Discussion
The results of this study show that either enteral ciprofloxacin or levofloxacin is effective for treatment of VAT in children, with the majority of infections resolving with the first course of treatment. Fluoroquinolones were well tolerated with no documented QTc prolongation, tendonitis, or tendon rupture. Several patients did require use of seizure rescue mediation; it is challenging, however, to determine if use of these medications was tied to use of enteral fluoroquinolones, as 71% of patients in this study had a neuromuscular comorbidity on admission. Two patients died within 30 days of completion of the course of enteral fluoroquinolones, one of which was unrelated to respiratory infection. The second patient developed septic shock and multiorgan failure as a result of multi-drug resistant pneumonia or tracheitis. This patient was originally treated with enteral fluoroquinolones as initial cultures were susceptible, though later organisms developed resistance.
Nseir and colleagues showed that appropriate antibiotic treatment reduced risk of transition from VAT to VAP (OR 0.12, NNT = 5)7. With only 58% of cultures in this study sensitive to fluoroquinolones, it is challenging to conclude that fluoroquinolones were appropriate in all these patients, though clinically only eight patients were readmitted with a lower respiratory tract infection. However, with 88% of patients receiving appropriate treatment based on patient-specific culture results, it was likely not treatment failure due to inadequate antimicrobial coverage that was responsible for breakthrough infections. The rate of progression from VAT to VAP in this study is also less than that shown in adult ICU patients, in which approximately one-third of patients experienced infection progression14. There is also evidence that other strategies, such as proper isolation techniques and infection control practices, significantly decrease VAT15,16, which was not accounted for in the present study.
Citing a weak recommendation with low quality of evidence, guidelines from the Infectious Diseases Society of America and the American Thoracic Society suggest not providing antibiotic treatment for VAT in adults2. This guideline utilized Nsier et al.’s 2005 criteria for diagnosis17, which were updated in 2015 (18); the guidelines have not yet been updated accordingly. This guideline was developed using one randomized controlled trial that included 58 patients and four observational studies, all conducted in adults. In the included randomized controlled trial, those that received antibiotic therapy had lower ICU mortality, less subsequent VAP, and more mechanical ventilation-free days than those who did not receive antibiotics, with no difference in duration of mechanical ventilation or length of ICU stay. The guidelines state concern regarding multidrug resistant organisms (MDROs) with antimicrobial treatment, since the aforementioned five studies showed that 61% of isolates were MDROs. While this present study did not assess organism resistance to other antibiotics, only 15 (7%) isolates were reported to be resistant to the fluoroquinolone used, with only one known patient proceeding to develop a clinically-relevant fluoroquinolone-resistant infection. The most commonly isolated organism in this study was P. aeruginosa , which is similar to the results of other studies in both pediatric8 and adult critically ill patients7,19,20. S. aureus was also commonly isolated, again corroborated by pediatric and adult evidence7,8,19.
While eight days has been shown be comparable to 15 days of therapy for the treatment of VAP in adults, little is known regarding the appropriate duration of therapy for VAT in either adults or children21. Eight days of therapy was noted to be effective in multiple studies15,22, though this has not been compared to other therapy durations. Patients in this study received treatment for a median of eight days and showed low rates of readmission due to respiratory infection, potentially indicating this duration is adequate in pediatric patients. Of note, Tamma et al. showed that treatment of VAT with antibiotics for at least seven days led to an increase of MDROs8, so weighing the risks of under-treatment and the development of MDROs, a shorter duration may be more appropriate. Tamma et al.’s study, however, was conducted in pediatric ICU patients, whereas only 9% of the patients in this study were treated in the ICU.
There is question about how to distinguish VAT from VAP23 (Keane 2018). A 2014 survey of providers in 16 countries reported diagnosing VAT based on both microbiological and clinical criteria (79.2%), and over half (50.3%) believe antibiotics should be utilized for treatment of VAT24. One of the challenges with treatment of VAT continues to be the variation in criteria for diagnosis, and there is no consensus on reference values or quantitative data that should be used23,25. Depending on the diagnostic criteria utilized1,3,18,20,26, 26% to 74% of patients in this study would have been diagnosed with VAT. This diagnostic challenge continues to complicate the clinical picture of appropriate treatment for these patients, and many times treatment is initiated based on provider judgment due to the lack of robust evidence or consensus on the appropriate diagnostic criteria to use. This study supports the need for clear diagnostic criteria for VAT.
Since this study is retrospective, it is challenging to determine association between fluoroquinolone use and recurrence of respiratory infection, as many factors weigh into infection development. Similarly, it is difficult to parse out if use of fluoroquinolones was responsible for the documented adverse events without a sufficiently matched control group. This study also did not collect outpatient data, including medication adherence, medication administration in relation to other medications and enteral feeds, and follow-up in the outpatient setting. Therefore, it is challenging to determine if patients were adherent with their medication therapy, if it was appropriately administered, or if, once discharged, they received alternate antimicrobial therapy or were treated elsewhere for infection recurrence.
Conclusion
Fluoroquinolones are effective in treating ventilator-associated tracheobronchitis with minimal adverse events in the pediatric population. Further study is necessary to prospectively validate the results of this study and to determine appropriate diagnostic criteria for ventilator-associated tracheobronchitis.