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

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Abstract

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.

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A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant Staphylococcus aureus pneumonia.

Aidan Doherty, Marin H. Kollef, Scott T Micek … (2007)

The goal of this investigation was to determine whether more aggressive vancomycin dosing is associated with greater risk for renal toxicity in patients with health care-associated pneumonia (HCAP) attributed to methicillin-resistant Staphylococcus aureus (MRSA). This was a retrospective, single-center, observational cohort study. The following information was obtained for all study patients from automated hospital, microbiology, and pharmacy databases: age, sex, weight, serial serum creatinine (SCr), age- and sex-adjusted creatinine clearance (CrCl) during receipt of vancomycin, vancomycin serum trough concentrations, duration of vancomycin therapy, and Acute Physiology and Chronic Health Evaluation II scores. Renal toxicity was defined as either a 0.5-mg/dL increase from baseline in SCr or a >or=50% increase in SCr based on serial SCr measurements. Data for patients who met the definition of renal toxicity were compared with data for those who did not. Ninety-four patients (mean [SD]age, 59.0 [15.6] years; 59 [62.8%] men; 73 (77.7%) white; mean baseline CrCl, 70.3 [23.0] mL/min) were identified as having MRSA HCAP. Forty (42.6%) patients developed renal toxicity. Patients who developed renal toxicity were significantly more likely than patients who did not develop renal toxicity to have greater mean vancomycin serum trough concentrations (20.8 [9.9] g/mL vs 14.3 [6.7] g/mL, respectively; P or=15 g/mL (67.5% vs 40.7%; P = 0.01), and a prolonged duration (>or=14 days) of vancomycin treatment (45.0% vs 20.4%; P = 0.011). Logistic regression analysis identified a maximum vancomycin serum trough concentration of >or=15 g/mL as being independently associated with renal toxicity (adjusted odds ratio = 2.82; 95% CI, 1.02-7.74; P = 0.045). The overall mean change in CrCl for the study population was -13.5 (-16.0) mL/min (range, 0.0 to -62.6 mL/min). Patients with maximum measured vancomycin serum trough concentrations >or=15 g/mL (n = 49) had significantly greater absolute changes in CrCl compared with patients with maximum measured vancomycin serum trough concentrations <15 g/mL (n = 45) (-18.9 [-17.0] vs -7.6 [-12.5] mL/min, respectively; P < 0.001). The results suggest that aggressive vancomycin dosing and prolonged vancomycin administration may be associated with greater risk for renal toxicity in patients with MRSA HCAP. However, this retrospective study cannot establish causation, and a prospective, randomized, double-blind trial is needed.

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Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam.

Lindsey D Burgess, Richard Drew (2014)

To determine whether the addition of piperacillin-tazobactam leads to an increased incidence of nephrotoxicity in patients receiving vancomycin and to explore potential confounding factors that may increase the risk of vancomycin-induced nephrotoxicity. Single-center, retrospective cohort study. Large, academic, tertiary-care hospital. One hundred ninety-one adults hospitalized between July 1, 2009, and July 1, 2012, with normal baseline renal function who received a minimum of 48 hours of vancomycin for any indication were included in the analysis. Of these patients, 92 received a minimum of 48 hours of intravenous piperacillin-tazobactam concurrently with vancomycin, with piperacillin-tazobactam being initiated within 48 hours of the initiation of vancomycin (combination group); 99 received vancomycin without piperacillin-tazobactam (vancomycin group). A univariate analysis was performed to assess the effect of the following risk factors on the incidence of nephrotoxicity within the first 7 days of vancomycin treatment: concomitant nephrotoxic agents, advanced age, steady-state vancomycin trough concentration of 15 μg/ml or greater, elevated Charlson Comorbidity Index, and a total daily vancomycin dose of 4 g or greater. A multivariate model was constructed to compare the incidence of the primary end point of nephrotoxicity, defined as a minimum 1.5-fold increase in serum creatinine concentration, between groups. Nephrotoxicity developed in 8 (8.1%) of 99 patients in the vancomycin group and in 15 (16.3%) of 92 patients in the combination group (1-sided χ(2) test, p=0.041). In the univariate analysis, only vancomycin trough concentration of 15 μg/ml or greater (odds ratio 3.67) was associated with an increased risk of developing nephrotoxicity. In the multivariate analysis, patients with piperacillin-tazobactam added to vancomycin exhibited an increased incidence of nephrotoxicity, with an odds ratio of 2.48 (1-sided χ(2) test, p=0.032). We observed an increased incidence of nephrotoxicity in vancomycin-treated patients who received concomitant piperacillin-tazobactam. A steady-state vancomycin trough concentration of 15 μg/ml or greater was also associated with an increased risk of the development of nephrotoxicity. These findings should be confirmed in larger, randomized studies. © 2014 Pharmacotherapy Publications, Inc.

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Incidence and risk factors influencing the development of vancomycin nephrotoxicity in children.

Susan McKamy, Maria Hernandez, T Moriwaki … (2011)

To determine the incidence of vancomycin-associated nephrotoxicity in children and to examine potential risk factors for nephrotoxicity, including average serum trough concentrations ≥ 15 mg/L. Patients ≥ 1 week old to ≤ 19 years with normal baseline serum creatinine values who received vancomycin for ≥ 48 hours between December 2007 and April 2009 were retrospectively evaluated. Nephrotoxicity was defined as a serum creatinine increase of ≥ 0.5 mg/dL or ≥ 50% baseline increase over 2 days. Patients with average serum trough concentrations ≥ 15 mg/L were compared with a lower trough group. Nephrotoxicity occurred in 14% of 167 patients. More patients who attained high average (≥ 15 mg/L) rather than low average (<15 mg/L) vancomycin troughs had nephrotoxicity (28% versus 7.3%, P = .0001). Using multivariable regression analysis, patients with high troughs and those receiving furosemide in the intensive care unit were more likely to have nephrotoxicity (OR, 3.27 [95% CI, 1.19 to 8.95], P = .021, and odds ratio, 9.45 [95% confidence interval, 3.44 to 26.00], P < .0001, respectively). Renal function and serum troughs in children receiving vancomycin, especially those with targeted troughs of ≥ 15 mg/L, in intensive care, and receiving furosemide, should be closely monitored. Copyright © 2011 Mosby, Inc. All rights reserved.