Importance
The effectiveness of selective decontamination of the digestive tract (SDD) in critically ill adults receiving mechanical ventilation is uncertain.


Objective
To determine whether SDD is associated with reduced risk of death in adults receiving mechanical ventilation in intensive care units (ICUs) compared with standard care.


Data Sources
The primary search was conducted using MEDLINE, EMBASE, and CENTRAL databases until September 2022.


Study Selection
Randomized clinical trials including adults receiving mechanical ventilation in the ICU comparing SDD vs standard care or placebo.


Data Extraction and Synthesis
Data extraction and risk of bias assessments were performed in duplicate. The primary analysis was conducted using a bayesian framework.


Main Outcomes and Measures
The primary outcome was hospital mortality. Subgroups included SDD with an intravenous agent compared with SDD without an intravenous agent. There were 8 secondary outcomes including the incidence of ventilator-associated pneumonia, ICU-acquired bacteremia, and the incidence of positive cultures of antimicrobial-resistant organisms.


Results
There were 32 randomized clinical trials including 24 389 participants in the analysis. The median age of participants in the included studies was 54 years (IQR, 44-60), and the median proportion of female trial participants was 33% (IQR, 25%-38%). Data from 30 trials including 24 034 participants contributed to the primary outcome. The pooled estimated risk ratio (RR) for mortality for SDD compared with standard care was 0.91 (95% credible interval [CrI], 0.82-0.99; I2 = 33.9%; moderate certainty) with a 99.3% posterior probability that SDD reduced hospital mortality. The beneficial association of SDD was evident in trials with an intravenous agent (RR, 0.84 [95% CrI, 0.74-0.94]), but not in trials without an intravenous agent (RR, 1.01 [95% CrI, 0.91-1.11]) (P value for the interaction between subgroups = .02). SDD was associated with reduced risk of ventilator-associated pneumonia (RR, 0.44 [95% CrI, 0.36-0.54]) and ICU-acquired bacteremia (RR, 0.68 [95% CrI, 0.57-0.81]). Available data regarding the incidence of positive cultures of antimicrobial-resistant organisms were not amenable to pooling and were of very low certainty.


Conclusions and Relevance
Among adults in the ICU treated with mechanical ventilation, the use of SDD compared with standard care or placebo was associated with lower hospital mortality. Evidence regarding the effect of SDD on antimicrobial resistance was of very low certainty.

Association Between Selective Decontamination of the Digestive Tract and In-Hospital Mortality in Intensive Care Unit Patients Receiving Mechanical Ventilation: A Systematic Review and Meta-analysis.

BACKGROUND
Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear.


METHODS
In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed.


RESULTS
A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (82%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI] 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group.


CONCLUSIONS
Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).

Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.

Abstract Critically ill patients in intensive care units experience profound alterations of their gut microbiota that have been linked to a high risk of hospital-acquired (nosocomial) infections and adverse outcomes through unclear mechanisms. Abundant mouse and limited human data suggest that the gut microbiota can contribute to maintenance of systemic immune homeostasis, and that intestinal dysbiosis may lead to defects in immune defense against infections. Here we use integrated systems-level analyses of fecal microbiota dynamics in rectal swabs and single-cell profiling of systemic immune and inflammatory responses in a prospective longitudinal cohort study of critically ill patients to show that the gut microbiota and systemic immunity function as an integrated metasystem, where intestinal dysbiosis is coupled to impaired host defense and increased frequency of nosocomial infections. Longitudinal microbiota analysis by 16s rRNA gene sequencing of rectal swabs and single-cell profiling of blood using mass cytometry revealed that microbiota and immune dynamics during acute critical illness were highly interconnected and dominated by Enterobacteriaceae enrichment, dysregulated myeloid cell responses and amplified systemic inflammation, with a lesser impact on adaptive mechanisms of host defense. Intestinal Enterobacteriaceae enrichment was coupled with impaired innate antimicrobial effector responses, including hypofunctional and immature neutrophils and was associated with an increased risk of infections by various bacterial and fungal pathogens. Collectively, our findings suggest that dysbiosis of an interconnected metasystem between the gut microbiota and systemic immune response may drive impaired host defense and susceptibility to nosocomial infections in critical illness. 

https://www.nature.com/articles/s41591-023-02243-5.pdf

Dysbiosis of a microbiota–immune metasystem in critical illness is associated with nosocomial infections

Gut microbiota alterations have been reported in hospitalized COVID-19 patients, with reduced alpha diversity and altered microbiota composition related to respiratory failure. However, data regarding gut microbiota and mortality are scarce.Rectal swabs for gut microbiota analyses were collected within 48 h after hospital admission (baseline; n = 123) and three-month post-admission (n = 50) in a subset of patients included in the Norwegian SARS-CoV2 cohort study. Samples were analysed by sequencing the 16S rRNA gene. Gut microbiota diversity and composition at baseline were assessed in relation to need for intensive care unit (ICU) admission during hospitalization. The primary objective was to investigate whether the ICU-related gut microbiota was associated with 60-day mortality.Gut microbiota diversity (Shannon index) at baseline was lower in COVID-19 patients requiring ICU admission during hospitalization than in those managed in general wards. A dysbiosis index representing a balance of enriched and reduced taxa in ICU compared with ward patients, including decreased abundance of butyrate-producing microbes and enrichment of a partly oral bacterial flora, was associated with need of ICU admission independent of antibiotic use, dexamethasone use, chronic pulmonary disease, PO2/FiO2 ratio, C-reactive protein, neutrophil counts or creatinine levels (adjusted p < 0.001). The ICU-related dysbiosis index at baseline correlated with systemic inflammation and was associated with 60-day mortality in univariate analyses (Hazard ratio 3.70 [2.00-8.6], p < 0.001), as well as after separate adjustment for covariates. At the three-month follow-up, the dysbiosis index remained elevated in ICU patients compared with ward patients (adjusted p = 0.007).Although our data should be regarded as exploratory due to low number of clinical end points, they suggest that gut microbiota alterations during hospitalization could be related to poor prognosis after severe COVID-19. Larger studies of gut involvement during COVID-19 in relation to long-term clinical outcome are warranted. Trial registration NCT04381819 . Retrospectively registered May 11, 2020. 

/pdf/gut-microbiota-composition-during-hospitalization-is-3h0zz0jw.pdf

Gut microbiota composition during hospitalization is associated with 60-day mortality after severe COVID-19

ICU-acquired infections in immunocompromised patients.

Importance
Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain.


Objective
To determine whether SDD reduces in-hospital mortality in critically ill adults.


Design, Setting, and Participants
A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021.


Interventions
ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care.


Main Outcomes and Measures
The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs.


Results
Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, -1.7% [95% CI, -4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, -11.0%; 95% CI, -14.7% to -7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, -1.95%; 95% CI, -3.5% to -0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, -0.24%; 95% CI, -0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (-3.3% vs -1.59%; mean difference, -1.71% [1-sided 97.5% CI, -∞ to 4.31%] and 0.88% vs 0.55%; mean difference, -0.32% [1-sided 97.5% CI, -∞ to 5.47%]) in the first and second periods, respectively.


Conclusions and Relevance
Among critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit.


Trial Registration
ClinicalTrials.gov Identifier: NCT02389036.

/pdf/effect-of-selective-decontamination-of-the-digestive-tract-3tct12t5.pdf

Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Due to the rise in antimicrobial resistance (AMR), there has been an increased interest in phage therapy to treat multi-drug resistant infections. In Australia, phage therapy is predominantly used in small clinical studies or for compassionate use, however, despite its potential expansion in modern medicine, the perception of phage therapy among medical professionals remains largely unknown. Therefore, we conducted a national survey of Australian infectious diseases and clinical microbiology advanced trainees and specialists to assess their knowledge, areas of interest, and concerns around the use of phage therapy in clinical practice in Australia. Our survey received 92 responses from infectious diseases and clinical microbiology professionals across all states of Australia. The majority of those surveyed believed that the current national plan for controlling AMR is inadequate and that phage therapy may be an effective solution; with 97% of respondents indicating that they would consider using phage therapy meeting established guidelines for purity and safety (United States Food and Drug Administration and/or European Union guidelines). The respondents indicated a preference for bespoke therapy, with Gram-negative pathogens highlighted as priority targets. Alongside the phage therapy delivery protocols, therapeutic phage monitoring (TPM; like therapeutic drug monitoring (TDM)) was considered important. Cystic Fibrosis, lung-infections, prosthetic device related infections, and infections among patients following transplantation and/or immunosuppression were highly ranked in terms of priorities for clinical syndromes. Accessibility was highlighted as a barrier to phage therapy, specifically timely access (72%) and logistics of phage procurement and administration (70%). Altogether, these results suggest the support of phage therapy among infectious diseases and clinical microbiology advanced trainees and specialists in Australia, and highlights areas of focus and priority in order to advance phage therapy in modern medicine.

/pdf/attitudes-to-phage-therapy-among-australian-infectious-1sbq3bj2.pdf

Attitudes to phage therapy among Australian infectious diseases physicians

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Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Attitudes to phage therapy among Australian infectious diseases physicians