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.