Dataset Information

Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial.

ABSTRACT:

Purpose

We aimed to determine whether interferon gamma-1b prevents hospital-acquired pneumonia in mechanically ventilated patients.

Methods

In a multicenter, placebo-controlled, randomized trial conducted in 11 European hospitals, we randomly assigned critically ill adults, with one or more acute organ failures, under mechanical ventilation to receive interferon gamma-1b (100 µg every 48 h from day 1 to 9) or placebo (following the same regimen). The primary outcome was a composite of hospital-acquired pneumonia or all-cause mortality on day 28. The planned sample size was 200 with interim safety analyses after enrolling 50 and 100 patients.

Results

The study was discontinued after the second safety analysis for potential harm with interferon gamma-1b, and the follow-up was completed in June 2022. Among 109 randomized patients (median age, 57 (41-66) years; 37 (33.9%) women; all included in France), 108 (99%) completed the trial. Twenty-eight days after inclusion, 26 of 55 participants (47.3%) in the interferon-gamma group and 16 of 53 (30.2%) in the placebo group had hospital-acquired pneumonia or died (adjusted hazard ratio (HR) 1.76, 95% confidence interval (CI) 0.94-3.29; P = 0.08). Serious adverse events were reported in 24 of 55 participants (43.6%) in the interferon-gamma group and 17 of 54 (31.5%) in the placebo group (P = 0.19). In an exploratory analysis, we found that hospital-acquired pneumonia developed in a subgroup of patients with decreased CCL17 response to interferon-gamma treatment.

Conclusions

Among mechanically ventilated patients with acute organ failure, treatment with interferon gamma-1b compared with placebo did not significantly reduce the incidence of hospital-acquired pneumonia or death on day 28. Furthermore, the trial was discontinued early due to safety concerns about interferon gamma-1b treatment.

SUBMITTER: Roquilly A

PROVIDER: S-EPMC10112824 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial.

Roquilly Antoine A Francois Bruno B Huet Olivier O Launey Yoann Y Lasocki Sigismond S Weiss Emmanuel E Petrier Melanie M Hourmant Yannick Y Bouras Marwan M Lakhal Karim K Le Bel Cecilia C Flattres Duchaussoy Delphine D Fernández-Barat Laia L Ceccato Adrian A Flet Laurent L Jobert Alexandra A Poschmann Jeremie J Sebille Veronique V Feuillet Fanny F Koulenti Despoina D Torres Antoni A

Intensive care medicine 20230418 5

<h4>Purpose</h4>We aimed to determine whether interferon gamma-1b prevents hospital-acquired pneumonia in mechanically ventilated patients.<h4>Methods</h4>In a multicenter, placebo-controlled, randomized trial conducted in 11 European hospitals, we randomly assigned critically ill adults, with one or more acute organ failures, under mechanical ventilation to receive interferon gamma-1b (100 µg every 48 h from day 1 to 9) or placebo (following the same regimen). The primary outcome was a composit ...[more]

PMID: 37072597

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Project description:BackgroundPneumonia is the most common hospital-acquired infection affecting patients in the intensive care unit (ICU). However, current national guidelines for the treatment of hospital-acquired pneumonia (HAP) are several years old and the diagnosis of pneumonia in mechanically ventilated patients (VAP) has been subject to considerable recent attention. The optimal duration of antibiotic therapy for HAP in the critically ill is uncertain.ObjectivesTo assess the effectiveness of short versus prolonged-course antibiotics for HAP in critically ill adults, including patients with VAP.Search methodsWe searched CENTRAL (2015, Issue 5), MEDLINE (1946 to June 2015), MEDLINE in-process and other non-indexed citations (5 June 2015), EMBASE (2010 to June 2015), LILACS (1982 to June 2015) and Web of Science (1955 to June 2015).Selection criteriaWe considered all randomised controlled trials (RCTs) comparing a fixed 'short' duration of antibiotic therapy with a 'prolonged' course for HAP (including patients with VAP) in critically ill adults.Data collection and analysisTwo review authors conducted data extraction and assessment of risk of bias. We contacted trial authors for additional information.Main resultsWe identified six relevant studies involving 1088 participants. This included two new studies published after the date of our previous review (2011). There was substantial variation in participants, in the diagnostic criteria used to define an episode of pneumonia, in the interventions and in the reported outcomes. We found no evidence relating to patients with a high probability of HAP who were not mechanically ventilated. For patients with VAP, overall a short seven- or eight-day course of antibiotics compared with a prolonged 10- to 15-day course increased 28-day antibiotic-free days (two studies; N = 431; mean difference (MD) 4.02 days; 95% confidence interval (CI) 2.26 to 5.78) and reduced recurrence of VAP due to multi-resistant organisms (one study; N = 110; odds ratio (OR) 0.44; 95% CI 0.21 to 0.95), without adversely affecting mortality and other recurrence outcomes. However, for cases of VAP specifically due to non-fermenting Gram-negative bacilli (NF-GNB), recurrence was greater after short-course therapy (two studies, N = 176; OR 2.18; 95% CI 1.14 to 4.16), though mortality outcomes were not significantly different. One study found that a three-day course of antibiotic therapy for patients with suspected HAP but a low Clinical Pulmonary Infection Score (CPIS) was associated with a significantly lower risk of superinfection or emergence of antimicrobial resistance, compared with standard (prolonged) course therapy.Authors' conclusionsOn the basis of a small number of studies and appreciating the lack of uniform definition of pneumonia, we conclude that for patients with VAP not due to NF-GNB a short, fixed course (seven or eight days) of antibiotic therapy appears not to increase the risk of adverse clinical outcomes, and may reduce the emergence of resistant organisms, compared with a prolonged course (10 to 15 days). However, for patients with VAP due to NF-GNB, there appears to be a higher risk of recurrence following short-course therapy. These findings do not differ from those of our previous review and are broadly consistent with current guidelines. There are few data from RCTs comparing durations of therapy in non-ventilated patients with HAP, but on the basis of a single study, short-course (three-day) therapy for HAP appears not to be associated with worse clinical outcome, and may reduce the risk of subsequent infection or the emergence of resistant organisms when there is low probability of pneumonia according to the CPIS.

Project description:BackgroundFew small studies have described hospital-acquired infections (HAIs) occurring in patients with COVID-19.Research questionWhat characteristics in critically ill patients with COVID-19 are associated with HAIs and how are HAIs associated with outcomes in these patients?Study design and methodsMulticenter retrospective analysis of prospectively collected data including adult patients with severe COVID-19 admitted to eight Italian hub hospitals from February 20, 2020, through May 20, 2020. Descriptive statistics and univariate and multivariate Weibull regression models were used to assess incidence, microbial cause, resistance patterns, risk factors (ie, demographics, comorbidities, exposure to medication), and impact on outcomes (ie, ICU discharge, length of ICU and hospital stays, and duration of mechanical ventilation) of microbiologically confirmed HAIs.ResultsOf the 774 included patients, 359 patients (46%) demonstrated 759 HAIs (44.7 infections/1,000 ICU patient-days; 35% multidrug-resistant [MDR] bacteria). Ventilator-associated pneumonia (VAP; n = 389 [50%]), bloodstream infections (BSIs; n = 183 [34%]), and catheter-related BSIs (n = 74 [10%]) were the most frequent HAIs, with 26.0 (95% CI, 23.6-28.8) VAPs per 1,000 intubation-days, 11.7 (95% CI, 10.1-13.5) BSIs per 1,000 ICU patient-days, and 4.7 (95% CI, 3.8-5.9) catheter-related BSIs per 1,000 ICU patient-days. Gram-negative bacteria (especially Enterobacterales) and Staphylococcus aureus caused 64% and 28% of cases of VAP, respectively. Variables independently associated with infection were age, positive end expiratory pressure, and treatment with broad-spectrum antibiotics at admission. Two hundred thirty-four patients (30%) died in the ICU (15.3 deaths/1,000 ICU patient-days). Patients with HAIs complicated by septic shock showed an almost doubled mortality rate (52% vs 29%), whereas noncomplicated infections did not affect mortality. HAIs prolonged mechanical ventilation (median, 24 days [interquartile range (IQR), 14-39 days] vs 9 days [IQR, 5-13 days]; P < .001), ICU stay (24 days [IQR, 16-41 days] vs 9 days [IQR, 6-14 days]; P = .003), and hospital stay (42 days [IQR, 25-59 days] vs 23 days [IQR, 13-34 days]; P < .001).InterpretationCritically ill patients with COVID-19 are at high risk for HAIs, especially VAPs and BSIs resulting from MDR organisms. HAIs prolong mechanical ventilation and hospitalization, and HAIs complicated by septic shock almost double mortality.Trial registryClinicalTrials.gov; No.: NCT04388670; URL: www.clinicaltrials.gov.

Project description:BackgroundInterferon gamma‑1b has been proposed to treat critical illness-induced immunosuppression. We aimed to determine the effects on 90-day outcomes and the cost-effectiveness of interferon gamma‑1b compared to placebo in mechanically ventilated critically ill patients.MethodsA cost-effectiveness analysis (CEA) was embedded in the "PREV-HAP trial", a multicenter, placebo‑controlled, randomized trial, which randomly assigned critically ill adults under mechanical ventilation to receive interferon gamma or placebo. The CEA compared interferon-gamma with placebo using a collective perspective at a 90-day time horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER) expressed in terms of adjusted cost per adjusted Quality-Adjusted Life-Years (QALYs) gained. QALYs were estimated from the responses of patients and proxy respondents to the health-related quality of life questionnaire EQ-5D-3L.ResultsThe 109 patients in the PREV-HAP trial were included in the CEA. At day 90, all-cause mortality rates were 23.6% in the interferon group and 25% in the placebo group (Odds Ratio (OR) = 0.88 (0.40 -1.93) p = 0.67). The difference in the mean adjusted costs per patient at 90 days was €-1.638 (95%CI €-17.534 to €11.968) in favor of interferon gamma-1b. The mean difference in adjusted QALYs between interferon gamma-1b and the placebo group was + 0.019 (95%CI -0.005 to 0.043). The probability that interferon gamma-1b was cost-effective ranged from 0.60 to 0.71 for a willingness to pay a QALY between €20k and €150k for the base case analysis.ConclusionEarly administration of interferon gamma might be cost-effective in critically ill patients supporting the realization of other studies on this treatment. However, the generalization of the findings should be considered cautiously, given the small sample size due to the premature end of PREV-HAP. Trial registration ClinicalTrials.gov Identifier: NCT04793568, Registration date: 2021-02-24.

Project description:High variability of linezolid blood concentrations with partial subtherapeutic levels was observed in critically ill patients who received a standard intravenous dose of linezolid, contributing to drug resistance and toxicity. Continuous infusions of linezolid have been suggested as an alternative and provide good serum and alveolar levels without fluctuations in trough concentration. This study aimed to assess the effectiveness and safety of continuous linezolid infusion versus the standard regimen in critically ill patients. A prospective randomized controlled study was conducted on 179 patients with nosocomial pneumonia. Patients were randomized into two groups. The first group received IV linezolid 600 mg twice daily, while the second group received 600 mg IV as a loading dose, followed by a continuous infusion of 1200 mg/day (50 mg/h) for at least 8−10 days. The continuous infusion group showed a higher clinical cure rate than the intermittent infusion group (p = 0.046). Furthermore, efficacy was proven by greater improvement of P/F ratio (p = 0.030) on day 7 of treatment, a lower incidence of developing sepsis after beginning treatment (p = 0.009), and a shorter time to reach clinical cure (p < 0.001). Hematological parameters were also assessed during the treatment to evaluate the safety between the two groups. The incidence of thrombocytopenia was significantly lower in the continuous infusion group than in the intermittent infusion group. In addition, a stepwise logistic regression model revealed that the intermittent infusion of linezolid was significantly associated with thrombocytopenia (OR =4.128; 95% CI = 1.681−10.139; p =0.001). The current study is the first to assess the clinical aspects of continuous infusion of linezolid beyond pharmacokinetic studies. Continuous infusion of linezolid outperforms intermittent delivery in safety and improves clinical effectiveness in critically ill patients with Gram-positive nosocomial pneumonia.

Dataset Information

Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial.

Purpose

Methods

Results

Conclusions

Publications

Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial.

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