The Unfulfilled Promise of Inhaled Therapy in Ventilator-Associated Infections: Where Do We Go from Here?

Abstract

Respiratory infection is common in intubated/tracheotomized patients and systemic antibiotic therapy is often unrewarding. In 1967, the difficulty in treating Gram-negative respiratory infections led to the use of inhaled gentamicin, targeting therapy directly to the lungs. Fifty-three years later, the effects of topical therapy in the intubated patient remain undefined. Clinical failures with intravenous antibiotics persist and instrumented patients are now infected by many more multidrug-resistant Gram-negative species as well as methicillin-resistant Staphylococcus aureus . Multiple systematic reviews and meta-analyses suggest that there may be a role for inhaled delivery but “more research is needed.” Yet there is still no Food and Drug Administration (FDA) approved inhaled antibiotic for the treatment of ventilator-associated infection, the hallmark of which is the foreign body in the upper airway. Current pulmonary and infectious disease guidelines suggest using aerosols only in the setting of Gram-negative infections that are resistant to all systemic antibiotics or not to use them at all. Recently two seemingly well-designed large randomized placebo-controlled Phase 2 and Phase 3 clinical trials of adjunctive inhaled therapy for the treatment of ventilator-associated pneumonia failed to show more rapid resolution of pneumonia symptoms or effect on mortality. Despite evolving technology of delivery devices and more detailed understanding of the factors affecting delivery, treatment effects were no better than placebo. What is wrong with our approach to ventilator- associated infection? Is there a message from the large meta-analyses and these two large recent multisite trials? This review will suggest why current therapies are unpredictable and have not fulfilled the promise of better outcomes. Data suggest that future studies of inhaled therapy, in the milieu of worsening bacterial resistance, require new approaches with completely different indications and endpoints to determine whether inhaled therapy indeed has an important role in the treatment of ventilated patients.

Nosocomial pneumonia

“…Перспективы применения ингаляционных АБ при НП ИВЛ , несмотря на присутствие в ряде рекомендаций, также остаются противоречивыми. Выполненные в последнее время рандомизированные клинические исследования не продемонстрировали позитивного влияния на выживаемость и клинический успех в случае добавления ингаляционных АБ к системной АБТ [76]. Поэтому назначение этой лекарственной формы может обсуждаться только при отсутствии других, более эффективных терапевтических опций.…”

Diagnosis and antibiotic therapy of nosocomial pneumonia in adults: from recommendations to real practice. A review

“…Перспективы применения ингаляционных АБ при НП и НПИВЛ, несмотря на присутствие в ряде рекомендаций, также остаются неясными. Выполненные в последнее время рандомизированные клинические исследования не продемонстрировали позитивного влияния на выживаемость и клинический успех в случае добавления ингаляционных АБ к системной АБТ [35], поэтому их назначение скорее может обсуждаться при отсутствии других, более эффективных терапевтических опций.…”

Efficacy of adjunctive inhaled colistin and tobramycin for ventilator-associated pneumonia: systematic review and meta-analysis

“…However, contrary to more recent studies, these systematic reviews did not find any advantages in utilizing adjunctive inhaled antibiotics, including in terms of clinical cure rates. Furthermore, differing opinions among experts have raised concerns regarding the appropriateness of prescribing inhaled antibiotics for patients with VAP [ 11 ]. This study presents a comprehensive systematic review and meta-analysis, offering updated insights on the effectiveness of adjunctive inhaled colistin and tobramycin.…”