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.