduce the occurrence of VAP.

Addition of aminoglycosides reduces recurrence of infections with multidrug-resistant Gram-negative bacilli in patients with sepsis and septic shock.

OBJECTIVES: Aminoglycosides and ß-lactams have been recommended for treatment of sepsis/septic shock despite a lack of mortality benefit. Previous studies have examined resistance emergence for the same bacterial isolate using old dosing regimens and during a narrow follow-up window. We hypothesised that combination regimens employing aminoglycosides will decrease the cumulative incidence of infections due to multidrug-resistant (MDR) Gram-negative bacilli (GNB) compared with ß-lactams alone. METHODS: All adult patients admitted to Barnes Jewish Hospital between 2010 and 2017 with a diagnosis of sepsis/septic shock were included in this retrospective cohort study. Patients were divided into two treatment groups, with and without aminoglycosides. Patient demographics, severity of presentation, administered antibiotics, follow-up cultures with susceptibility results for a period of 4-60 days, and mortality were extracted. After propensity score matching, a Fine-Gray subdistribution proportional hazards model summarised the estimated incidence of subsequent infections with MDR-GNB in the presence of all-cause death as a competing risk. RESULTS: A total of 10 212 septic patients were included, with 1996 (19.5%) treated with at least two antimicrobials including one aminoglycoside. After propensity score matching, the cumulative incidence of MDR-GNB infections between 4-60 days was lower in the combination group (incidence at 60 days 0.073, 95% CI 0.062-0.085) versus patients not receiving aminoglycosides (0.116, 95% CI 0.102-0.130). Patients aged ≤65 years and with haematological malignancies had a larger treatment effect in subgroup analyses. CONCLUSION: Addition of aminoglycosides to ß-lactams may protect against subsequent infections due to MDR-GNB in patients with sepsis/septic shock.

Participant- and Disease-Related Factors as Independent Predictors of Treatment Outcomes in the RESTORE-IMI 2 Clinical Trial: A Multivariable Regression Analysis.

Background: In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was noninferior to piperacillin/tazobactam in treating hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. This post hoc analysis was conducted to determine independent predictors of efficacy outcomes in the RESTORE-IMI 2 trial, to assist in treatment decision making. Methods: A stepwise multivariable regression analysis was conducted to identify variables that were independently associated with day 28 all-cause mortality (ACM), favorable clinical response at early follow-up (EFU), and favorable microbiologic response at end of treatment (EOT). The analysis accounted for the number of baseline infecting pathogens and in vitro susceptibility to randomized treatment. Results: Vasopressor use, renal impairment, bacteremia at baseline, and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores ≥15 were associated with a greater risk of day 28 ACM. A favorable clinical response at EFU was associated with normal renal function, an APACHE II score <15, no vasopressor use, and no bacteremia at baseline. At EOT, a favorable microbiologic response was associated with IMI/REL treatment, normal renal function, no vasopressor use, nonventilated pneumonia at baseline, intensive care unit admission at randomization, monomicrobial infections at baseline, and absence of Acinetobacter calcoaceticus-baumannii complex at baseline. These factors remained significant after accounting for polymicrobial infection and in vitro susceptibility to assigned treatment. Conclusions: This analysis, which accounted for baseline pathogen susceptibility, validated well-recognized patient- and disease-related factors as independent predictors of clinical outcomes. These results lend further support to the noninferiority of IMI/REL to piperacillin/tazobactam and suggests that pathogen eradication may be more likely with IMI/REL. Clinical Trials Registration: NCT02493764.

Determinants of Mortality for Ventilated Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia.

Hospital-acquired pneumonia (HAP) is the most common hospital-acquired infection, accounting for 22% of all nosocomial infections. The available studies to date have not attempted to assess whether confounding factors may account for the observed difference in mortality for the two forms of nosocomial pneumonia associated with mechanical ventilation, namely ventilated HAP (vHAP) and ventilator-associated pneumonia (VAP). OBJECTIVES: To determine if vHAP is an independent predictor of mortality among patients with nosocomial pneumonia. DESIGN SETTING AND PARTICIPANTS: Single-center retrospective cohort study conducted at Barnes-Jewish Hospital, St. Louis, MO, between 2016 and 2019. Adult patients with a pneumonia discharge diagnosis were screened and patients diagnosed with vHAP and VAP were included. All patient data was extracted from the electronic health record. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality (ACM). RESULTS: One thousand one-hundred twenty unique patient admissions were included (410 vHAP, 710 VAP). Thirty-day ACM was greater for patients with vHAP compared with VAP (37.1% vs 28.5%; p = 0.003). Logistic regression analysis identified vHAP (adjusted odds ratio [AOR], 1.77; 95% CI, 1.51-2.07), vasopressor use (AOR, 2.34; 95% CI, 1.94-2.82), Charlson Comorbidity Index (1-point increments) (AOR, 1.21; 95% CI, 1.18-1.24), total antibiotic treatment days (1-d increments) (AOR, 1.13; 95% CI, 1.11-1.14), and Acute Physiology and Chronic Health Evaluation II score (1-point increments) (AOR, 1.04; 95% CI, 1.03-1.06) as independent predictors of 30-day ACM. The most common bacterial pathogens identified as causes of vHAP and VAP were Staphylococcus aureus, Enterobacterales species, and Pseudomonas aeruginosa. CONCLUSIONS AND RELEVANCE: In this single-center cohort study with low rates of initial inappropriate antibiotic therapy, vHAP had greater 30-day ACM compared with VAP after adjusting for potential confounding variables including disease severity and comorbidities. This finding suggests that clinical trials enrolling patients with vHAP need to account for this outcome difference in their trial design and data interpretation.

Outcomes in participants with ventilated nosocomial pneumonia and organ failure treated with ceftolozane/tazobactam versus meropenem: a subset analysis of the phase 3, randomized, controlled ASPECT-NP trial.

BACKGROUND: The pivotal ASPECT-NP trial showed ceftolozane/tazobactam was non-inferior to meropenem for the treatment of ventilated hospital-acquired/ventilator-associated bacterial pneumonia (vHABP/VABP). Here, we evaluated treatment outcomes by degree of respiratory or cardiovascular dysfunction. METHODS: This was a subset analysis of data from ASPECT-NP, a randomized, double-blind, non-inferiority trial (ClinicalTrials.gov NCT02070757). Adults with vHABP/VABP were randomized 1:1 to 3 g ceftolozane/tazobactam or 1 g meropenem every 8 h for 8-14 days. Outcomes in participants with a baseline respiratory component of the Sequential Organ Failure Assessment (SOFA) score (R-SOFA) ≥ 2 (indicative of severe respiratory failure), cardiovascular component of the SOFA score (CV-SOFA) ≥ 2 (indicative of shock), or R-SOFA ≥ 2 plus CV-SOFA ≥ 2 were compared by treatment arm. The efficacy endpoint of primary interest was 28-day all-cause mortality. Clinical response, time to death, and microbiologic response were also evaluated. RESULTS: There were 726 participants in the intention-to-treat population; 633 with R-SOFA ≥ 2 (312 ceftolozane/tazobactam, 321 meropenem), 183 with CV-SOFA ≥ 2 (84 ceftolozane/tazobactam, 99 meropenem), and 160 with R-SOFA ≥ 2 plus CV-SOFA ≥ 2 (69 ceftolozane/tazobactam, 91 meropenem). Baseline characteristics, including causative pathogens, were generally similar in participants with R-SOFA ≥ 2 or CV-SOFA ≥ 2 across treatment arms. The 28-day all-cause mortality rate was 23.7% and 24.0% [difference: 0.3%, 95% confidence interval (CI) - 6.4, 6.9] for R-SOFA ≥ 2, 33.3% and 30.3% (difference: - 3.0%, 95% CI - 16.4, 10.3) for CV-SOFA ≥ 2, and 34.8% and 30.8% (difference: - 4.0%, 95% CI - 18.6, 10.3), respectively, for R-SOFA ≥ 2 plus CV-SOFA ≥ 2. Clinical cure rates were as follows: 55.8% and 54.2% (difference: 1.6%, 95% CI - 6.2, 9.3) for R-SOFA ≥ 2, 53.6% and 55.6% (difference: - 2.0%, 95% CI - 16.1, 12.2) for CV-SOFA ≥ 2, and 53.6% and 56.0% (difference: - 2.4%, 95% CI - 17.6, 12.8), respectively, for R-SOFA ≥ 2 plus CV-SOFA ≥ 2. Time to death was comparable in all SOFA groups across both treatment arms. A higher rate of microbiologic eradication/presumed eradication was observed for CV-SOFA ≥ 2 and R-SOFA ≥ 2 plus CV-SOFA ≥ 2 with ceftolozane/tazobactam compared to meropenem. CONCLUSIONS: The presence of severe respiratory failure or shock did not affect the relative efficacy of ceftolozane/tazobactam versus meropenem; either agent may be used to treat critically ill patients with vHABP/VABP. TRIAL REGISTRATION: ClinicalTrials.gov NCT02070757. Registered 25 February 2014, https://clinicaltrials.gov/ct2/show/NCT02070757.

Clinician Perspectives on Barriers and Enablers to Implementing an Inpatient Oncology Early Warning System: A Mixed-Methods Study.

PURPOSE: To elicit end-user and stakeholder perceptions regarding design and implementation of an inpatient clinical deterioration early warning system (EWS) for oncology patients to better fit routine clinical practices and enhance clinical impact. METHODS: In an explanatory-sequential mixed-methods study, we evaluated a stakeholder-informed oncology early warning system (OncEWS) using surveys and semistructured interviews. Stakeholders were physicians, advanced practice providers (APPs), and nurses. For qualitative data, we used grounded theory and thematic content analysis via the constant comparative method to identify determinants of OncEWS implementation. RESULTS: Survey respondents generally agreed that an oncology-focused EWS could add value beyond clinical judgment, with nurses endorsing this notion significantly more strongly than other clinicians (nurse: median 5 on a 6-point scale [6 = strongly agree], interquartile range 4-5; doctors/advanced practice providers: 4 [4-5]; P = .005). However, some respondents would not trust an EWS to identify risk accurately (n = 36 [42%] somewhat or very concerned), while others were concerned that institutional culture would not embrace such an EWS (n = 17 [28%]).Interviews highlighted important aspects of the EWS and the local context that might facilitate implementation, including (1) a model tailored to the subtleties of oncology patients, (2) transparent model information, and (3) nursing-centric workflows. Interviewees raised the importance of sepsis as a common and high-risk deterioration syndrome. CONCLUSION: Stakeholders prioritized maximizing the degree to which the OncEWS is understandable, informative, actionable, and workflow-complementary, and perceived these factors to be key for translation into clinical benefit.

The Practice Change and Clinical Impact of Lung-Protective Ventilation Initiated in the Emergency Department: A Secondary Analysis of Individual Patient-Level Data From Prior Clinical Trials and Cohort Studies.

OBJECTIVES: Mechanically ventilated emergency department (ED) patients experience high morbidity and mortality. In a prior trial at our center, ED-based lung-protective ventilation was associated with improved care delivery and outcomes. Whether this strategy has persisted in the years after the trial remains unclear. The objective was to assess practice change and clinical outcomes associated with ED lung-protective ventilation. DESIGN: Secondary analysis of individual patient-level data from prior clinical trials and cohort studies. SETTING: ED and ICUs of a single academic center. PATIENTS: Mechanically ventilated adults. INTERVENTIONS: A lung-protective ventilator protocol used as the default approach in the ED. MEASUREMENTS AND MAIN RESULTS: The primary ventilator-related outcome was tidal volume, and the primary clinical outcome was hospital mortality. Secondary outcomes included ventilator-, hospital-, and ICU-free days. Multivariable logistic regression, propensity score (PS)-adjustment, and multiple a priori subgroup analyses were used to evaluate outcome as a function of the intervention. A total of 1,796 patients in the preintervention period and 1,403 patients in the intervention period were included. In the intervention period, tidal volume was reduced from 8.2 mL/kg predicted body weight (PBW) (7.3-9.1) to 6.5 mL/kg PBW (6.1-7.1), and low tidal volume ventilation increased from 46.8% to 96.2% ( p < 0.01). The intervention period was associated with lower mortality (35.9% vs 19.1%), remaining significant after multivariable logistic regression analysis (adjusted odds ratio [aOR], 0.43; 95% CI, 0.35-0.53; p < 0.01). Similar results were seen after PS adjustment and in subgroups. The intervention group had more ventilator- (18.8 [10.1] vs 14.1 [11.9]; p < 0.01), hospital- (12.2 [9.6] vs 9.4 [9.5]; p < 0.01), and ICU-free days (16.6 [10.1] vs 13.1 [11.1]; p < 0.01). CONCLUSIONS: ED lung-protective ventilation has persisted in the years since implementation and was associated with improved outcomes. These data suggest the use of ED-based lung-protective ventilation as a means to improve outcome.

The importance of viruses in ventilator-associated pneumonia.

OBJECTIVE: Ventilator-associated pneumonia (VAP) remains a challenge. The importance of viruses in VAP is not established. We sought to determine the prevalence of viruses in VAP and the outcomes of viral VAP. DESIGN: Retrospective study of VAP over 3 years. The frequency of a viral process represented the primary endpoint. Clinical outcomes served as secondary endpoints. We identified variables independently associated with a virus and conducted sensitivity analyses to assess the interaction between type of infection and patient characteristics. SETTING: Tertiary-care referral center. PATIENTS: The final cohort consisted of 710 patients and a virus was isolated in 5.1%. INTERVENTIONS: None. RESULTS: The most common viruses included: rhinovirus, influenza A, and cytomegalovirus. Baseline characteristics were similar between those with and without viral infections. In logistic regression, immunosuppression (adjusted odds ratio [aOR], 2.97; 95% confidence interval [CI], 1.44-6.14) and stem-cell transplantation (SCT, aOR, 3.58; 95% CI, 1.17-10.99) were independently associated with a virus. The presence of either variable performed poorly as a screening test for a virus. In-hospital (22.4% vs 21.6%; P = .869) and 30-day (32.8% vs 27.9%; P = .448) mortality rates were similar between the cohorts, respectively. Sensitivity analyses restricted to patients without a mixed viral and bacterial infection or those who were immunocompetent yielded similar results. CONCLUSION: Although infrequent, a range of viruses may cause VAP. Viruses more often complicate SCT and immunosuppression, but one can isolate viruses in immunocompetent subjects. Viral VAP produces severe infection and results in high mortality rates. Clinical features do not differentiate viral from nonviral VAP.

Use of Inhaled Epoprostenol in Patients With COVID-19 Receiving Humidified, High-Flow Nasal Oxygen Is Associated With Progressive Respiratory Failure.

BACKGROUND: The clinical benefit of using inhaled epoprostenol (iEpo) through a humidified high-flow nasal cannula (HHFNC) remains unknown for patients with COVID-19. RESEARCH QUESTION: Can iEpo prevent respiratory deterioration for patients with positive SARS-CoV-2 findings receiving HHFNC? STUDY DESIGN AND METHODS: This multicenter retrospective cohort analysis included patients aged 18 years or older with COVID-19 pneumonia who required HHFNC treatment. Patients who received iEpo were propensity score matched to patients who did not receive iEpo. The primary outcome was time to mechanical ventilation or death without mechanical ventilation and was assessed using Kaplan-Meier curves and Cox proportional hazard ratios. The effects of residual confounding were assessed using a multilevel analysis, and a secondary analysis adjusted for outcome propensity also was performed in a multivariable model that included the entire (unmatched) patient cohort. RESULTS: Among 954 patients with positive SARS-CoV-2 findings receiving HHFNC therapy, 133 patients (13.9%) received iEpo. After propensity score matching, the median number of days until the composite outcome was similar between treatment groups (iEpo: 5.0 days [interquartile range, 2.0-10.0 days] vs no-iEpo: 6.5 days [interquartile range, 2.0-11.0 days]; P = .26), but patients who received iEpo were more likely to meet the composite outcome in the propensity score-matched, multilevel, and multivariable unmatched analyses (hazard ratio, 2.08 [95% CI, 1.73-2.50]; OR, 4.72 [95% CI, 3.01-7.41]; and OR, 1.35 [95% CI, 1.23-1.49]; respectively). INTERPRETATION: In patients with COVID-19 receiving HHFNC therapy, use of iEpo was associated with the need for invasive mechanical ventilation.

Outcomes in participants with failure of initial antibacterial therapy for hospital-acquired/ventilator-associated bacterial pneumonia prior to enrollment in the randomized, controlled phase 3 ASPECT-NP trial of ceftolozane/tazobactam versus meropenem.

BACKGROUND: Ceftolozane/tazobactam, a combination antibacterial agent comprising an anti-pseudomonal cephalosporin and ß-lactamase inhibitor, is approved for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Participants in the ASPECT-NP trial received ceftolozane/tazobactam (3 g [2 g ceftolozane/1 g tazobactam] every 8 h) or meropenem (1 g every 8 h). Participants failing prior antibacterial therapy for the current HABP/VABP episode at study entry had lower 28-day all-cause mortality (ACM) rates with ceftolozane/tazobactam versus meropenem treatment. Here, we report a post hoc analysis examining this result. METHODS: The phase 3, randomized, controlled, double-blind, multicenter, noninferiority trial compared ceftolozane/tazobactam versus meropenem for treatment of adults with ventilated HABP/VABP; eligibility included those failing prior antibacterial therapy for the current HABP/VABP episode at study entry. The primary and key secondary endpoints were 28-day ACM and clinical response at test of cure (TOC), respectively. Participants who were failing prior therapy were a prospectively defined subgroup; however, subgroup analyses were not designed for noninferiority testing. The 95% CIs for treatment differences were calculated as unstratified Newcombe CIs. Post hoc analyses were performed using multivariable logistic regression analysis to determine the impact of baseline characteristics and treatment on clinical outcomes in the subgroup who were failing prior antibacterial therapy. RESULTS: In the ASPECT-NP trial, 12.8% of participants (93/726; ceftolozane/tazobactam, n = 53; meropenem, n = 40) were failing prior antibacterial therapy at study entry. In this subgroup, 28-day ACM was higher in participants who received meropenem versus ceftolozane/tazobactam (18/40 [45.0%] vs 12/53 [22.6%]; percentage difference [95% CI]: 22.4% [3.1 to 40.1]). Rates of clinical response at TOC were 26/53 [49.1%] for ceftolozane/tazobactam versus 15/40 [37.5%] for meropenem (percentage difference [95% CI]: 11.6% [- 8.6 to 30.2]). Multivariable regression analysis determined concomitant vasopressor use and treatment with meropenem were significant factors associated with risk of 28-day ACM. Adjusting for vasopressor use, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-fourth the risk of dying after treatment with meropenem. CONCLUSIONS: This post hoc analysis further supports the previously demonstrated lower ACM rate for ceftolozane/tazobactam versus meropenem among participants who were failing prior therapy, despite the lack of significant differences in clinical cure rates. CLINICALTRIALS: gov registration NCT02070757 . Registered February 25, 2014, clinicaltrials.gov/ct2/show/NCT02070757 .

How to use new antibiotics in the therapy of serious multidrug resistant Gram-negative infections?

PURPOSE OF REVIEW: Multidrug resistant Gram-negative infections are becoming more common and pose a serious threat to both individual patients and the population as a whole. Treatment of these infections can be difficult and result in significant morbidity and mortality. The purpose of this review is to discuss information and strategies for using new antibiotics to combat these infections. RECENT FINDINGS: Eight new antibiotics represent possible means to treat multidrug resistant Gram-negative infections. Although no new mechanisms of action are present amongst these new antibiotics, novel additions to previously utilized mechanisms have been shown to be viable options for treatment of highly resistant organisms. SUMMARY: The novel antibiotics considered in this review have varying data on their use as empiric treatment of patients at high risk for multidrug resistant organisms and as final therapy for identified multidrug resistant organisms. Cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, and imipenem-relabactam have the best support evidence for use in this patient population.

The threat of multidrug-resistant/extensively drug-resistant Gram-negative respiratory infections: another pandemic.

Antibiotic resistance is recognised as a global threat to human health by national healthcare agencies, governments and medical societies, as well as the World Health Organization. Increasing resistance to available antimicrobial agents is of concern for bacterial, fungal, viral and parasitic pathogens. One of the greatest concerns is the continuing escalation of antimicrobial resistance among Gram-negative bacteria resulting in the endemic presence of multidrug-resistant (MDR) and extremely drug-resistant (XDR) pathogens. This concern is heightened by the identification of such MDR/XDR Gram-negative bacteria in water and food sources, as colonisers of the intestine and other locations in both hospitalised patients and individuals in the community, and as agents of all types of infections. Pneumonia and other types of respiratory infections are among the most common infections caused by MDR/XDR Gram-negative bacteria and are associated with high rates of mortality. Future concerns are already heightened due to emergence of resistance to all existing antimicrobial agents developed in the past decade to treat MDR/XDR Gram-negative bacteria and a scarcity of novel agents in the developmental pipeline. This clinical scenario increases the likelihood of a future pandemic caused by MDR/XDR Gram-negative bacteria.

Antimicrobial stewardship for sepsis in the intensive care unit: Survey of critical care and infectious diseases physicians.

OBJECTIVE: To evaluate the attitudes of infectious diseases (ID) and critical care physicians toward antimicrobial stewardship in the intensive care unit (ICU). DESIGN: Anonymous, cross-sectional, web-based surveys. SETTING: Surveys were completed in March-November 2017, and data were analyzed from December 2017 to December 2019. PARTICIPANTS: ID and critical care fellows and attending physicians. METHODS: We included 10 demographic and 17 newly developed, 5-point, Likert-scaled items measuring attitudes toward ICU antimicrobial stewardship and transdisciplinary collaboration. Exploratory principal components analysis (PCA) was used for data reduction. Multivariable linear regression models explored demographic and attitudinal variables. RESULTS: Of 372 respondents, 315 physicians had complete data (72% attendings, 28% fellows; 63% ID specialists, and 37% critical care specialists). Our PCA yielded a 3-item factor measuring which specialty should assume ICU antimicrobial stewardship (Cronbach standardized α = 0.71; higher scores indicate that ID physicians should be stewards), and a 4-item factor measuring value of ICU transdisciplinary collaborations (α = 0.62; higher scores indicate higher value). In regression models, ID physicians (vs critical care physicians), placed higher value on ICU collaborations and expressed discomfort with uncertain diagnoses. These factors were independently associated with stronger agreement that ID physicians should be ICU antimicrobial stewards. The following factors were independently associated with higher value of transdisciplinary collaboration: female sex, less discomfort with uncertain diagnoses, and stronger agreement with ID physicians as ICU antimicrobial stewards. CONCLUSIONS: ID and critical care physicians endorsed their own group for antimicrobial stewardship, but both groups placed high value on ICU transdisciplinary collaborations. Physicians who were more uncomfortable with uncertain diagnoses reported preference for ID physicians to coordinate ICU antimicrobial stewardship; however, physicians who were less uncomfortable with uncertain diagnoses placed greater value on ICU collaborations.

New antimicrobial treatment options for severe Gram-negative infections.

PURPOSE OF REVIEW: This review will provide rationale for the development of new antibiotics to treat severe or multidrug-resistant (MDR) Gram-negative infections. It will also provide an overview of recently approved and pipeline antibiotics for severe/MDR Gram-negative infections. RECENT FINDINGS: MDR Gram-negative infections are recognized as critical threats by global and national organizations and carry a significant morbidity and mortality risk. Increasing antibiotic resistance amongst Gram-negative bacteria, including carbapenem-resistant Acinetobacter baumannii , extended-spectrum ß-lactamase-producing Enterobacterales, carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa , with difficult-to-treat-resistance has made both empiric and definitive treatment of these infections increasingly problematic. In recent years, several antibiotics have been approved for treatment of MDR Gram-negative infections and ongoing clinical trials are poised to provide additional options to clinicians' armamentarium. These agents include various ß-lactam/ß-lactamase inhibitor combinations, eravacycline, plazomicin and cefiderocol. SUMMARY: Severe/MDR Gram-negative infections continue to be important infections due to their impact on patient outcomes, especially in critically ill and immunocompromised hosts. The availability of new antibiotics offers an opportunity to improve empiric and definitive treatment of these infections.

Impact of Stress Ulcer Prophylaxis Discontinuation Guidance in Mechanically Ventilated, Critically Ill Patients: A Pre-Post Cohort Study.

Purpose: Recent data highlight unclear efficacy and potential negative sequelae of stress ulcer prophylaxis (SUP) in the intensive care unit (ICU). Minimizing SUP exposure has pertinent clinical and other implications. This study assessed medication use and clinical outcomes before and after implementation of a practice guideline promoting early discontinuation of SUP in mechanically ventilated ICU patients. Methods: Retrospective, single-center, pre-post cohort study within a medical ICU at a large, academic medical center. Adult patients requiring mechanical ventilation and receiving SUP via a histamine-2 receptor antagonist (H2RA) or proton pump inhibitor (PPI) were eligible for inclusion. The clinical practice guideline was implemented on January 1, 2020. The impact of implementation was assessed via percent of patient-days with inappropriate SUP. Incidence of clinically important GI bleed was the primary safety outcome. Results: A total of 137 pre-guideline and 112 post-guideline patients were included. Comorbidity burden was similar between groups. A higher prevalence of baseline vasopressor receipt (39% vs 67%, P < .01) and acute kidney injury (56% vs 69%, P = .04) was observed in post-guideline patients. Post-guideline patients experienced a significantly lower percentage of patient-days of inappropriate SUP (25% vs 50%, P < .01) as well as higher rates of SUP discontinuation before extubation (71% vs 12%, P < .01) and during ICU stay (93% vs 50%, P < .01). Post-guideline patients observed a significantly lower incidence of SUP at hospital discharge (4% vs 35%, P < .01). No differences in bleeding outcomes were observed, though post-guideline patients experienced longer durations of mechanical ventilation, ICU stay, and hospital stay. Conclusions: Implementation of an early SUP discontinuation guideline was associated with significant improvements in SUP prescribing practices. Baseline differences between groups likely explain observed differences in clinical outcomes.