Vancomycin seems to be a timeless drug. For many years, people have predicted its demise, though it remains one of the most frequently prescribed antibiotics in the hospital setting, saving lives and keeping pharmacists with steady work. Vancomycin came onto the market in the late 1950s after it was found to ‘vanquish’ gram-positive bacteria, including penicillin-resistant staphylococci. However, it was infrequently used because of its toxicity, potentially from impurities in the product (nicknamed ‘Mississippi mud’), and lack of clinical need (low rates of resistant gram-positive bacteria). It wasn’t until the early 1980s when an increase in drug resistance and improved purification processes facilitated vancomycin use, which dramatically increased over the next two decades. With the removal of impurities from the product, nephrotoxicity was thought to be limited to coadministration with other nephrotoxins (particularly aminoglycosides), or rarely, caused by acute interstitial nephritis (AIN).
However, in 2011, a case series of biopsy-proven acute tubular necrosis (ATN) caused by vancomycin was published, changing how people thought about vancomycin nephrotoxicity. Animal data supported this mechanism, describing renal proximal tubular ischemia from vancomycin-induced oxidative stress. In addition to direct toxicity, a novel pathogenic mechanism for vancomycin nephrotoxicity has been suggested, with concentric vancomycin aggregates causing cast nephropathy.
Rates of vancomycin-induced nephrotoxicity vary in published reports. The incidence of nephrotoxicity across studies is widely quoted as between 5% and 43% based on a 2013 systematic review. In prospective study compared to linezolid, vancomycin-induced AKI was seen in 18.2% of patients, with rates of AKI in the linezolid lower at 8.4%. Interestingly in the CAMERA2 study, nephrotoxicity in the monotherapy arm (predominantly vancomycin monotherapy), only occurred in 6% of patients.
Higher vancomycin trough concentrations are commonly associated with higher rates of kidney injury. Every vancomycin concentration above 0mg/L has an increased risk of nephrotoxicity. A major criticism of the assumption that higher vancomycin concentrations are related to decreased renal function is that as vancomycin is 90% renally excreted, so any decrease in renal function will increase vancomycin concentration. Other identified risk factors for vancomycin-induced nephrotoxicity include duration of therapy (ie longer than 7 days), greater patient weight (ie over 100 kg), pre-existing kidney disease or previous episode of AKI, concomitant use of nephrotoxins and longer duration of admission in an ICU. A 2021 multicenter retrospective analysis found the majority of vancomycin induced AKIs occurred within 7 days of starting therapy, with a peak at day 3.
More recently, the risk of nephrotoxicity with vancomycin has been shown to be reduced with the use of 24-hour area under the curve (AUC₀₋₂₄) concentration monitoring. Trough concentrations are currently used in Australia for monitoring vancomycin as a surrogate for AUC—the pharmacodynamic parameter associated with efficacy for vancomycin. To ensure an adequate AUC (ie above 400mg*hr/L), higher trough concentrations are recommended than may be required, potentially resulting in excessively high vancomycin doses and exposure. When patients receiving trough-guided therapy were compared to patients receiving AUC-guided therapy, AUC-guided therapy resulted in approximately half the rate of nephrotoxicity compared to those in the trough-guided arm (after adjustment for severity, comorbidities and concomitant nephrotoxins). The daily vancomycin dose, median trough and AUC at 48 hours were significantly lower in the AUC-guided therapy arm, driving the reduction in nephrotoxicity. The 2020 revised consensus guideline ‘Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections’, from the US now recommends AUC-guided monitoring of vancomycin to ensure efficacy and reduce nephrotoxicity, with a target of 400-600mg*hr/L. In a post-hoc analysis of the CAMERA2 trial, a vancomycin AUC of 470 mg*hr/L was significantly associated with an increased risk of AKI. These results are important as they show the risk of AKI even within the recommended vancomycin AUC range.
In animal models, vancomycin-induced kidney injury was better correlated to Cmax (peak concentration) or AUC₀₋₂₄ than trough concentration. It remains to be seen which of these parameters is most predictive of nephrotoxicity in humans, which will have implications for developing optimal vancomycin dosing strategies.
So where does all this leave us? Certainly, for many of us, vancomycin remains a valuable and time-tested tool in the antimicrobial shed. However, how can we make sure our patients, and their kidneys, survive a course of therapy? Despite advances in understanding, we haven’t found a silver bullet just yet. AUC-based monitoring is time consuming, and the benefits are related to the use of lower doses, could the same be seen with 8-hourly regimens or continuous infusions? Also, in the aftermath of CAMERA2, how much nephrotoxicity was coming from vancomycin and penicillin interactions, erroneously blamed on vancomycin. Ideally, with limiting vancomycin and flucloxacillin combination therapy, optimising dosing regimens to minimise toxicity, and avoidance in patients with multiple risk factors, we can reduce vancomycin nephrotoxicity. It may take a bit more work to get there, however, surely vancomycin has earned its place on our research agendas.