Severe nosocomial pneumonia – emphasis on nebulized tobramycin

Objective: To estimate the efficacy and safety of nebulized tobramycin (NT) as an adjunct to systemic antibiotics in the treatment of severe nosocomial pneumonia (NP). Methods: 25 mechanically ventilated patients (out of 150 screened) were enrolled in the current observational single-center study. They were randomized to receive either NT (300 mg, BID; group 1, n=15) as an adjunct to systemic antibiotics or for a correction of the regimen of systemic antibiotics (group 2, n=10). The primary outcome measure was resolution of NP and acute respiratory insufficiency. The CPIS, signs of systemic inflammatory response syndrome (SIRS) and oxygenation index were used as objective indicators of the clinical progress. Results: The following signs of NT efficacy were detected in 87% of group 1 patients: a decrease of SIRS and CPIS scores within (2.3±1.2) d of NT therapy (P<0.05); decrease of microbes titer to 103–104 CFU/mL (P<0.05); increase of microbes sensitivity to systemic antibiotics in 40% of patients; positive X-ray dynamics in 60% of patients within (9.0±2.5) d of NT therapy. No serious side effects of NT were observed. Conclusions: Administration of NT as an adjunct to systemic antibiotics is efficient and safe in 87% of patients with severe NP caused by multiresistant gram-negative bacteria

Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): A phase 3, randomised, double-blind, placebo-controlled trial

Background Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection. Methods In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with ClinicalTrials.gov, number NCT01289782. Findings Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1-38·6; p<0·0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration. Interpretation Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin. Funding Janssen Infectious Diseases-Diagnostics. © 2014 Elsevier Ltd