antibiotic stewardship: preventing vancomycin-induced acute kidney injury in hospitalized pediatric patients
pediatric forum Winter 2018
Children commonly receive multiple antibiotics when hospitalized.1 Although use of antibiotics in the setting of sepsis and other severe infections is lifesaving, it is not without risk. Such risks include allergic reactions, bone marrow suppression, diarrhea, nausea and vomiting, acute kidney injury (AKI), ototoxicity and the emergence of antibiotic resistant organisms. Of these, antibiotic-induced AKI has garnered special attention because it has been established that preventable medication-induced AKI is associated with an increased risk for developing chronic kidney disease and death.2,3,4 In light of this, efforts have been made to identify the various risk factors associated with AKI in hospitalized patients, with a more recent focus on certain antibiotic combinations.
For the management of serious bacterial infections, combination antibiotic therapy is often initially employed as empiric therapy. A frequently used combination includes vancomycin for suspected gram-positive infections and an extended spectrum beta lactam to cover gram-negatives. Piperacillin alone is reported by the manufacturer’s prescribing information to increase blood urea nitrogen and serum creatinine in approximately 1.8 percent of the population.5 Vancomycin alone has been associated with AKI in up to 22 percent of pediatric patients and when paired with other nephrotoxic agents, this risk has been shown to increase.6
This known hazard has prompted Dayton Children’s Antibiotic Stewardship Team (AST) to conduct daily pharmacokinetic monitoring of all vancomycin serum concentrations and to implement guidelines for vancomycin use as part of the seven- part strategy to improve the safe and effective use of antibiotics at Dayton Children’s. While this approach has been successful in reducing the severity of AKI, the incidence remains unchanged. Addressing and eliminating some common risk factors that were initially noted in 2013 to 2014, less common factors have emerged as prominent causes for currently jeopardizing safe vancomycin use.
review of the literature
The pairing of vancomycin with piperacillin-tazobactam has recently been reported as a suspected nephrotoxic combination. A meta-analysis of ten observational cohort studies, including 2,688 adult patients, reported a significant association of the development of AKI with the combined use of vancomycin and piperacillin-tazobactam versus vancomycin alone. In the same meta-analysis, four studies involving a total of 570 adult patients compared the association for the development of AKI with combination of vancomycin plus piperacillin-tazobactam versus the combination of vancomycin plus another beta lactam. No significant association was noted in the latter group, suggesting vancomycin may be paired with other extended spectrum beta lactams without increased risk for AKI.7
In 2014, Pratt et al reported the first case series of piperacillin-tazobactam induced AKI in children.8 Four pediatric patients being treated for febrile neutropenia developed AKI shortly after piperacillin-tazobactam administration, with only one patient with biopsy evidence of interstitial nephritis. The authors, although attributing all four cases of AKI to possible interstitial nephritis, theorized that the severity of AKI was exacerbated by the addition of vancomycin. Goal vancomycin serum concentrations were not reported.
A young patient admitted to the pediatric intensive care unit for concerns of potential pneumonia was the subject of the first published case report of a child experiencing AKI while receiving both vancomycin and piperacillin-tazobactam in 2016.9 On the third hospital day, the piperacillin-tazobactam was maximized at 100 mg/kg/dose IV every six hours and the vancomycin dose was increased to 18.5 mg/kg/dose IV every six hours following a subtherapeutic trough.
On hospital day four, her serum creatinine had increased from a baseline of 0.4 mg/dl to 1.16 mg/ dl, with a corresponding serum vancomycin trough concentration of 37 mcg/ ml. No other nephrotoxins were identified in her drug regimen, so both the piperacillin-tazobactam and vancomycin were discontinued and replaced by other antibiotics. Her follow-up vancomycin trough 36 hours after her last dose was 5 mcg/ml and the serum creatinine declined to 0.49 mg/dl on hospital day ten.
Nephrotoxicity occurred in 3.8 percent of patients receiving vancomycin alone and 23.6 percent of patients receiving the combination therapy (P=0.0001) in a retrospective single center cohort study of 79 pediatric patients treated with vancomycin and 106 patients treated with vancomycin and piperacillin-tazobactam. The authors noted that concomitant nephrotoxic medication, critical illness warranting intensive care admission, and vancomycin troughs of >15 mcg/ ml could not be excluded as additional risk factors. Limitations of the study included short duration of treatment, lack of inclusion of intravenous contrast as a potential nephrotoxin, and unequal treatment group sizes.10
A retrospective cohort study of children aged 6 months to 18 years who were hospitalized for more than three days and received vancomycin in addition to one other antipseudomonal beta lactam antibiotic was just published in October 2017. Among this cohort of 1,915 patients from six pediatric hospitals, 157 patients developed antibiotic associated AKI. After adjusting for age, level of care, receipt of other nephrotoxins and hospital, the antibiotic combination of vancomycin plus piperacillin-tazobactam was associated with a higher odds ratio of AKI each day compared with vancomycin plus one other antipseudomonal beta lactam combination.11
antibiotic stewardship team response
Shortly after the stewardship team was developed in 2011, an evidence-based guideline for dosing and monitoring of vancomycin was implemented. The Infectious Disease Society of America (IDSA) recommended that goal troughs of 15-20 mcg/ml must be set not only for severe infections but for all infections caused by methicillin resistant Staphylococcus aureus (MRSA).12 The rationale is based on the fact that the vancomycin minimum inhibitory concentration (MIC) for MRSA at Dayton Children’s is ≥ 1 mcg/ml for greater than 50 percent of our isolates. In order to achieve the recommended area under the serum concentration time curve to MIC ratio (AUC:MIC) of 400, goal troughs of 10-20 mcg/ml must be achieved for adequate efficacy. A standard dose of 15 mg/kg total body weight intravenously every six hours in children less than 16 years of age, and 15 mg/kg total body weight every eight hours in children age 16 years or older was recommended to comply with the IDSA MRSA guidelines for pediatric patients.13
Using these initial recommendations, we encountered three cases of vancomycin-induced nephrotoxicity, two of which required acute hemodialysis in the summer of 2015. A multidisciplinary team was developed to devise new recommendations for improvement in vancomycin monitoring and dosing. All patients who had received vancomycin from 2013 to 2015 were reviewed. Out of 564 patients meeting criteria, a total of 15 patients met the definition of vancomycin-induced AKI according to the Kidney Disease Improving Global Outcomes Group (KDIGO) criteria.14 The criteria adopted by the Dayton Children’s AST were that of KDIGO, which defines AKI as greater than or equal to 1.5 times the baseline serum creatinine or an absolute increase in serum creatinine of 0.3 mg/dl. The records of these 15 patients were then reviewed in depth for all possible risk factors.
In September 2015, expanded monitoring criteria were approved by the ad hoc multidisciplinary committee and implemented by the AST (Table 1).
A quality improvement project was then undertaken to determine if the intervention resulted in reduced incidence or severity of vancomycin-induced AKI. The results of that project can be found in Figure 1. Implementation of the expanded vancomycin monitoring criteria reduced the severity of vancomycin-induced AKI as measured by the ratio of the maximum serum creatinine to baseline creatinine in patients who had vancomycin troughs of > 20 mcg/ml. A significant decrease in the median maximum serum creatinine to baseline creatinine ratio from 6.0 to 1.80 was noted in the following two years from implementation of the expanded monitoring tool. The incidence, however, has remained fairly constant at nine cases per year prior to the intervention to an average of eight (10-6) per year after the intervention.
The most common risk factors for vancomycin-induced AKI both before and after implementation of the expanded monitoring criteria are listed in Table 2. Following implementation, four of the most common risk factors declined in incidence; however, concurrent use of piperacillin-tazobactam emerged from the last to the number one risk factor for vancomycin-induced AKI. All six patients experiencing this adverse effect in 2017 had been receiving the combination. In five patients, the AKI developed within 24 to 48 hours of initiating the combination. Although the addition of piperacillin-tazobactam to vancomycin was originally recognized as a potential risk factor, the rapidity with which the nephrotoxicity can occur was not previously appreciated.
The mechanism by which the combination of piperacillin-tazobactam and vancomycin appear to increase nephrotoxicity is unknown. Piperacillin has been shown to decrease tubular secretion of flucloxacillin by competitive inhibition of the tubular secretion site by piperacillin in healthy volunteers. This inhibition appears to be greater at higher piperacillin doses.15 A similar phenomenon has been reported for methotrexate and piperacillin in the rabbit model. The renal clearance of methotrexate was significantly reduced in the presence of piperacillin.16 If similar renal clearance inhibition occurs with vancomycin, increased nephrotoxicity may result.
Next steps for the Dayton Children’s AST include identifying and promoting via clinical practice guidelines safe and effective alternative combinations of antibiotics for empiric gram-negative and gram-positive infections, which could reduce both the incidence and severity of vancomycin-induced AKI.
- Lasky T, Ernst FR, Greenspan J, Wang S, GonzalezL. Estimating pediatric inpatient medication use in the United States. Pharmacoepidemiol Drug Saf. 2011;20(1):76-82.
- Pannu N, Nadim MK. An overview of drug-induced acute kidney injury. Crit Care Med. 2008;36(4 sup-pl):S216-S223.
Menon S, Kirkendall E, Nguyen H, Goldstein S. Acute kidney injury associated with high nephrotoxic medication exposure leads to chronic kidney disease after 6 months. J Pediatr. 2014;165(3):522-527.
Ali T, Khan I, Simpson W, et al. Incidence and outcomes in acute kidney injury: A comprehensive population-based study. J Am Soc Nephrol. 2007;2(3):431-9.
Pfizer. Zosyn (Piperacillin-tazobactam) prescribing information. Philadelphia, PA: 2016.
McKamy S, Hernandez E, Jahng M, Moriwaki T, Dev-eikis A, Le J. Incidence and risk factors influencing the development of vancomycin nephrotoxicity in children. J Pediatr. 2011;158(3):422-426.
Giuliano C, Patel C, Kale-Pradhan P. Is the combination of piperacillin-tazobactam and vancomycin associated with the development of acute kidney injury? A meta-analysis. Pharmacotherapy. 2016;36(12):12171228.
Pratt J, Stricherz M, Verghese P, Burke M. Suspected piperacillin-tazobactam induced nephrotoxicity in the pediatric oncology population. Pediatr Blood Cancer. 2014;61:366-368.
Ibach B, Henry E, Johnson P. Acute kidney injury in a child receiving vancomycin and piperacillin-tazobact-am. J Pediatr Pharmacol Ther. 2016;21(3):169-175.
- McQueen K, Clark D. Does combination therapy with vancomycin and piperacillin-tazobactam increase the risk of nephrotoxicity versus vancomycin alone in pediatric patients? J Pediatr Pharmacol Ther. 2016;21(4):332-338.
Downes KJ, Cowden C, Laskin BL, et al. Association of acute kidney injury with concomitant vancomy-cin and piperacillin/tazobactam treatment among hospitalized children. JAMA Pediatr. Published online October 02, 2017. doi:10.1001/jamapediat-rics.2017.3219.
Moise-Broder P, Forrest A, Birmingham M, Schentag J. Pharmacodynamics of vancomcyin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;42:925-42.
Liu C, Bayer A, Cosgrove S, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;3E18-55.
Kellum J, Lamiere N, Group KAGW. Diagnosis, evaluation, and management of acute injury: A KDIGO summary (part 1). Crit Care. 2013:17(1):2014.
Najjar T, Abou-Adua H, Ghilzai N. Influence of pip-eracillin on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate. Cancer Chemother Pharma-col. 1998;42(5):423-428.
- Landersdorfer C, Kirkpatrick C, Kinzig M, Bulitta J, Holzgrabe U, Sorgel F. Inhibition of flucloxacillin tubular renal secretion by piperacillin. Br J Clin Phar-macol. 2008;66(5):648-659.