Dataset Information

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??g/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 ?g · 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 ?g/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 ?3?g/ml in the q48h cohort (72% versus 0%, P?

SUBMITTER: Asempa TE

PROVIDER: S-EPMC6761540 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Asempa Tomefa E TE Kuti Joseph L JL Seroogy Julie D JD Komirenko Allison S AS Nicolau David P DP

Antimicrobial agents and chemotherapy 20190923 10

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 und ...[more]

PMID: 31358580

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Project description:Hospital readmissions following severe infections are a major economic burden on the health care system and have a negative influence on patients' quality of life. Understanding the risk factors for readmission, particularly the extent to which they could be prevented, is of a great importance. In this study we evaluated potentially preventable risk factors for 60-day readmission in patients surviving hospitalization for complicated urinary tract infection (cUTI). This was a multinational, multicentre retrospective cohort study conducted in Europe and the Middle East. Our cohort included survivors of hospitalization due to cUTI during the years 2013-2014. The primary outcome was 60-day readmission following index hospitalization. Patient characteristics that could have influenced readmission: demographics, infection presentation and management, microbiological and clinical data; were collected via computerized medical records from infection onset up to 60 days after hospital discharge. Overall, 742 patients were included. The cohort median age was 68 years (interquartile range, (IQR) 55-80) and 43.3% (321/742) of patients were males. The all-cause 60-day readmission rate was 20.1% (149/742) and more than half were readmitted for infection [57.1%, (80/140)]. Recurrent cUTI was the most frequent cause for readmission [46.4% (65/140)]. Statistically significant risk factors associated with 60-day readmission in multivariable analysis were: older age (odds ratio (OR) 1.02 for an one-year increment, confidence interval (CI) 1.005-1.03), diabetes mellitus (OR 1.63, 95% CI 1.04-2.55), cancer (OR 1.7, 95% CI 1.05-2.77), previous urinary tract infection (UTI) in the last year (OR 1.8, 95% CI: 1.14-2.83), insertion of an indwelling bladder catheter (OR 1.62, 95% CI 1.07-2.45) and insertion of percutaneous nephrostomy (OR 3.68, 95% CI 1.67-8.13). In conclusion, patients surviving hospitalization for cUTI are frequently re-hospitalized, mostly for recurrent urinary infections associated with a medical condition that necessitated urinary interventions. Interventions to avoid re-admissions should target these patients.

Project description:Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum β-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to <18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of ≥50 ml/min/1.73 m2 only): for children ≥12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children <12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.

Project description:Increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a new aminoglycoside, has in vitro activity against multidrug-resistant Enterobacteriaceae, including isolates resistant to currently available aminoglycosides, as well as extended-spectrum ?-lactamase-producing and carbapenem-resistant Enterobacteriaceae We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis. Patients were randomized 1:1:1 to receive intravenous plazomicin (10 or 15 mg/kg of body weight) or intravenous levofloxacin (750 mg) once daily for 5 days. Coprimary efficacy endpoints were microbiological eradication at the test of cure (TOC; 5 to 12 days after the last dose) in the modified intent-to-treat (MITT) and microbiologically evaluable (ME) populations. Overall, 145 patients were randomized to treatment. In the groups receiving plazomicin at 10 mg/kg, plazomicin at 15 mg/kg, and levofloxacin, microbiological eradication rates were, respectively, 50.0% (6 patients with microbiological eradication at TOC/12 patients treated [95% confidence interval {CI}, 21.1 to 78.9%]), 60.8% (31/51 [95% CI, 46.1 to 74.2%]), and 58.6% (17/29 [95% CI, 38.9 to 76.5%]) in the MITT population and 85.7% (6/7 [95% CI, 42.1 to 99.6%]), 88.6% (31/35 [95% CI, 73.3 to 96.8%]), and 81.0% (17/21 [95% CI, 58.1 to 94.6%]) in the ME population. In the MITT population, 66.7% (95% CI, 34.9 to 90.1%), 70.6% (95% CI, 56.2 to 82.5%), and 65.5% (95% CI, 45.7 to 82.1%) of the patients in the three groups, respectively, were assessed by the investigator to be clinically cured at TOC. Adverse events were reported in 31.8%, 35.1%, and 47.7% of the patients in the three groups, respectively. Serum creatinine values were generally stable over the course of the study. No plazomicin-treated patients with evaluable audiometry data had postbaseline sensorineural, conductive, or mixed hearing loss. In summary, plazomicin demonstrated microbiological and clinical success and an overall safety profile supportive of further clinical development. (This study has been registered at ClinicalTrials.gov under identifier NCT01096849.).

Dataset Information

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

Publications

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

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