Editorial Commentary
Increased Vancomycin Exposure and Nephrotoxicity in Children: Therapeutic Does Not Mean Safe Kevin J. Downes,1,2 Stuart L. Goldstein,3,4 and Alexander A. Vinks2,4 Divisions of 1Infectious Diseases; 2Clinical Pharmacology; 3Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Ohio; and 4College of Medicine, University of Cincinnati, Ohio Corresponding Author: Kevin J. Downes, MD, Division of Infectious Diseases, The Children’s Hospital of Philadelphia, Abramson Research Building, Room 1202, Philadelphia, PA 19104. Email: [email protected]. Received November 4, 2014; accepted November 25, 2014; electronically published December 29, 2014.
Vancomycin-associated nephrotoxicity has been the subject of renewed debate over recent years. In 2011, the Infectious Diseases Society of America recommended vancomycin doses of 15 mg/kg per dose every 6 hours for children with serious or invasive infections due to methicillinresistant Staphylococcus aureus [1]. These guidelines also suggest targeting trough concentrations (Cmin) of 15–20 µg/mL for children to maximize the likelihood of achieving a 24-hour vancomycin area under the curve over the minimum inhibitory concentration (AUC24/MIC) 400 for isolates with a vancomycin MIC 1 µg/mL, which is the pharmacokinetic/pharmacodynamic (PK/PD) index that best predicts efficacy in adults. After incorporation of these more aggressive dosing recommendations into clinical practice, several authors have reported an association between larger vancomycin doses, increased vancomycin troughs, and nephrotoxicity in pediatric patients [2, 3]. Consequently, discussion surrounds whether the recommended troughs of 15–20 µg/mL are optimal for pediatric patients and lead to added risk of toxicity. Acute kidney injury (AKI) has important short- and long-term ramifications in children. Patients who sustain
AKI are at risk for prolonged intensive care unit (ICU) and hospital admission [4], increased mortality [4, 5], and development of chronic kidney disease [5, 6]. Critically ill children who develop AKI during vancomycin therapy, specifically, have higher mortality [2, 7]. Therefore, a tenuous balance exists between the successful treatment of infection and the safe administration of vancomycin in our most vulnerable patients. In this issue of the Journal of the Pediatric Infectious Diseases Society, Le et al [8] applied population-based PK/PD modeling with Bayesian estimation to examine the relationship between vancomycin drug exposure (AUC24 and Cmin) and nephrotoxicity. Utilizing a retrospective cohort design, the authors combined established population PK-modeling techniques with Bayesian estimation to estimate PK parameters for individuals in the study. After a series of analyses, the authors concluded that both vancomycin AUC24 800 mg h/L and Cmin 15 μg/mL are strong independent predictors of nephrotoxicity in children. These findings substantiate an exposure-response relationship between vancomycin and renal toxicity and support the need to identify the optimal dosing and monitoring strategies in children. However, this study
Journal of the Pediatric Infectious Diseases Society, Vol. 5, No. 1, pp. 65–7, 2016. DOI:10.1093/jpids/piu122 © The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: [email protected].
has some limitations and raises additional questions. The authors utilized a onecompartment model with firstorder kinetics in this study. A one-compartment model assumes that the drug in the blood is in rapid equilibrium with the tissues, whereas first-order kinetics refers to a proportional relationship between drug concentration in the blood and elimination. Meanwhile, both AUC24 and Cmin are related directly to dose and inversely to total body clearance. Although Cmin is affected by dosing interval and AUC24 is not, these parameters are highly related to one another. This association actually provides the basis for using trough concentrations as a proxy for AUC24 in clinical practice. The strong correlation between AUC24 and Cmin in the current study (Spearman’s coefficient = 0.963, P < .001) confirms this interrelationship and raises questions about if and how these parameters confer independent nephrotoxic risks. Animal studies demonstrate that vancomycin causes nephrotoxicity via dose-dependent oxidative stress on renal proximal tubules cells [9], so the association between increased vancomycin exposure and AKI is expected. However, teasing out whether AUC24, Cmin, or both drive toxicity
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and how duration of exposure plays a role may require further study. It is challenging to ascertain the independent risk of vancomycin exposure on nephrotoxicity among a population of both ICU and nonICU patients. Critically ill patients are at higher risk for AKI, and the causes are often multifactorial: decreased renal perfusion, multiorgan dysfunction, concomitant receipt of multiple nephrotoxins, and sepsis [10]. Le et al [8] appropriately adjust for ICU admission and concomitant nephrotoxins in their multivariate model, and they assess for potential effect modification. However, to adequately account for the multiple factors that both differ between ICU and non-ICU patients and could confound the relationship between vancomycin exposure and nephrotoxicity in a retrospective study is difficult. The time-to-toxicity reported in this study was short (median, 3 days). Serum creatinine is a suboptimal marker of kidney injury: it is nonspecific and detectable changes are often delayed. Therefore, it is plausible that higher AUC24 and Cmin values in patients with early toxicity actually reflect impaired vancomycin clearance in the setting of undetected renal dysfunction present at vancomycin initiation. The close proximity between AKI onset and vancomycin measurement (steady state, 72 hours) also makes it hard to establish a causal relationship between increased vancomycin exposure and early nephrotoxicity. However, it highlights the need for close monitoring of high-risk patients, those who are critically ill, receiving other nephrotoxins, or with high vancomycin trough/AUC24, throughout the course of therapy. The current study by Le et al [8] provides strong support for an exposure-nephrotoxicity relationship for vancomycin. These findings are consistent with previous pediatric
studies [2, 3]. With the use of higher doses and the resultant increased drug exposure (AUC24 and Cmin), all children are at risk for AKI during vancomycin therapy. So, how do we improve its use in children? First and foremost, prospective controlled trials are needed to identify and validate the optimal PK/PD targets for vancomycin in children. The AUC24/ MIC >400 is the PK/PD index most closely related to efficacy in adults. Yet, AUC24/MIC is not routinely used clinically due to practical limitations in measuring AUC24. Most pediatricians continue to focus on troughs of 15–20 μg/mL despite the associated risks of toxicity and ongoing debate about the appropriateness of this surrogate target. With improved therapeutic goals, clinicians can implement personalized dose-optimization strategies to maximize efficacy and minimize toxicity (and antimicrobial resistance). For example, the use of clinical software packages that incorporate population PK model data and use Bayesian estimation techniques can help predict an individual patient’s vancomycin clearance and AUC24 early (eg, on day 1) and more effectively allow attainment of optimal target exposures in children. Second, infectious diseases specialists need to be cognizant of the untoward effects of nephrotoxic AKI in children. Patients with serious and life-threatening infections may require aggressive antimicrobial dosing to rapidly achieve therapeutic drug concentrations and optimize bacterial killing. However, increased vancomycin exposure can precipitate the onset of renal dysfunction and further complicate management. The added risks for mortality and development of chronic kidney disease from AKI are not negligible. Serial monitoring of drug levels and markers of kidney injury and function in high-risk patients are crucial. In addition, consideration
should be given to discontinuation of other nephrotoxins during vancomycin courses when feasible. Finally, improved identification of children at highest risk for AKI can support optimal dosing and alternative drug selection. It is easy to rationalize use of other antibiotics for treatment of vancomycin-resistant infections, but vancomycin may not be the ideal agent for all children with sensitive isolates either. Serum creatinine can be an unreliable marker of kidney injury and function in children. Functional biomarkers, such as cystatin C, which show improved correlation with vancomycin clearance compared with serum creatinine, can provide better means to determine optimal vancomycin doses or identify children at risk for subsequent AKI in whom alternative antibiotics are warranted. Sensitive damage biomarkers, such as urinary neutrophil gelatinase-associated lipocalin, can promote early detection of AKI and prompt proactive dose adjustments. Although additional research is needed, the use of biomarkers and clinical PK/PD dosing software has great potential to facilitate the optimization of vancomycin in children. Acknowledgments Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Financial support. This work was funded by the National Institute of Child Health and Human Development of the National Institutes of Health (award number 5T32HD069054; to K. J. D.), Cincinnati Training Program in Pediatric Clinical and Developmental Pharmacology and in part by the Agency for Healthcare Research and Quality Center for Education and Research on Therapeutics (grant AHRQ CERT 1U19HS021114; to S. L. G.). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Vancomycin Exposure and Nephrotoxicity
References 1. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18–55. 2. Knoderer CA, Nichols KR, Lyon KC, et al. Are elevated vancomycin serum trough concentrations achieved within the first 7 days of therapy associated with acute kidney injury in children? J Pediatr Infect Dis Soc 2014; 3:127–31. 3. McKamy S, Hernandez E, Jahng M, et al. Incidence and risk factors influencing the development of vancomycin
4.
5.
6.
7.
nephrotoxicity in children. J Pediatr 2011; 158:422–6. Bresolin N, Bianchini AP, Haas CA. Pediatric acute kidney injury assessed by pRIFLE as a prognostic factor in the intensive care unit. Pediatr Nephrol 2013; 28:485–92. Askenazi DJ, Feig DI, Graham NM, et al. 3–5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 2006; 69:184–9. Menon S, Kirkendall ES, Nguyen H, Goldstein SL. Acute kidney injury associated with high nephrotoxic medication exposure leads to chronic kidney disease after 6 months. J Pediatr 2014; 165:522–7.e2. Totapally BR, Machado J, Lee H, et al. Acute kidney injury during vancomycin
therapy in critically ill children. Pharmacotherapy 2013; 33:598–602. 8. Le J, Ny P, Capparelli E, et al. Pharmacodynamic characteristics of nephrotoxicity associated with vancomycin use in children. J Pediatr Infect Dis Soc 2015; 4:e109–e116. 9. Nishino Y, Takemura S, Minamiyama Y, et al. Targeting superoxide dismutase to renal proximal tubule cells attenuates vancomycin-induced nephrotoxicity in rats. Free Radic Res 2003; 37: 373–9. 10. Hui-Stickle S, Brewer ED, Goldstein SL. Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis 2005; 45: 96–101.
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Increased Vancomycin Exposure and Nephrotoxicity in Children: Therapeutic Does Not Mean Safe Kevin J. Downes,1,2 Stuart L. Goldstein,3,4 and Alexander A. Vinks2,4 Divisions of 1Infectious Diseases; 2Clinical Pharmacology; 3Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Ohio; and 4College of Medicine, University of Cincinnati, Ohio Corresponding Author: Kevin J. Downes, MD, Division of Infectious Diseases, The Children’s Hospital of Philadelphia, Abramson Research Building, Room 1202, Philadelphia, PA 19104. Email: [email protected]. Received November 4, 2014; accepted November 25, 2014; electronically published December 29, 2014.
Vancomycin-associated nephrotoxicity has been the subject of renewed debate over recent years. In 2011, the Infectious Diseases Society of America recommended vancomycin doses of 15 mg/kg per dose every 6 hours for children with serious or invasive infections due to methicillinresistant Staphylococcus aureus [1]. These guidelines also suggest targeting trough concentrations (Cmin) of 15–20 µg/mL for children to maximize the likelihood of achieving a 24-hour vancomycin area under the curve over the minimum inhibitory concentration (AUC24/MIC) 400 for isolates with a vancomycin MIC 1 µg/mL, which is the pharmacokinetic/pharmacodynamic (PK/PD) index that best predicts efficacy in adults. After incorporation of these more aggressive dosing recommendations into clinical practice, several authors have reported an association between larger vancomycin doses, increased vancomycin troughs, and nephrotoxicity in pediatric patients [2, 3]. Consequently, discussion surrounds whether the recommended troughs of 15–20 µg/mL are optimal for pediatric patients and lead to added risk of toxicity. Acute kidney injury (AKI) has important short- and long-term ramifications in children. Patients who sustain
AKI are at risk for prolonged intensive care unit (ICU) and hospital admission [4], increased mortality [4, 5], and development of chronic kidney disease [5, 6]. Critically ill children who develop AKI during vancomycin therapy, specifically, have higher mortality [2, 7]. Therefore, a tenuous balance exists between the successful treatment of infection and the safe administration of vancomycin in our most vulnerable patients. In this issue of the Journal of the Pediatric Infectious Diseases Society, Le et al [8] applied population-based PK/PD modeling with Bayesian estimation to examine the relationship between vancomycin drug exposure (AUC24 and Cmin) and nephrotoxicity. Utilizing a retrospective cohort design, the authors combined established population PK-modeling techniques with Bayesian estimation to estimate PK parameters for individuals in the study. After a series of analyses, the authors concluded that both vancomycin AUC24 800 mg h/L and Cmin 15 μg/mL are strong independent predictors of nephrotoxicity in children. These findings substantiate an exposure-response relationship between vancomycin and renal toxicity and support the need to identify the optimal dosing and monitoring strategies in children. However, this study
Journal of the Pediatric Infectious Diseases Society, Vol. 5, No. 1, pp. 65–7, 2016. DOI:10.1093/jpids/piu122 © The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: [email protected].
has some limitations and raises additional questions. The authors utilized a onecompartment model with firstorder kinetics in this study. A one-compartment model assumes that the drug in the blood is in rapid equilibrium with the tissues, whereas first-order kinetics refers to a proportional relationship between drug concentration in the blood and elimination. Meanwhile, both AUC24 and Cmin are related directly to dose and inversely to total body clearance. Although Cmin is affected by dosing interval and AUC24 is not, these parameters are highly related to one another. This association actually provides the basis for using trough concentrations as a proxy for AUC24 in clinical practice. The strong correlation between AUC24 and Cmin in the current study (Spearman’s coefficient = 0.963, P < .001) confirms this interrelationship and raises questions about if and how these parameters confer independent nephrotoxic risks. Animal studies demonstrate that vancomycin causes nephrotoxicity via dose-dependent oxidative stress on renal proximal tubules cells [9], so the association between increased vancomycin exposure and AKI is expected. However, teasing out whether AUC24, Cmin, or both drive toxicity
66
Downes et al
and how duration of exposure plays a role may require further study. It is challenging to ascertain the independent risk of vancomycin exposure on nephrotoxicity among a population of both ICU and nonICU patients. Critically ill patients are at higher risk for AKI, and the causes are often multifactorial: decreased renal perfusion, multiorgan dysfunction, concomitant receipt of multiple nephrotoxins, and sepsis [10]. Le et al [8] appropriately adjust for ICU admission and concomitant nephrotoxins in their multivariate model, and they assess for potential effect modification. However, to adequately account for the multiple factors that both differ between ICU and non-ICU patients and could confound the relationship between vancomycin exposure and nephrotoxicity in a retrospective study is difficult. The time-to-toxicity reported in this study was short (median, 3 days). Serum creatinine is a suboptimal marker of kidney injury: it is nonspecific and detectable changes are often delayed. Therefore, it is plausible that higher AUC24 and Cmin values in patients with early toxicity actually reflect impaired vancomycin clearance in the setting of undetected renal dysfunction present at vancomycin initiation. The close proximity between AKI onset and vancomycin measurement (steady state, 72 hours) also makes it hard to establish a causal relationship between increased vancomycin exposure and early nephrotoxicity. However, it highlights the need for close monitoring of high-risk patients, those who are critically ill, receiving other nephrotoxins, or with high vancomycin trough/AUC24, throughout the course of therapy. The current study by Le et al [8] provides strong support for an exposure-nephrotoxicity relationship for vancomycin. These findings are consistent with previous pediatric
studies [2, 3]. With the use of higher doses and the resultant increased drug exposure (AUC24 and Cmin), all children are at risk for AKI during vancomycin therapy. So, how do we improve its use in children? First and foremost, prospective controlled trials are needed to identify and validate the optimal PK/PD targets for vancomycin in children. The AUC24/ MIC >400 is the PK/PD index most closely related to efficacy in adults. Yet, AUC24/MIC is not routinely used clinically due to practical limitations in measuring AUC24. Most pediatricians continue to focus on troughs of 15–20 μg/mL despite the associated risks of toxicity and ongoing debate about the appropriateness of this surrogate target. With improved therapeutic goals, clinicians can implement personalized dose-optimization strategies to maximize efficacy and minimize toxicity (and antimicrobial resistance). For example, the use of clinical software packages that incorporate population PK model data and use Bayesian estimation techniques can help predict an individual patient’s vancomycin clearance and AUC24 early (eg, on day 1) and more effectively allow attainment of optimal target exposures in children. Second, infectious diseases specialists need to be cognizant of the untoward effects of nephrotoxic AKI in children. Patients with serious and life-threatening infections may require aggressive antimicrobial dosing to rapidly achieve therapeutic drug concentrations and optimize bacterial killing. However, increased vancomycin exposure can precipitate the onset of renal dysfunction and further complicate management. The added risks for mortality and development of chronic kidney disease from AKI are not negligible. Serial monitoring of drug levels and markers of kidney injury and function in high-risk patients are crucial. In addition, consideration
should be given to discontinuation of other nephrotoxins during vancomycin courses when feasible. Finally, improved identification of children at highest risk for AKI can support optimal dosing and alternative drug selection. It is easy to rationalize use of other antibiotics for treatment of vancomycin-resistant infections, but vancomycin may not be the ideal agent for all children with sensitive isolates either. Serum creatinine can be an unreliable marker of kidney injury and function in children. Functional biomarkers, such as cystatin C, which show improved correlation with vancomycin clearance compared with serum creatinine, can provide better means to determine optimal vancomycin doses or identify children at risk for subsequent AKI in whom alternative antibiotics are warranted. Sensitive damage biomarkers, such as urinary neutrophil gelatinase-associated lipocalin, can promote early detection of AKI and prompt proactive dose adjustments. Although additional research is needed, the use of biomarkers and clinical PK/PD dosing software has great potential to facilitate the optimization of vancomycin in children. Acknowledgments Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Financial support. This work was funded by the National Institute of Child Health and Human Development of the National Institutes of Health (award number 5T32HD069054; to K. J. D.), Cincinnati Training Program in Pediatric Clinical and Developmental Pharmacology and in part by the Agency for Healthcare Research and Quality Center for Education and Research on Therapeutics (grant AHRQ CERT 1U19HS021114; to S. L. G.). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Vancomycin Exposure and Nephrotoxicity
References 1. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18–55. 2. Knoderer CA, Nichols KR, Lyon KC, et al. Are elevated vancomycin serum trough concentrations achieved within the first 7 days of therapy associated with acute kidney injury in children? J Pediatr Infect Dis Soc 2014; 3:127–31. 3. McKamy S, Hernandez E, Jahng M, et al. Incidence and risk factors influencing the development of vancomycin
4.
5.
6.
7.
nephrotoxicity in children. J Pediatr 2011; 158:422–6. Bresolin N, Bianchini AP, Haas CA. Pediatric acute kidney injury assessed by pRIFLE as a prognostic factor in the intensive care unit. Pediatr Nephrol 2013; 28:485–92. Askenazi DJ, Feig DI, Graham NM, et al. 3–5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 2006; 69:184–9. Menon S, Kirkendall ES, Nguyen H, Goldstein SL. Acute kidney injury associated with high nephrotoxic medication exposure leads to chronic kidney disease after 6 months. J Pediatr 2014; 165:522–7.e2. Totapally BR, Machado J, Lee H, et al. Acute kidney injury during vancomycin
therapy in critically ill children. Pharmacotherapy 2013; 33:598–602. 8. Le J, Ny P, Capparelli E, et al. Pharmacodynamic characteristics of nephrotoxicity associated with vancomycin use in children. J Pediatr Infect Dis Soc 2015; 4:e109–e116. 9. Nishino Y, Takemura S, Minamiyama Y, et al. Targeting superoxide dismutase to renal proximal tubule cells attenuates vancomycin-induced nephrotoxicity in rats. Free Radic Res 2003; 37: 373–9. 10. Hui-Stickle S, Brewer ED, Goldstein SL. Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis 2005; 45: 96–101.
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