Safety
The utility of IV aminoglycoside therapy is often limited by the well-recognized risk of ototoxicity and nephrotoxicity3,10-11. Understanding the pharmacodynamics and pharmacokinetics of IV aminoglycoside therapy is essential to establish a balance between efficacy and toxicity. The results of this study unexpectedly demonstrated an increased incidence of AKI in the pediatric cohort, when compared to the adult cohort (45.5% versus 25.9%), which was likely secondary to the increased incidence of multi-daily dosing of IV tobramycin in pediatric patients. Once-daily dosing of IV aminoglycoside therapy has previously been demonstrated to reduce nephrotoxicity, without sacrificing efficacy, in both pediatric and adult patients with CF 13-19. Similar to previous studies, patients within our study who received IV tobramycin dosed multiple times daily had a significantly increased risk of AKI in comparison to patients receiving IV tobramycin dosed at least every 24 hours, with 50% versus 28.7% developing AKI, respectively (p=0.047). Our findings correlate with one Cochrane analysis comparing once versus multi-daily dosing of aminoglycoside therapy in pediatric and adult patients with CF, which found a significantly lower rise in creatinine with once-daily aminoglycoside therapy in children, perpetuating the recommendation to utilize once daily dosing of aminoglycosides, whenever possible, in pediatric patients 16.
Given the lack of correlation between time undetectable and efficacy found within this study, modification of institution guidelines may be considered to discourage multi-daily dosing of IV tobramycin, thereby mitigating AKI incidence and improving clinical efficacy, in pediatric patients. Changes in dosing interval resulting in multi-daily dosing should not be recommended without considering both pharmacokinetic and clinical features of each patient. Practice changes, including the administration of once daily fluid boluses, have been incorporated within the children’s hospital at our institution in the past year to mitigate the risk of AKI in pediatric CF patients receiving IV aminoglycoside therapy.
There were several limitations to this study including the retrospective nature which restricted data collection to information readily available within the electronic medical record (EMR). Additionally, prior to practice changes made within recent years, patients were often permitted to complete courses of IV therapy at home, limiting the ability to closely monitor IV tobramycin efficacy and toxicity as well as adherence to chest physiotherapy which may have impacted changes in FEV1. Lastly, alterations in pharmacokinetic parameters may have contributed to the lack of statistical significance found between therapeutic measurements of efficacy (Cmax and AUC24) and changes in FEV1 found within this study. Of the 151 patient encounters analyzed, 56 patient encounters (37%) had volumes of distribution (Vd) which were not considered physiologic, defined as a Vd between 0.3-0.65 L/kg. Non-physiologic volumes of distribution may result in falsely altered Cmax and AUC24 measurements, resulting in lack of correlation between these measured variables and clinical success, defined as return of FEV1 to baseline. Overall 71 patient encounters (49%) had measured AUC24 ≥80 and Cmax ≥8 times the highest Pseudomonas MIC, resulting in the need for a larger patient population than what was originally anticipated to establish statistical significance.