Assessment of Detectable Serum Tobramycin Concentrations in Patients Receiving Inhaled Tobramycin for Ventilator-Associated Pneumonia

Abstract

BACKGROUND: Inhaled tobramycin can be used for empiric or definitive therapy of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. This is believed to minimize systemic exposure and potential adverse drug toxicities including acute kidney injury (AKI). However, detectable serum tobramycin concentrations have been reported after inhaled tobramycin therapy with AKI. METHODS: This retrospective, observational study evaluated mechanically ventilated adult subjects admitted to ICUs at a large, urban academic medical center that received empiric inhaled tobramycin for VAP. Subjects were separated into detectable (ie, 6 0.6 mg/L) or undetectable serum tobramycin concentration groups, and characteristics were compared. Independent predictors for detectable serum tobramycin concentration and new onset AKI during or within 48 h of therapy discontinuation were assessed. RESULTS: Fifty-nine inhaled tobramycin courses in 53 subjects were included in the analysis, of which 39 (66.1%) courses administered to 35 (66.0%) subjects had detectable serum tobramycin concentrations. Subjects with detectable serum tobramycin concentrations were older (57.1 y 6 11.4 vs 45.9 615.0, P 5 .004), had higher PEEP (9.2 cm H 2 O [7.0-11.0] vs 8.0 [5.6-8.9], P 5 .049), chronic kidney disease stage 6 2 (10 [29.4%] vs 0 [0%], P 5 .009), and higher serum creatinine before inhaled tobramycin therapy (1.26 mg/dL [0.84-2.18] vs 0.76 [0.47-1.28], P 5 .004). Age (odds ratio 1.09 [95% CI 1.02-1.16], P 5 .009) and PEEP (odds ratio 1.47 [95% CI 1.08-2.0], P 5.01) were independent predictors for detectable serum tobramycin concentration. Thirty-seven subjects had no previous renal disease or injury, of which 9 (24.3%) developed an AKI. Sequential Organ Failure Assessment score (odds ratio 1.72 [95% CI 1.07-2.76], P 5 .03) was the only independent predictor for AKI. CONCLUSIONS: Detectable serum tobramycin concentrations were frequently observed in critically ill, mechanically ventilated subjects receiving empiric inhaled tobramycin for VAP. Subject age and PEEP were independent predictors for detectable serum tobramycin concentration. Serum monitoring and empiric dose reductions should be considered in older patients and those requiring higher PEEP.

Tobramycin Systemic Absorption in Lung Transplant Recipients Treated With Inhaled Tobramycin: A Cohort Study

“…In our study, mechanical ventilation was also associated with higher trough drug levels in LTR. Additionally, in a recent study involving non-transplant patients on mechanical ventilation treated with inhaled tobramycin, 66% of patients had detectable drug levels [ 23 ]. Our study results also suggest that IMV, could promote the systemic absorption of tobramycin.…”

“…Variables such as the time from transplantation until performing drug levels or the time from initiation of nebulized tobramycin are likely influenced by invasive mechanical ventilation. The systemic absorption of inhaled tobramycin during mechanical ventilation could be attributed to improved aerosol delivery, changes in pulmonary physiology, and increased vascular permeability due to lung tissue damage [ 18 , 23 ]. These two studies [ 18 , 23 ] did not demonstrate a statistically significant association between detectable levels of tobramycin and acute renal failure.…”

“…The systemic absorption of inhaled tobramycin during mechanical ventilation could be attributed to improved aerosol delivery, changes in pulmonary physiology, and increased vascular permeability due to lung tissue damage [ 18 , 23 ]. These two studies [ 18 , 23 ] did not demonstrate a statistically significant association between detectable levels of tobramycin and acute renal failure. However, in one of the studies, the levels were not analyzed as a continuous variable, and in both cases, the drug levels were not trough drug levels.…”

Inhaled Tobramycin for Treatment of Ventilator-Associated Pneumonia: The Interplay of Patient, Drug, and Device

“…In this retrospective analysis, detectable serum concentrations were noted in older subjects, those with chronic kidney disease stage $ 2, subjects with higher serum creatinine levels, and those who were receiving higher PEEP. 12 On multivariate logistic regression analysis, older age and higher PEEP were independent predictors of detectable serum tobramycin levels. In 37 subjects with no previous history of renal disease or injury, the Sequential Organ Failure Assessment (SOFA) score was the only independent predictor for development of AKI in 9 subjects.…”

“…11 The safety of antibiotics administered by inhalation is predicated on the belief that absorption of drugs from the lungs is limited and low plasma levels could avoid systemic adverse reactions such as acute kidney injury (AKI). In this issue of the Journal, Droege and colleagues 12 report their experience with inhaled tobramycin as empiric treatment for VAP at a large, urban medical center. Inhaled tobramycin was administered to 53 subjects (total 59 courses), and the characteristics of subjects who had detectable serum concentrations ($ 0.6 mg/L) were compared with subjects with undetectable serum levels (ie, < 0.6 mg/L).…”