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

Chanderraj, Rishi; Baker, Jennifer M.; Kay, Stephen G.; Brown, Christopher; Hinkle, Kevin J.; Fergle, Daniel; McDonald, Roderick A.; Falkowski, Nicole R.; Metcalf, Joseph D.; Kaye, Keith S.; Woods, Robert J.; Prescott, H.C.; Sjoding, Michael W.; Dickson, Robert P.

doi:10.1183/13993003.00910-2022

Cited by 49 publications

(41 citation statements)

References 81 publications

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“…Although rectal swabs were collected within 48 h after hospital admission, different treatment modalities could have contributed to gut microbiota differences between ICU and ward patients. Even short courses of antibiotics may alter the gut microbiota composition, and in particular, anti-anaerobic antibiotics have been shown to increase mortality in ICU patients, possibly due to effect on gut and airway microbiota [ 32 ]. Also dexamethasone could impact the gut microbiota composition and has been reported to interfere with gut permeability [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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Background 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. Methods 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. Results 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). Conclusions 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 registrationNCT04381819. Retrospectively registered May 11, 2020.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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“…Head-to-head comparison has shown SDD to be superior to SOD in reducing VAP incidence and improving clinical outcomes including mortality. Empiric administration of antianaerobic antibiotics in critically ill patients was recently shown to be associated with decreased overall survival, increased risk of VAP, and enrichment by pathogenic Enterobacteriaceae in gut microbial communities and respiratory cultures diagnostic of VAP [23 ▪▪ ]. This randomized and observational evidence defies conventional thinking that VAP mostly develops due to contiguous spread of upper respiratory tract pathogens into the lower respiratory tract and highlights the gut as a probable pool of pathogens for secondary infections in the ICU [21 ▪▪ ].…”

Section: Empirical Evidence Indicative Of Gut–lung Axis In Critical I...mentioning

confidence: 98%

“…A common issue in critical care practice is the extensive use of often empiric, broad-spectrum antibiotics. Recent retrospective research in critically ill patients has shown that use of antianaerobic antibiotics is associated with decreased overall survival and increased risk of VAP, with detectable impact on gut microbial communities and lower respiratory tract microbiology [23 ▪▪ ]. Such research shows that even when governed by principles of targeting and stewardship, clinical choices on antibiotics from different classes are undertaken with limited appreciation of their off-target effects on the gut microbiome.…”

Section: Conclusion – the Road Towards Therapeutic Manipulation Of Th...mentioning

confidence: 99%

Gut–lung crosstalk during critical illness

Nath

Kitsios

Bos

2023

Current Opinion in Critical Care

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Purpose of reviewStudy of organ crosstalk in critical illness has uncovered complex biological communication between different organ systems, but the role of microbiota in organ crosstalk has received limited attention. We highlight the emerging understanding of the gut–lung axis, and how the largest biomass of the human body in the gut may affect lung physiology in critical illness.Recent findingsDisruption of healthy gut microbial communities and replacement by disease-promoting pathogens (pathobiome) generates a maladaptive transmitter of messages from the gut to the lungs, connected via the portal venous and the mesenteric lymphatic systems. Gut barrier impairment allows for microbial translocation (living organisms or cellular fragments) to the lungs. Host-microbiota interactions in the gut mucosa can also impact lung physiology through microbial metabolite secretion or host-derived messengers (hormones, cytokines or immune cells). Clinical examples like the prevention of ventilator-associated pneumonia by selective decontamination of the digestive tract show that the gut–lung axis can be manipulated therapeutically.SummaryA growing body of evidence supports the pathophysiological relevance of the gut–lung axis, yet we are only at the brink of understanding the therapeutic and prognostic relevance of the gut microbiome, metabolites and host-microbe interactions in critical illness.

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“…When administered empirically in clinical practice, both antibiotics are commonly considered to have comparable activity against gram-negative organisms, including Pseudomonas, although cefepime does not cover anaerobic organisms and piperacillin–tazobactam does. Whether coverage of anaerobic organisms in acutely ill patients is associated with higher3 mortality, lower4–7 mortality or no difference in mortality is uncertain.…”

Section: Introductionmentioning

confidence: 99%

Protocol and statistical analysis plan for the Antibiotic Choice On ReNal outcomes (ACORN) randomised clinical trial

et al. 2023

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IntroductionAntibiotics are time-critical in the management of sepsis. When infectious organisms are unknown, patients are treated with empiric antibiotics to include coverage for gram-negative organisms, such as antipseudomonal cephalosporins and penicillins. However, in observational studies, some antipseudomonal cephalosporins (eg, cefepime) are associated with neurologic dysfunction while the most common antipseudomonal penicillin (piperacillin–tazobactam) is associated with acute kidney injury (AKI). No randomised control trials have compared these regimens. This manuscript describes the protocol and analysis plan for a trial designed to compare the effects of antipseudomonal cephalosporins and antipseudomonal penicillins among acutely ill patients receiving empiric antibiotics.Methods and analysisThe Antibiotic Choice On ReNal outcomes trial is a prospective, single-centre, non-blinded randomised trial being conducted at Vanderbilt University Medical Center. The trial will enrol 2500 acutely ill adults receiving gram-negative coverage for treatment of infection. Eligible patients are randomised 1:1 to receive cefepime or piperacillin–tazobactam on first order entry of a broad-spectrum antibiotic covering gram-negative organisms. The primary outcome is the highest stage of AKI and death occurring between enrolment and 14 days after enrolment. This will be compared between patients randomised to cefepime and randomised to piperacillin–tazobactam using an unadjusted proportional odds regression model. The secondary outcomes are major adverse kidney events through day 14 and number of days alive and free of delirium and coma in 14 days after enrolment. Enrolment began on 10 November 2021 and is expected to be completed in December 2022.Ethics and disseminationThe trial was approved by the Vanderbilt University Medical Center institutional review board (IRB#210591) with a waiver of informed consent. Results will be submitted to a peer-reviewed journal and presented at scientific conferences.Trial registration numberNCT05094154.

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

Cited by 49 publications

References 81 publications

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

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

Gut–lung crosstalk during critical illness

Protocol and statistical analysis plan for the Antibiotic Choice On ReNal outcomes (ACORN) randomised clinical trial

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