Avoid common mistakes on your manuscript.
Dear Editor,
The relatively poor response rates seen with intravenous (IV) antibiotic (AB) therapy and the emergence of multidrug-resistant (MDR) microorganisms requires the development of new treatment strategies for ventilator-associated pneumonia (VAP) [1].
We investigated in a prospective double-blind randomized-controlled trial performed in a single center, whether empiric adjunctive therapy with inhalation tobramycin could ameliorate prognosis in VAP patients (ClinicalTrials.gov Identifier: NCT02440828). Patients with a clinically defined VAP were randomly assigned to a treatment group receiving twice-daily tobramycin inhalation 300 mg and standard IV AB therapy for 8 days or to a control group which received twice-daily placebo inhalation and standard IV AB treatment for 8 days. Inclusion and exclusion criteria are described in the protocol as supplementary file. Primary outcome was treatment failure at day 4, defined as one of the following four criteria present at day 4: (1) no improvement of the PaO2/FiO2 ratio, (2) persistence of fever (≥ 38 °C) or hypothermia (< 35.5 °C) together with purulent respiratory secretions, (3) increase in the pulmonary infiltrates on chest radiograph of ≥ 50%, and (4) occurrence of septic shock or multiple organ dysfunction syndrome, defined as three or more organ system failures not present on day 1. Secondary outcomes were 30-day mortality and number of ventilation free days at day 28. The target sample size would be 84 patients, which provides an 80% power to detect a difference of 32% in cure rate between treatments. The study was approved by independent and local ethics committee (ethical approval number = NL48009.078.14).
The study was terminated prematurely due to insufficient inclusion. Twenty-six patients were included (treatment, n = 13; control, n = 13) (Table 1). Treatment failure was present in four patients (31%) of the treatment group and in eight control patients (62%) (p = 0.24, relative risk = 0.5). There was no difference in 30-day mortality (treatment, n = 4 (31%) vs control, n = 4 (31%). The number of ventilation free days at day 28 was 18 days [0–21] in the treatment group and 17 days [5–22] in the control group.
A meta-analysis conducted by Xu et al. suggests that treatment with aerosolized tobramycin resulted in clinical recovery benefits, but this was mostly based on observational studies [2]. Two recent prospective trials did not show a benefit of inhaled AB therapy as adjunctive treatment for VAP [3, 4]. The findings of our explorative double-blind randomized-controlled trial failed to show a beneficial effect of adjunctive tobramycin inhalation therapy in the treatment of VAP. However, due to the small number of patients, the current study was underpowered. The relative risk for therapy failure at day 4 in the study group compared to the control group is 0.5 (95% CI 0.19–1.3), meaning that therapy failure occurred twice as often in the control group. The next step is to investigate whether inhalation antibiotics could be beneficial in certain subgroups, such as an infection with MDR microorganisms, as has also been recommended in a recent review [5].
We thank D. van Duijn and P. Ormskerk for study assistance and S. Baart for statistical support.
References
Kalil AC, Metersky ML, Klompas M et al (2016) 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 63(5):e61–e111
Xu F, He LL, Che LQ, Li W, Ying SM, Chen ZH, Shen HH (2018) Aerosolized antibiotics for ventilator-associated pneumonia: a pairwise and Bayesian network meta-analysis. Crit Care 22:301
Kollef MH, Ricard JD, Roux D, Francois B, Ischaki E, Rozgonyi Z et al (2016) A randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of Gram-negative ventilator-associated pneumonia: IASIS Trial. Chest 151:1239–1246. https://doi.org/10.1016/j.chest.2016.11.026
Bayer (BAY41-6551). Inhaled Amikacin Solution BAY41-6551 as Adjunctive Therapy in the Treatment of Gram-Negative Pneumonia (INHALE-1). Clinical Trials.gov. NCT01799993 (2018).
Sweeney DA, Kalil AC (2019) Why don't we have more inhaled antibiotics to treat ventilator-associated pneumonia? Clin Microbiol Infect. https://doi.org/10.1016/j.cmi.2019.04.018
Funding
This study was partly funded by Chiesi pharmaceuticals.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare that at the time of the study there were no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Stokker, J., Karami, M., Hoek, R. et al. Effect of adjunctive tobramycin inhalation versus placebo on early clinical response in the treatment of ventilator-associated pneumonia: the VAPORISE randomized-controlled trial. Intensive Care Med 46, 546–548 (2020). https://doi.org/10.1007/s00134-019-05914-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-019-05914-5