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Antimicrob Agents Chemother. 2019 Jul 29. pii: AAC.00148-19. doi: 10.1128/AAC.00148-19. [Epub ahead of print]

Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection.

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Center for Anti-infective Research and Development, Hartford Hospital, Hartford, CT.
Achaogen Inc., South San Francisco, CA.
Center for Anti-infective Research and Development, Hartford Hospital, Hartford, CT


Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases ≥0.5 mg/dL above baseline. Herein, the utility of the Hartford Nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3μg/mL and optimize area under the curve (AUC) was assessed. The AUC reference range was defined as the 5-95th percentile AUC observed in the Phase 3 cUTI trial (EPIC) (121-368μg*h/mL). Observed 10h plazomicin concentrations from patients in EPIC (N=281) were plotted on the nomogram to determine an eligible dosing interval (Q24H, Q36H, Q48H). Based on CLcr, a 15 or 10mg/kg dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (Q36H and Q48H) in 31% of patients. Compared with the 15mg/kg Q24H regimen received by patients with CLcr ≥60mL/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs ≥3μg/mL (Q36H: 27% vs 0%, p=0.021; Q48H: 57% vs 0%, p=0.002), while significantly increasing the number of patients within the AUC range. Compared with the 8-12mg/kg Q24H regimen (received by patients with CLcr >30 to 59mL/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs ≥3μg/mL in the Q48H cohort (72% vs 0%, p<0.001), while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford Nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3μg/mL.


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