scholarly journals Does Combination Therapy With Vancomycin and Piperacillin-Tazobactam Increase the Risk of Nephrotoxicity Versus Vancomycin Alone in Pediatric Patients?

2016 ◽  
Vol 21 (4) ◽  
pp. 332-338 ◽  
Author(s):  
Katherine E. McQueen ◽  
Dana W. Clark
Keyword(s):  
Combination Therapy ◽  
Serum Creatinine ◽  
Pediatric Patients ◽  
Combination Group ◽  
Single Center ◽  
Exact Test ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
Serum Vancomycin ◽  
Vancomycin Group

OBJECTIVES: To determine if the incidence of nephrotoxicity is higher in pediatric patients treated with the combination of vancomycin and piperacillin-tazobactam, compared to patients treated with vancomycin alone. Secondary objectives were to determine if admission to an intensive care unit (ICU), higher serum vancomycin trough concentrations (>15 mg/L), or receipt of other nephrotoxic agents were related to the development of nephrotoxicity. METHODS: This was a retrospective, single-center, cohort study of 79 patients treated with vancomycin and 106 patients treated with vancomycin and pipracillin/tazobacatam (TZP). Serum creatinine was trended to determine if patients had nephrotoxicity, which was defined as at least a 100% increase in serum creatinine or an increase of ≥0.5 mg/dL from the baseline value. Fisher's exact test was used to compare the incidence of nephrotoxicity in the vancomycin group to the combination group. Secondary objectives were evaluated by using relative risk (RR). RESULTS: Nephrotoxicity developed in 3 of 79 patients (3.8%) in the vancomycin group and in 25 of 106 patients (23.6%) on combination therapy (p = 0.0001). In patients receiving only vancomycin, there was no statistically significant increase in nephrotoxicity for patients in the ICU (RR 1.85, 95% confidence interval [CI] 0.175–19.62, p = 0.61), those with higher vancomycin troughs (RR 2.32, CI 0.226–23.86, p = 0.48), or those receiving other nephrotoxic medications (RR 2.94, CI 0.2779–31.05, p = 0.37). In the combination group, having higher serum vancomycin trough concentrations increased the risk of nephrotoxicity (RR 5.22, CI 2.407–11.306, p < 0.0001). CONCLUSIONS: Combination therapy with vancomycin and TZP is potentially more nephrotoxic than vancomycin alone. ICU admissions, high vancomycin troughs (>15 mg/L), and concomitant nephrotoxic medications cannot be excluded as risk factors for the observed increase in nephrotoxicity in patients receiving vancomycin and TZP.

scholarly journals LGG-49. SAFETY AND EFFICACY OF TRAMETINIB (T) MONOTHERAPY AND DABRAFENIB + TRAMETINIB (D+T) COMBINATION THERAPY IN PEDIATRIC PATIENTS WITH BRAF V600-MUTANT LOW-GRADE GLIOMA (LGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii375-iii375
Author(s):  
Eric Bouffet ◽  
James A Whitlock ◽  
Christopher Moertel ◽  
Birgit Geoerger ◽  
Isabelle Aerts ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Pediatric Patients ◽  
Objective Response ◽  
Safety Data ◽  
Dose Finding ◽  
Combination Group ◽  
Clinical Activity ◽  
Low Grade ◽  
Open Label ◽  
Independent Review

Abstract BACKGROUND Children with BRAF V600-mutant LGG have suboptimal response to standard chemotherapy. Previously, D (BRAF V600 inhibitor) monotherapy has demonstrated clinical benefit in this population. We report interim analysis results of pediatric patients with recurrent/refractory BRAF V600-mutant LGG treated with either T (MEK1/2 inhibitor) monotherapy or D+T combination therapy. METHODS This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772) in pediatric patients (<18 y) with refractory/recurrent tumors. The dose-finding phase, including dose confirmation stratified by age, was followed by disease-specific cohorts at recommended dose levels. Efficacy was determined by both investigator and independent review using RANO criteria. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. RESULTS Of 49 pediatric patients with BRAF V600-mutant LGG (T, n=13; D+T, n=36) enrolled, pooled efficacy data was available for both treatments while safety data was available for 30 patients (T, n=10; D+T, n=20). Most patients (n=8/10) receiving T monotherapy withdrew/discontinued the treatment in contrast to 3/20 in the D+T group. Pyrexia occurred in 50% of patients (n=5/10) in the monotherapy group and was a frequent AE in the combination group (75%; n=15/20). Objective response rate per independent review was 15% (95% CI, 2%–45%) with T monotherapy and 25% (95% CI, 12%–42%) with D+T combination therapy. Seven patients (54%) on monotherapy and 33 patients (92%) on combination therapy had stable disease or better. CONCLUSION In pediatric patients with previously treated BRAF V600-mutant LGG, T monotherapy and D+T combination therapy demonstrated clinical activity, with pyrexia being a common AE.

scholarly journals Incidence and Risk Factors for Vancomycin Nephrotoxicity in Acutely Ill Pediatric Patients

2017 ◽  
Vol 34 (1) ◽  
pp. 9-16 ◽  
Author(s):  
Henock Woldu ◽  
B. Joseph Guglielmo
Keyword(s):  
Risk Factors ◽  
Confidence Interval ◽  
Serum Creatinine ◽  
Odds Ratio ◽  
Kidney Injury ◽  
Severe Toxicity ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
The Mean ◽  
Mean Time

Background: Particularly with the current increased vancomycin dosing trends, the true risk of the agent’s nephrotoxicity is not well characterized and remains of concern. Objective: To determine the incidence of vancomycin nephrotoxicity in acutely ill hospitalized children and to secondarily characterize the risk factors for this complication. Methods: A single-center retrospective cohort study conducted at UCSF Benioff Children’s Hospital from June 2012 to June 2015. Inpatients 3 months to <19 years who received intravenous vancomycin for ≥48 hours were included. The primary outcome was incidence of nephrotoxicity, defined as an increase in serum creatinine by ≥50% from baseline. Univariate and multivariate analyses were conducted to identify risk factors for vancomycin nephrotoxicity. Results: A total of 291 patients (272 nonnephrotoxic and 19 nephrotoxic) were included in the analysis. Of the 19 patients, 12 (4.1%) were found to have moderate to severe toxicity. The median duration of therapy was 3 (3-5) and 4 (3-6) days for the group with “no nephrotoxicity” and “nephrotoxicity,” respectively. The mean time for the serum creatinine to return to normal in patients with nephrotoxicity was 5.1 days. In the multivariate analysis, only final trough concentration ≥15mg/dL (odds ratio = 3.49, 95% confidence interval = 1.2-10.1; P = .021) and receipt of piperacillin/tazobactam (odds ratio = 3.14, 95% confidence interval = 1.02-9.6; P = .046) were significantly associated with nephrotoxicity. Conclusion: The rate of moderate to severe vancomycin-associated nephrotoxicity in acutely ill children is relatively uncommon and reversible. Kidney injury is associated with increased vancomycin trough concentrations and concomitant receipt of nephrotoxins, particularly piperacillin/tazobactam.

scholarly journals Challenges of Vancomycin Dosing and Therapeutic Monitoring in Neonates

2020 ◽  
Vol 25 (6) ◽  
pp. 476-484
Author(s):  
Jennifer T. Pham
Keyword(s):  
Pediatric Patients ◽  
Late Onset ◽  
Therapeutic Monitoring ◽  
Pharmacokinetic Parameters ◽  
Coagulase Negative Staphylococci ◽  
Optimal Dosing ◽  
Increased Risk ◽  
Dosing Regimens ◽  
Vancomycin Trough ◽  
Trough Concentrations

Late-onset sepsis in neonates can lead to significant morbidity and mortality, especially in preterm infants. Vancomycin is commonly prescribed for the treatment of Gram-positive organisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, and ampicillin-resistant Enterococcus species in adult and pediatric patients. Currently, there is no consensus on optimal dosing and monitoring of vancomycin in neonates. Different vancomycin dosing regimens exist for neonates, but with many of these regimens, obtaining therapeutic trough concentrations can be difficult. In 2011, the Infectious Diseases Society of America recommended vancomycin trough concentrations of 15 to 20 mg/L or an AUC/MIC ratio of ≥400 for severe invasive diseases (e.g., MRSA) in adult and pediatric patients. Owing to recent reports of increased risk of nephrotoxicity associated with vancomycin trough concentrations of 15 to 20 mg/L and AUC/MIC of ≥400, a revised consensus guideline, recently published in 2020, no longer recommends monitoring vancomycin trough concentrations in adult patients. The guideline recommends an AUC/MIC of 400 to 600, which has been found to achieve clinical efficacy while reducing nephrotoxicity. However, these recommendations were derived solely from adult literature, as there are limited clinical outcomes data in pediatric and neonatal patients. Furthermore, owing to the variation of vancomycin pharmacokinetic parameters among the neonatal population, these recommendations for achieving vancomycin AUC/MIC of 400 to 600 in neonates require further investigation. This review will discuss the challenges of achieving optimal vancomycin dosing and monitoring in neonatal patients.

Intravenous Vancomycin Associated With the Development of Nephrotoxicity in Patients With Class III Obesity

2017 ◽  
Vol 51 (11) ◽  
pp. 937-944 ◽  
Author(s):  
Yookyung Christy Choi ◽  
Stephen Saw ◽  
Daniel Soliman ◽  
Angela L. Bingham ◽  
Laura Pontiggia ◽  
...  
Keyword(s):  
Concomitant Administration ◽  
Class I ◽  
Class Iii ◽  
Obesity Class ◽  
Class Iii Obesity ◽  
Dosing Strategies ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
Serum Vancomycin ◽  
Nonobese Patients

Background:A consensus statement recommends initial intravenous (IV) vancomycin dosing of 15-20 mg/kg every 8- 24 hours, with an optional 25- to 30-mg/kg loading dose. Although some studies have shown an association between weight and the development of vancomycin-associated nephrotoxicity, results have been inconsistent. Objective: To evaluate the correlation between incidence of nephrotoxicity associated with weight-based IV vancomycin dosing strategies in nonobese and obese patients. Methods: This retrospective cohort study evaluated hospitalized adult patients admitted who received IV vancomycin. Patients were stratified into nonobese (body mass index [BMI] <25 kg/m2), obesity class I and II (BMI 30-39.9kg/m2), and obesity class III (BMI≥40 kg/m2) groups; patients who were overweight but not obese were excluded. Incidence of nephrotoxicity and serum vancomycin trough concentrations were evaluated. Results: Of a total of 62 documented cases of nephrotoxicity (15.1%), 13 (8.7%), 23 (14.3%), and 26 (26.3%) cases were observed in nonobese, obesity class I and II, and obesity class III groups, respectively ( P=0.002). Longer durations of therapy ( P<0.0001), higher initial maintenance doses in both total milligrams/day ( P=0.0137) and milligrams/kilogram ( P=0.0307), and any trough level >20 mg/L ( P<0.0001) were identified as predictors of development of nephrotoxicity. Concomitant administration of piperacillin/tazobactam, diuretics, and IV contrast were associated with development of nephrotoxicity ( P<0.005, all). Patients with class III obesity were 3-times as likely to develop nephrotoxicity when compared with nonobese patients (odds ratio [OR]=2.99; CI=1.12-7.94) and obesity class I and II patients (OR=3.14; CI=1.27-7.75). Conclusions: Obesity and other factors are associated with a higher risk of vancomycin-associated nephrotoxicity.

scholarly journals Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates

2014 ◽  
Vol 58 (11) ◽  
pp. 6454-6461 ◽  
Author(s):  
Adam Frymoyer ◽  
Adam L. Hersh ◽  
Mohammed H. El-Komy ◽  
Shabnam Gaskari ◽  
Felice Su ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Serum Creatinine ◽  
Monte Carlo Simulations ◽  
Serum Creatinine Level ◽  
Creatinine Level ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Concentration Time ◽  
Vancomycin Trough ◽  
Trough Concentrations

ABSTRACTNational treatment guidelines for invasive methicillin-resistantStaphylococcus aureus(MRSA) infections recommend targeting a vancomycin 24-h area under the concentration-time curve (AUC0–24)-to-MIC ratio of >400. The range of vancomycin trough concentrations that best predicts an AUC0–24of >400 in neonates is not known. This understanding would help clarify target trough concentrations in neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine the relationships between trough and AUC0–24in the study neonates. Monte Carlo simulations were performed to examine the effect of dose, postmenstrual age (PMA), and serum creatinine level on trough and AUC0–24achievement. A total of 1,702 vancomycin concentrations from 249 neonates were available for analysis. The median (interquartile range) PMA was 39 weeks (32 to 42 weeks) and weight was 2.9 kg (1.6 to 3.7 kg). Vancomycin clearance was predicted by weight, PMA, and serum creatinine level. At a trough of 10 mg/liter, 89% of the study neonates had an AUC0–24of >400. Monte Carlo simulations demonstrated that troughs ranging from 7 to 11 mg/liter were highly predictive of an AUC0–24of >400 across a range of PMA, serum creatinine levels, and vancomycin doses. However, a trough of ≥10 mg/liter was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs of >20 mg/liter. A vancomycin trough of ∼10 mg/liter is likely adequate for most neonates with invasive MRSA infections based on considerations of the AUC0–24. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses is difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.

scholarly journals Use of Body Surface Area for Dosing of Vancomycin

2019 ◽  
Vol 24 (4) ◽  
pp. 296-303
Author(s):  
Elizabeth L. Sawrey ◽  
Mary W. Subramanian ◽  
Kacy A. Ramirez ◽  
Brandy S. Snyder ◽  
Brittany B. Logston ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Surface Area ◽  
Body Surface ◽  
Pediatric Patients ◽  
Obese Patients ◽  
Dosing Regimen ◽  
Trough Serum ◽  
Dosing Regimens ◽  
Vancomycin Trough ◽  
Trough Concentrations

OBJECTIVES Vancomycin weight-based dosing regimens often fail to achieve therapeutic trough serum concentration in children ≤12 years of age and rigorous studies evaluating efficacy and safety of body surface area (BSA)–based dosing regimens have not been performed. We compared vancomycin trough serum concentrations in pediatric patients receiving a weight- or BSA-based dosing regimen. METHODS This was a single-center, retrospective study evaluating pediatric patients, ages 1 to 12 years, who received vancomycin from September 2012 to October 2015. Patients received a minimum of 3 consecutive doses at the same scheduled interval within a dosing regimen prior to a measured vancomycin serum trough concentration. The primary outcome was percentage of initial vancomycin trough concentrations ≥10 mg/L. The secondary outcomes were percentage of supratherapeutic, therapeutic, and subtherapeutic vancomycin serum concentration for all patients, including a subset of overweight and obese patients, and number of nephrotoxic occurrences. RESULTS BSA-based dosing regimens resulted in 50% of the initial vancomycin trough concentrations ≥ 10 mg/L compared with 17% for the weight-based dosing regimens (p &lt; 0.0001). No statistically significant differences were noted between the 2 dosing regimens for supratherapeutic, therapeutic, or subtherapeutic trough concentrations for all patients, and for the subset of overweight and obese patients. Nephrotoxic occurrences were noted in 7% of the weight-based dosing regimens compared with none in the BSA-based dosing regimens. CONCLUSIONS A BSA-based vancomycin dosing regimen resulted in significantly more initial vancomycin trough concentrations ≥10 mg/L and trended towards higher initial vancomycin trough concentrations without observable nephrotoxicity.

scholarly journals Evaluation of Vancomycin Dosing in Pediatric Cystic Fibrosis Patients

2016 ◽  
Vol 21 (2) ◽  
pp. 155-161 ◽  
Author(s):  
Erin J. McDade ◽  
Jennifer L. Hewlett ◽  
Siby P. Moonnumakal ◽  
Carol J. Baker
Keyword(s):  
Cystic Fibrosis ◽  
Pulmonary Function ◽  
Pediatric Patients ◽  
Primary Objective ◽  
Vancomycin Trough ◽  
Vancomycin Dosage ◽  
Trough Concentrations ◽  
The Mean ◽  
The Impact ◽  
Vancomycin Treatment

OBJECTIVES: The presence of methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis (CF) patients' sputa is associated with a decline in pulmonary function and increased mortality. Vancomycin is the preferred treatment for MRSA pneumonia in children. No published studies have evaluated the vancomycin dose needed to achieve goal vancomycin trough concentrations (VTCs; 15–20 mg/L) in pediatric patients with CF. The primary objective is to determine whether a vancomycin dosage of 60 mg/kg/day achieves a goal VTC in pediatric CF patients. Secondary objectives include determining the average dosage required to reach a goal VTC and the impact of achieving a goal VTC on estimated glomerular filtration rate (eGFR) and pulmonary function. METHODS: A retrospective review of pediatric patients with CF who received vancomycin was conducted. RESULTS: A total of 90 vancomycin treatment courses were analyzed. Standard vancomycin dosing (60 mg/kg/day) achieved goal VTC in 11 courses (12.2%). The mean dosage required to achieve a goal VTC for all courses was 70.6 ± 16.7 mg/kg/day. Patients who achieved goal VTCs were more often older, weighed more, and had higher serum creatinine concentrations at therapy initiation. On average, a dosage of 70.6 mg/kg/day was required to achieve a goal VTC. Despite dosages up to 120 mg/kg/day, no significant changes in renal function occurred. Achieving a goal VTC had no significant impact on eGFR or pulmonary function during therapy. CONCLUSIONS: Vancomycin dosing of 60 mg/kg/day does not reliably achieve a VTC of 15 to 20 mg/L in pediatric CF patients. Younger CF patients may require higher vancomycin doses.

Effect of concomitant vancomycin and piperacillin–tazobactam on frequency of acute kidney injury in pediatric patients

2019 ◽  
Vol 76 (16) ◽  
pp. 1204-1210 ◽  
Author(s):  
Kaitlyn M Buhlinger ◽  
Kathryn A Fuller ◽  
Cassidy B Faircloth ◽  
Jessica R Wallace
Keyword(s):  
Acute Kidney Injury ◽  
Serum Creatinine ◽  
Trough Concentration ◽  
Pediatric Patients ◽  
Group Versus ◽  
Kidney Injury ◽  
Secondary Outcome ◽  
Study Cohort ◽  
Creatinine Concentration ◽  
Vancomycin Trough

Abstract Purpose Results of a study of rates of acute kidney injury (AKI) in pediatric patients treated with vancomycin plus piperacillin–tazobactam or vancomycin plus alternative antipseudomonal β-lactams (APBLs) are reported. Methods A retrospective, single-center cohort study was performed. Pediatric patients were included in the study cohort if they received combination therapy for at least 48 hours, had documented baseline and follow-up serum creatinine levels, and had a documented serum vancomycin trough concentration. The primary outcome was the frequency of AKI, defined as a 50% or greater increase in serum creatinine concentration from baseline or an increase of at least 0.5 mg/dL from baseline. The secondary outcome was time to AKI onset. Results A total of 474 patients were included. Among 100 patients who received vancomycin plus piperacillin–tazobactam, the rate of AKI was higher than the rate in the group treated with vancomycin plus alternative APBLs (27% versus 7%, p < 0.0001). The median time to AKI onset was shorter in the piperacillin–tazobactam group versus the alternative APBL group (3.8 versus 7.9 days, p = 0.0065). Patients who were administered piperacillin–tazobactam were almost 6 times as likely to develop AKI (odds ratio [OR], 5.955; 95% confidence interval [CI], 2.774–12.784), and patients who had a maximum vancomycin trough concentration greater than 20 mg/L were 7.5 times as likely to develop AKI (OR, 7.552; 95% CI, 3.625–15.734). Conclusion Pediatric patients treated with concomitant vancomycin and piperacillin–tazobactam had a higher rate of AKI, with faster AKI onset, than those who received vancomycin in combination with other APBLs.

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