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.

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.

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.

Race Does Not Impact Sepsis Outcomes When Considering Socioeconomic Factors in Multilevel Modeling.

OBJECTIVES: To determine whether race is a major determinant of sepsis outcomes when controlling for socioeconomic factors. DESIGN: Retrospective cohort study. SETTING: Barnes-Jewish Hospital a 1,350 bed academic medical center. PATIENTS: Eleven-thousand four-hundred thirty-two patients hospitalized between January 2010 and April 2017 with sepsis and septic shock. INTERVENTIONS: Multilevel random effects modeling was employed whereby patients were nested within ZIP codes. Individual patient characteristics and socioeconomic variables aggregated at the ZIP code level (education, employment status, income, poverty level, access to healthcare) were included in the model. MEASUREMENTS AND MAIN RESULTS: In hospital mortality, length of stay, need for vasopressors, and mechanical ventilation were the main endpoints. Black patients had more comorbidities than White patients except for cirrhosis and malignancy. In unadjusted comparisons, White individuals were more likely to require mechanical ventilation and had higher mortality rates and longer hospital stays for both low- and high-income groups. When nesting within ZIP codes and accounting for socioeconomic variables, race did not have a significant effect on mortality. Non-White races had lower odds ratio for mechanical ventilation. CONCLUSIONS: Our study demonstrates that race is not an independent risk factor for sepsis mortality, as well as sepsis-related length of stay. We should expand our inquiry into determinants of sepsis outcomes by including socioeconomic variables.

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.

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.

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.

Evaluation of Total Body Weight versus Adjusted Body Weight Liposomal Amphotericin B Dosing in Obese Patients.

Liposomal amphotericin B (LAmB) is used for various fungal infections, but it is unclear which dosing weight to use in obese patients. The purpose of this study was to compare clinical outcomes of adjusted body weight (adjBW) versus total body weight (TBW) dosing of LAmB. This single-center, retrospective cohort study included patients who received LAmB for definitive therapy and whose TBW exceeded 120% of their ideal body weight (IBW). Analyses were conducted for 3 mg/kg for adjBW versus TBW and 5 mg/kg for adjBW versus TBW. A total of 238 patients were included. For the 68 patients who received LAmB at 3 mg/kg, there were no differences in safety or efficacy outcomes. For the 170 patients who received LAmB at 5 mg/kg, significantly more patients in the TBW group experienced the primary outcome of nephrotoxicity (57% versus 35% [P value of 0.016]) and had significantly higher rates of early discontinuation of LAmB due to toxicity (33% versus 17% [P = 0.030]). There was a trend toward increased 90-day mortality in the adjBW group (60% versus 45% [P = 0.079]); however, adjBW dosing was not associated with increased mortality in an adjusted model. Given the lower rates of nephrotoxicity but a possible trend toward increased mortality in patients whose TBW exceeds 120% of their IBW, dosing LAmB by adjBW may be reasonable in patients who are not critically ill and who have lower-risk infections. In critically ill patients or those with fungal pathogens or sites of infection associated with higher mortality risk, dosing by TBW can be considered.

New Perspectives on Antimicrobial Agents: Ceftolozane-Tazobactam.

Ceftolozane-tazobactam (C/T) is a new fifth-generation cephalosporin/beta-lactamase inhibitor combination approved by the Food and Drug Administration and the European Medicines Agency for treatment of complicated intraabdominal infections, complicated urinary tract infections, and hospital-acquired pneumonia in adult patients. This review will briefly describe the pharmacology of C/T and focus on the emerging clinical trial and real-world data supporting its current utilization. Additionally, our synthesis of these data over time has set our current usage of C/T at Barnes-Jewish Hospital (BJH). C/T is primarily employed as directed monotherapy at BJH when Pseudomonas aeruginosa isolates are identified with resistance to other beta-lactams. C/T can also be used empirically in specific clinical situations at BJH prior to microbiological detection of an antibiotic-resistant P. aeruginosa isolate. These situations include critically ill patients in the intensive care unit (ICU) setting, where there is a high likelihood of infection with multidrug-resistant (MDR) P. aeruginosa; patients failing therapy with a carbapenem; specific patient populations known to be at high risk for infection with MDR P. aeruginosa (e.g., lung transplant and cystic fibrosis patients); and patients know to have previous infection or colonization with MDR P. aeruginosa.

Nosocomial Infection.

OBJECTIVE: The first 70 years of critical care can be considered a period of "industrial revolution-like" advancement in terms of progressing the understanding and care of critical illness. Unfortunately, like the industrial revolution's impact on the environment, advancing ICU care of increasingly elderly, immunosuppressed, and debilitated individuals has resulted in a greater overall burden and complexity of nosocomial infections within modern ICUs. Given the rapid evolution of nosocomial infections, the authors provide an updated review. DATA SOURCES AND STUDY SELECTION: We searched PubMed and OVID for peer-reviewed literature dealing with nosocomial infections in the critically ill, as well as the websites of government agencies involved with the reporting and prevention of nosocomial infections. Search terms included nosocomial infection, antibiotic resistance, microbiome, antibiotics, and intensive care. DATA EXTRACTION AND DATA SYNTHESIS: Nosocomial infections in the ICU setting are evolving in multiple domains including etiologic pathogens plus novel or emerging pathogens, prevalence, host risk factors, antimicrobial resistance, interactions of the host microbiome with nosocomial infection occurrence, and understanding of pathogenesis and prevention strategies. Increasing virulence and antimicrobial resistance of nosocomial infections mandate increasing efforts toward their prevention. CONCLUSIONS: Nosocomial infections are an important determinant of outcome for patients in the ICU setting. Systematic research aimed at improving the prevention and treatment of nosocomial infections is still needed.

Racial Disparities in Readmissions Following Initial Hospitalization for Sepsis.

OBJECTIVES: To assess whether Black race is associated with a higher rate of all-cause readmission compared with White race following community-onset sepsis. DESIGN: Retrospective cohort study. SETTING: One-thousand three-hundred bed urban academic medical centers. PATIENTS: Three-thousand three-hundred ninety patients hospitalized with community-onset sepsis between January 1, 2010, and December 31, 2017. INTERVENTIONS: Community-onset sepsis was defined as patients admitted through the emergency department with an International Classification of Disease, ninth revision, Clinical Modification code for either severe sepsis (995.92) or septic shock (785.52). Beginning in 2015, we used International Classification of Disease, Tenth Revision, Clinical Modification codes R65.20 (severe sepsis) and R65.21 (septic shock). We excluded those individuals hospitalized at another acute care facility that were transferred to our facility. Race was abstracted electronically, and patients who expired or self-identified as a race other than Black or White race were excluded. Patients who experienced a subsequent hospitalization at our facility were considered to be readmitted. MEASUREMENTS AND MAIN RESULTS: Compared with White race, Black race demonstrated a significantly higher rate of all-cause readmission (60.8% vs 71.1%; p < 0.001), including a higher rate of readmission for sepsis (14.0% vs 19.8%; p < 0.001). Black patients also resided in zip codes with a lower median household income and were more likely to use public insurance compared with White race. Similar rates of comorbid diseases and disease burden were observed between the two groups, but vasopressors were less likely to be administered to Black patients. Multivariable analysis showed that Black race was associated with a 50% increased odds (odds ratio, 1.52, 99% CI, 1.25-1.84) in all-cause readmission risk compared with White race. CONCLUSIONS: Black race was associated with a higher rate of all-cause and sepsis readmission, possibly as a result of unaddressed health disparities, compared with White race. Programs addressing healthcare disparities should use readmission as another marker of equity.

Timing of antibiotic therapy in the ICU.

Severe or life threatening infections are common among patients in the intensive care unit (ICU). Most infections in the ICU are bacterial or fungal in origin and require antimicrobial therapy for clinical resolution. Antibiotics are the cornerstone of therapy for infected critically ill patients. However, antibiotics are often not optimally administered resulting in less favorable patient outcomes including greater mortality. The timing of antibiotics in patients with life threatening infections including sepsis and septic shock is now recognized as one of the most important determinants of survival for this population. Individuals who have a delay in the administration of antibiotic therapy for serious infections can have a doubling or more in their mortality. Additionally, the timing of an appropriate antibiotic regimen, one that is active against the offending pathogens based on in vitro susceptibility, also influences survival. Thus not only is early empiric antibiotic administration important but the selection of those agents is crucial as well. The duration of antibiotic infusions, especially for ß-lactams, can also influence antibiotic efficacy by increasing antimicrobial drug exposure for the offending pathogen. However, due to mounting antibiotic resistance, aggressive antimicrobial de-escalation based on microbiology results is necessary to counterbalance the pressures of early broad-spectrum antibiotic therapy. In this review, we examine time related variables impacting antibiotic optimization as it relates to the treatment of life threatening infections in the ICU. In addition to highlighting the importance of antibiotic timing in the ICU we hope to provide an approach to antimicrobials that also minimizes the unnecessary use of these agents. Such approaches will increasingly be linked to advances in molecular microbiology testing and artificial intelligence/machine learning. Such advances should help identify patients needing empiric antibiotic therapy at an earlier time point as well as the specific antibiotics required in order to avoid unnecessary administration of broad-spectrum antibiotics.

Impact of Baseline Characteristics on Future Episodes of Bloodstream Infections: Multistate Model in Septic Patients With Bloodstream Infections.

BACKGROUND: Looking only at the index infection, studies have described risk factors for infections caused by resistant bacteria. We hypothesized that septic patients with bloodstream infections may transition across states characterized by different microbiology and that their trajectory is not uniform. We also hypothesized that baseline risk factors may influence subsequent blood culture results. METHODS: All adult septic patients with positive blood cultures over a 7-year period were included in the study. Baseline risk factors were recorded. We followed all survivors longitudinally and recorded subsequent blood culture results. We separated states into bacteremia caused by gram-positive cocci, susceptible gram-negative bacilli (sGNB), resistant GNB (rGNB), and Candida spp. Detrimental transitions were considered when transitioning to a culture with a higher mortality risk (rGNB and Candida spp.). A multistate Markov-like model was used to determine risk factors associated with detrimental transitions. RESULTS: A total of 990 patients survived and experienced at least 1 transition, with a total of 4282 transitions. Inappropriate antibiotics, previous antibiotic exposure, and index bloodstream infection caused by either rGNB or Candida spp. were associated with detrimental transitions. Double antibiotic therapy (beta-lactam plus either an aminoglycoside or a fluoroquinolone) protected against detrimental transitions. CONCLUSION: Baseline characteristics that include prescribed antibiotics can identify patients at risk for subsequent bloodstream infections caused by resistant bacteria. By altering the initial treatment, we could potentially influence future bacteremic states.

Risk Factors and Outcomes for Ineffective Empiric Treatment of Sepsis Caused by Gram-Negative Pathogens: Stratification by Onset of Infection.

Sepsis and septic shock remain serious consequences of infections, with reported mortality rates in excess of 40 percent. Timely antibiotic therapy in cases of sepsis and septic shock is recognized as an important determinant of outcome. However, the administration of ineffective empirical treatment (IET) (an initial antibiotic regimen that is not active against the identified pathogen[s] based on in vitro susceptibility testing results) is associated with excess mortality compared to effective empirical treatment (EET). We examined all hospitalized patients at Barnes-Jewish Hospital with a sterile site (blood or pleural, abdominal, cerebrospinal, synovial, and pericardial fluid) culture positive for Gram-negative (GN) bacteria combined with a primary or secondary ICD-9-CM code for severe sepsis (995.92) or septic shock (785.52) between January 2010 and October 2015. Variables significantly associated with early-onset (<48 h of hospitalization) IET of GN sterile site sepsis and septic shock included age, recent hospitalization, and prior intravenous antibiotics. Late-onset IET was associated with increasing numbers of hospitalization days before infection onset and prior intravenous antibiotic administration. For patients with early-onset infection, we found no difference in rates of survival between patients receiving IET and EET. However, patients in the late-onset infection group receiving IET had a statistically lower rate of survival than those receiving EET. These data suggest that risk factors and outcomes for IET can vary based on the time of onset of infection. Our results also highlight the importance of prior intravenous antibiotic exposure as a risk factor for IET in infections by GN bacteria regardless of the time of onset of infection.

Importance of Site of Infection and Antibiotic Selection in the Treatment of Carbapenem-Resistant Pseudomonas aeruginosa Sepsis.

In a retrospective analysis of 215 patients with carbapenem-resistant Pseudomonas aeruginosa sepsis, we observed a significantly higher risk of mortality associated with respiratory tract infection (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.04 to 1.39; P = 0.010) and lower risk with urinary tract infection (RR, 0.80; 95% CI, 0.71 to 0.90; P = 0.004). Aminoglycoside monotherapy was associated with increased mortality, even after adjusting for confounders (adjusted RR, 1.72; 95% CI, 1.03 to 2.85; P = 0.037), consistent across multiple sites of infection.

Sepsis-Associated Coagulopathy Severity Predicts Hospital Mortality.

OBJECTIVES: To assess whether sepsis-associated coagulopathy predicts hospital mortality. DESIGN: Retrospective cohort study. SETTING: One-thousand three-hundred beds urban academic medical center. PATIENTS: Six-thousand one-hundred forty-eight consecutive patients hospitalized between January 1, 2010, and December 31, 2015. INTERVENTIONS: Mild sepsis-associated coagulopathy was defined as an international normalized ratio greater than or equal to 1.2 and less than 1.4 plus platelet count less than or equal to 150,000/µL but greater than 100,000/µL; moderate sepsis-associated coagulopathy was defined with either an international normalized ratio greater than or equal to 1.4 but less than 1.6 or platelets less than or equal to 100,000/µL but greater than 80,000/µL; severe sepsis-associated coagulopathy was defined as an international normalized ratio greater than or equal to 1.6 and platelets less than or equal to 80,000/µL. MEASUREMENTS AND MAIN RESULTS: Hospital mortality increased progressively from 25.4% in patients without sepsis-associated coagulopathy to 56.1% in patients with severe sepsis-associated coagulopathy. Similarly, duration of hospitalization and ICU care increased progressively as sepsis-associated coagulopathy severity increased. Multivariable analyses showed that the presence of sepsis-associated coagulopathy, as well as sepsis-associated coagulopathy severity, was independently associated with hospital mortality regardless of adjustments made for baseline patient characteristics, hospitalization variables, and the sepsis-associated coagulopathy-cancer interaction. Odds ratios ranged from 1.33 to 2.14 for the presence of sepsis-associated coagulopathy and from 1.18 to 1.51 for sepsis-associated coagulopathy severity for predicting hospital mortality (p < 0.001 for all comparisons). CONCLUSIONS: The presence of sepsis-associated coagulopathy identifies a group of patients with sepsis at higher risk for mortality. Furthermore, there is an incremental risk of mortality as the severity of sepsis-associated coagulopathy increases.

Predicting Resistance to Piperacillin-Tazobactam, Cefepime and Meropenem in Septic Patients With Bloodstream Infection Due to Gram-Negative Bacteria.

BACKGROUND: Predicting antimicrobial resistance in gram-negative bacteria (GNB) could balance the need for administering appropriate empiric antibiotics while also minimizing the use of clinically unwarranted broad-spectrum agents. Our objective was to develop a practical prediction rule able to identify patients with GNB infection at low risk for resistance to piperacillin-tazobactam (PT), cefepime (CE), and meropenem (ME). METHODS: The study included adult patients with sepsis or septic shock due to bloodstream infections caused by GNB admitted between 2008 and 2015 from Barnes-Jewish Hospital. We used multivariable logistic regression analyses to describe risk factors associated with resistance to the antibiotics of interest (PT, CE, and ME). Clinical decision trees were developed using the recursive partitioning algorithm CHAID (χ2 Automatic Interaction Detection). RESULTS: The study included 1618 consecutive patients. Prevalence rates for resistance to PT, CE, and ME were 28.6%, 21.8%, and 8.5%, respectively. Prior antibiotic use, nursing home residence, and transfer from an outside hospital were associated with resistance to all 3 antibiotics. Resistance to ME was specifically linked with infection attributed to Pseudomonas or Acinetobacter spp. Discrimination was similar for the multivariable logistic regression and CHAID tree models, with both being better for ME than for PT and CE. Recursive partitioning algorithms separated out 2 clusters with a low probability of ME resistance and 4 with a high probability of PT, CE, and ME resistance. CONCLUSIONS: With simple variables, clinical decision trees can be used to distinguish patients at low, intermediate, or high risk of resistance to PT, CE, and ME.

Enhanced antimicrobial de-escalation for pneumonia in mechanically ventilated patients: a cross-over study.

BACKGROUND: Antibiotics are commonly administered to hospitalized patients with infiltrates for possible bacterial pneumonia, often leading to unnecessary treatment and increasing the risk for resistance emergence. Therefore, we performed a study to determine if an enhanced antibiotic de-escalation practice could improve antibiotic utilization in mechanically ventilated patients with suspected pneumonia cared for in an academic closed intensive care unit (ICU). METHODS: This was a prospective cross-over trial comparing routine antibiotic management (RAM) and enhanced antimicrobial de-escalation (EAD) performed within two medical ICUs (total 34 beds) at Barnes-Jewish Hospital, an academic referral center. Patients in the EAD group had their antibiotic orders and microbiology results reviewed daily by a dedicated team comprised of a second-year critical care fellow, an ICU attending physician and an ICU pharmacist. Antibiotic de-escalation recommendations were made when appropriate based on microbiologic test results and clinical response to therapy. RESULTS: There were 283 patients evaluable, with suspected pneumonia requiring mechanical ventilation: 139 (49.1%) patients in the RAM group and 144 (50.9%) in the EAD group. Early treatment failure based on clinical deterioration occurred in 33 (23.7%) and 40 (27.8%) patients, respectively (P = 0.438). In the remaining patients, antimicrobial de-escalation occurred in 70 (66.0%) and 70 (67.3%), respectively (P = 0.845). There was no difference between groups in total antibiotic days ((median (interquartile range)) 7.0 days (4.0, 9.0) versus 7.0 days (4.0, 8.8) (P = 0.616)); hospital mortality (25.2% versus 35.4% (P = 0.061)); or hospital duration (12.0 days (6.0, 20.0) versus 11.0 days (6.0, 22.0) (P = 0.918). CONCLUSIONS: The addition of an EAD program to a high-intensity daytime staffing model already practicing a high-level of antibiotic stewardship in an academic ICU was not associated with greater antibiotic de-escalation or a reduction in the overall duration of antibiotic therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02685930 . Registered on 26 January 2016.