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.