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Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial.
Niederman, Michael S; Alder, Jeff; Bassetti, Matteo; Boateng, Francis; Cao, Bin; Corkery, Kevin; Dhand, Rajiv; Kaye, Keith S; Lawatscheck, Robert; McLeroth, Patrick; Nicolau, David P; Wang, Chen; Wood, G Christopher; Wunderink, Richard G; Chastre, Jean.
Afiliação
  • Niederman MS; Division of Pulmonary and Critical Care Medicine, New York Presbyterian/Weill Cornell Medical Center, New York, NY, USA. Electronic address: msn9004@med.cornell.edu.
  • Alder J; Anti-Infective Consulting, Margaretville, NY, USA.
  • Bassetti M; Infectious Diseases Clinic, Department of Health Sciences, University of Genoa and Policlinico San Martino Hospital, Genoa, Italy; Department of Health Sciences, University of Genoa, Genoa, Italy.
  • Boateng F; Bayer Healthcare Inc, Whippany, NJ, USA.
  • Cao B; Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China.
  • Corkery K; Novartis Pharmaceuticals, San Carlos, CA, USA.
  • Dhand R; Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA.
  • Kaye KS; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Lawatscheck R; Bayer AG, Berlin, Germany.
  • McLeroth P; Covance, Princeton, NJ, USA.
  • Nicolau DP; Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
  • Wang C; Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China.
  • Wood GC; Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center, University of Tennessee, Memphis, TN, USA.
  • Wunderink RG; Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • Chastre J; Intensive Care Unit, Sorbonne University Hospitals, Paris, France.
Lancet Infect Dis ; 20(3): 330-340, 2020 03.
Article em En | MEDLINE | ID: mdl-31866328
BACKGROUND: Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients. METHODS: INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28-32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, numbers NCT01799993 and NCT00805168. FINDINGS: Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28-32 (odds ratio 0·841, 95% CI 0·554-1·277; p=0·43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients). INTERPRETATION: Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia. FUNDING: Bayer AG.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Administração por Inalação / Amicacina / Infecções por Bactérias Gram-Negativas / Pneumonia Associada à Ventilação Mecânica / Antibacterianos Tipo de estudo: Clinical_trials / Guideline / Observational_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Administração por Inalação / Amicacina / Infecções por Bactérias Gram-Negativas / Pneumonia Associada à Ventilação Mecânica / Antibacterianos Tipo de estudo: Clinical_trials / Guideline / Observational_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2020 Tipo de documento: Article