Acute renal failure due to vancomycin toxicity in the setting of unmonitored vancomycin infusion

Abstract

Vancomycin-induced nephrotoxicity is a commonly feared and largely preventable adverse effect of vancomycin therapy. We present the case of a 56-year-old woman who developed acute renal failure requiring hemodialysis as a result of unmonitored vancomycin infusions for the treatment of osteomyelitis.

Vancomycin is valued for its effectiveness in the treatment of severe infections caused by methicillin-resistant Staphylococcus aureus. Vancomycin-associated nephrotoxicity can be avoided with attention to risk factors and with careful monitoring of patients receiving the antibiotic.

CASE DESCRIPTION

A 56-year-old woman presented to the emergency department from a skilled nursing facility with dyspnea. She had been discharged from the hospital to the nursing facility 18 days earlier for long-term intravenous antibiotic treatment with piperacillin-tazobactam and vancomycin for left middle toe osteomyelitis. She had hypertension, type 2 diabetes mellitus, hyperlipidemia, chronic obstructive pulmonary disease, irritable bowel syndrome, depression, anxiety, and osteomyelitis of her left first and second toes, which had been resected. In the emergency department, the patient indicated that her legs had been swollen for the past 10 days. She had decreased urination over the past week and was anuric since the day prior to presentation. She also had a dry cough, orthopnea, pleuritic pain, and a 43-pound weight increase since her previous admission. She had been given hydrochlorothiazide a few times for volume overload at the nursing home, but this did not improve her symptoms. The patient was sent to the emergency department for an acutely elevated creatinine of 4.0 mg/dL. She had been receiving scheduled intravenous vancomycin infusions without having her vancomycin trough levels monitored at the nursing facility.

At the emergency department, her blood pressure was 155/63 mm Hg; pulse, 70 beats/minute; temperature, 97.3°F; and respiratory rate, 19 breaths/minute. Her oxygen saturation was 82% on room air, which improved to 97% on 3 L oxygen via nasal cannula. Her height was 177.8 cm, weight was 152.86 kg, and body mass index was 48.3 kg/m². The patient was slightly somnolent. Her heart sounds were distant but regular and without murmurs. She had bilateral crackles upon auscultation of her lungs. The extremities had 3+ pitting edema up to her knees bilaterally. She had a slight tremor in her upper extremities bilaterally with asterixis. She had a well-healed skin ulcer of her left middle toe. Her creatinine was 6.8 mg/dL, and the vancomycin trough level was 74.6 μg/mL. Her creatinine during the previous hospitalization was 0.8 mg/dL.

Her antibiotics and hydrochlorothiazide were discontinued. Hemodialysis was initiated and her symptoms improved with daily dialysis over the next 7 days. Her urine was positive for eosinophils, and tests for antineutrophil cytoplasmic antibodies were positive. Renal biopsy revealed acute tubulointerstitial nephritis with severe acute tubular injury. She was given pulse-dose methylprednisolone and then was transitioned to oral prednisone for allergic nephritis. The patient's symptoms continued to improve. She was started on intravenous daptomycin and meropenem, with plans to switch to oral antibiotics at outpatient follow-up after discharge. Her urinary function returned to normal, her creatinine stabilized to 4.0 mg/dL, and her vancomycin blood level returned to normal. The patient was discharged home with home health with plans for close outpatient follow-up.

DISCUSSION

Vancomycin has been used for over 60 years to treat methicillin-resistant S. aureus and various resistant gram-positive infections. This antibiotic is commonly linked to nephrotoxicity, leading to the need for aggressive monitoring with regularly measured vancomycin trough levels (1–3). There are various methods to assess for vancomycin-induced renal toxicity, and inconsistencies in defining renal toxicity make it difficult to compare studies. A standardized definition was proposed in the 2009 vancomycin consensus review, which defined vancomycin-induced nephrotoxicity as a minimum of two increases in serum creatinine of at least 0.5 mg/dL or a 50% or greater increase in the serum creatinine from baseline after several days of vancomycin therapy (4).

Vancomycin is eliminated primarily through glomerular filtration and active tubular secretion. The half-life in adults with normal renal function is 4 to 8 hours (5, 6). The exact mechanism of vancomycin-induced nephrotoxicity is not completely understood; however, current data suggest that use of the antibiotic causes oxidative effects on the proximal renal tubule resulting in renal tubular ischemia. The drug has also been shown to interfere with the normal reabsorption function of the proximal renal tubule epithelium and alter the mitochondrial function of these cells. Ultimately, vancomycin-induced renal toxicity is likely due to a combination of these oxidative effects and allergic interstitial nephritis. The incidence of nephrotoxicity varies widely from 5% to 43%, depending on study parameters.

Risk factors for vancomycin-associated nephrotoxicity can be divided into three classifications: vancomycin exposure-related factors, host-related factors, and the use of concurrent nephrotoxins (1, 2, 8). Vancomycin exposure-related factors include larger vancomycin exposures, such as troughs >15 mg/L and prolonged duration of treatment. Doses of vancomycin in excess of 4 g/day have been linked to increased toxicity. Metrics that incorporate patient trough levels in the monitoring of vancomycin dosing can be useful; however, it remains unclear whether the high trough levels are the cause or result of nephrotoxicity. The American Thoracic Society and the Infectious Diseases Society of America recommend vancomycin trough levels between 15 and 20 mg/L for hospital and ventilator-associated pneumonias, bacteremia, endocarditis, osteomyelitis, and meningitis (7). Treatment with vancomycin beyond 1 week increases the incidence of nephrotoxicity from 6% to 21%, and the incidence is close to 30% with more than 2 weeks of therapy (2). Once-weekly monitoring of trough concentration is recommended in stable patients (7).

Host-related factors include a previous history of acute kidney injury or preexisting renal insufficiency, as well as sepsis and critical illnesses. Medications that are associated with an increased risk of vancomycin-associated nephrotoxicity include loop diuretics, acyclovir, amphotericin B, and aminoglycosides. The concurrent use of aminoglycosides with vancomycin has been associated with a 20% to 30% increase in renal injury (1, 9). Piperacillin-tazobactam itself is rarely associated with renal toxicity; however, the medication is frequently given with vancomycin for enhanced activity against gram-negative and anaerobic bacteria. Studies show a twofold increase in nephrotoxicity frequency in patients receiving vancomycin plus piperacillin-tazobactam. Piperacillin-tazobactam decreases the renal clearance of vancomycin, resulting in vancomycin accumulation. The concurrent use of nephrotoxins should be avoided during vancomycin therapy, and when unavoidable, these therapies should be monitored daily to limit the duration and risk of adverse effects (5).

Most mild cases of vancomycin nephrotoxicity resolve upon discontinuation of the medication. Aggressive drug elimination is indicated in patients with severely elevated plasma vancomycin concentrations compounded by impaired clearance due to oliguria, as this further increases the risk of permanent renal damage. Standard membrane dialysis is ineffective in clearing large mass molecules such as vancomycin, but high-flux hemodialysis allows for improved elimination of large molecules, with a reported vancomycin removal rate of up to 79% (10).