INTRODUCTION:
Pseudomonas aeruginosa (PsA) is frequently implicated as a cause of pulmonary infection and subsequent irreversible decline in lung function in patients with cystic fibrosis (CF) 1-3. Intravenous (IV) aminoglycoside therapy has been shown to be relatively safe and efficacious, when monitored appropriately, for the treatment of PsA acute pulmonary exacerbations (APEs) in CF patients 3. As aminoglycosides are concentration-dependent agents, the efficacy of therapy is enhanced when peak concentrations are maximized. Dosing strategies that maximize the peak concentration and minimize the trough concentration may enhance bactericidal activity while also reducing the risk of nephrotoxicity and ototoxicity 4,5. Historically, a max concentration (Cmax) ≥8-foldthe minimal inhibitory concentration (MIC) has been the pharmacokinetic-pharmacodynamic (PK-PD) target utilized to predict IV aminoglycoside efficacy 4-6. However, recent studies have suggested the benefit of utilizing area under the curve (AUC24) to monitor total drug exposure to IV aminoglycoside therapy in CF patients, as both drug concentration and clearance are reflected 7-8. This paradigm shift is supported by the fact that for our newest aminoglycoside, plazomicin, the FDA package labeling recommends monitoring the AUC24:MIC ratio as it has been shown to best correlate with efficacy in animal and in vitro models against gram-negative pathogens 9. Given the importance of balancing efficacy and toxicity, further studies assessing the clinical utility of AUC24 in CF patients receiving high-dose extended interval dosing of IV aminoglycoside therapy are warranted.
The primary objective of this study is to compare the predictive value of AUC24 versus Cmax, in relation to mean change in forced expiratory volume over one second (FEV1) in CF patients being treated for a PsA APE. Secondary objectives include: (1) to describe the incidence of acute kidney injury (AKI) and (2) to describe the relationship between time undetectable and the incidence of acute kidney injury (AKI) as well as the return of FEV1 to baseline.