In mechanically ventilated children, respiratory tract infections including ventilator-associated pneumonia (VAP) and ventilator-associated tracheitis (VAT) are common and contribute to hospital re-admission and systemic antibiotic courses.1,2 Preventative inhaled antibiotics are recommended in patients with cystic fibrosis (CF) to reduce sputum bacterial load and rate of exacerbations, but limited studies have evaluated use for VAT or VAP prevention in patients without CF.1–3 Development of pathogen resistance in endotracheal cultures has been demonstrated in 4 studies evaluating repeated exposure to inhaled antibiotics in patients without CF.3–6 The purpose of this study is to describe the prevalence and clinical characteristics of critically ill children without CF initiated on inhaled tobramycin for VAT prevention.
This retrospective, study included patients ≤18 years admitted to the pediatric, cardiac, or neonatal intensive care units at a tertiary care academic medical center from July 1, 2016 to February 29, 2024 who received inhaled tobramycin (TOBI, Novartis Pharmaceuticals Corporation) 300 mg twice daily administered via vibrating mesh nebulizer (Aerogen, Galway, Ireland). To be included in this study, patients had to have received inhaled tobramycin for ≥2 weeks or ≥3 separate courses lasting ≥7 days each. This duration was based on a previous study which reported that pathogen resistance from sputum samples in adult patients receiving inhaled tobramycin ≥ 2 weeks.6 Patients were excluded if they had CF, incomplete medical records, initial tracheal aspirate cultures with tobramycin resistance, or no subsequent cultures following inhaled tobramycin initiation.
Demographic data, inhaled tobramycin regimens, and concomitant parenteral and enteral antibiotic therapies were recorded. To assess for resistance, the tracheal aspirate cultures obtained immediately prior to initiating aerosolized tobramycin was collected as baseline. All subsequent tracheal aspirate cultures following completion of the first inhaled tobramycin course, were collected. At the study institution, tracheal aspirate cultures were obtained by respiratory therapists via endotracheal or tracheostomy tube, and culture and susceptibility were conducted by the institution’s microbiology laboratory according to the Clinical Laboratory Standards Institute.7 Resistance was defined as an organism that was susceptible to tobramycin at initiation and was reported as intermediate or resistant on subsequent cultures.
The primary objective was to identify the number of patients with tobramycin resistance on subsequent tracheal cultures. The secondary objectives included describing demographics, clinical characteristics, tobramycin regimens, and systemic antibiotics. Descriptive statistics were performed using SAS version 9.4 (SAS Institute, Inc, Cary, NC).
Twenty-one patients were included for analysis; 4 (19.0%) developed resistance. Table 1 presents baseline demographics of those patients with and without resistance. Overall, the median age and weight was 9.7 months and 7.7 kg, respectively. A tracheostomy tube was the mode of ventilation in the majority (n = 18; 85.7%) of patients at the time of inhaled tobramycin initiation.
Table 1.
Demographic Data (N = 21)
| Variable |
Overall Data
(N = 21) |
Patients Without Resistance
(n = 17) |
Patients With Resistance (n = 4) |
|---|---|---|---|
| Number (%) or Median (IQR) | |||
| Female | 8 (38.1) | 6 (35.3) | 2 (50.0) |
| Age at initiation, mo | 9.7 (7.1–13.3) | 9.9 (7.1–12.5) | 11.1 (8.3–21.4) |
| Prematurity status: | |||
| Premature | 10 (47.6) | 8 (47.1) | 2 (50.0) |
| PMA, wk (n = 10) | 35.7 (30.8–36.0) | 32.6 (31.4–33.8) | |
| Weight, kg | 7.8 (7.4–8.6) | 7.8 (7.4–8.5) | 7.5 (6.7–11.0) |
| Length, cm | 64.5 (60.0–71.0) | 64.0 (60.0–70.5) | 68.5 (62.5–77.0) |
| Length of stay, days: | |||
| Hospital LOS | 203.0 (111.0–341.0) | 203.0 (182.0–297.0) | 290.5 (90.0–503.0) |
| Intensive care unit LOS | 201.0 (111.0–341.0) | 201.0 (127.0–297.0) | 290.5 (29.0-89.5–503.0) |
| Admission diagnoses: | |||
| Respiratory failure | 8 (38.1) | 7 (41.2) | 1 (25.0) |
| Cardiothoracic surgery | 7 (33.3) | 5 (29.4) | 2 (50.0) |
| Congenital abnormalities | 2 (9.5) | 2 (11.8) | — |
| Other | 4 (19.0) | 3 (17.6) | 1 (25.0) |
| Mode of ventilation: | |||
| Endotracheal tube | 7 (33.3) | 3 (17.6) | 4 (100.0) |
| Tracheostomy tube | 14 (66.7) | 14 (82.4) | — |
LOS, length of stay; PMA, postmenstrual age
Table 2 provides an overview of the individual patient data for all included patients. All patients were initiated on 300 mg aerosolized tobramycin every 12 hours. This equated to an overall median (IQR) initial weight-based dose of 38.5 mg/kg (33.3–41.1). Overall, inhaled tobramycin was initiated at a median (IQR) of 115.0 hospital days (42.0–192.0) and continued for a median of 37.0 days (28.0–61.0). The median (IQR) number of inhaled tobramycin courses was 2.0 (1–2.5).
Table 2.
Case Synopses of Patients With and Without Inhaled Tobramycin Resistance (N = 21)
| Demographics | Inhaled Tobramycin | Total Antibiotics | Anti-pseudomonal Intravenous Antibiotics | Intravenous Tobramycin | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient | Age at initiation (mo) | Body Weight (kg) | Mode of Ventilation at Initiation | Admission Diagnosis | Hospital Length of Stay (days) | Admission to Initiation (days) | Initial Dose (mg/kg) | Number of courses | Duration (days) | Days | % Admission | Days | % Admission | Days | % Admission |
| Resistant patients | |||||||||||||||
| 1 | 9.1 | 7.3 | ETT | Respiratory failure | 470 | 214 | 41.1 | 6 | 52 | 148 | 31.5 | 20 | 4.3 | 9 | 1.9 |
| 2 | 5.6 | 4.9 | ETT | CT surgery | 602 | 91 | 61.2 | 17 | 210.5 | 253 | 42.0 | 158 | 26.2 | 41 | 6.8 |
| 3 | 12.9 | 7.7 | ETT | Respiratory failure | 111 | 42 | 39.0 | 1 | 30.5 | 98 | 88. | 40 | 36.0 | 9 | 8.1 |
| 4 | 45.8 | 20.9 | ETT | Bleeding around GJ stoma | 27 | 0 | 14.35 | 1 | 24 | 12 | 44.4 | 7 | 25.9 | — | — |
| Susceptible patients | |||||||||||||||
| 5 | 7.7 | 8.5 | Trach | CT surgery | 369 | 234 | 35.3 | 3 | 110 | 169 | 45.8 | 125 | 33.9 | 7 | 1.9 |
| 6 | 12.4 | 9 | Trach | CT surgery | 225 | 115 | 33.3 | 2 | 55 | 76 | 33.8 | 53 | 23.6 | 35 | 15.6 |
| 7 | 11.6 | 7.8 | ETT | Respiratory failure | 76 | 23 | 38.5 | 1 | 14.5 | 30 | 39.5 | 15 | 19.7 | — | — |
| 8 | 16.6 | 8.3 | Trach | Respiratory failure | 217 | 111 | 36.14 | 5 | 61 | 139 | 64.1 | 122 | 56.2 | 97 | 44.7 |
| 9 | 9.8 | 7.8 | Trach | Septic shock | 195 | 159 | 38.5 | 2 | 31 | 173 | 88.7 | 91 | 46.7 | 9 | 4.6 |
| 10 | 9.3 | 10 | Trach | CT surgery | 203 | 158 | 30 | 1 | 37 | 80 | 39.4 | 59 | 29.1 | 23 | 11.3 |
| 11 | 12 | 8 | Trach | CT surgery | 297 | 192 | 37.5 | 2 | 34 | 175 | 58.9 | 144 | 48.5 | 31 | 10.4 |
| 12 | 14.5 | 7.4 | Trach | Respiratory failure | 21 | 0 | 40.5 | 1 | 28 | 21 | 100.0 | 11 | 52.4 | — | — |
| 13 | 7 | 7.5 | Trach | CT surgery | 403 | 212 | 40 | 3 | 107.5 | 188 | 46.7 | 153 | 38.0 | 54 | 13.4 |
| 14 | 12.2 | 7.6 | Trach | Respiratory failure | 454 | 371 | 39.4 | 2 | 54.5 | 213 | 46.9 | 102 | 22.5 | 37 | 8.1 |
| 15 | 2.1 | 3.7 | Trach | CT surgery | 217 | 64 | 81.1 | 4 | 78 | 177 | 81.6 | 82 | 37.8 | 23 | 10.6 |
| 16 | 4.6 | 6.2 | Trach | Congenital anomalies | 182 | 141 | 48.4 | 1 | 28.5 | 44 | 24.2 | 24 | 13.2 | 4 | 2.2 |
| 17 | 3.5 | 4.7 | Trach | Congenital anomalies | 201 | 106 | 63.8 | 1 | 40 | 70 | 34.8 | 45 | 22.4 | 6 | 3.0 |
| 18 | 41.3 | 15.4 | Trach | C. diff colitis | 17 | 0 | 15.4 | 1 | 15 | 16 | 94.1 | — | — | — | — |
| 19 | 5.6 | 6.6 | ETT | Atresia of esophagus with transesophageal fistula | 191 | 170 | 45.5 | 1 | 22 | 127 | 66.5 | 97 | 50.8 | 19 | 9.9 |
| 20 | 78.5 | 24 | ETT | Respiratory failure | 30 | 15 | 12.5 | 1 | 16 | 20 | 66.7 | 20 | 66.7 | 11 | 36.7 |
| 21 | 7.1 | 7.5 | Trach | Heart failure secondary to Tetralogy of Fallot | 341 | 217 | 7.5 | 2 | 73 | 90 | 26.4 | 63 | 18.5 | 2 | 0.6 |
C. diff, Clostridioides difficile; CT surgery, cardiothoracic surgery; ETT, endotracheal tube; GJ, gastrojejunostomy; trach, tracheostomy
All patients received systemic antibiotics during their hospitalization with a median (IQR) of 98.0 days (44.0–173.0), which corresponded to 47.0% (39.0%–67.0%) of their admission (Table 2). Twenty patients (95.2%) received anti-pseudomonal antibiotics for a median (IQR) of 61.0 days (23.0–107.0), comprising 31.5% (22.4%–47.1%) of their admission. Seventeen patients (81.0%) received intravenous tobramycin for a median (IQR) of 19.0 days (9.0–35.0) or 8.1% (3.0%–11.3%) of their admission.
The Supplemental Table provides microbiologic data from tracheal aspirate cultures. The mean number of tracheal aspirate cultures per patient was 3.2 ± 1.8. Most patients (n = 16; 76.2%) grew Pseudomonas aeruginosa at baseline. Subsequent tracheal cultures contained resistant organisms for 4 patients and included P aeruginosa (n = 1), Serratia marcescens (n = 1), Mycobacterium chelonae (n = 1), and Escherichia coli (n = 1).
This is one of the first studies to evaluate bacterial resistance in tracheal aspirates from non-CF critically ill children receiving inhaled tobramycin for VAT prevention. Previous studies have evaluated the use of inhaled antibiotics in children and adults without CF, but only a few have evaluated the development of pathogen resistance.1,3–6 Resistance was noted to occur in 0% to 31.6% of patients in these studies.3–6 There is a paucity of literature evaluating risk factors specific to inhaled antibiotics. Jutras et al3 conducted a case-series of 6 children (median age: 11 months) with a tracheostomy receiving prophylactic inhaled antibiotics for a median (IQR) of 74 days (22–173). They noted 1 patient (16.7%) had a tracheal aspirate culture with new resistance to ceftazidime but did not find resistance with tobramycin. Patients in our study received a longer median duration of antibiotics than by Jutras and et al.3 As the present report was a retrospective observational study, it is difficult to determine the impact that the inhaled tobramycin may have had on resistance patterns versus systemic antibiotics.
We acknowledge several limitations. First, this was a single center study with a small sample size and may not be representative of other institutions. Second, in 2023 the Clinical and Laboratory Standards Institute lowered the tobramycin susceptibility breakpoints for P aeruginosa and Enterobacterales.7 However, our institution had not implemented these changes during the study period. Third, it was not possible to identify if the pathogens initially isolated were the same organisms found in subsequent samples.
These findings highlight the importance of antimicrobial stewardship and ongoing surveillance of pathogen resistance patterns for endotracheal cultures. Further research is warranted to explore the mechanisms of resistance and guide judicious use of inhaled antibiotics.
Supplementary Material
Acknowledgments.
At the time of this study, Dr Parman was a PGY2 Pediatric Pharmacy Resident in the Critical Care Pediatric Specialization Pathway at the University of Oklahoma College of Pharmacy and OU Health.
ABBREVIATIONS
- CF
cystic fibrosis;
- VAP
ventilator-associated pneumonia;
- VAT
ventilator-associated tracheitis
Footnotes
Disclosure. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors attest to meeting the four criteria recommended by the ICMJE for authorship of this manuscript.
Ethical Approval and Informed Consent. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and has been approved by our institution’s review board. Given the nature of this study, informed consent, assent, and parental permissions were not required.
Supplemental Material. DOI: 10.5683/JPPT-25-00068.S1
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