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The INHALE trial: multiple reasons for a negative result

2020; Elsevier BV; Volume: 20; Issue: 7 Linguagem: Inglês

10.1016/s1473-3099(20)30481-3

1474-4457

Jean‐Jacques Rouby, Antoine Monsel, Stéphan Ehrmann, Adrien Bouglé, Pierre‐François Laterre,

Pneumonia and Respiratory Infections

The INHALE trial, a Bayer-sponsored phase 3 trial in critically ill patients with pneumonia caused by Gram-negative bacteria by Michael Niederman and colleagues,1Niederman MS Alder J Bassetti M et al.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.Lancet Infect Dis. 2020; 20: 330-340Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar did not find aerosolised amikacin as an adjunctive therapy to intravenous antibiotics to be superior to intravenous antibiotics alone. The study design, the doses of amikacin, and the technique of nebulisation are all likely to explain this negative result. The main trial inclusion criterion was pneumonia caused by, or showing two risk factors for, a multidrug-resistant, Gram-negative bacteria. The presence (or the risk) of a multidrug-resistant pathogen infecting the lungs was justification for administering two intravenous antibiotics in both the amikacin treatment group and the placebo group.2Kalil AC Metersky ML Klompas M et al.Executive summary: management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.Clin Infect Dis. 2016; 63: 575-582Crossref PubMed Scopus (180) Google Scholar Antimicrobial bitherapy is not superior to monotherapy in ventilator-associated pneumonia caused by non-resistant, Gram-negative bacteria.3Paul M Lador A Grozinsky-Glasberg S Leibovici L Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis.Cochrane Database Syst Rev. 2014; 1CD003344PubMed Google Scholar In the IHNALE trial,1Niederman MS Alder J Bassetti M et al.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.Lancet Infect Dis. 2020; 20: 330-340Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar 49% of identified pathogens were not multidrug-resistant and a treatment success of 77% in the placebo group reflected the high efficiency of intravenous bitherapy. Therefore, an additional benefit from aerosolised amikacin could not be reasonably expected. The pulmonary drug delivery system used in the INHALE trial increases the respirable mass4Luyt CE Clavel M Guntupalli K et al.Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia.Crit Care. 2009; 13: R200Crossref PubMed Scopus (96) Google Scholar but markedly lengthens the time of nebulisation by restricting aerosol generation to the inspiratory phase (appendix). With the pulmonary drug delivery system, the authors previously reported that nebulisation of amikacin at a dose of about 12 mg/kg per day requires two 60 min nebulisations. With a non-synchronised mesh nebuliser, nebulisation of amikacin at 25 mg/kg per day took only 30–45 min thanks to the bolus effect (video).5Lu Q Yang J Liu Z et al.Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa.Am J Resp Crit Care Med. 2011; 184: 106-115Crossref PubMed Scopus (149) Google Scholar With the pulmonary drug delivery system, nebulisation of amikacin at the high doses recommended to treat multidrug-resistant, ventilator-associated, Gram-negative pneumonia (40 mg/kg/day)6Rouby JJ Sole-Lleonart C Rello J Ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: understanding nebulization of aminoglycosides and colistin.Intensive Care Med. 2020; 46: 766-770Crossref PubMed Scopus (9) Google Scholar would have been unfeasible, requiring two 3·5 h nebulisations per day. Prolonging nebulisation time beyond 60 min should be avoided as heating and humidification of the inspired gas are interrupted during aerosol delivery.7Rello J Rouby JJ Sole-Lleonart C et al.Key considerations on nebulization of antimicrobial agents to mechanically ventilated patients.Clin Microbiol Infect. 2017; 23: 640-646Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar Amikacin is a concentration-dependant antibiotic and the administration of about 6 mg/kg twice daily, as in the INHALE trial, is suboptimal. In 28 patients with ventilator-associated pneumonia treated by nebulised amikacin, amikacin tracheal concentrations were found to be 25 times higher and epithelial lining fluid concentrations were found to be four times higher than the minimum inhibitory concentration of multidrug-resistant, Gram-negative bacteria.4Luyt CE Clavel M Guntupalli K et al.Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia.Crit Care. 2009; 13: R200Crossref PubMed Scopus (96) Google Scholar These concentrations were interpreted as reflecting high amikacin distal lung deposition and justified the administration of 12 mg/kg per day in the INHALE trial. Interestingly, epithelial lining fluid concentrations of tobramycin in ventilated sheep receiving a single nebulisation were 100 times greater than interstitial space fluid concentrations measured by microdialysis.8Dhanani JA Diab S Chaudhary J et al.Lung pharmacokinetics of tobramycin by intravenous and nebulized dosing in a mechanically ventilated healthy ovine model.Anesthesiology. 2019; 131: 344-355Crossref PubMed Scopus (6) Google Scholar These data are highly suggestive of a massive bronchial contamination of the fiberscope and the bronchoalveolar lavage; therefore, elevated epithelial lining fluid concentrations of a nebulised drug can be considered an artefact.9Rouby JJ Monsel A Nebulized antibiotics: epithelial lining fluid concentrations overestimate lung tissue concentrations.Anesthesiology. 2019; 131: 229-232Crossref PubMed Scopus (4) Google Scholar Finally, the insufficient optimisation of ventilator settings during the nebulisation could have further reduced amikacin distal lung deposition by potentiating the impaction of aerosolised particles on bronchial walls. In the INHALE trial, lung tissue amikacin concentrations were likely to be below the minimal inhibitory concentrations of causative pathogens, explaining the trial failure. We suggest that future randomised controlled trials exclusively include patients with ventilator-associated pneumonia caused by documented multidrug-resistant, Gram-negative bacteria; compare intravenous bitherapy with and without a once daily nebulisation of amikacin at 40 mg/kg per day; deliver aerosol using a non-synchronised mesh nebuliser; and optimise ventilator settings during nebulisation. SE declares having received consultancies from Aerogen, La Diffusion Technique Française, and Bayer Healthcare; research support from Aerogen, Fisher and Paykel Healthcare, and Hamilton Medical; and travel reimbursements from Aerogen and Fisher and Paykel. P-FL received an unrestricted grant from Aerogen for a research study. All other authors declare no competing interests. Download .pdf (.34 MB) Help with pdf files Supplementary appendix eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIxZGVjYjI1MzY4NzlmNTlhY2I4YzRjM2Q4MTJmYjIzNiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjMzNjc1Njg0fQ.YmIXKUPfdbZKonlF7NVPbxf58pChWGKnegLDVfzBg3BySjmyhNaJA4pl0qiGjbN18J5qyFZx5Svl2wwJdU_JPeYj7_lzEcPQ7118vo4szmcIBy3H6PS1SeDYD_dtmTNFyy8r6AYkINgPX-wxdtALccQreumorhl2HjcfN127rNk-vIdccpGToJKf1kilFrP6X4qgjDTRZlh01EgvGYeVgcD1MSIx4F51_j07U3wFECEZk7ag-ZJ9CzhTp2s0pMHsyw8iDzCgyuVOBQ8NOgrNJlDBL_AbsNaTo7O2wixgKbe37apQxr7R6XDafpurDRo6xxbilvpcVm9si8hBJ5lYlA Download .mp4 (8.04 MB) Help with .mp4 files Supplementary video The INHALE trial: multiple reasons for a negative result – Authors' replyJean-Jacques Rouby and colleagues have commented on the negative result of our study of inhaled amikacin as adjunctive therapy for mechanically ventilated patients with Gram-negative pneumonia.1 They have concluded that errors in trial design and the specifics of the inhalation device, the pulmonary drug delivery system, account for these findings. The authors suggest that future trials could be positive if they used a different method and followed specific recommendations, most of which are not proven to be superior for drug delivery or practical for trial design. Full-Text PDF