By Richard R. Watkins, MD, MS, FACP, FIDSA

Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports no financial relationships relevant to this field of study.

SYNOPSIS: A retrospective cohort study from a large healthcare system found that elevated vancomycin troughs were common and associated with a higher body mass index and reduced baseline renal function, and led to more acute kidney injury and a longer hospital length of stay.

SOURCE: Zonozi R, Wu A, Shin JI, et al. Elevated vancomycin trough levels in a tertiary health system: Frequency, risk factors, and prognosis. Mayo Clin Proc 2019;94:17-26.

Vancomycin is one of the most commonly prescribed antibiotics for hospitalized patients. It was referred to informally as “Mississippi mud” when first introduced because of impurities that caused significant nephrotoxicity. Modern formulations are much purer and, hence, less nephrotoxic, but this issue remains a legitimate concern. Monitoring vancomycin trough levels is seen as a possible way to mitigate the risk. Zonozi et al aimed to determine the risk factors that lead to elevated vancomycin troughs and assess patient outcomes for those who have them.

The study was a retrospective cohort analysis from a large healthcare system that included hospitalized patients aged 18 years or older who received IV vancomycin and had at least one vancomycin trough measured. An elevated trough was defined as > 30 mg/L, while a sensitivity analysis used a lower cutoff of > 20 mg/L. A trough was defined as a vancomycin level drawn at least eight hours after the last dose.

Researchers used the first elevated level as the index event if multiple troughs were high. They calculated a baseline estimated glomerular filtration rate (eGFR) based on the closest antecedent value to the time of the first dose of vancomycin. Acute kidney injury (AKI) was defined as a creatinine increase of 0.3 mg/dL within 48 hours or a 50% increase within seven days of the elevated vancomycin level.

Of the 21,285 patients who received vancomycin during the study period of August 2007 to October 2014, 7,422 had at least one vancomycin trough drawn. Of these, 755 (10.2%) were elevated. Higher troughs occurred more frequently in younger patients, women, and those with diabetes or heart failure. Furthermore, elevated troughs occurred in 332 of 1,668 patients (19.9%) who received more than seven days of vancomycin.

Compared to patients with a normal vancomycin level, those with an elevated trough had a longer therapy duration (median 6.0 days vs. 3.4 days; P < 0.001), received higher doses (mean 1.72 g vs. 1.58 g; P < 0.001), and had a higher body mass index (BMI) and a lower eGFR. Propensity matching determined that a vancomycin trough > 30 mg/L was associated with a higher risk for developing AKI (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.09-2.20; P = 0.02), a longer hospital stay (relative risk [RR], 1.14; 95% CI, 1.02-1.28; P = 0.03), but similar in-hospital mortality. Researchers observed a linear relationship such that the higher the trough, the longer the hospital stay (RR, 1.59; 95% CI, 1.40-1.80 for a trough of 50 mg/L). When the trough level was lowered to > 20 mg/L, the risk associations were slightly attenuated.

COMMENTARY

Dosing vancomycin appropriately sometimes can be a challenge in routine practice, especially in patients with unstable renal function. The study by Zonozi et al is interesting because the authors reported the rate of elevated vancomycin troughs and subsequent outcomes using real-world data from a large healthcare system. Notably, the finding that elevated troughs were more common in those with higher BMIs may be related to the way the vancomycin dose is calculated. This is because the Cockcroft-Gault formula overestimates the glomerular filtration rate at higher BMIs.

Furthermore, it is very difficult to truly know whether an elevated vancomycin trough is the cause or consequence of renal dysfunction. The onset of AKI often is preceded by an increase in creatinine by one to two days, such that it often is unclear whether an unrecognized subclinical event led to an accumulation of vancomycin. However, Zonozi et al recognized this dilemma and took appropriate steps to increase the plausibility that the nephrotoxicity was caused by vancomycin. For example, the sensitivity analysis included only patients with creatinine values available within 24 hours of the drug level. These data were consistent with the overall finding that high troughs led to AKI.

There remains a need for more accurate vancomycin dosing models than are currently available. The authors of an accompanying editorial discussed cystatin C, an alternative biomarker recently validated in an independent cohort that was used to construct a simple dosing nomogram that was made available to clinicians through the electronic medical record. Cystatin C is a relatively new renal biomarker that is inexpensive and responds more quickly than creatinine to renal function changes. Cystatin C is not affected by factors such as sex, age, dietary intake, muscle mass, or deconditioning.1 After implementation, the frequency of initial vancomycin troughs within goal among intensive care unit patients increased from 28% to 50%. One hopes that this innovative strategy will be validated in other settings in the near future.

Despite the large sample size, there are some limitations to the study that need to be mentioned. First, there were no data on concurrent nephrotoxic agents. For example, there is an increased risk for nephrotoxicity when vancomycin is combined with piperacillin-tazobactam.2 Second, it is more common in clinical practice to consider a trough of > 20 mg/L than 30 mg/L as elevated. Finally, the observational design still might be affected by unmeasured confounding variables despite the advanced statistical methods employed by the authors. In summary, the study by Zonozi et al found that elevated vancomycin troughs are common and have important negative consequences, especially for patients who are overweight or have baseline kidney disease.

This study adds to the growing body of evidence associating modern formulations of vancomycin with nephrotoxicity and reinforces the practice of monitoring vancomycin troughs to avoid supratherapeutic levels and the resulting increase in hospital morbidity.

REFERENCES

  1. Barreto EF, Rule AD, Voils SA, et al. Innovative use of novel biomarkers to improve the safety of renally eliminated and nephrotoxic medications. Pharmacotherapy 2018;38:794-803.
  2. Watkins RR, Deresinski S. Increasing evidence of the nephrotoxicity of piperacillin/tazobactam and vancomycin combination therapy — What is the clinician to do? Clin Infect Dis 2017;65:2137-2143.