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.

Tracheostomy for COVID-19 respiratory failure: timing, ventilatory characteristics, and outcomes.

BACKGROUND: Whereas data from the pre-pandemic era have demonstrated that tracheostomy can accelerate liberation from the ventilator, reduce need for sedation, and facilitate rehabilitation, concerns for healthcare worker safety have led to disagreement on tracheostomy placement in COVID-19 patients. Data on COVID-19 patients undergoing tracheostomy may inform best practices. Thus, we report a retrospective institutional cohort experience with tracheostomy in ventilated patients with COVID-19, examining associations between time to tracheostomy and duration of mechanical ventilation in relation to patient characteristics, clinical course, and survival. METHODS: Clinical data were extracted for all COVID-19 tracheostomies performed at a quaternary referral center from April-July 2020. Outcomes studied included mortality, adverse events, duration of mechanical ventilation, and time to decannulation. RESULTS: Among 64 COVID-19 tracheostomies (13% of COVID-19 hospitalizations), patients were 64% male and 42% African American, with a median age of 54 (range, 20-89). Median time to tracheostomy was 22 (range, 7-60) days and median duration of mechanical ventilation was 39.4 (range, 20-113) days. Earlier tracheostomy was associated with shortened mechanical ventilation (R2=0.4, P<0.01). Median decannulation time was 35.3 (range, 7-79) days. There was 19% mortality and adverse events in 45%, mostly from bleeding in therapeutically anticoagulated patients. CONCLUSIONS: Tracheostomy was associated with swifter liberation from the ventilator and acceptable safety for physicians in this series of critically ill COVID-19 patients. Patient mortality was not increased relative to historical data on acute respiratory distress syndrome (ARDS). Future studies are required to establish conclusions of causality regarding tracheostomy timing with mechanical ventilation, complications, or mortality in COVID-19 patients.

Comparing Clinical Features and Outcomes in Mechanically Ventilated Patients with COVID-19 and Acute Respiratory Distress Syndrome.

Rationale: Patients with severe coronavirus disease (COVID-19) meet clinical criteria for the acute respiratory distress syndrome (ARDS), yet early reports suggested they differ physiologically and clinically from patients with non-COVID-19 ARDS, prompting treatment recommendations that deviate from standard evidence-based practices for ARDS. Objectives: To compare respiratory physiology, clinical outcomes, and extrapulmonary clinical features of severe COVID-19 with non-COVID-19 ARDS. Methods: We performed a retrospective cohort study, comparing 130 consecutive mechanically ventilated patients with severe COVID-19 with 382 consecutive mechanically ventilated patients with non-COVID-19 ARDS. Initial respiratory physiology and 28-day outcomes were compared. Extrapulmonary manifestations (inflammation, extrapulmonary organ injury, and coagulation) were compared in an exploratory analysis. Results: Comparison of patients with COVID-19 and non-COVID-19 ARDS suggested small differences in respiratory compliance, ventilatory efficiency, and oxygenation. The 28-day mortality was 30% in patients with COVID-19 and 38% in patients with non-COVID-19 ARDS. In adjusted analysis, point estimates of differences in time to breathing unassisted at 28 days (adjusted subdistributional hazards ratio, 0.98 [95% confidence interval (CI), 0.77-1.26]) and 28-day mortality (risk ratio, 1.01 [95% CI, 0.72-1.42]) were small for COVID-19 versus non-COVID-19 ARDS, although the confidence intervals for these estimates include moderate differences. Patients with COVID-19 had lower neutrophil counts but did not differ in lymphocyte count or other measures of systemic inflammation. Conclusions: In this single-center cohort, we found no evidence for large differences between COVID-19 and non-COVID-19 ARDS. Many key clinical features of severe COVID-19 were similar to those of non-COVID-19 ARDS, including respiratory physiology and clinical outcomes, although our sample size precludes definitive conclusions. Further studies are needed to define COVID-19-specific pathophysiology before a deviation from evidence-based treatment practices can be recommended.