Higher-Dose Vancomycin Ups Risk for Pediatric Kidney Damage

Diana Swift

January 06, 2015

Children given high doses of the antibiotic vancomycin are at greater risk for acute kidney injury (AKI), a small retrospective review from Johns Hopkins Children's Center, Baltimore, Maryland, has reported. Highlighting the need for caution, the study, published online September 3, 2014, and in the December 2014 issue of the Annals of Pharmacotherapy, also found that longer treatment increased risk.

Led by Elizabeth A. Sinclair, PharmD, a pediatric clinical pharmacist now with Texas Children's Hospital, Houston, investigators reported that 13.7% of 175 pediatric inpatients receiving intravenous vancomycin for at least 48 hours developed AKI. This figure mirrors that reported in 2011 by McKamy and colleagues.

In multivariate regression analysis, the likelihood of AKI increased 16% with each 5 mg/kg per day increase in dose (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.01 - 1.33). Thus, a 20-kg child receiving 1600 mg vancomycin per day would have a 16% higher risk for kidney damage than a child of the same age and weight receiving 1200 mg daily.

AKI risk also rose 11% with each additional day of vancomycin therapy (OR, 1.11; 95% CI, 1.01 - 1.22) and increased substantially with the use of concomitant nephrotoxic medications, such as antineoplastic, antiviral, and antifungal drugs (OR, 5.02; 95% CI, 1.09 - 23.19).

"Patients receiving higher doses should be carefully monitored for nephrotoxicity," the authors write, adding that the risk–benefit balance of higher dosing should be carefully considered on an individual patient basis.

The average daily dose among children who developed AKI was more than 10 mg/kg higher than that given to children without AKI (65.3 mg/kg per day vs 54.7 mg/kg per day; P = .004). Patients with AKI also received a median of 1 (interquartile range, 0 - 2) nephrotoxic drug concurrently with vancomycin compared with a median of 0 for patients without AKI (interquartile range, 0 - 1; P = .042).

The researchers based the study on the electronic medical records of 175 patients, aged 3 months to less than 19 years, who were treated with vancomycin in 2009 to 2010. All had normal baseline kidney function, but 24 developed AKI according to pediatric-modified RIFLE criteria (risk, injury, failure, loss of kidney function, and end-stage kidney disease). The patients prescribed vancomycin for invasive infections, such as pneumonia, bacteremia, febrile neutropenia, and skin and soft tissue infections, all underwent regular testing to monitor kidney function.

Characteristics such as age, weight, and indication for vancomycin were similar in patients both with and without AKI, whereas those with AKI had higher glomerular filtration rates at baseline (median, 217 vs 168 mL/minute per 1.73 m2; P = .002).

In 2009, the growing prevalence of drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus, prompted new dosing guidelines for adults that sought to keep vancomycin serum trough concentrations higher in patients with infections suspected of being resistant. Some pediatric hospitals have followed suit, implementing higher doses to achieve trough concentrations of 15 to 20 mg/L in children. In 2010, for example, the Hopkins center introduced guidelines recommending doses of 45 to 80 mg/kg per day for children with normal kidney function.

Caution is in order, however. "As recommendations for higher trough concentrations with vancomycin therapy are not based on strong evidence from clinical trials in pediatric patients, it is important to weigh the risks and benefits for each patient of using increased vancomycin to achieve a higher trough goal," the investigators write.

Commenting in a Johns Hopkins press release, senior investigator Carlton Lee, PharmD, MPH, a pediatric clinical pharmacist and associate professor of pediatrics at the Children's Center, said, "Our results bear out the difficult balancing act between ensuring the dose is high enough to successfully treat these serious and, at times, life-threatening infections against the small but real risk for kidney damage." He cited the need for developing "new drugs that achieve the same therapeutic effect without taking a toll on the kidneys and other organs."

In the same release, Dr Sinclair said the results highlight the need for solid data from clinical trials in children to provide dosing guidelines not extrapolated from those for adults.

A study coauthor is supported by a grant from the National Center for Research Resources, National Institutes of Health. The other authors have disclosed no relevant financial relationships.

Ann Pharmacother. 2014;48:1555-1562. Abstract

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