SummaryBackgroundInfluenza causes significant morbidity and mortality despite currently available treatments. Anecdotal reports suggest plasma with high antibody titers towards influenza may be of benefit in the treatment of severe influenza.MethodsWe conducted a randomized, open-label, multicenter phase 2 trial at 29 academic medical centers in the United States to assess the safety and efficacy of anti-influenza plasma with hemagglutination inhibition (HAI) antibody titers of ≥ 1:80 to the infecting strain. Hospitalized children and adults (including pregnant women) with severe influenza A or B (defined as hypoxia or tachypnea) were randomly assigned to receive either 2 units (or pediatric equivalent) of anti-influenza plasma plus standard care (P+S), versus standard care alone (S), and were followed for 28 days. The primary endpoint was time to normalization of patients’ respiratory status (respiratory rate of ≤ 20 for adults or age defined thresholds of 20–38 for children), and a room air saturation of oxygen ≥ 93%. ClinicalTrials.gov Identifier: NCT01052480FindingsBetween January 13, 2011 and March 2, 2015, 113 participants were screened, and 98 were randomized. Of the participants with confirmed influenza, 28 of 42 (67%) of P+S participants normalized their respiratory status by Day 28, as compared to 24 of 45 (53%) of S participants (p=0·069). The estimated hazard ratio comparing P+S to S was 1·71 (95% CI: 0·96 to 3·06). Six participants died, 1 (2%) and 5 (10%) from the P+S and S arms respectively (p=0·093). P+S participants had non-significant reductions in days in hospital (median 6 vs. 11 days, p=0·13) and days on mechanical ventilation (median 0 vs. 3 days, p=0·14), and significantly improved clinical status at Day 7 (p=0·020). Fewer P+S participants experienced SAEs compared to S recipients (20% vs. 38%, p= 0·041), the most frequent of which were acute respiratory distress syndrome (1 [2%] vs 2 [4%]) and stroke (1 [2%] vs 2 [4%]).InterpretationResults from this Phase II randomized trial of immune plasma for the treatment of severe influenza provides support for a possible benefit of immunotherapy across the primary and secondary endpoints. A Phase III randomized trial is now underway to further evaluate this intervention.
Summary Background Influenza continues to have a significant socioeconomic and health impact despite a long established vaccine program and approved antivirals. Preclinical data suggest combination antivirals might be more effective than oseltamivir alone in the treatment of influenza. Methods We conducted a randomized, double-blinded, multicenter phase 2 trial of combination antivirals versus monotherapy for the treatment of influenza. Participants ≥18 years with influenza at increased risk of complications from influenza were randomized by an online computer-generated randomization system to receive either oseltamivir, amantadine, and ribavirin or oseltamivir alone for 5 days, and followed for 28 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at Day 3. Among the secondary outcomes, there were safety and time to alleviation of influenza clinical symptoms. ClinicalTrials.gov Identifier: NCT01227967. Findings Between March 2011 and April 2016 we randomized 633 participants. Seven participants were excluded from analysis: 3 were given treatment without randomization, 3 withdrew before taking any medication, and 1 was lost to follow-up. The primary analysis included 394 participants, excluding 47 in the pilot phase, 172 without confirmed influenza, and 13 without an endpoint sample. 80 of 200 (40.0%) participants in the combination arm had virus detectable at Day 3 compared to 97 of 194 (50.0%) (95%C.I. 0.2–19.8%, p=0.046) in the control arm. There was no benefit, however, in multiple clinical secondary endpoints, such as median duration of symptoms (4.5 days in the combination arm vs 4.0 days in the oseltamivir arm; p = 0.21). Interpretation Although oseltamivir, amantadine, and ribavirin showed a statistically significant decrease in viral shedding at Day 3 relative to oseltamivir, this difference was not associated with improved clinical benefit. More work is needed to understand the lack of clinical benefit when a difference in virologic outcome was identified. Funding National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States.
BackgroundPrevious studies have established a correlation between vancomycin troughs and nephrotoxicity. However, data are currently lacking regarding the effect of guideline-recommended weight-based dosing on nephrotoxicity in methicillin-resistant Staphylococcus aureus bacteremia (MRSAB).MethodsAdults who were at least 18 years of age with methicillin-resistant Staphylococcus aureus bacteremia and received of empiric vancomycin therapy for at least 48 hours (01/07/2002 and 30/06/2008) were included in this multicenter, retrospective cohort study. The association between guideline-recommended, weight-based vancomycin dosing (at least 15 mg/kg/dose) and nephrotoxicity (increase in serum creatinine (SCr) by more than 0.5 mg/dl or at least a 50% increase from baseline on at least two consecutive laboratory tests) was evaluated. Potential independent associations were evaluated using a multivariable general linear mixed-effect model.ResultsOverall, 23% of patients developed nephrotoxicity. Thirty-four percent of the 337 patients who met study criteria received weight-based dosing. The cohort was composed of 69% males with a median age of 55 years. The most common sources of MRSAB included skin/soft tissue (32%), catheter-related bloodstream bacteremia (20%), pulmonary (18%). Eighty-six percent of patients received twice daily dosing. Similar rates of nephrotoxicity were observed regardless of the receipt of guideline-recommended dosing (22% vs. 24%, OR 0.91 [95% CI 0.53-1.56]). This finding was confirmed in the multivariable analysis (OR 1.52 [95% CI 0.75-3.08]). Independent predictors of nephrotoxicity were (OR, 95% CI) vancomycin duration of greater than 15 days (3.36, 1.79-6.34), weight over 100 kg (2.74, 1.27-5.91), Pitt bacteremia score of 4 or greater (2.73, 1.29-5.79), vancomycin trough higher than 20 mcg/ml (2.36, 1.07-5.20), and age over 52 years (2.10, 1.08-4.08).ConclusionsOver one out of five patients in this study developed nephrotoxicity while receiving vancomycin for MRSAB. The receipt of guideline-recommended, weight-based vancomycin was not an independent risk factor for the development of nephrotoxicity.
BackgroundNo studies have evaluated the effect of guideline-recommended weight-based dosing on in-hospital mortality of patients with methicillin-resistant Staphylococcus aureus bacteremia.MethodsThis was a multicenter, retrospective, cohort study of patients with methicillin-resistant Staphylococcus aureus bacteremia receiving at least 48 hours of empiric vancomycin therapy between 01/07/2002 and 30/06/2008. We compared in-hospital mortality for patients treated empirically with weight-based, guideline-recommended vancomycin doses (at least 15 mg/kg/dose) to those treated with less than 15 mg/kg/dose. We used a general linear mixed multivariable model analysis with variables identified a priori through a conceptual framework based on the literature.ResultsA total of 337 patients who were admitted to the three hospitals were included in the cohort. One-third of patients received vancomycin empirically at the guideline-recommended dose. Guideline-recommended dosing was not associated with in-hospital mortality in the univariable (16% vs. 13%, OR 1.26 [95%CI 0.67-2.39]) or multivariable (OR 0.71, 95%CI 0.33-1.55) analysis. Independent predictors of in-hospital mortality were ICU admission, Pitt bacteremia score of 4 or greater, age 53 years or greater, and nephrotoxicity.ConclusionsEmpiric use of weight-based, guideline-recommended empiric vancomycin dosing was not associated with reduced mortality in this multicenter study.
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