EDITORIAL Vancomycin: Over 50 Years Later and Still a Work in Progress Michael J. Rybak,1,* John C. Rotschafer,2 and Keith A. Rodvold3 1
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy & Health Sciences, Detroit, Michigan; 2Department of Experimental Therapeutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; 3Department of Pharmacy Practice, Colleges of Pharmacy & Medicine, University of Illinois at Chicago, Chicago, Illinois
KEY WORDS Vancomycin dosing, pediatric vancomycin dosing, vancomycin consensus guidelines, vancomycin MAP Bayesian estimates. (Pharmacotherapy 2013;33(12):1253–1255) doi: 10.1002/phar.1382 The vancomycin consensus guidelines for dosing and monitoring vancomycin in adult patients with Staphylococcus aureus infections were first published in 2009.1 This document was considered a milestone and represented the first attempt to standardize dosing and monitoring for vancomycin since its release for clinical use in 1958. The consensus document had many limitations including that the recommendations were for vancomycin dosing and monitoring of infections caused by Staphylococcus aureus in adult patients only and did not address any other gram-positive pathogen or provide specific recommendations for pediatric patients. In addition, the dosing and monitoring of vancomycin in morbidly obese patients, the use of continuous infusion, and specific dosing and recommendations for patients undergoing dialysis were only addressed in a cursory fashion. Further, because of the lack of supporting data in the literature, there were no pharmacokinetic and pharmacodynamic targets identified for any specific infectious disease state. Instead, a universal pharmacokinetic-pharmacodynamic target—area under the concentration-time curve to minimum inhibitory concentration (AUC:MIC) ratio of 400 *Author for correspondence: Michael J. Rybak, Department of Pharmacy Practice, Eugene College of Pharmacy & Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48098; e-mail: [email protected]. Ó 2013 American College of Clinical Pharmacy
or greater—was endorsed as the desired end point. As few institutions actually determine the AUC of vancomycin, a steady-state trough vancomycin serum concentration of 15–20 mg/L was recommended as a generic surrogate marker. Since the publication of the 2009 consensus guidelines, a number of investigators have attempted to fill in some of the gaps listed above as well as to verify the suggested dosing and monitoring targets. In this special section dedicated to vancomycin, a cross-sectional survey study by Dr. Susan Davis and colleagues describes the vancomycin dosing and monitoring practices implemented since the publication of the consensus guideline recommendations.2 The report summarizes the responses to questions regarding vancomycin therapeutic monitoring that were received from 163 participants representing academic and nonacademic hospitals in both urban and rural settings. Although it appeared that many of the recommendations were being followed, several areas for concern were identified by the authors. Overall, this study, as well as a previously published study,3 reveals some interesting information regarding compliance with the suggested guidelines and identifies areas for clarification and improvement as well as areas for future research to address these concerns. In the second article in this section, Dr. Theresa Madigan and colleagues from the Mayo Clinic evaluated the effect of age and weight on
1254
PHARMACOTHERAPY Volume 33, Number 12, 2013
vancomycin serum concentrations in pediatric patients.4 These investigators retrospectively reviewed the medical records of pediatric patients who received vancomycin 40 mg/kg/day or 60 mg/kg/day, stratified by age and weight. They reported that the higher vancomycin dose tended to achieve significantly higher trough vancomycin serum concentrations, but a large majority of the patients had concentrations outside of the recommended therapeutic range (10–20 mg/L). In addition, the variability in the trough concentrations appeared to be dependent on differences in age, weight, and creatinine clearance. The authors recommended that these parameters along with clinical indication need to be considered for vancomycin dosing and monitoring in pediatric patients. The third article is a retrospective, observational, case-control study conducted by Dr. Daniel Heble and colleagues that compares trough vancomycin serum concentrations in 42 overweight and obese pediatric patients with those in 84 pediatric patients with normal body weight.5 Vancomycin dosing was based on total body weight and an age-specific algorithm developed at their institution. The authors concluded that when dosing of vancomycin was based on total body weight, overweight and obese pediatric patients more often had elevated initial trough serum concentrations that exceeded 20 mg/L. They recommended that special attention should be given to this specific patient population to ensure that safe and effective vancomycin serum concentrations are achieved and recommended additional pharmacokinetic and pharmacodynamics studies to optimize therapy in this highly specialized group of patients. The fourth article by Dr. Lauren Camaione and colleagues evaluated vancomycin dosing and pharmacokinetics in 115 children and young adults who each had 2–9 serum concentration measurements.6 These investigators employed a previously described one-compartment pharmacokinetic model to derive individual maximum a posteriori probability (MAP)-Bayesian pharmacokinetic parameter estimates and to evaluate covariate relationships of body size descriptors (weight, height, and body surface area [BSA]). Of interest, vancomycin clearance was a nonlinear function of weight and a linear-proportionate function of BSA. However, the volume of the central compartment was a nonlinear function of weight. In addition, the AUC from time 0 to 24 hours (AUC24) achieved with weight-based
dosing of vancomycin 60–70 mg/kg varied with patient weight, although isometric AUC24 was predicted with BSA. The authors concluded that BSA-based dosing was more likely to achieve the isometric AUC24 across body size distributions of children and young adults. The final article by Dr. Chris Stockmann and colleagues determined the population pharmacokinetics and potential patient covariates that influence the pharmacokinetics of vancomycin in 67 children (median age 13.9 yrs) with cystic fibrosis.7 Peak and trough vancomycin serum concentrations were adequately described by a one-compartment pharmacokinetic model with first-order elimination. The authors observed that vancomycin clearance increased with body weight. The observed values for vancomycin clearance were lower than those in previous studies in younger children without cystic fibrosis. The observed values for volume of distribution were similar to those reported in other pediatric and adult populations. Despite being more than 50 years beyond the introduction of vancomycin into clinical practice, we still face significant challenges in attempting to optimize therapy of this antibiotic in our patients. Funding for large, contemporary, prospective, clinical pharmacokinetic and pharmacodynamic studies in specific and unique patient populations is at best limited to nonexistent. This, in part, may explain why most of these studies were retrospective and had specific limitations. Regardless, our understanding of vancomycin has grown over the past decades, and we have learned that the way in which the drug is modeled or the method used to determine the MIC for a pathogen are important variables in the interpretation and in the comparison of the reported data. Although the articles in this special section of Pharmacotherapy do not address all of the identified gaps in knowledge regarding vancomycin pharmacokinetic-pharmacodynamic targets, dosing, and monitoring, the articles do contribute new knowledge regarding dosing in pediatric populations, including specialized populations such as patients with cystic fibrosis. They also identify areas for improvement as well as areas where further research is required to optimize the pharmacokinetics and pharmacodynamics of vancomycin. References 1. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus
VANCOMYCIN 50 YEARS LATER Rybak et al review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009; 1:82–98. 2. Davis SL, Scheetz MH, Bosso JA, Goff DA, Rybak MJ. Adherence to the 2009 consensus guidelines for vancomycin dosing and monitoring practices: a cross-sectional survey of U.S hospitals. Pharmacotherapy 2013;33:1256–1263. 3. Yang Y, McBride MV, Rodvold KA, et al. Hospital policies and practices on prevention and treatment of infections caused by methicillin-resistant Staphylococcus aureus. Am J Health Syst Pharm 2010;12:1017–24.
1255
4. Madigan T, Sieve RM, Graner KK, Banerjee R. The effect of age and weight on vancomycin serum trough concentrations in pediatric patients. Pharmacotherapy 2013;33:1264–1272. 5. Heble DE Jr, McPherson C, Nelson MP, Hunstad DA. Vancomycin trough concentrations in overweight or obese pediatric patients. Pharmacotherapy 2013;33:1273–1277. 6. Camaione L, Elliott K, Mitchell-Van Steele A, Lomaestro B, Pai MP. Vancomycin dosing in children and young adults: back to the drawing board. Pharmacotherapy 2013;33:1278–1287. 7. Stockmann C, Sherwin CM, Zobell JT, et al. Population pharmacokinetics of intermittent vancomycin in children with cystic fibrosis. Pharmacotherapy 2013;33:1288–1296.
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy & Health Sciences, Detroit, Michigan; 2Department of Experimental Therapeutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; 3Department of Pharmacy Practice, Colleges of Pharmacy & Medicine, University of Illinois at Chicago, Chicago, Illinois
KEY WORDS Vancomycin dosing, pediatric vancomycin dosing, vancomycin consensus guidelines, vancomycin MAP Bayesian estimates. (Pharmacotherapy 2013;33(12):1253–1255) doi: 10.1002/phar.1382 The vancomycin consensus guidelines for dosing and monitoring vancomycin in adult patients with Staphylococcus aureus infections were first published in 2009.1 This document was considered a milestone and represented the first attempt to standardize dosing and monitoring for vancomycin since its release for clinical use in 1958. The consensus document had many limitations including that the recommendations were for vancomycin dosing and monitoring of infections caused by Staphylococcus aureus in adult patients only and did not address any other gram-positive pathogen or provide specific recommendations for pediatric patients. In addition, the dosing and monitoring of vancomycin in morbidly obese patients, the use of continuous infusion, and specific dosing and recommendations for patients undergoing dialysis were only addressed in a cursory fashion. Further, because of the lack of supporting data in the literature, there were no pharmacokinetic and pharmacodynamic targets identified for any specific infectious disease state. Instead, a universal pharmacokinetic-pharmacodynamic target—area under the concentration-time curve to minimum inhibitory concentration (AUC:MIC) ratio of 400 *Author for correspondence: Michael J. Rybak, Department of Pharmacy Practice, Eugene College of Pharmacy & Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48098; e-mail: [email protected]. Ó 2013 American College of Clinical Pharmacy
or greater—was endorsed as the desired end point. As few institutions actually determine the AUC of vancomycin, a steady-state trough vancomycin serum concentration of 15–20 mg/L was recommended as a generic surrogate marker. Since the publication of the 2009 consensus guidelines, a number of investigators have attempted to fill in some of the gaps listed above as well as to verify the suggested dosing and monitoring targets. In this special section dedicated to vancomycin, a cross-sectional survey study by Dr. Susan Davis and colleagues describes the vancomycin dosing and monitoring practices implemented since the publication of the consensus guideline recommendations.2 The report summarizes the responses to questions regarding vancomycin therapeutic monitoring that were received from 163 participants representing academic and nonacademic hospitals in both urban and rural settings. Although it appeared that many of the recommendations were being followed, several areas for concern were identified by the authors. Overall, this study, as well as a previously published study,3 reveals some interesting information regarding compliance with the suggested guidelines and identifies areas for clarification and improvement as well as areas for future research to address these concerns. In the second article in this section, Dr. Theresa Madigan and colleagues from the Mayo Clinic evaluated the effect of age and weight on
1254
PHARMACOTHERAPY Volume 33, Number 12, 2013
vancomycin serum concentrations in pediatric patients.4 These investigators retrospectively reviewed the medical records of pediatric patients who received vancomycin 40 mg/kg/day or 60 mg/kg/day, stratified by age and weight. They reported that the higher vancomycin dose tended to achieve significantly higher trough vancomycin serum concentrations, but a large majority of the patients had concentrations outside of the recommended therapeutic range (10–20 mg/L). In addition, the variability in the trough concentrations appeared to be dependent on differences in age, weight, and creatinine clearance. The authors recommended that these parameters along with clinical indication need to be considered for vancomycin dosing and monitoring in pediatric patients. The third article is a retrospective, observational, case-control study conducted by Dr. Daniel Heble and colleagues that compares trough vancomycin serum concentrations in 42 overweight and obese pediatric patients with those in 84 pediatric patients with normal body weight.5 Vancomycin dosing was based on total body weight and an age-specific algorithm developed at their institution. The authors concluded that when dosing of vancomycin was based on total body weight, overweight and obese pediatric patients more often had elevated initial trough serum concentrations that exceeded 20 mg/L. They recommended that special attention should be given to this specific patient population to ensure that safe and effective vancomycin serum concentrations are achieved and recommended additional pharmacokinetic and pharmacodynamics studies to optimize therapy in this highly specialized group of patients. The fourth article by Dr. Lauren Camaione and colleagues evaluated vancomycin dosing and pharmacokinetics in 115 children and young adults who each had 2–9 serum concentration measurements.6 These investigators employed a previously described one-compartment pharmacokinetic model to derive individual maximum a posteriori probability (MAP)-Bayesian pharmacokinetic parameter estimates and to evaluate covariate relationships of body size descriptors (weight, height, and body surface area [BSA]). Of interest, vancomycin clearance was a nonlinear function of weight and a linear-proportionate function of BSA. However, the volume of the central compartment was a nonlinear function of weight. In addition, the AUC from time 0 to 24 hours (AUC24) achieved with weight-based
dosing of vancomycin 60–70 mg/kg varied with patient weight, although isometric AUC24 was predicted with BSA. The authors concluded that BSA-based dosing was more likely to achieve the isometric AUC24 across body size distributions of children and young adults. The final article by Dr. Chris Stockmann and colleagues determined the population pharmacokinetics and potential patient covariates that influence the pharmacokinetics of vancomycin in 67 children (median age 13.9 yrs) with cystic fibrosis.7 Peak and trough vancomycin serum concentrations were adequately described by a one-compartment pharmacokinetic model with first-order elimination. The authors observed that vancomycin clearance increased with body weight. The observed values for vancomycin clearance were lower than those in previous studies in younger children without cystic fibrosis. The observed values for volume of distribution were similar to those reported in other pediatric and adult populations. Despite being more than 50 years beyond the introduction of vancomycin into clinical practice, we still face significant challenges in attempting to optimize therapy of this antibiotic in our patients. Funding for large, contemporary, prospective, clinical pharmacokinetic and pharmacodynamic studies in specific and unique patient populations is at best limited to nonexistent. This, in part, may explain why most of these studies were retrospective and had specific limitations. Regardless, our understanding of vancomycin has grown over the past decades, and we have learned that the way in which the drug is modeled or the method used to determine the MIC for a pathogen are important variables in the interpretation and in the comparison of the reported data. Although the articles in this special section of Pharmacotherapy do not address all of the identified gaps in knowledge regarding vancomycin pharmacokinetic-pharmacodynamic targets, dosing, and monitoring, the articles do contribute new knowledge regarding dosing in pediatric populations, including specialized populations such as patients with cystic fibrosis. They also identify areas for improvement as well as areas where further research is required to optimize the pharmacokinetics and pharmacodynamics of vancomycin. References 1. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus
VANCOMYCIN 50 YEARS LATER Rybak et al review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009; 1:82–98. 2. Davis SL, Scheetz MH, Bosso JA, Goff DA, Rybak MJ. Adherence to the 2009 consensus guidelines for vancomycin dosing and monitoring practices: a cross-sectional survey of U.S hospitals. Pharmacotherapy 2013;33:1256–1263. 3. Yang Y, McBride MV, Rodvold KA, et al. Hospital policies and practices on prevention and treatment of infections caused by methicillin-resistant Staphylococcus aureus. Am J Health Syst Pharm 2010;12:1017–24.
1255
4. Madigan T, Sieve RM, Graner KK, Banerjee R. The effect of age and weight on vancomycin serum trough concentrations in pediatric patients. Pharmacotherapy 2013;33:1264–1272. 5. Heble DE Jr, McPherson C, Nelson MP, Hunstad DA. Vancomycin trough concentrations in overweight or obese pediatric patients. Pharmacotherapy 2013;33:1273–1277. 6. Camaione L, Elliott K, Mitchell-Van Steele A, Lomaestro B, Pai MP. Vancomycin dosing in children and young adults: back to the drawing board. Pharmacotherapy 2013;33:1278–1287. 7. Stockmann C, Sherwin CM, Zobell JT, et al. Population pharmacokinetics of intermittent vancomycin in children with cystic fibrosis. Pharmacotherapy 2013;33:1288–1296.
