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

Abstract

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 of ≥0.5 mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 μg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 μg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC (n = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 μg/ml (q36h, 27% versus 0%, P = 0.021; q48h, 57% versus 0%, P = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3μg/ml in the q48h cohort (72% versus 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 <3 μg/ml.

Plazomicin: a new aminoglycoside in the fight against antimicrobial resistance

“…Following the initial dose, the dosing interval may be adjusted 1.5-fold based on therapeutic drug monitoring (TDM) to maintain 26 In an attempt to protocolize TDM for plazomicin, the group from Hartford Hospital adapted their aminoglycoside dosing nomogram for dosing interval selection to better assess patients in need of renal adjustment. 33,34 Importantly, patients with CL Cr <15 mL/min or who are on renal replacement therapy were excluded from phase I studies, so recommendations for dosing adjustments in these patients are currently unavailable.…”

Carbapenem-Resistant Enterobacterales: Considerations for Treatment in the Era of New Antimicrobials and Evolving Enzymology

“…Use of the nomogram reduced the incidence of potentially toxic trough concentrations while maintaining similar target AUCs. Additionally, the application of the Hartford nomogram appears useful in less sick patients with UTIs [37].…”

Plazomicin—a New Aminoglycoside—for Treating Complicated Urinary Tract Infections

“…AGs such as gentamicin, amikacin, and tobramycin exhibited reduced activity against these isolates, with only 49.4%, 59.7%, and 0% susceptibility to gentamicin, amikacin, and tobramycin, respectively (15). Plazomicin suppresses protein synthesis in bacteria and exhibits efficient bactericidal efficacy against numerous ESBL producing and aminoglycoside-and carbapenem-resistant bacterial isolates (16). Unfortunately, there are few reviews of the literature on this topic.…”