antibiotic stewardship: preventing vancomycin-induced acute kidney injury in hospitalized pediatric patients

Article contributed by: 

Jon Woltmann, MD, - division of infectious disease, Dayton Children’s Hospital

Patricia Christoff, RPh, Pharm D, BCPPS - clinical pharmacist and antibiotic stewardship, Dayton Children's Hospital

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.

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References