Vancomycin and the Risk of AKI: Now Clearer than Mississippi Mud

• vancomycin
• acute renal failure
• nephrotoxicity
• drug nephrotoxicity
• Acute Kidney Injury
• Mississippi
• Risk
• Vancomycin

Drug selection and dosing should be carried out with a firm understanding of the risk–benefit profile in individual patients in order to ensure a maximal likelihood of safety during treatment. Unfortunately, all drugs possess inherent risks. Unintended adverse effects not only tip the risk–benefit profile in an unfavorable direction, but often have major consequences, leading to increased morbidity, hospital admissions, length of stay, mortality, and health care costs (1). Drug-associated AKI is no exception. Medications have been implicated in up to 20% of hospital admissions because of AKI (2) and in 26% of all cases of in-hospital AKI (3), and the financial implications are enormous (4,5). Clearly, a better understanding of individual drug- and patient-related risk factors would enable clinicians to optimize treatment efficacy and safety when use of drugs with known toxicity is unavoidable.

The glycopeptide antibiotic vancomycin is the mainstay of therapy for infections because of methicillin-resistant Staphylococcus aureus. The drug was discovered >60 years ago by Eli Lilly scientists, who were in search of new antibacterial agents with activity against staphylococci because of the growing threat of penicillin-resistant organisms (6). Vancomycin, nicknamed “Mississippi mud” because early preparations were impure and brown in color, exhibited exceptional bactericidal activity against Gram-positive organisms, including penicillin-resistant staphylococci in vitro and in humans. Given the lack of effective therapeutic alternatives, this prompted the US Food and Drug Administration to quickly approve vancomycin in 1958, only 6 years after its discovery. Because of concerns with early reports of ototoxicity and nephrotoxicity, along with nearly simultaneous approval of methicillin, enthusiasm for vancomycin waned. It was infrequently prescribed, considered by most to be a niche drug restricted for use in patients with β-lactam allergies or infected with drug-resistant organisms (6). However, the emergence of methicillin-resistant S. aureus in the late 1970s, along with the development of newer formulations with improved purity, stimulated a >100-fold increase in the use of vancomycin over the subsequent 20 years (6,7). As depicted in Figure 1, this has been mirrored by a staggering rise in the number of vancomycin-related articles published annually since 1980. Although the number of published articles related specifically to “vancomycin nephrotoxicity” has also risen sharply (Figure 1), our understanding of the attributable risk of AKI because of vancomycin therapy has been as clear as Mississippi mud. In this issue of the Clinical Journal of the American Society of Nephrology, Ray et al. (8) report that intravenous vancomycin treatment is associated with a legitimate, albeit modest, increased risk of kidney injury.

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Figure 1.

The number of reports with “vancomycin” in the title (left y-axis), and the number of reports of “vancomycin nephrotoxicity” (right y-axis) indexed in PubMed and published annually from 1980 to 2014 (19).

Currently, most agree that use of vancomycin monotherapy at conventional doses (e.g., 15 mg/kg every 12 hours) is safe and that nephrotoxicity is uncommon. Early studies reported incidence rates of 5%–20% (9,10), but even these numbers may be inflated by inconsistent use of criteria for assessing toxicity, AKI definitions, lack of control groups, and inadequate control of factors that may independently increase risk of AKI (e.g., procedures and patient comorbidities, particularly preexisting CKD). The current meta-analysis by Ray et al. addresses these issues, and in so doing provides clarity to our understanding of the risk of vancomycin-associated AKI. Importantly, the analysis included only cohort studies and randomized clinical trials that compared vancomycin to a non-nephrotoxic antibiotic, and this likely minimized bias because of confounding by indication. The authors report that parenteral vancomycin treatment is associated with a relative risk (RR) of AKI of 2.45 (95% confidence interval [95% CI], 1.69 to 3.55) and a corresponding attributable risk percentage of 0.59 (8). Although the RR of 2.45 may appear low in comparison to other known nephrotoxins, such as aminoglycosides (RR of up to ten) (11), the findings likely represent a conservative estimate and must be translated accordingly.

The meta-analysis has important implications that reflect its limitations. Perhaps most importantly, the study primarily included patients who received conventional vancomycin dosing and may not lend insight into the potential nephrotoxicity associated with more aggressive dosing and increased systemic exposure commonly observed in contemporary clinical practice. This topic has received considerable attention since the 2009 Infectious Diseases Society of America–endorsed clinical practice guidelines recommended maintaining trough vancomycin concentrations >10 mg/ml to avoid the development of resistance, and from 15 to 20 mg/ml in complicated infections caused by S. aureus infections to achieve the targeted area under the concentration-time curve-to-minimum inhibitory concentration ratio of ≥400 (12). Several studies strongly suggest that the higher recommended vancomycin trough concentrations and corresponding systemic exposure (13–15), or the larger doses required to achieve them (16), result in an increased risk of kidney injury. For instance, van Hal et al. (14) reported that troughs >15 mg/L were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% CI, 1.95 to 3.65) compared with troughs <15 mg/L. Similarly, Hanrahan et al. (15) reported that risk of vancomycin-associated AKI in critically ill patients increased as serum concentrations increased, with RR increasing from 1.07 to 1.53 and 2.21 (no 95% CI provided) in patients with trough concentrations of 15, 25, and >30 mg/L. These data support the notion that the RR of AKI of 2.45 observed in the setting of conventional dosing is likely to be much higher using contemporary dosing strategies, possibly because of the resulting increase in serum concentrations.

Another important limitation to bear in mind when considering the reported RR of 2.45 is that the analysis by Ray et al. primarily included studies that compared risk of AKI with vancomycin to the non-nephrotoxic antibiotic linezolid. It is well known that patients receiving concomitant nephrotoxic medications are more likely to develop vancomycin nephrotoxicity than patients who do not receive nephrotoxins (9,14). Recently, the risk of nephrotoxicity was shown to double in the setting of concomitant vancomycin and piperacillin-tazobactam therapy, rising from 8.1% in patients treated with vancomycin to 16.3% in those treated with both drugs (OR of 2.48 for the development of nephrotoxicity; one-sided chi-squared test, P=0.03; 95% CI>1.11) (17). Even more alarming is the risk of developing AKI with simultaneous use of vancomycin and aminoglycosides (OR, 18.9; 95% CI, 2.98 to 119.81) (18). Clearly, kidney toxicity profiles of individual drugs may change when used in combination with other medications, and heightened awareness is warranted in this situation.

In summary, the study by Ray et al. provides insight into the risk of AKI associated with vancomycin treatment. All drugs are associated with risks, and clinicians must be aware of not only the risk–benefit in specific patient cases, but also of factors that might alter the risk–benefit over time. Recent efforts to develop a standardized phenotype for drug-induced kidney disease will facilitate earlier recognition and improved risk–benefit assessment in the future (3). Clinicians are urged to carefully dose and proactively monitor vancomycin therapy, particularly in our most vulnerable patients at greatest risk for developing AKI, including the very young and old, critically ill, those with underlying CKD, and patients receiving multiple nephrotoxic medications.

• Copyright © 2016 by the American Society of Nephrology