Preventing New Gram-negative Resistance Through Beta-lactam De-escalation in Hospitalized Patients With Sepsis: A Retrospective Cohort Study.

BACKGROUND: Whether antibiotic de-escalation reduces the risk of subsequent antibiotic resistance is uncertain. We sought to determine if beta-lactam (BL) antibiotic de-escalation is associated with decreased incidence of new Gram-negative resistance in hospitalized patients with sepsis. METHODS: In a retrospective cohort study, patients with sepsis who were treated with at least 3 consecutive days of BL antibiotics, the first 2 days of which were with a broad-spectrum BL agent defined as a spectrum score (SS) of ≥7 were enrolled. Patients were grouped into three categories: (1) de-escalation of beta-lactam spectrum score (BLSS), (2) no change in BLSS, or (3) escalation of BLSS. The primary outcome was the isolation of a new drug-resistant Gram-negative bacteria from a clinical culture within 60 days of cohort entry. Fine-Gray proportional hazards regression modeling while accounting for in-hospital death as a competing risk was performed. FINDINGS: Six hundred forty-four patients of 7742 (8.3%) patients developed new gram-negative resistance. The mean time to resistance was 23.7 days yielding an incidence rate of 1.85 (95% confidence interval [CI]: 1.71-2.00) per 1000 patient-days. The lowest incidence rate was observed in the de-escalated group 1.42 (95% CI: 1.16-1.68) per 1000 patient-days. Statistically significant reductions in the development of new gram-negative resistance were associated with BL de-escalation compared to no-change (hazards ratio (HR) 0.59 [95% CI: .48-.73]). CONCLUSIONS: De-escalation was associated with a decreased risk of new resistance development compared to no change. This represents the largest study to date showing the utility of de-escalation in the prevention of antimicrobial resistance.

Impact of Gram-Negative Bacilli Resistance Rates on Risk of Death in Septic Shock and Pneumonia.

Background: Sepsis is a major cause of morbidity and mortality worldwide. When selecting empiric antibiotics for sepsis, clinicians are encouraged to use local resistance rates, but their impact on individual outcomes is unknown. Improved methods to predict outcomes are needed to optimize treatment selection and improve antibiotic stewardship. Methods: We expanded on a previously developed theoretical model to estimate the excess risk of death in gram-negative bacilli (GNB) sepsis due to discordant antibiotics using 3 factors: the prevalence of GNB in sepsis, the rate of antibiotic resistance in GNB, and the mortality difference between discordant and concordant antibiotic treatments. We focused on ceftriaxone, cefepime, and meropenem as the anti-GNB treatment backbone in sepsis, pneumonia, and urinary tract infections. We analyzed both publicly available data and data from a large urban hospital. Results: Publicly available data were weighted toward culture-positive cases. Excess risk of death with discordant antibiotics was highest in septic shock and pneumonia. In septic shock, excess risk of death was 4.53% (95% confidence interval [CI], 4.04%-5.01%), 0.6% (95% CI, .55%-.66%), and 0.19% (95% CI, .16%-.21%) when considering resistance to ceftriaxone, cefepime, and meropenem, respectively. Results were similar in pneumonia. Local data, which included culture-negative cases, showed an excess risk of death in septic shock of 0.75% (95% CI, .57%-.93%) for treatment with discordant antibiotics in ceftriaxone-resistant infections and 0.18% (95% CI, .16%-.21%) for cefepime-resistant infections. Conclusions: Estimating the excess risk of death for specific sepsis phenotypes in the context of local resistance rates, rather than relying on population resistance data, may be more informative in deciding empiric antibiotics in GNB infections.

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.

Pharmacy technicians trained as community health workers: A prospective multicenter cohort study.

BACKGROUND: Community health workers (CHWs) are health professionals who are experts in linking patients to health resources. Although CHWs are employed in a variety of health institutions, access to their services may be challenging for patients in underserved locations. Community pharmacies are uniquely positioned to mitigate this barrier as they provide readily accessible care for patients residing in these areas. OBJECTIVES: To 1) quantify and report the CHW services provided by certified pharmacy technicians (CPhTs) in an underserved population and 2) provide an initial framework for the implementation of CHW services in community pharmacies or similar health care settings. METHODS: This prospective cohort study reports the findings of training CPhTs as CHWs in 3 independent community pharmacies from January 1, 2021 to July 1, 2021. CPhT-CHWs conducted monthly visits by phone, patient home, or pharmacy and documented services using a standardized assessment form. Descriptive statistics were used to summarize the baseline characteristics of the patient population, service codes, types of services and referrals made, and time spent per visit by CPhT-CHWs. RESULTS: A total of 198 patient visits by phone, patient home, or at the pharmacy were completed in a 6-month timespan. During these visits, the CPhT-CHW provided 351 services (203 primary services and 149 secondary services) and completed 51 referrals. The average time spent per visit (standard deviation) was 15.5 (11.5) 68.9 (35.4), and 30.6 (16.8) minutes for phone, home, and pharmacy visits, respectively. Patient home visits resulted in the highest average primary services per visit, longest time spent with the patient, and accounted for a majority of social services. CONCLUSION: CPhT-CHWs were able to use various methods to contact these patients to further develop patient-to-provider and patient-to-pharmacy relationships. Training CPhTs as CHWs can be an effective way to increase patient contact and provide additional health services.

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.

Evaluation of an individual examination remediation policy in a professional pharmacy course.

INTRODUCTION: Maintaining institutional remediation policies is required for pharmacy education accreditation, but specific policies and students' perceptions of remediation are not well described in the literature. The purpose of this research was to determine whether the individual examination remediation policy utilized in a biomedical literature evaluation course was a viable approach to ensuring positive student experiences and success. METHODS: This study utilized a pre-/post-quantitative survey design. An 11-item pre-remediation questionnaire was offered to all students enrolled in the course in 2022. A matched post-survey was administered to students eligible to remediate individual examinations. Survey items were assessed using a five-point Likert rating. Remediation examination grades were analyzed in aggregate. Descriptive statistics were utilized as appropriate. RESULTS: One hundred of the 108 (92.5%) enrolled students completed the pre-remediation survey. Students strongly agreed they would prefer to remediate individual examinations instead of taking one cumulative course remediation examination (median 5) and that remediating would improve their understanding of course material (median 5). Nineteen (44%) of 43 students eligible for individual examination remediation chose to remediate, and 16 (37%) responded to the post-remediation survey. Among those eligible, the most common reason for remediating was desire to receive a better score. Significantly more students improved their examination scores through remediation. CONCLUSIONS: Students in the course preferred to remediate individual examinations, but only 44% of students eligible to remediate chose to do so. Future studies with larger sample sizes and course outcome data are warranted to further explore examination remediation in professional pharmacy courses.

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.

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.

Spectrum scores: Toward a better definition of de-escalation.

Spectrum scores measure antimicrobial utilization while also quantifying the spectrum of activity. Accordingly, changes in spectrum score can be used to identify antimicrobial de-escalation. We show that spectrum-score-based de-escalation has a 95.7% positive percentage agreement and 81.6% negative percentage agreement versus de-escalation defined as stopping either antistaphylococcal or antipseudomonal agents.

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.

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.

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.

ß-Lactam Therapeutic Drug Monitoring in Critically Ill Patients: Weighing the Challenges and Opportunities to Assess Clinical Value.

OBJECTIVE: ß-lactams are the cornerstone of empiric and targeted antibiotic therapy for critically ill patients. Recently, there have been calls to use ß-lactam therapeutic drug monitoring (TDM) within 24-48 hours after the initiation of therapy in critically ill patients. In this article, we review the dynamic physiology of critically ill patients, ß-lactam dose response in critically ill patients, the impact of pathogen minimum inhibitory concentration (MIC) on ß-lactam TDM, and pharmacokinetics in critically ill patients. Additionally, we highlight available clinical data to better inform ß-lactam TDM for critically ill patients. DATA SOURCES: We retrospectively analyzed patients admitted for sepsis or septic shock at a single academic medical center who were treated with ß-lactam antibiotics. STUDY SELECTION: Indexed studies in PubMed in English language were selected for review on topics relative to critical care physiology, ß-lactams, pharmacokinetics/pharmacodynamics, TDM, and antibiotic susceptibility. DATA EXTRACTION: We reviewed potentially related studies on ß-lactams and TDM and summarized their design, patients, and results. This is a synthetic, nonsystematic, review. DATA SYNTHESIS: In the retrospective analysis of patients treated with ß-lactam antibiotics, approximately one-third of patients received less than 48 hours of ß-lactam therapy. Of those who continued beyond 48 hours, only 13.7% had patient-specific factors (augmented renal clearance, fluid overload, morbid obesity, and/or surgical drain), suggesting a potential benefit of ß-lactam TDM. CONCLUSIONS: These data indicate that a strategy of comprehensive ß-lactam TDM for critically ill patients is unwarranted as it has not been shown yet to improve patient-oriented outcomes. This review demonstrates that ß-lactam TDM in the ICU, while laudable, layers ambiguous ß-lactam exposure thresholds upon uncertain/unknown MIC data within a dynamic, unpredictable patient population for whom TDM results will not be available fast enough to significantly affect care. Judicious, targeted TDM for those with risk factors for ß-lactam over- or underexposure is a better approach but requires further study. Clinically, choosing the correct antibiotic and dosing ß-lactams aggressively, which have a wide therapeutic index, to overcome critical illness factors appears to give critically ill patients the best likelihood of survival.

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.

Ceftriaxone resistance and adequacy of initial antibiotic therapy in community onset bacterial pneumonia.

ABSTRACT: Much remains unknown about the impact of initial antibiotic adequacy on mortality in community onset bacterial pneumonia (COBP). Therefore, we performed a study to determine how the adequacy of initial antibiotic therapy affects in-hospital mortality for patients with COBP.We carried out a retrospective cohort study among the 11 BJC Healthcare community and academic hospitals in Missouri and Illinois. The electronic medical records for BJC Healthcare were queried to obtain a set of patient admissions with culture positive (respiratory or blood) COBP admitted from January 1, 2016 through December 31, 2019. Patients with COBP required an International Classification of Diseases (ICD)-10 diagnostic code for pneumonia, admission to the hospital through an emergency department, a chest radiograph with an infiltrate, an abnormal white blood cell count or temperature, an order for 1 or more new antibiotics, and a positive respiratory or blood culture. Antibiotic selection was deemed adequate if the patient had organisms susceptible to at least one of the antibiotics received according to in vitro testing using standard laboratory breakpoints.Among 36,645 screened pneumonia admissions, 1843 met criteria for culture positive COBP. Eight hundred nineteen (44.4%) had ceftriaxone-resistant (CTX-R) organisms and 1024 had ceftriaxone-sensitive (CTX-S) organisms. The most common CTX-R pathogens were methicillin resistant Staphylococcus aureus (46.9%), Pseudomonas species (38.4%), and Escherichia coli (4.5%). On the day of admission 71% of all patients were given adequate antibiotic treatment (62.2% of CTX-R and 77.9% of CTX-S). Unnecessarily broad initial treatment was administered to 57.1% of CTX-S patients. In a logistic regression model accounting for comorbidities and severity of illness, inadequate therapy on the day of admission was associated with higher in-hospital mortality (P = .005). Among CTX-S patients who were adequately treated, initial use of unnecessarily broad antibiotics was associated with increased in-hospital mortality (P = .003).Ceftriaxone resistance was common in this cohort of culture positive COBP patients. Inappropriate coverage on day of admission was associated with greater likelihood of in-hospital mortality.

Machine learning to predict vasopressin responsiveness in patients with septic shock.

STUDY OBJECTIVES: The objective of this study was to develop and externally validate a model to predict adjunctive vasopressin response in patients with septic shock being treated with norepinephrine for bedside use in the intensive care unit. DESIGN: This was a retrospective analysis of two adult tertiary intensive care unit septic shock populations. SETTING: Barnes-Jewish Hospital (BJH) from 2010 to 2017 and Beth Israel Deaconess Medical Center (BIDMC) from 2001 to 2012. PATIENTS: Two septic shock populations (548 BJH patients and 464 BIDMC patients) that received vasopressin as second-line vasopressor. INTERVENTION: Patients who were vasopressin responsive were compared with those who were nonresponsive. Vasopressin response was defined as survival with at least a 20% decrease in maximum daily norepinephrine requirements by one calendar day after vasopressin initiation, without a third-line vasopressor. MEASUREMENTS: Two supervised machine learning models (gradient-boosting machine [XGBoost] and elastic net penalized logistic regression [EN]) were trained in 1000 bootstrap replications of the BJH data and externally validated in the BIDMC data to predict vasopressin responsiveness. MAIN RESULTS: Vasopressin responsiveness was similar among each cohort (BJH 45% and BIDMC 39%). Mortality was lower for vasopressin responders compared with nonresponders in the BJH (51% vs. 73%) and BIDMC (45% vs. 83%) cohorts, respectively. Both models demonstrated modest discrimination in the training (XGBoost area under receiver operator curve [AUROC] 0.61 [95% confidence interval (CI) 0.61-0.61], EN 0.59 [95% CI 0.58-0.59]) and external validation (XGBoost 0.68 [95% CI 0.63-0.73], EN 0.64 [95% CI 0.59-0.69]) datasets. CONCLUSION: Vasopressin nonresponsiveness is common and associated with increased mortality. The models' modest performances highlight the complexity of septic shock and indicate that more research will be required before clinical decision support tools can aid in anticipating patient-specific responsiveness to vasopressin.

Antibiotic Optimization in the Intensive Care Unit.

Effective antimicrobial therapy remains paramount to successful treatment of patients with critical illness, such as pneumonia and sepsis. Unfortunately, critically ill patients often exhibit altered pharmacokinetics and pharmacodynamics (PK/PD) that make this endeavor challenging. Particularly in sepsis, alterations in volume of distribution (Vd) and protein binding lead to unpredictable effects on serum levels of various antimicrobials. Additionally, metabolic pathways and excretion may be significantly impacted due to end-organ failure. These dynamic factors may increase the likelihood of deleterious effects such as treatment failure or toxicity. Meeting these challenging scenarios has led to various strategies meant to improve clinical cure without untoward consequences. Vancomycin and ß-lactam antimicrobials are frequently utilized and have been the focus of dose optimization strategies including extended infusion (EI) or continuous infusion (CI). Available data suggests that administration of vancomycin by CI may reduce the risk of nephrotoxicity without increasing the risk of treatment failure, although retrospective data are largely utilized in supporting this method. Other efforts to optimize vancomycin have focused on transitioning from trough-based therapeutic drug monitoring (TDM) to area-under-the-curve: minimum inhibitory concentration (AUC:MIC) ratios. Despite the creation of more user-friendly methods of calculation and data suggesting reduced rates of nephrotoxicity, widespread implementation is limited, in part due to clinician comfort. Use of ß-lactams in patients with sepsis is similarly problematic due to observational data demonstrating fluctuations in serum levels in the setting of critical illness. Implementing TDM of agents such as piperacillin-tazobactam, cefepime, and meropenem has been suggested as a method of improving time above MIC (T >MIC). This practice is limited by the lack of access to commercial assays and the failure of rigorous studies to demonstrate improved treatment success. Clinicians should be aware of these challenges and should refine their dosing strategies based on individualized patient factors to reduce treatment failure.