The Gut Microbiome Modulates Body Temperature Both in Sepsis and Health.

Rationale: Among patients with sepsis, variation in temperature trajectories predicts clinical outcomes. In healthy individuals, normal body temperature is variable and has decreased consistently since the 1860s. The biologic underpinnings of this temperature variation in disease and health are unknown. Objectives: To establish and interrogate the role of the gut microbiome in calibrating body temperature. Methods: We performed a series of translational analyses and experiments to determine whether and how variation in gut microbiota explains variation in body temperature in sepsis and in health. We studied patient temperature trajectories using electronic medical record data. We characterized gut microbiota in hospitalized patients using 16S ribosomal RNA gene sequencing. We modeled sepsis using intraperitoneal LPS in mice and modulated the microbiome using antibiotics, germ-free, and gnotobiotic animals. Measurements and Main Results: Consistent with prior work, we identified four temperature trajectories in patients hospitalized with sepsis that predicted clinical outcomes. In a separate cohort of 116 hospitalized patients, we found that the composition of patients' gut microbiota at admission predicted their temperature trajectories. Compared with conventional mice, germ-free mice had reduced temperature loss during experimental sepsis. Among conventional mice, heterogeneity of temperature response in sepsis was strongly explained by variation in gut microbiota. Healthy germ-free and antibiotic-treated mice both had lower basal body temperatures compared with control animals. The Lachnospiraceae family was consistently associated with temperature trajectories in hospitalized patients, experimental sepsis, and antibiotic-treated mice. Conclusions: The gut microbiome is a key modulator of body temperature variation in both health and critical illness and is thus a major, understudied target for modulating physiologic heterogeneity in sepsis.

In critically ill patients, anti-anaerobic antibiotics increase risk of adverse clinical outcomes.

BACKGROUND: Critically ill patients routinely receive antibiotics with activity against anaerobic gut bacteria. However, in other disease states and animal models, gut anaerobes are protective against pneumonia, organ failure and mortality. We therefore designed a translational series of analyses and experiments to determine the effects of anti-anaerobic antibiotics on the risk of adverse clinical outcomes among critically ill patients. METHODS: We conducted a retrospective single-centre cohort study of 3032 critically ill patients, comparing patients who did and did not receive early anti-anaerobic antibiotics. We compared intensive care unit outcomes (ventilator-associated pneumonia (VAP)-free survival, infection-free survival and overall survival) in all patients and changes in gut microbiota in a subcohort of 116 patients. In murine models, we studied the effects of anaerobe depletion in infectious (Klebsiella pneumoniae and Staphylococcus aureus pneumonia) and noninfectious (hyperoxia) injury models. RESULTS: Early administration of anti-anaerobic antibiotics was associated with decreased VAP-free survival (hazard ratio (HR) 1.24, 95% CI 1.06-1.45), infection-free survival (HR 1.22, 95% CI 1.09-1.38) and overall survival (HR 1.14, 95% CI 1.02-1.28). Patients who received anti-anaerobic antibiotics had decreased initial gut bacterial density (p=0.00038), increased microbiome expansion during hospitalisation (p=0.011) and domination by Enterobacteriaceae spp. (p=0.045). Enterobacteriaceae were also enriched among respiratory pathogens in anti-anaerobic-treated patients (p<2.2×10-16). In murine models, treatment with anti-anaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia (p<0.05) and increased the lethality of hyperoxia (p=0.0002). CONCLUSIONS: In critically ill patients, early treatment with anti-anaerobic antibiotics is associated with increased mortality. Mechanisms may include enrichment of the gut with respiratory pathogens, but increased mortality is incompletely explained by infections alone. Given consistent clinical and experimental evidence of harm, the widespread use of anti-anaerobic antibiotics should be reconsidered.

Lung Microbiota Predict Clinical Outcomes in Critically Ill Patients.

Rationale: Recent studies have revealed that, in critically ill patients, lung microbiota are altered and correlate with alveolar inflammation. The clinical significance of altered lung bacteria in critical illness is unknown.Objectives: To determine if clinical outcomes of critically ill patients are predicted by features of the lung microbiome at the time of admission.Methods: We performed a prospective, observational cohort study in an ICU at a university hospital. Lung microbiota were quantified and characterized using droplet digital PCR and bacterial 16S ribosomal RNA gene quantification and sequencing. Primary predictors were the bacterial burden, community diversity, and community composition of lung microbiota. The primary outcome was ventilator-free days, determined at 28 days after admission.Measurements and Main Results: Lungs of 91 critically ill patients were sampled using miniature BAL within 24 hours of ICU admission. Patients with increased lung bacterial burden had fewer ventilator-free days (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88), which remained significant when the analysis was controlled for pneumonia and severity of illness. The community composition of lung bacteria predicted ventilator-free days (P = 0.003), driven by the presence of gut-associated bacteria (e.g., species of the Lachnospiraceae and Enterobacteriaceae families). Detection of gut-associated bacteria was also associated with the presence of acute respiratory distress syndrome.Conclusions: Key features of the lung microbiome (bacterial burden and enrichment with gut-associated bacteria) predict outcomes in critically ill patients. The lung microbiome is an understudied source of clinical variation in critical illness and represents a novel therapeutic target for the prevention and treatment of acute respiratory failure.

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Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime.

Importance: Experimental and observational studies have suggested that empirical treatment for bacterial sepsis with antianaerobic antibiotics (eg, piperacillin-tazobactam) is associated with adverse outcomes compared with anaerobe-sparing antibiotics (eg, cefepime). However, a recent pragmatic clinical trial of piperacillin-tazobactam and cefepime showed no difference in short-term outcomes at 14 days. Further studies are needed to help clarify the empirical use of these agents. Objective: To examine the use of piperacillin-tazobactam compared with cefepime in 90-day mortality in patients treated empirically for sepsis, using instrumental variable analysis of a 15-month piperacillin-tazobactam shortage. Design, Setting, and Participants: In a retrospective cohort study, hospital admissions at the University of Michigan from July 1, 2014, to December 31, 2018, including a piperacillin-tazobactam shortage period from June 12, 2015, to September 18, 2016, were examined. Adult patients with suspected sepsis treated with vancomycin and either piperacillin-tazobactam or cefepime for conditions with presumed equipoise between piperacillin-tazobactam and cefepime were included in the study. Data analysis was conducted from December 17, 2022, to April 11, 2023. Main Outcomes and Measures: The primary outcome was 90-day mortality. Secondary outcomes included organ failure-free, ventilator-free, and vasopressor-free days. The 15-month piperacillin-tazobactam shortage period was used as an instrumental variable for unmeasured confounding in antibiotic selection. Results: Among 7569 patients (4174 men [55%]; median age, 63 [IQR 52-73] years) with sepsis meeting study eligibility, 4523 were treated with vancomycin and piperacillin-tazobactam and 3046 were treated with vancomycin and cefepime. Of patients who received piperacillin-tazobactam, only 152 (3%) received it during the shortage. Treatment groups did not differ significantly in age, Charlson Comorbidity Index score, Sequential Organ Failure Assessment score, or time to antibiotic administration. In an instrumental variable analysis, piperacillin-tazobactam was associated with an absolute mortality increase of 5.0% at 90 days (95% CI, 1.9%-8.1%) and 2.1 (95% CI, 1.4-2.7) fewer organ failure-free days, 1.1 (95% CI, 0.57-1.62) fewer ventilator-free days, and 1.5 (95% CI, 1.01-2.01) fewer vasopressor-free days. Conclusions and Relevance: Among patients with suspected sepsis and no clear indication for antianaerobic coverage, administration of piperacillin-tazobactam was associated with higher mortality and increased duration of organ dysfunction compared with cefepime. These findings suggest that the widespread use of empirical antianaerobic antibiotics in sepsis may be harmful.

Empirical antibiotic therapy for sepsis: save the anaerobic microbiota.

Antibiotics are fundamental in sepsis management; however, the optimal empirical treatment remains debated. Despite anaerobes rarely being the causative pathogen of sepsis, antibiotics targeting them are frequently used, which might lead to unintended consequences. Multiple studies have shown that depletion of commensal anaerobic gut microbes by anti-anaerobic antibiotics influences systemic immunity and is associated with increased mortality in patients with sepsis. However, this knowledge has not yet been translated into clinical practice. When considering empirical coverage of anaerobic pathogens in sepsis, most physicians advocate for a better-safe-than-sorry approach. In this Viewpoint, we argue that anti-anaerobic antibiotics could often result in being sorry rather than safe. We provide an overview of the limited necessity of anaerobic coverage and the potential detrimental effects of anaerobic depletion in sepsis. We aim to raise anaerobic awareness to reduce the unnecessary use of anti-anaerobic antibiotics in empirical sepsis treatment and improve patient outcomes.

INFLAMMATORY RESPONSES TO POLYMICROBIAL INTRA-ABDOMINAL SEPSIS ARE HIGHLY VARIABLE BUT STRONGLY CORRELATED TO ENTEROBACTERIACEAE OUTGROWTH.

ABSTRACT: Sepsis is a common, heterogeneous, and frequently lethal condition of organ dysfunction and immune dysregulation due to infection. The causes of its heterogeneity, including the contribution of the pathogen, remain unknown. Using cecal slurry, a widely used murine model of intraperitoneal polymicrobial sepsis, as well as 16S ribosomal RNA sequencing and measurement of immune markers, we performed a series of translational analyses to determine whether microbial variation in cecal slurry composition (representing intra-abdominal pathogens) mediated variation in septic response. We found wide variation in cecal slurry community composition that changed markedly over the 24-h course of infection. This variation in cecal slurry bacteria led to large variation in physiologic and inflammatory responses. Severity of inflammatory response was positively correlated with intraperitoneal enrichment with Enterobacteriaceae. Likewise, in a human cohort of patients with intra-abdominal abscesses, Enterobacteriaceae was also associated with increased inflammatory markers. Taken together, these data demonstrate that intra-abdominal Enterobacteriaceae drives inflammation in sepsis both in animal models and human subjects. More broadly, our results demonstrate that pathogen identity is a major driver of the host response in polymicrobial sepsis and should not be overlooked as a major source of phenotypic heterogeneity.

Obesity is associated with reduced brain tissue oxygen tension after severe brain injury.

BACKGROUND: Obesity has been associated with compromised tissue oxygenation and reduced organ perfusion. The brain is critically dependent on oxygen delivery, and reduced brain tissue oxygen tension (P(bt)O(2)) may result in poor outcome after brain injury. We tested the hypothesis that obesity is associated with compromised P(bt)O(2) after severe brain injury. METHODS: Patients with severe brain injury (GCS score ≤ 8) who underwent continuous P(bt)O(2) monitoring were retrospectively identified from a prospective single-center database. Patients, were classified by body mass index (BMI = weight (kg)/m(2)) and were included if they were obese (BMI ≥ 30) or non-obese (BMI = < 30). RESULTS: Sixty-nine patients (mean age 46.4 ± 17.0 years) were included. Mean daily P(bt)O(2) was 25.8 (9.6) mmHg for the 28 obese and 31.8 (12.3) mmHg for the 41 non-obese patients (P = 0.03). Initial P(bt)O(2) and mean daily maximum P(bt)O(2) measurements also were significantly lower in obese patients than in non-obese patients. Univariate predictors of compromised P(bt)O(2) (defined as minutes P(bt)O(2) < 20 mmHg) included elevated BMI (P = 0.02), presence of ARDS (P < 0.01), mean PaO(2) (P < 0.01), maximum FiO(2) (P < 0.01), mean PaO(2):FiO(2) (P < 0.01), and mean CVP (P < 0.01). In multivariable analysis, BMI was significantly associated with compromised P(bt)O(2) (P = 0.02). Sex, age, and mean CVP were also identified as significant predictors of compromised P(bt)O(2); ARDS and PF ratio were not. CONCLUSIONS: In patients with severe brain injury, obesity was found to be an independent predictor of compromised P(bt)O(2). This effect may be mediated through obesity-related pulmonary dysfunction and inadequate compensatory mechanisms.

The bacterial density of clinical rectal swabs is highly variable, correlates with sequencing contamination, and predicts patient risk of extraintestinal infection.

BACKGROUND: In ecology, population density is a key feature of community analysis. Yet in studies of the gut microbiome, bacterial density is rarely reported. Studies of hospitalized patients commonly use rectal swabs for microbiome analysis, yet variation in their bacterial density-and the clinical and methodologic significance of this variation-remains undetermined. We used an ultra-sensitive quantification approach-droplet digital PCR (ddPCR)-to quantify bacterial density in rectal swabs from 118 hospitalized patients. We compared bacterial density with bacterial community composition (via 16S rRNA amplicon sequencing) and clinical data to determine if variation in bacterial density has methodological, clinical, and prognostic significance. RESULTS: Bacterial density in rectal swab specimens was highly variable, spanning five orders of magnitude (1.2 × 104-3.2 × 109 16S rRNA gene copies/sample). Low bacterial density was strongly correlated with the detection of sequencing contamination (Spearman ρ = - 0.95, p < 10-16). Low-density rectal swab communities were dominated by peri-rectal skin bacteria and sequencing contaminants (p < 0.01), suggesting that some variation in bacterial density is explained by sampling variation. Yet bacterial density was also associated with important clinical exposures, conditions, and outcomes. Bacterial density was lower among patients who had received piperacillin-tazobactam (p = 0.017) and increased among patients with multiple medical comorbidities (Charlson score, p = 0.0040) and advanced age (p = 0.043). Bacterial density at the time of hospital admission was independently associated with subsequent extraintestinal infection (p = 0.0028), even when controlled for severity of illness and comorbidities. CONCLUSIONS: The bacterial density of rectal swabs is highly variable, and this variability is of methodological, clinical, and prognostic significance. Microbiome studies using rectal swabs are vulnerable to sequencing contamination and should include appropriate negative sequencing controls. Among hospitalized patients, gut bacterial density is associated with clinical exposures (antibiotics, comorbidities) and independently predicts infection risk. Bacterial density is an important and under-studied feature of gut microbiome community analysis. Video abstract.

The Clinical Impact of Implementation of a Multidisciplinary Endocarditis Team.

BACKGROUND: Infectious endocarditis is associated with substantial in-hospital mortality of 15%-20%. Effective management requires coordination between multiple medical and surgical subspecialties, which can often lead to disjointed care. Previous European studies have identified multidisciplinary endocarditis teams as a tool for reducing endocarditis mortality. METHODS: The multidisciplinary endocarditis team was formed in May 2018. The group developed an evidence-based algorithm for management of endocarditis that was used to provide recommendations for hospitalized patients over a 1-year period. Mortality outcomes were then retroactively assessed and compared to a historical control utilizing propensity matching. RESULTS: Between June 2018 and June 2019 the team provided guideline-based recommendations on 56 patients with Duke Criteria-definite endocarditis and at least 1 American Heart Association indication for surgery. The historical control included 68 patients with definite endocarditis and surgical indications admitted between July 1, 2014, and June 30, 2015. In-hospital mortality decreased significantly from 29.4% in 2014-2015 to 7.1% in 2018-2019 (P < .0001). There was a non-significant increase in the rate of surgical intervention after implementation of the team (41.2% vs 55.4%; P = 0.12). Propensity score matching demonstrated similar results. CONCLUSIONS: Implementation of a multidisciplinary endocarditis team was associated with a significant 1-year decrease in all-cause in-hospital mortality for patients with definite endocarditis and surgical indications, in the presence of notable differences between the 2 studied cohorts. In conjunction with previous studies demonstrating their effectiveness, these data support the idea that widespread adoption of endocarditis teams in North America could improve outcomes for this patient population.

Gut Microbiota Predict Enterococcus Expansion but Not Vancomycin-Resistant Enterococcus Acquisition.

Vancomycin-resistant Enterococcus (VRE) is a leading cause of hospital-acquired infections and continues to spread despite widespread implementation of pathogen-targeted control guidelines. Commensal gut microbiota provide colonization resistance to VRE, but the role of gut microbiota in VRE acquisition in at-risk patients is unknown. To address this gap in our understanding, we performed a case-control study of gut microbiota in hospitalized patients who did (cases) and did not (controls) acquire VRE. We matched case subjects to control subjects by known risk factors and "time at risk," defined as the time elapsed between admission until positive VRE screen. We characterized gut bacterial communities using 16S rRNA gene amplicon sequencing of rectal swab specimens. We analyzed 236 samples from 59 matched case-control pairs. At baseline, case and control subjects did not differ in gut microbiota when measured by community diversity (P = 0.33) or composition (P = 0.30). After hospitalization, gut communities of cases and controls differed only in the abundance of the Enterococcus-containing operational taxonomic unit (OTU), with the gut microbiota of case subjects having more of this OTU than time-matched control subjects (P = 0.01). Otherwise, case and control communities after the time at risk did not differ in diversity (P = 0.33) or community structure (P = 0.12). Among patients who became VRE colonized, those having the Blautia-containing OTU on admission had lower Enterococcus relative abundance once colonized (P = 0.004). Our results demonstrate that the 16S profile of the gut microbiome does not predict VRE acquisition in hospitalized patients, likely due to rapid and profound microbiota change. The gut microbiome does not predict VRE acquisition, but it may be associated with Enterococcus expansion, suggesting that these should be considered two distinct processes.IMPORTANCE The Centers for Disease Control and Prevention estimates that VRE causes an estimated 54,000 infections and 539 million dollars in attributable health care costs annually. Despite improvements in hand washing, environmental cleaning, and antibiotic use, VRE is still prevalent in many hospitals. There is a pressing need to better understand the processes by which patients acquire VRE. Multiple lines of evidence suggest that intestinal microbiota may help some patients resist VRE acquisition. In this large case-control study, we compared the 16S profile of intestinal microbiota on admission in patients that did and did not subsequently acquire VRE. The 16S profile did not predict subsequent VRE acquisition, in part due to rapid and dramatic change in the gut microbiome following hospitalization. However, Blautia spp. present on admission predicted decreased Enterococcus abundance after VRE acquisition, and Lactobacillus spp. present on admission predicted Enterococcus dominance after VRE acquisition. Thus, VRE acquisition and domination may be distinct processes.

Anemia and hematoma volume in acute intracerebral hemorrhage.

OBJECTIVE: Anemia increases risk of bleeding complications in the critically ill. In primary intracerebral hemorrhage (ICH), the most fatal type of stroke, outcome is largely dependent on the volume of hemorrhage into the brain. We investigated the relationship between anemia and clinical course of acute ICH. METHODS: Six hundred ninety-four consecutive subjects were identified from an ongoing single-center prospective cohort study of nontraumatic ICH during a 6-year period. Anemia was defined according to World Health Organization criteria. Study end points were ICH volume, as measured on the baseline computed tomography scan, and 30-day mortality. RESULTS: Anemia was present in 177 (25.8%) patients on admission. Patients with anemia were older (p = 0.005) and more likely to have coronary artery disease (p < 0.0001). In multivariable analysis, anemia (p = 0.009), lobar location of ICH (p < 0.001), white blood cell count (p < 0.001), and admission diastolic blood pressure (p < 0.001) were associated with larger ICH volume. Although after accounting for ICH volume, none of these variables was a significant predictor of 30-day mortality in multivariable analysis, the size of the marginal reduction in the odds ratio for anemia suggests that it may have a small effect on mortality through mechanisms in addition to ICH volume. CONCLUSIONS: Anemia is common in acute ICH and its presence at admission is an independent predictor of larger volume of ICH. Given the central role of ICH volume in outcome, clarification of the mechanisms underlying this relationship may offer novel therapeutic targets for reducing ICH morbidity and mortality.

Vancomycin-Resistant Enterococcus Acquisition in a Tertiary Care Hospital: Testing the Roles of Antibiotic Use, Proton Pump Inhibitor Use, and Colonization Pressure.

BACKGROUND: Vancomycin-resistant Enterococcus (VRE) is a leading cause of healthcare-associated infections, and asymptomatic colonization precedes infection. VRE continues to spread despite widespread application of pathogen-specific control guidelines. A better understanding of the risk factors for transmission is needed. METHODS: A retrospective matched case-control study was performed from June 2013 through December 2016 in a single institution. Patients in 6 intensive care units, 1 hematology and oncology unit, and 1 bone marrow transplant unit were screened by means of rectal swab sampling on admission and weekly thereafter. Case patients had a negative swab sample followed by a positive sample >3 days after admission. Controls were closely matched to case patients based on time from admission to the second swab sample, unit in which the second sample was obtained, and date of admission. Comorbidity data, procedures, healthcare settings and exposures, culture data, and duration of antibiotic and proton pump inhibitor (PPI) therapy were abstracted from the electronic medical record. A multivariable risk factor model for conversion was generated using purposeful selection. RESULTS: A total of 551 case patients were matched with controls. The largest modifiable effects on VRE acquisition were ≥1 day of vancomycin therapy (odd ratio, 1.98; P < .001), ≥1 day of aerobic antibiotic therapy (1.90; P < .001), and a dose-dependent effect of PPI therapy (odds ratio per day of therapy, 1.09; P < .001). Colonization pressures from patients identified to be carriers and placed in contact precautions did not confer increased risk. CONCLUSIONS: Decreasing PPI use and preventing the inappropriate initiation of antibiotic therapy are modifiable targets to decrease VRE transmission in the hospital.

Prediction of functional outcome in patients with primary intracerebral hemorrhage: the FUNC score.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is the most fatal and disabling stroke subtype. Widely used tools for prediction of mortality are fundamentally limited in that they do not account for effects of withdrawal of care and are not designed to predict functional recovery. We developed an acute clinical score to predict likelihood of functional independence. METHODS: We prospectively characterized 629 consecutive patients with ICH at hospital presentation. Predictors of functional independence (Glasgow Outcome Score > or = 4) at 90 days were used to develop a logistic regression-based risk stratification scale in a random subset of two thirds and validated in the remaining one third of the cohort. RESULTS: At 90 days, 162 (26%) patients achieved independence. Age, Glasgow Coma Scale, ICH location, volume (all P<0.0001), and pre-ICH cognitive impairment (P=0.005) were independently associated with Glasgow Outcome Score > or = 4. The FUNC score was developed as a sum of individual points (0-11) based on strength of association with outcome. In both the development and validation cohorts, the proportion of patients who achieved Glasgow Outcome Score > or = 4 increased steadily with FUNC score. No patient assigned a FUNC score < or = 4 achieved functional independence, whereas > 80% with a score of 11 did. The predictive accuracy of the FUNC score remained unchanged when restricted to ICH survivors only, consistent with absence of confounding by early withdrawal of care. CONCLUSIONS: FUNC score is a valid clinical assessment tool that identifies patients with ICH who will attain functional independence and thus, can provide guidance in clinical decision-making and patient selection for clinical trials.

Effect of statins on intracerebral hemorrhage outcome and recurrence.

BACKGROUND AND PURPOSE: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved outcome after ischemic stroke and subarachnoid hemorrhage but an increased risk of incident intracerebral hemorrhage (ICH). We investigated (1) whether statin use before ICH was associated with functional independence at 90 days, and (2) whether survivors exposed to statins after ICH had an increased risk of recurrence. METHODS: We analyzed 629 consecutive ICH patients with 90-day outcome data enrolled in a prospective cohort study between 1998 to 2005. Statin use was determined by patient interview at the time of ICH and supplemented by medical record review. Independent status was defined as Glasgow Outcome Scale 4 or 5. ICH survivors were followed by telephone interview every 6 months. RESULTS: Statins were used by 149/629 (24%) before ICH. There was no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%, P=0.84) or mortality (46% versus 45%, P=0.93). Medical comorbidities and warfarin use were more common in statin users. Hematoma volumes were similar (median 28 cm(3) in pre-ICH statin users compared to 22 cm(3) in nonusers, P=0.18). The multivariable-adjusted odds ratio for independent status in pre-ICH statin users was 1.16 (95% CI 0.65 to 2.10, P=0.62). ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34 to 1.99, P=0.66). CONCLUSIONS: Pre-ICH statin use is not associated with improved ICH functional outcome or mortality. Post-ICH statin use is not associated with an increased risk of ICH recurrence.