Evaluation of vancomycin individualized model-based dosing approach in neonates
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1 Introduction
Late-onset neonatal sepsis is a major cause of morbidity and mortality in newborns worldwide, with a mortality rate of approximately 15% in very-low-birth-weight (VLBW) neonates (birth weight of <1500 g).1–3 Despite being an old drug, vancomycin remains the drug of choice for treating late-onset sepsis in neonatal intensive care units (NICU) whenever methicillin-resistant Staphylococcus aureus (MRSA) or coagulase-negative staphylococci (MRCONS) is suspected.4,5 Although it has been used for more than 50 years, its dosing in neonates is challenging for many reasons, including wide pharmacokinetic variability among the neonatal population, lack of consensus on optimal dosing and therapeutic drug monitoring (TDM), and the narrow therapeutic index.4,6,7 Studies have reported that the major predictors of vancomycin pharmacokinetics in neonates include body weight, maturation (as indicated by postmenstrual age [PMA], gestational age [GA], and postnatal age [PNA]), and serum creatinine (SCr).8–10 The most commonly used tertiary neonatal dosing references present their vancomycin dosing recommendations considering only 2–3 items of these variables. For example, Micromedex NeoFax (IBM Corp., Armonk, NY, USA) and Pediatric & Neonatal Lexi-Drugs (Lexicomp, Ohio, USA) recommend their dosing based on a combination of PMA and PNA, whereas the British National Formulary (BNF) for Children (BNF Publications, UK) relies solely on PMA. The American Academy of Pediatrics' Red Book and Nelson's Neonatal Antimicrobial Therapy depend only on GA and SCr. As a result, the recommended daily doses can differ widely by up to 30%–50% between these references. Frymoyer et al. reported that the probability of achieving vancomycin therapeutic target in neonates with these empiric dosing is only 20%–50%.11 Studies have documented that model-based dosing would be an appropriate approach to optimize vancomycin initial dosing.12–15 This method incorporates all variables known to impact vancomycin pharmacokinetics for dose calculation. However, the application of model-based dosing in clinical practice is still limited, which could be attributed to the complexity of the required calculations and the need to use costly software.
晚髮型新生兒敗血症是全世界新生兒發病和死亡的主要原因，極低出生體重（VLBW）新生兒（出生體重<1500 克）的死亡率約為 15％。 1–3 雖然 Vancomycin 是一種老藥，但只要懷疑感染了Oxacillin抗藥性金黃色葡萄球菌 (MRSA) 或凝固酶陰性葡萄球菌 (MRCONS)，它仍然是治療新生兒加護病房 (NICU) 中晚髮型敗血症的首選藥物。 4 5 雖然這個藥物已使用 50 多年，但由於多種原因，其在新生兒中的給藥仍然具有挑戰性，包括新生兒群體中藥物動力學差異很大、缺乏對最佳劑量和治療藥物監測 (TDM) 的共識，以及治療指數較窄。 4 6 7 研究報告顯示，新生兒 Vancomycin 藥物動力學的主要預測因子包括體重、成熟度（以經後週齡 [PMA]、懷孕週 [GA] 和出生後週齡 [PNA] 表示）和 Scr (SCr)。 8–10 最常用的三級新生兒給藥參考文獻僅考慮了 2-3 項這些變數來提出 Vancomycin 給藥建議。例如，Micromedex NeoFax（IBM Corp.，紐約州阿蒙克，美國）和兒科及新生兒 Lexi-Drugs（Lexicomp，俄亥俄州，美國）建議根據 PMA 和 PNA 合併區分次使用，而英國國家兒童藥典 (BNF)（BNF Publications，英國）則完全依賴 PMA。美國兒科學會紅皮書和納爾遜的新生兒抗菌治療僅依賴 GA 和 SCr。因此，這些參考文獻中的建議每日劑量可能相差高達 30%-50%。 Frymoyer 等人 報告指出，這些經驗性給藥方式在新生兒達到 Vancomycin 治療目標的機率僅為 20%–50%。 11 研究證明，根據模式的給藥是改良 Vancomycin 起始劑量的合適方法。 12–15 此方法結合了已知影響 Vancomycin 藥物動力學的所有變數，用於劑量計算。然而，根據模式的劑量在臨床照護中的使用仍然有限，這可能歸因於所需計算的複雜性和需要使用昂貴的軟體。
1.
Oza, S. ∙ Lawn, J.E. ∙ Hogan, D.R. ...
Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000-2013
Bull World Health Organ. 2015; 93:19-282.
Liu, L. ∙ Johnson, H.L. ∙ Cousens, S. ...
Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000
Lancet. 2012; 379:2151-21613.
Hornik, C.P. ∙ Fort, P. ∙ Clark, R.H. ...
Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units
Early Hum Dev. 2012; 88:S69-S744.
Padari, H. ∙ Oselin, K. ∙ Tasa, T. ...
Coagulase negative staphylococcal sepsis in neonates: do we need to adapt vancomycin dose or target?
BMC Pediatr. 2016; 16:2065.
Sankar, M.J. ∙ Agarwal, R. ∙ Deorari, A.K. ...
Sepsis in the newborn
Indian J Pediatr. 2008; 75:261-2664.
Padari, H. ∙ Oselin, K. ∙ Tasa, T. ...
Coagulase negative staphylococcal sepsis in neonates: do we need to adapt vancomycin dose or target?
BMC Pediatr. 2016; 16:2066.
Pham, J.T.
Challenges of vancomycin dosing and therapeutic monitoring in neonates
J Pediatr Pharmacol Ther. 2020; 25:476-4847.
Agrawal, M. ∙ Rattan, A.
How to treat sepsis in the background of resistance?: role of pharmacodynamics/pharmacokinetics in treating sepsis
Indian J Pediatr. 2020; 87:111-1168.
Frymoyer, A. ∙ Hersh, A.L. ∙ El-Komy, M.H. ...
Association between vancomycin trough concentration and area under the concentration-time curve in neonates
Antimicrob Agents Chemother. 2014; 58:6454-64619.
Kato, H. ∙ Hagihara, M. ∙ Nishiyama, N. ...
Assessment of optimal initial dosing regimen with vancomycin pharmacokinetics model in very low birth weight neonates
J Infect Chemother. 2017; 23:154-16010.
Abdulla, A. ∙ Edwina, E.E. ∙ Flint, R.B. ...
Model-Informed precision dosing of antibiotics in pediatric patients: a narrative review
Front Pediatr. 2021; 9:62463911.
Frymoyer, A. ∙ Stockmann, C. ∙ Hersh, A.L. ...
Individualized empiric vancomycin dosing in neonates using a model-based approach
J Pediatric Infect Dis Soc. 2019; 8:97-10412.
Gonzalez, D. ∙ Rao, G.G. ∙ Bailey, S.C. ...
Precision dosing: public Health need, proposed framework, and anticipated impact
Clin Transl Sci. 2017; 10:443-45413.
Alsultan, A. ∙ Alghamdi, W.A. ∙ Alghamdi, J. ...
Clinical pharmacology applications in clinical drug development and clinical care: a focus on Saudi Arabia
Saudi Pharm J. 2020; 28:1217-122714.
Darwich, A.S. ∙ Ogungbenro, K. ∙ Vinks, A.A. ...
Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future
Clin Pharmacol Ther. 2017; 101:646-65615.
Neely, M.
Scalpels not hammers: the way forward for precision drug prescription
Clin Pharmacol Ther. 2017; 101:368-372晚髮型新生兒敗血症是全世界新生兒發病和死亡的主要原因，極低出生體重（VLBW）新生兒（出生體重<1500 克）的死亡率約為 15％。 1–3
1.
Oza, S. ∙ Lawn, J.E. ∙ Hogan, D.R. ...
Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000-2013
Bull World Health Organ. 2015; 93:19-282.
Liu, L. ∙ Johnson, H.L. ∙ Cousens, S. ...
Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000
Lancet. 2012; 379:2151-21613.
Hornik, C.P. ∙ Fort, P. ∙ Clark, R.H. ...
Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units
Early Hum Dev. 2012; 88:S69-S744.
Padari, H. ∙ Oselin, K. ∙ Tasa, T. ...
Coagulase negative staphylococcal sepsis in neonates: do we need to adapt vancomycin dose or target?
BMC Pediatr. 2016; 16:2065.
Sankar, M.J. ∙ Agarwal, R. ∙ Deorari, A.K. ...
Sepsis in the newborn
Indian J Pediatr. 2008; 75:261-2664.
Padari, H. ∙ Oselin, K. ∙ Tasa, T. ...
Coagulase negative staphylococcal sepsis in neonates: do we need to adapt vancomycin dose or target?
BMC Pediatr. 2016; 16:2066.
Pham, J.T.
Challenges of vancomycin dosing and therapeutic monitoring in neonates
J Pediatr Pharmacol Ther. 2020; 25:476-4847.
Agrawal, M. ∙ Rattan, A.
How to treat sepsis in the background of resistance?: role of pharmacodynamics/pharmacokinetics in treating sepsis
Indian J Pediatr. 2020; 87:111-1168.
Frymoyer, A. ∙ Hersh, A.L. ∙ El-Komy, M.H. ...
Association between vancomycin trough concentration and area under the concentration-time curve in neonates
Antimicrob Agents Chemother. 2014; 58:6454-64619.
Kato, H. ∙ Hagihara, M. ∙ Nishiyama, N. ...
Assessment of optimal initial dosing regimen with vancomycin pharmacokinetics model in very low birth weight neonates
J Infect Chemother. 2017; 23:154-16010.
Abdulla, A. ∙ Edwina, E.E. ∙ Flint, R.B. ...
Model-Informed precision dosing of antibiotics in pediatric patients: a narrative review
Front Pediatr. 2021; 9:62463911.
Frymoyer, A. ∙ Stockmann, C. ∙ Hersh, A.L. ...
Individualized empiric vancomycin dosing in neonates using a model-based approach
J Pediatric Infect Dis Soc. 2019; 8:97-10412.
Gonzalez, D. ∙ Rao, G.G. ∙ Bailey, S.C. ...
Precision dosing: public Health need, proposed framework, and anticipated impact
Clin Transl Sci. 2017; 10:443-45413.
Alsultan, A. ∙ Alghamdi, W.A. ∙ Alghamdi, J. ...
Clinical pharmacology applications in clinical drug development and clinical care: a focus on Saudi Arabia
Saudi Pharm J. 2020; 28:1217-122714.
Darwich, A.S. ∙ Ogungbenro, K. ∙ Vinks, A.A. ...
Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future
Clin Pharmacol Ther. 2017; 101:646-65615.
Neely, M.
Scalpels not hammers: the way forward for precision drug prescription
Clin Pharmacol Ther. 2017; 101:368-372Likewise, in 2009, the initial vancomycin guideline by the Infectious Diseases Society of America (IDSA) and American Society of Health-System Pharmacists recommended vancomycin trough concentrations of 15–20 mg/L or a 24-h area under the curve/minimum inhibitory concentration ratio (AUC0–24/MIC) of >400 for severe invasive MRSA infections.16 Later on, owing to subsequent reports of increased incidence of nephrotoxicity associated with vancomycin trough concentrations of >15 mg/L, the updated guidelines published in 2020 no longer recommends targeting vancomycin troughs 15–20 mg/L. It instead recommends a therapeutic target of an AUC0–24 of 400–600 mg h/L for MRSA with MIC of ≤1 mg/L. This target has been found to achieve maximum clinical efficacy while minimizing nephrotoxicity.17 Early optimization of vancomycin exposure in such a highly variable and vulnerable population is extremely important. It would increase efficacy, minimize toxicity, and minimize bacterial resistance, particularly when treating invasive MRSA or MRCONS infections. A possible approach to optimize vancomycin dosing and target attainment would be calculating the initial dosing regimen using model-based approach and then perform the TDM through AUC calculation and accordingly adjust subsequent doses. Therefore, this study aimed to evaluate a population pharmacokinetic model-based dosing approach in achieving vancomycin therapeutic target in neonates compared with other commonly used tertiary neonatal dosing references. This model was then utilized to develop simple Excel calculators to individualize and optimize vancomycin initial dosing in neonates.
同樣，2009 年，美國傳染病學會 (IDSA) 和美國衛生系統藥學會發布的初始 Vancomycin 指引建議，對於嚴重侵入性 MRSA 感染， Vancomycin 最低濃度為 15-20 mg/L 或 24 小時曲線下面積/最低抑菌濃度比 (AUC 0–24/MIC) >400。 16 後來，由於隨後研究指出 Vancomycin 最低濃度>15 mg/L 會造成腎毒性發生率增加，因此 2020 年發布的最新指引不再建議以 Vancomycin 最低濃度為目標濃度 15–20 mg/L。相反，它建議對於 MRSA 且 MIC ≤ 1 mg/L 的 AUC 0–24 治療目標為 400-600 mg h/L。該目標已可來達到最大的臨床療效，同時儘量降低腎毒性。 17 在如此差異很大和虛弱的族群，儘早改良 Vancomycin 暴露極為重要。它可以改善療效，儘量減少毒性，並儘量減少細菌抗藥性，尤其在治療侵入性 MRSA 或 MRCONS 感染時。改良 Vancomycin 劑量和目標達成的一個可能方法是使用根據模式的方法計算初始處方，然後透過 AUC 計算執行 TDM，並相關地校正後續劑量。因此，本研究目的在評估針對族群藥物動力學模式的使用方法與其他常用的三級新生兒給藥參考相比，在達到 Vancomycin 新生兒治療目標方面的效果。然後利用該模式開發簡單的 Excel 計算器，以個人化和改良新生兒 Vancomycin 的起始劑量。
16.
Liu, C. ∙ Bayer, A. ∙ Cosgrove, S.E. ...
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-e5517.
Rybak, M.J. ∙ Le, J. ∙ Lodise, T.P. ...
Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American society of health-system Pharmacists, the infectious diseases society of America, the pediatric infectious diseases society, and the society of infectious diseases Pharmacists
Am J Health Syst Pharm. 2020; 77:835-864同樣，2009 年，美國傳染病學會 (IDSA) 和美國衛生系統藥學會發布的初始 Vancomycin 指引建議，對於嚴重侵入性 MRSA 感染， Vancomycin 最低濃度為 15-20 mg/L 或 24 小時曲線下面積/最低抑菌濃度比 (AUC 0–24/MIC) >400。 16
16.
Liu, C. ∙ Bayer, A. ∙ Cosgrove, S.E. ...
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-e5517.
Rybak, M.J. ∙ Le, J. ∙ Lodise, T.P. ...
Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American society of health-system Pharmacists, the infectious diseases society of America, the pediatric infectious diseases society, and the society of infectious diseases Pharmacists
Am J Health Syst Pharm. 2020; 77:835-8642 Methods
2.1 Dataset settings and design
Data were retrospectively collected from two major hospitals in Riyadh, Saudi Arabia: King Saud University Medical City and King Faisal Specialist Hospital. From both hospitals, data were collected from the electronic medical records. For King Saud University Medical City, data were collected from January 2016 to December 2018. For King Faisal Specialist Hospital, data were collected from January 2018 to July 2020. Data were retrieved for neonates (0–30 days) who were admitted to the NICU and received vancomycin for proven or suspected MRSA or MRCONS infections. Patients were included if they received vancomycin for more than 48 h and had at least one vancomycin serum trough concentration measured at steady state. Collected data include PNA, PMA, weight, SCr, vancomycin dose and concentrations. The practice in King Saud University Medical City is to collect both vancomycin peak and trough concentrations for TDM. Whereas in King Faisal Specialist Hospital, the practice is to collect trough concentrations only. Peak samples were collected 1 h after the end of infusions, and trough concentrations were collected 30 min before the next dose at steady state. Neonates were excluded if they had renal impairment (defined as SCr >1.5 mg/dL or urine output <1 mL/kg/h for 24 h), or required extracorporeal membrane oxygenation or renal replacement therapy during the vancomycin course. In both hospitals, samples were analyzed using a chemiluminescent microparticle immunoassay. The measurement range of the assay is 0.24–100 ug/mL.
數據是從沙烏地阿拉伯利雅德的兩家主要醫院回顧性收集的：沙烏地國王大學醫學城和費薩爾國王專科醫院。兩家醫院都從電子病歷中收集了數據。對於沙烏地國王大學醫學城，資料收集時間為 2016 年 1 月至 2018 年 12 月。對於費薩爾國王專科醫院，資料收集時間為 2018 年 1 月至 2020 年 7 月。數據來自入住 NICU 並接受 Vancomycin 治療以確診或疑似感染 MRSA 或 MRCONS 的新生兒（0-30 天）。如果病人接受 Vancomycin 治療超過 48 小時並且在平衡下測量到至少一次 Vancomycin 血清最低濃度，則將其納入。收集的封包括 PNA、PMA、體重、SCr、 Vancomycin 劑量和濃度。沙烏地阿拉伯國王大學醫學城的做法是收集 Vancomycin 的最高濃度和最低濃度，用於 TDM。而在費薩爾國王專科醫院，慣例是只收集最低濃度。在輸注結束後 1 小時收集最高(Peak)樣本，並在穩定狀態下下次給藥前 30 分鐘收集最低濃度。如果新生兒有腎功能不全（定義為 SCr >1.5 mg/dL 或 24 小時尿量 <1 mL/kg/h），或在 Vancomycin 療程期間需要葉克膜(ECMO)或腎臟替代治療，則將其排除在外。兩家醫院都以化學發光微粒免疫分析法對樣本進行分析。此檢查法的測量範圍為 0.24–100 ug/mL。
數據是從沙烏地阿拉伯利雅德的兩家主要醫院回顧性收集的：沙烏地國王大學醫學城和費薩爾國王專科醫院。兩家醫院都從電子病歷中收集了數據。對於沙烏地國王大學醫學城，資料收集時間為 2016 年 1 月至 2018 年 12 月。對於費薩爾國王專科醫院，資料收集時間為 2018 年 1 月至 2020 年 7 月。數據來自入住 NICU 並接受 Vancomycin 治療以確診或疑似感染 MRSA 或 MRCONS 的新生兒（0-30 天）。如果病人接受 Vancomycin 治療超過 48 小時並且在平衡下測量到至少一次 Vancomycin 血清最低濃度，則將其納入。收集的封包括 PNA、PMA、體重、SCr、 Vancomycin 劑量和濃度。沙烏地阿拉伯國王大學醫學城的做法是收集 Vancomycin 的最高濃度和最低濃度，用於 TDM。而在費薩爾國王專科醫院，慣例是只收集最低濃度。在輸注結束後 1 小時收集最高(Peak)樣本，並在穩定狀態下下次給藥前 30 分鐘收集最低濃度。如果新生兒有腎功能不全（定義為 SCr >1.5 mg/dL 或 24 小時尿量 <1 mL/kg/h），或在 Vancomycin 療程期間需要葉克膜(ECMO)或腎臟替代治療，則將其排除在外。兩家醫院都以化學發光微粒免疫分析法對樣本進行分析。此檢查法的測量範圍為 0.24–100 ug/mL。
2.2 Model-based dosing
For each patient, we estimated the predicted clearance (Cl) and volume of distribution (V) using the population pharmacokinetic model developed by Frymoyer et al.8 Here, the pharmacokinetic parameters are estimated using only the patients’ demographics. The formulas for Cl and V are shown below:
對於每位病人，分析 Frymoyer 等人開發的群體藥物動力學模式估算預測清除率 (Cl) 和分佈體積 (V)。 8 在這裡，僅使用病人的人口統計資料來估算藥物動力學參數。 Cl 和 V 的化學式如下圖所示：
其中體重以公斤為單位，PMA 以周為單位，SCr 以 mg/dl 為單位。這裡估計藥物動力學參數被視為每位病人的預測值，併用於根據模式的給藥。將上述 Cl 和 V 公式嵌入 Microsoft Excel（補充文件），然後如下計算劑量：
8.
Frymoyer, A. ∙ Hersh, A.L. ∙ El-Komy, M.H. ...
Association between vancomycin trough concentration and area under the concentration-time curve in neonates
Antimicrob Agents Chemother. 2014; 58:6454-6461對於每位病人，分析 Frymoyer 等人開發的群體藥物動力學模式估算預測清除率 (Cl) 和分佈體積 (V)。 8
8.
Frymoyer, A. ∙ Hersh, A.L. ∙ El-Komy, M.H. ...
Association between vancomycin trough concentration and area under the concentration-time curve in neonates
Antimicrob Agents Chemother. 2014; 58:6454-6461其中體重以公斤為單位，PMA 以周為單位，SCr 以 mg/dl 為單位。這裡估計藥物動力學參數被視為每位病人的預測值，併用於根據模式的給藥。將上述 Cl 和 V 公式嵌入 Microsoft Excel（補充文件），然後如下計算劑量：
1)
Based on the predicted Cl, the optimal daily dose to achieve an AUC of 500 was calculated as follows: total daily dose = Cl × 500.
根據預測的 Cl，達到 AUC 500 的最佳每日劑量計算如下：日總劑量 = Cl × 500。
根據預測的 Cl，達到 AUC 500 的最佳每日劑量計算如下：日總劑量 = Cl × 500。
2)
For dosing frequency, the lowest frequency that achieved a trough of less than 15 mg/L were selected. for example, if the predicted trough for 8-h dosing is more than 15 mg/L and the predicted trough for 12-h dosing is less than 15 mg/L, we will select the 12-h dosing. The tested dosing frequencies were as follows: 6, 8, 12, 18, and 24 h.
對於劑量頻率，選擇達到最低(Trough)低於 15 mg/L的最低頻率。例如，如果 8 小時劑量的預測最低(Trough)大於 15 mg/L，而 12 小時劑量的預測最低(Trough)小於 15 mg/L，我們將選擇 12 小時劑量。測試的給藥頻率如下：6、8、12、18 和 24 小時。
對於劑量頻率，選擇達到最低(Trough)低於 15 mg/L的最低頻率。例如，如果 8 小時劑量的預測最低(Trough)大於 15 mg/L，而 12 小時劑量的預測最低(Trough)小於 15 mg/L，我們將選擇 12 小時劑量。測試的給藥頻率如下：6、8、12、18 和 24 小時。
3)
For all patients, the maximum per one dose is 20 mg/kg.
對於所有病人，每次最高劑量為 20mg/kg。
對於所有病人，每次最高劑量為 20mg/kg。
2.3 Dose calculation based on commonly used tertiary references
2.3 根據常用三級參考文獻計算劑量
For each patient, we calculated the initial vancomycin dosing regimen based on the following most commonly used tertiary neonatal dosing references: IBM Micromedex NeoFax, Lexicomp Pediatric & Neonatal Lexi-Drugs, BNF for Children, the American Academy of Pediatrics' Red Book, and Nelson's Neonatal Antimicrobial Therapy (Table 1).
對於每位病人，我們根據以下最常用的三級新生兒給藥參考計算了初始 Vancomycin 處方：IBM Micromedex NeoFax、Lexicomp Pediatric & Neonatal Lexi-Drugs、BNF for Children、美國兒科學會紅皮書和 Nelson 新生兒抗菌治療（表 1）。
對於每位病人，我們根據以下最常用的三級新生兒給藥參考計算了初始 Vancomycin 處方：IBM Micromedex NeoFax、Lexicomp Pediatric & Neonatal Lexi-Drugs、BNF for Children、美國兒科學會紅皮書和 Nelson 新生兒抗菌治療（表 1）。
| Reference | PMAa (weeks) | PNAb (days) | SCr (mg/dL) | Dose (mg/kg/dose) | Interval (hours) |
|---|---|---|---|---|---|
| NeoFax | ≤29 | ≤14 | 10–15 | 18 | |
| >14 | 12 | ||||
| 30–36 | ≤14 | 10–15 | 12 | ||
| >14 | 8 | ||||
| 37–44 | ≤7 | 10–15 | 12 | ||
| >7 | 8 | ||||
| ≥45 | All | 10–15 | 6 | ||
| Lexicomp | ≤29 | ≤21 | 15 | 18 | |
| >21 | 12 | ||||
| 30–36 | ≤14 | 15 | 12 | ||
| >14 | 8 | ||||
| 37–45 | ≤7 | 15 | 12 | ||
| >7 | 8 | ||||
| BNF for Children | <29 | 15 | 24 | ||
| 29–35 | 15 | 12 | |||
| 35–45 | 15 | 8 | |||
| Red Book/Nelson's Neonatal Antimicrobial Therapy 紅皮書/納爾遜新生兒抗菌治療 | ≤28 | <0.5 | 15 | 12 | |
| 0.5–0.7 | 20 | 24 | |||
| 0.8–1.0 | 15 | 24 | |||
| 1.1–1.4 | 10 | 24 | |||
| >1.4 | 15 | 48 | |||
| >28 | <0.7 | 15 | 12 | ||
| 0.7–0.9 | 20 | 24 | |||
| 1.0–1.2 | 15 | 24 | |||
| 1.3–1.6 | 10 | 24 | |||
| >1.6 | 15 | 48 |
Table 1
Vancomycin dosing regimens by most commonly used neonatal dosing references.
Vancomycin 處方符合最常用的新生兒給藥參考。
Vancomycin 處方符合最常用的新生兒給藥參考。
a
PMA, postmenstrual age. PMA is gestational age plus postnatal age.
PMA，經後齡。 PMA 是懷孕週齡加上出生後週齡。
PMA，經後齡。 PMA 是懷孕週齡加上出生後週齡。
b
PNA, postnatal age.
2.4 Empirical bayesian estimates and true AUC estimation
2.4 經驗貝氏估計和真實 AUC 估計
The Bayesian method combines two sets of information, prior population pharmacokinetic estimates and individual TDM data. This method has been previously validated in pediatrics.18,19 Bayesian estimation was performed using Monolix Suite 2020R1 (Lixoft, France). The Frymoyer et al. model was used as the prior population model.8 Patients' data, including demographics and the measured drug concentrations, were uploaded into the Monolix software. The individual Bayesian Cl and V were estimated for each patient. The estimated pharmacokinetic parameters here are considered the true values for each patient. These values were used to calculate the true AUC for each patient based on the recommended dose. The predicted AUC and trough were also calculated based on the dose recommendations by six methods: model-based dosing, NeoFax, Lexicomp, BNF, Red Book/Nelson's Neonatal Antimicrobial Therapy, and clinician recommended dose. The clinician recommended dose is what each patient actually received (Note: NeoFax was the approved neonatal dosing reference at King Saud University Medical City, whereas Lexicomp was the approved dosing reference at King Faisal Specialist Hospital). The trough concentration was calculated using short term IV infusion one compartment formulas, the AUC was calculated as follows: the total daily recommended dose/Cl. An AUC of >400 mg h/L was considered therapeutic. The threshold for nephrotoxicity was AUC of 800 mg h/L.20 The percentage of patients with trough concentrations of >20 mg/L with each dosing recommendation was also calculated.
貝氏方法結合了兩組訊息，即原本的群體藥物動力學估計值和病人 TDM 數據。該方法之前已在兒科中得到驗證。 18 19 使用 Monolix Suite 2020R1（法國 Lixoft）進行貝氏估計。 Frymoyer 等人模式被使用於原本的人口模式。 8 病人的數據（包括人口統計和測量藥物濃度）被上傳到 Monolix 軟體中。為每位病人估算單獨的貝氏 Cl 和 V。這裡估計藥物動力學參數被視為每位病人的真實值。這些值用於根據建議劑量計算每位病人的真實 AUC。也根據六種方法的劑量建議計算預測的 AUC 和最低(Trough)：根據模式的劑量、NeoFax、Lexicomp、BNF、紅皮書/尼爾森的新生兒抗菌治療和臨床醫師建議劑量。臨床醫師建議的劑量是每位病人實際接受的劑量（註：NeoFax 是沙烏地國王大學醫學城核可的新生兒劑量參考，而 Lexicomp 是費薩爾國王專科醫院核可的劑量參考）。以短期靜脈輸注一室公式計算最低濃度，AUC 計算如下：每日總建議劑量/Cl。 AUC > 400 mg h/L 則認為具有治療效果。腎毒性的閾值為 AUC 800 mg h/L。 20 也計算了按照每項劑量建議，最低濃度 > 20 mg/L 的病人百分比。
18.
Alsultan, A. ∙ Abouelkheir, M. ∙ Alqahtani, S. ...
Optimizing vancomycin monitoring in pediatric patients
Pediatr Infect Dis J. 2018; 37:880-88519.
Stockmann, C. ∙ Hersh, A.L. ∙ Sherwin, C.M. ...
Targeting vancomycin AUC in neonates − A model-based bayesian approach for personalized therapeutic drug monitoring
American Society for Clinical Pharmacology and Therapeutics, Atlanta, GA, 20158.
Frymoyer, A. ∙ Hersh, A.L. ∙ El-Komy, M.H. ...
Association between vancomycin trough concentration and area under the concentration-time curve in neonates
Antimicrob Agents Chemother. 2014; 58:6454-646120.
Le, J. ∙ Ny, P. ∙ Capparelli, E. ...
Pharmacodynamic characteristics of nephrotoxicity associated with vancomycin use in children
J Pediatric Infect Dis Soc. 2015; 4, e109–e116貝氏方法結合了兩組訊息，即原本的群體藥物動力學估計值和病人 TDM 數據。該方法之前已在兒科中得到驗證。 18
18.
Alsultan, A. ∙ Abouelkheir, M. ∙ Alqahtani, S. ...
Optimizing vancomycin monitoring in pediatric patients
Pediatr Infect Dis J. 2018; 37:880-88519.
Stockmann, C. ∙ Hersh, A.L. ∙ Sherwin, C.M. ...
Targeting vancomycin AUC in neonates − A model-based bayesian approach for personalized therapeutic drug monitoring
American Society for Clinical Pharmacology and Therapeutics, Atlanta, GA, 20158.
Frymoyer, A. ∙ Hersh, A.L. ∙ El-Komy, M.H. ...
Association between vancomycin trough concentration and area under the concentration-time curve in neonates
Antimicrob Agents Chemother. 2014; 58:6454-646120.
Le, J. ∙ Ny, P. ∙ Capparelli, E. ...
Pharmacodynamic characteristics of nephrotoxicity associated with vancomycin use in children
J Pediatric Infect Dis Soc. 2015; 4, e109–e116Continuous variables were presented as mean ± standard deviation, whereas categorical variables were presented as proportions. To compare the probability of achieving the therapeutic target between the six dosing recommendations, we used the McNemar statistical test. We also performed subgroup analysis to assess if the performance of the dosing calculator is consistent across different demographic groups. That includes using scatter plots of predicted AUC VS serumc creatinine, bodyweight and PMA. In addition, we compared the performance of the model for VLBW VS normal weight, extreme premature neonates with PMA <28 weeks VS PMA >28 weeks and patients with SCr below and above 0.8 mg/dL All statistical analysis and plots were produced using the R software version 4.2.0 (The R Foundation of Statistical Computing, Vienna, Austria).
連續變數以平均值±標準差表示，而分類變數則以比例表示。為了比較六種劑量建議達到治療目標的機率，分析了 McNemar 統計檢定。我們還進行次族群分析，以評估劑量計算器的性能在不同的人口群體中是否一致。其中包括使用預測 AUC 與 Scr 、體重和 PMA 的散佈圖。此外，我們比較 VLBW 與正常體重、PMA <28 週與 PMA >28 週的極度早產兒以及 SCr 低於和高於 0.8 mg/dL 的病人的模式表現。所有統計分析和圖表均使用 R 軟體版本 4.2.0（奧地利維也納統計計算 R 基金會）產生。
連續變數以平均值±標準差表示，而分類變數則以比例表示。為了比較六種劑量建議達到治療目標的機率，分析了 McNemar 統計檢定。我們還進行次族群分析，以評估劑量計算器的性能在不同的人口群體中是否一致。其中包括使用預測 AUC 與 Scr 、體重和 PMA 的散佈圖。此外，我們比較 VLBW 與正常體重、PMA <28 週與 PMA >28 週的極度早產兒以及 SCr 低於和高於 0.8 mg/dL 的病人的模式表現。所有統計分析和圖表均使用 R 軟體版本 4.2.0（奧地利維也納統計計算 R 基金會）產生。
3 Results
In the analysis, 225 neonates were included: 90 from King Saud University Medical City and 135 from King Faisal Specialist Hospital. The average PNA was 12 ± 9 days, PMA was 34 ± 4.74 weeks and SCr was 0.52 ± 0.23 mg/dL. The average weight was 1.86 ± 0.98 kg and 46% of the patients were VLBW neonates. The full baseline demographic characteristics of all patients are shown in Table 2.
分析中共納入 225 名新生兒：90 名來自沙烏地阿拉伯國王大學醫學城，135 名來自費薩爾國王專科醫院。平均 PNA 為 12 ± 9 天，PMA 為 34 ± 4.74 週，SCr 為 0.52 ± 0.23 mg/dL。平均體重為 1.86±0.98 公斤，46%的病人為 VLBW 新生兒。所有病人的完整基準線人人口學資料如表 2 所示。
分析中共納入 225 名新生兒：90 名來自沙烏地阿拉伯國王大學醫學城，135 名來自費薩爾國王專科醫院。平均 PNA 為 12 ± 9 天，PMA 為 34 ± 4.74 週，SCr 為 0.52 ± 0.23 mg/dL。平均體重為 1.86±0.98 公斤，46%的病人為 VLBW 新生兒。所有病人的完整基準線人人口學資料如表 2 所示。
| Patient characteristics (n = 225) 病人之特性（n = 225） | Value |
|---|---|
| Postnatal age (days) | 12 (9)a |
| PMA (weeks) | 34 (4.74)a |
| Gestational age [n (%)] | |
| <28 weeks | 25 (11%) |
| 28–36 weeks | 119 (53%) |
| >36 weeks | 81 (36%) |
| Serum creatinine (mg/dL) | 0.52 (0.23)a |
| Weight (kg) | 1.86 (0.98)a |
| Weight <1500 g, [n (%)] 重量<1500 公克，[n(%)] | 103 (46%) |
Table 2
Baseline demographic characteristics of the patients.
病人的基準線人人口學資料。
病人的基準線人人口學資料。
a
Mean (SD).
3.1 Comparing dosing strategies
The proportion of patients who achieved the vancomycin therapeutic target of AUC0–24 > 400 mg h/L per dosing strategy was highest with model-based dosing (89%) compared with 11%–59% with NeoFax, 56% with Lexicomp, 55% with BNF for Children, 28% with the American Academy of Pediatrics' Red Book or Nelson's Neonatal Antimicrobial Therapy, 27% with clinician recommendation at King Saud University Medical City, and 67% with clinician recommendations at King Faisal Specialist Hospital (p < 0.01 for all pairwise comparisons). The NeoFax recommends the dosing in the range of 10–15 mg/kg/dose. While 59% of the neonates achieved the therapeutic target using 15 mg/kg doses, only 11% were within the therapeutic range when we used the 10 mg/kg doses. The probability of having a trough concentration of >20 mg/L was 6% with the model-based dosing; it was the highest (12%) with the clinician's recommendations at King Faisal Specialist Hospital, followed by BNF for Children at 10%; the lowest probability was 1% with NeoFax 10 mg/kg dosing and Red Book/Nelson's Neonatal Antimicrobial Therapy. The probability of having and AUC >800 was low for all dosing regimens <4%. The variability in AUC (expressed as the percent coefficient of variation) was the lowest with the model-based dosing (21%) compared with those with NeoFax (30%), Lexicomp (29%), BNF for Children (33%), Red Book/Nelson's Neonatal Antimicrobial Therapy (29%), and clinician recommended dose when combining both hospitals (35%) (Fig. 1, boxplot). In addition, with model-based dosing, the AUC was similar across different PMA, weight, and SCr values (Fig. 2); the R2 was less than 0.1 for all three covariates. We had one outlier patient with an AUC of >1000 mg h/L, causing a slight trend for a positive correlation for PMA. Only four patients in the model based group had an AUC >800 mg h/L, all had a SCr <0.6 mg/dL including the outlier with an AUC >1000 mg h/L. We noticed a similar trend with the other dosing recommendations, almost all patients with an AUC >800 mg h/L had SCr <0.6 mg/dL (5 out of 7 with BNF, 3 out of 3 with Lexicomb, 4 out of 5 with NeoFax 10 and 15 mg/kg).
採用模式為基礎的給藥策略，達到 Vancomycin 治療目標 AUC 0–24 > 400 mg h/L 的病人比例最高 (89%)，而採用 NeoFax 給藥策略時為 11%–59%，採用 Lexicomp 給藥策略時為 56%，採用 BNF for Children 給藥策略時為 55%，美國兒科醫學指引%，採用費薩爾國王專科醫院臨床醫師建議時為 67%（所有成對比較 p < 0.01）。 NeoFax 建議劑量範圍為 10-15 mg/kg/dose 。雖然使用 15 mg/kg 劑量時 59% 的新生兒達到了治療目標，但使用 10 mg/kg 劑量時只有 11% 的新生兒達到治療範圍。以模式為基礎的劑量控制時，最低濃度達到 >20 mg/L 的機率為 6%；其中費薩爾國王專科醫院臨床醫師的建議最高（12%），其次是 BNF 兒童醫院，佔 10%；採用 NeoFax 10 mg/kg 劑量和紅皮書/尼爾森新生兒抗菌治療時，最低機率為 1%。對於所有處方來說，AUC >800 的機率都很低（<4%）。與 NeoFax（30%）、Lexicomp（29%）、BNF for Children（33%）、Red Book/Nelson's Neonatal Antibiotic Therapy（29%）以及結合兩家醫院的臨床醫師建議劑量（35%）相比，根據模式的劑量的 AUC 變異性（以百分比變異係數表示最低（21%）（圖 1）。此外，根據模式的給藥，不同 PMA、體重和 SCr 值之間的 AUC 相似（圖 2）；對於所有三個多種變項來說，R 2 都小於 0.1。我們有一名異常病人的 AUC >1000 mg h/L，造成 PMA 呈現輕微成正相關趨勢。 根據模式的組別中只有 4 名病人的 AUC > 800 mg h/L，所有病人的 SCr 均 < 0.6 mg/dL，包括 AUC > 1000 mg h/L 的異常值。我們注意到其他劑量建議也有類似的趨勢，幾乎所有 AUC >800 mg h/L 的病人 SCr 均 <0.6 mg/dL（BNF 組 7 名病人中有 5 名，Lexicomb 組 3 名病人中有 3 名，NeoFax 10 和 15 mg/kg 組 5 名病人中有 3 名）。
採用模式為基礎的給藥策略，達到 Vancomycin 治療目標 AUC 0–24 > 400 mg h/L 的病人比例最高 (89%)，而採用 NeoFax 給藥策略時為 11%–59%，採用 Lexicomp 給藥策略時為 56%，採用 BNF for Children 給藥策略時為 55%，美國兒科醫學指引%，採用費薩爾國王專科醫院臨床醫師建議時為 67%（所有成對比較 p < 0.01）。 NeoFax 建議劑量範圍為 10-15 mg/kg/dose 。雖然使用 15 mg/kg 劑量時 59% 的新生兒達到了治療目標，但使用 10 mg/kg 劑量時只有 11% 的新生兒達到治療範圍。以模式為基礎的劑量控制時，最低濃度達到 >20 mg/L 的機率為 6%；其中費薩爾國王專科醫院臨床醫師的建議最高（12%），其次是 BNF 兒童醫院，佔 10%；採用 NeoFax 10 mg/kg 劑量和紅皮書/尼爾森新生兒抗菌治療時，最低機率為 1%。對於所有處方來說，AUC >800 的機率都很低（<4%）。與 NeoFax（30%）、Lexicomp（29%）、BNF for Children（33%）、Red Book/Nelson's Neonatal Antibiotic Therapy（29%）以及結合兩家醫院的臨床醫師建議劑量（35%）相比，根據模式的劑量的 AUC 變異性（以百分比變異係數表示最低（21%）（圖 1）。此外，根據模式的給藥，不同 PMA、體重和 SCr 值之間的 AUC 相似（圖 2）；對於所有三個多種變項來說，R 2 都小於 0.1。我們有一名異常病人的 AUC >1000 mg h/L，造成 PMA 呈現輕微成正相關趨勢。 根據模式的組別中只有 4 名病人的 AUC > 800 mg h/L，所有病人的 SCr 均 < 0.6 mg/dL，包括 AUC > 1000 mg h/L 的異常值。我們注意到其他劑量建議也有類似的趨勢，幾乎所有 AUC >800 mg h/L 的病人 SCr 均 <0.6 mg/dL（BNF 組 7 名病人中有 5 名，Lexicomb 組 3 名病人中有 3 名，NeoFax 10 和 15 mg/kg 組 5 名病人中有 3 名）。
Figure 1 AUC distribution per dosing strategy. Top and bottom of the boxplots show the 25th and 75th percentile, the dark band in the middle shows the median. The points outside the whiskers are outliers, they are defined in R as:. values that exceeds 1.5 x interquartile range below Q1 or above Q3.
圖 1 每種給藥策略的 AUC 分佈。箱線圖的頂部和底部顯示第 25 和第 75 個百分位數，中間的深色帶顯示中位數。晶須外的點是異常值，它們在 R 中定義為：。低於 Q1 或高於 Q3 且超過 1.5 x 1/4距的值。
圖 1 每種給藥策略的 AUC 分佈。箱線圖的頂部和底部顯示第 25 和第 75 個百分位數，中間的深色帶顯示中位數。晶須外的點是異常值，它們在 R 中定義為：。低於 Q1 或高於 Q3 且超過 1.5 x 1/4距的值。
Figure 2 AUC versus bodyweight, PMA, and serum creatinine. Blue line is the Locally Weighted Scatterplot Smoothing (LOWESS). The shaded region shows the 95% confidence interval around the LOWESS line.
圖 2 AUC 與體重、PMA 和 Scr 的關係。藍線是局部加權散佈圖平滑線（LOWESS）。陰影區域顯示 LOWESS 線周圍的 95% 信賴區間。
圖 2 AUC 與體重、PMA 和 Scr 的關係。藍線是局部加權散佈圖平滑線（LOWESS）。陰影區域顯示 LOWESS 線周圍的 95% 信賴區間。
Subgroup analyses showed that VLBW neonates had a lower probability of achieving the therapeutic target with model-based dosing (69%), which was, however, still higher than other dosing recommendations (64% with NeoFax 15 mg/kg, 8% with NeoFax 10 mg/kg, 56% with Lexicomp, 50% with BNF for Children, and 36% with Red Book/Nelson's Neonatal Antimicrobial Therapy). For extreme premature neonates with PMA <28 weeks, the probability of achieving the therapeutic target with model-based dosing was 74%. It was 75% with NeoFax 15 mg/kg and <52% for all other dosing recommendations. Target attainment did not differ for patients with SCr above or below 0.8 mg/dL.
次族群分析顯示，VLBW 新生兒採用根據模式的給藥達到治療目標的機率較低（69%），但仍高於其他給藥建議（NeoFax 15 mg/kg 為 64%，NeoFax 10 mg/kg 為 8%，Lexicomp 為 56%，BNF for Children 為 50%，Red Book/3% 治療/36%，BRedren 為 50%，/37%）。對於 PMA <28 週的極度早產兒，根據模式的給藥達到治療目標的機率為 74％。使用 NeoFax 15 mg/kg 時，比例為 75%，而使用其他所有劑量建議時，比例均小於 52%。對於 SCr 高於或低於 0.8 mg/dL 的病人，目標達成情況並未有差別。
次族群分析顯示，VLBW 新生兒採用根據模式的給藥達到治療目標的機率較低（69%），但仍高於其他給藥建議（NeoFax 15 mg/kg 為 64%，NeoFax 10 mg/kg 為 8%，Lexicomp 為 56%，BNF for Children 為 50%，Red Book/3% 治療/36%，BRedren 為 50%，/37%）。對於 PMA <28 週的極度早產兒，根據模式的給藥達到治療目標的機率為 74％。使用 NeoFax 15 mg/kg 時，比例為 75%，而使用其他所有劑量建議時，比例均小於 52%。對於 SCr 高於或低於 0.8 mg/dL 的病人，目標達成情況並未有差別。
The average total daily recommended dose per kg body weight was comparable among all groups, ranging between 33 and 38 mg/kg/day, except for the NeoFax 10 mg/kg and Red Book/Nelson's Neonatal Antimicrobial Therapy, which were lower, ranging between 22.3 and 26.5 (Table 3). For all dosing methods, the probability of having an AUC of >800 mg h/L was low (<3%).
各組每公斤體重的平均每日建議總劑量相當，在 33-38 mg/kg/day 之間，但 NeoFax 10 mg/kg和紅皮書/尼爾森新生兒抗菌治療排除，這兩種劑量較低，介於 22.3-26.5 之間（表 3）。對於所有使用方法，AUC >800 mg h/L 的機率較低 (<3%)。
各組每公斤體重的平均每日建議總劑量相當，在 33-38 mg/kg/day 之間，但 NeoFax 10 mg/kg和紅皮書/尼爾森新生兒抗菌治療排除，這兩種劑量較低，介於 22.3-26.5 之間（表 3）。對於所有使用方法，AUC >800 mg h/L 的機率較低 (<3%)。
| Average total daily dose mg/kg/day (SD) 平均每日總劑量 mg/kg/day (SD) | Average AUC mg.hr/L (SD, 95% CI) | % achieved target AUC of >400 | % trough of >20 mg/L % 最低(Trough) >20 mg/L | |
|---|---|---|---|---|
| Model-based dosing | 38 (11.6) | 501 (108,289–713) | 89 | 6 |
| NeoFax 15 mg/kg | 33.5 (9) | 454 (137, 186–723) 454（137,186-723） | 59 | 7 |
| NeoFax 10 mg/kg | 22.3 (6) | 303 (91, 125–481) | 11 | 1 |
| Lexicomp | 33 (9.5) | 442 (130, 187–697) 442（130,187-697） | 56 | 7 |
| BNF for Children | 34 (11) | 453 (150, 159–747) 453（150,159-747） | 55 | 10 |
| Red Book/Nelson's Neonatal Antimicrobial Therapy 紅皮書/納爾遜新生兒抗菌治療 | 26.5 (5.5) | 362 (105, 156–568) 362（105,156-568） | 28 | 1 |
| Clinician recommended dose at KSUMCa KSUMC 臨床醫師建議劑量 a | 26 (15) | 361 (130, 106–616) 361（130,106-616） | 27 | 3 |
| Clinician recommended dose at KFSHb KFSH 臨床醫師建議劑量 b | 38 (13.5) | 473 (150, 179–767) 473（150,179-767） | 67 | 12 |
Table 3
Probability of achieving therapeutic target per dosing recommendations.
依照劑量建議達到治療目標的機率。
依照劑量建議達到治療目標的機率。
a
King Saud University Medical City.
b
King Faisal Specialist Hospital.
4 Discussion
We developed a simple Excel calculator to optimize vancomycin dosing in neonates (Supplementary file). Our individualized model-based dose calculator incorporates all vancomycin pharmacokinetic predictors in neonates (i.e., weight, PMA, and SCr). This individualized dosing approach was predicted to achieve the target AUC0–24 of >400 mg h/L in 89% of the neonates included in this study compared with 11%–59% using other neonatal dosing references. In addition, using this approach minimizes the variability in AUC. Our results are consistent with the findings of Leroux et al. and Frymoyer et al. studies.11,21 Leroux et al. 21have developed an Excel calculator based on the population pharmacokinetic model by Zhao et al.22 Applying this model in clinical practice in three NICUs has improved vancomycin target attainment from 41% to 72%. However, it is important to note that the dosing calculator developed by Leroux et al. recommends vancomycin regimen as a loading dose plus 24-h continuous infusions. However, reserving an intravenous line only for antibiotic continuous infusion is not always feasible for critically ill neonates. Besides, they have considered vancomycin serum concentration of 15–25 mg/L rather than the AUC as the therapeutic target. Frymoyer et al. have reported that the probability of achieving the AUC therapeutic target was 94% using NeoVanco software compared with 18%–55% using other tertiary dosing references11. The results of the present study are more compatible with Frymoyer et al.’s findings. However, it is important to note that a simple Excel sheet calculator was used in this study, while Frymoyer et al. used an online dosing software (NeoVanco). This could explain the slightly higher target achieved in their study of 94% compared with 89% in our analysis. Dosing software has advantages over simple calculators, such as Excel, as they include both Bayesian and Monte Carlo simulations that would allow for more precise calculations. However, the associated cost of such software and the need for internet connection might be the main drawback especially in low-income settings. In addition, the calculator developed in the present study concisely provides the dosing recommendation. The formula embedded in the Excel sheet calculator was designed to directly calculate the dose that will achieve an AUC0–24 of 500 mg h/L (which is the midpoint between 400 and 600 mg h/L according to the updated IDSA guidelines) and a trough level of <15 mg/L. These values were selected to ensure adequate vancomycin exposure with the minimum risk of nephrotoxicity.
我們開發了一個簡單的 Excel 計算器來改良新生兒 Vancomycin 的劑量（補充文件）。我們根據個人化模式的劑量計算器結合了新生兒所有 Vancomycin 藥物動力學預測因子（即體重、PMA 和 SCr）。預計這種個別化使用方法可使本研究中 89% 的新生兒達成目標 AUC 0–24 >400 mg h/L，而使用其他新生兒給藥參考時這一比例僅為 11%–59%。此外，使用這種方法可大幅減少 AUC 改變。本研究結果與 Leroux 等人的研究結果一致。和 Frymoyer 等人研究。 11 21 Leroux 等人 21 根據趙等人的群體藥物動力學模式開發了 Excel 計算器。 22 在三個新生兒加護病房的臨床實務中使用此模式， Vancomycin 目標達成率從 41% 提升到 72%。然而，值得注意的是 Leroux 等人開發的劑量計算器。建議以 Vancomycin 治療方式作為起始劑量加 24 小時持續輸注。然而，對於重症新生兒來說，僅用於靜脈輸液管用於抗生素持續輸注並不總是可行的。此外，他們也考慮將 Vancomycin 血中濃度 15-25mg/L 而非 AUC 作為治療目標。 Frymoyer 等人報告指出，使用 NeoVanco 軟體達到 AUC 治療目標的機率為 94%，而使用其他三級給藥參考文獻的機率為 18%–55% 11 。本研究結果與 Frymoyer 等人的研究結果較為一致。然而，值得注意的是，本研究使用簡單的 Excel 表格計算器，而 Frymoyer 等人。使用線上劑量軟體（NeoVanco）。 這可以解釋為什麼他們的研究中達到的目標為 94%，而我們的分析為 89%。劑量軟體比 Excel 等簡單的計算器有優勢，因為它們包含貝氏和蒙特卡羅模擬，可以進行更精確的計算。然而，這樣的軟體的相關成本和對網路連線的需求可能是主要的缺點，尤其是在低收入地區。此外，本研究開發的計算器簡明扼要地提供了劑量建議。 Excel 工作表計算器中嵌入的公式目的在直接計算達到 AUC 0–24 500 mg h/L（根據更新的 IDSA 指引，這是 400 和 600 mg h/L 之間的中點）和最低濃度 <15 mg/L 。選擇這些值是為了確保 Vancomycin 充分暴露，同時將腎毒性風險降至最低。
11.
Frymoyer, A. ∙ Stockmann, C. ∙ Hersh, A.L. ...
Individualized empiric vancomycin dosing in neonates using a model-based approach
J Pediatric Infect Dis Soc. 2019; 8:97-10421.
Leroux, S. ∙ Jacqz-Aigrain, E. ∙ Biran, V. ...
Clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates
Antimicrob Agents Chemother. 2016; 60:2039-204222.
Zhao, W. ∙ Lopez, E. ∙ Biran, V. ...
Vancomycin continuous infusion in neonates: dosing optimisation and therapeutic drug monitoring
Arch Dis Child. 2013; 98:449-45311.
Frymoyer, A. ∙ Stockmann, C. ∙ Hersh, A.L. ...
Individualized empiric vancomycin dosing in neonates using a model-based approach
J Pediatric Infect Dis Soc. 2019; 8:97-104我們開發了一個簡單的 Excel 計算器來改良新生兒 Vancomycin 的劑量（補充文件）。我們根據個人化模式的劑量計算器結合了新生兒所有 Vancomycin 藥物動力學預測因子（即體重、PMA 和 SCr）。預計這種個別化使用方法可使本研究中 89% 的新生兒達成目標 AUC 0–24 >400 mg h/L，而使用其他新生兒給藥參考時這一比例僅為 11%–59%。此外，使用這種方法可大幅減少 AUC 改變。本研究結果與 Leroux 等人的研究結果一致。和 Frymoyer 等人研究。 11
11.
Frymoyer, A. ∙ Stockmann, C. ∙ Hersh, A.L. ...
Individualized empiric vancomycin dosing in neonates using a model-based approach
J Pediatric Infect Dis Soc. 2019; 8:97-10421.
Leroux, S. ∙ Jacqz-Aigrain, E. ∙ Biran, V. ...
Clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates
Antimicrob Agents Chemother. 2016; 60:2039-204222.
Zhao, W. ∙ Lopez, E. ∙ Biran, V. ...
Vancomycin continuous infusion in neonates: dosing optimisation and therapeutic drug monitoring
Arch Dis Child. 2013; 98:449-45311.
Frymoyer, A. ∙ Stockmann, C. ∙ Hersh, A.L. ...
Individualized empiric vancomycin dosing in neonates using a model-based approach
J Pediatric Infect Dis Soc. 2019; 8:97-104Optimizing vancomycin dosing would be even more challenging in VLBW neonates. Evidence on optimum initial dosing of the vancomycin regimen in this special population is sparse. The neonatal cohort of the present study included 103 VLBW neonates. The model-based dosing of the present study was predicted to achieve the target AUC0–24 of >400 mg h/L in 69% of this subgroup population. This percentage is lower than the whole neonatal population, but it is still higher than those with other dosing recommendations using the tertiary dosing references [8%–64%]. In general, target attainment was lower for this subgroup population across all dosing recommendations. This could be attributed to the altered pharmacokinetics of this unique population. Kato et al. recommended a vancomycin dose of 10 mg/kg/dose q8h as the initial dosage regimen for vancomycin in VLBW neonates based on a population pharmacokinetic analysis.9 This model was predicted to achieve vancomycin therapeutic target in 86.7% of neonates. However, they developed their model based on data from only 10 VLBW neonates. Whereas Sasano et al. developed a population pharmacokinetics model for vancomycin dosing based on the data from 19 VLBW neonates and infants. They recommended a dose of 5.0–7.5 mg/kg/dose q12 h, especially when the SCr is > 0.6 mg/dL. They also concluded that the recommended doses based on the current target AUC may not be appropriate for VLBW infants.23 Therefore, further exploration of pharmacokinetic models in this unique population is highly warranted. Another group that might be challenging to dose is patients with low Scr values. In our results, almost all patients with high AUCs (>800) had SCr <0.6. This was consistent across all dosing recommendations Its important to note, that most patients with low SCr <0.6 had normal AUC values, but almost all outliers with high AUC had low SCr.
對於極低出生體重 (VLBW) 新生兒來說，改良 Vancomycin 劑量將更具挑戰性。關於這一特殊族群 Vancomycin 最佳起始劑量的證據很少。本研究的新生兒群組包括 103 名極低出生體重 (VLBW) 新生兒。預計本研究根據模式的給藥將在這個次族群族群的 69% 中達成目標 AUC 0–24 >400 mg h/L。這一比例低於整個新生兒群體，但仍高於使用三級劑量參考的其他劑量建議的比例[8%–64%]。整體而言，所有劑量建議中該次族群族群的目標達成率較低。這可能歸因於該獨特群體藥物動力學改變。 Kato 等人根據群體藥物動力學分析，建議 Vancomycin 劑量為 10 mg/kg/dose q8h 作為 VLBW 新生兒 Vancomycin 的初始處方。 9 此模式預測 86.7%的新生兒將達到 Vancomycin 治療目標。然而，他們僅根據 10 名 VLBW 新生兒的數據開發了該模式。而 Sasano 等人。根據 19 名 VLBW 新生兒和嬰兒的數據，建立了 Vancomycin 給藥的群體藥物動力學模式。他們建議劑量為 5.0–7.5 mg/kg/dose q12 h，尤其當 SCr > 0.6 mg/dL 時。他們還顯示，根據目前目標 AUC 的建議劑量可能不適合 VLBW 嬰兒。 23 因此，非常有必要進一步探討此特殊族群藥物動力學模式。另一組可能對劑量有挑戰性的病人是 Scr 值較低的病人。 在本研究結果中，幾乎所有具有高 AUC（> 800）的病人的 SCr 均 <0.6。這與其他劑量建議都是一致的，值得注意的是，多數 SCr 值低於 0.6 的病人 AUC 值正常，但幾乎所有 AUC 值的異常值均低於 SCr。
9.
Kato, H. ∙ Hagihara, M. ∙ Nishiyama, N. ...
Assessment of optimal initial dosing regimen with vancomycin pharmacokinetics model in very low birth weight neonates
J Infect Chemother. 2017; 23:154-16023.
Sasano, H. ∙ Aoki, K. ∙ Arakawa, R. ...
Population pharmacokinetic analysis and dose regimen optimization in Japanese infants with an extremely low birth weight
Antimicrob Agents Chemother. 2021; 65, e02523-20對於極低出生體重 (VLBW) 新生兒來說，改良 Vancomycin 劑量將更具挑戰性。關於這一特殊族群 Vancomycin 最佳起始劑量的證據很少。本研究的新生兒群組包括 103 名極低出生體重 (VLBW) 新生兒。預計本研究根據模式的給藥將在這個次族群族群的 69% 中達成目標 AUC 0–24 >400 mg h/L。這一比例低於整個新生兒群體，但仍高於使用三級劑量參考的其他劑量建議的比例[8%–64%]。整體而言，所有劑量建議中該次族群族群的目標達成率較低。這可能歸因於該獨特群體藥物動力學改變。 Kato 等人根據群體藥物動力學分析，建議 Vancomycin 劑量為 10 mg/kg/dose q8h 作為 VLBW 新生兒 Vancomycin 的初始處方。 9
9.
Kato, H. ∙ Hagihara, M. ∙ Nishiyama, N. ...
Assessment of optimal initial dosing regimen with vancomycin pharmacokinetics model in very low birth weight neonates
J Infect Chemother. 2017; 23:154-16023.
Sasano, H. ∙ Aoki, K. ∙ Arakawa, R. ...
Population pharmacokinetic analysis and dose regimen optimization in Japanese infants with an extremely low birth weight
Antimicrob Agents Chemother. 2021; 65, e02523-20Vancomycin is a hydrophilic molecule mostly eliminated by the kidneys. Glomerular filtration rate in neonates varies depending on degree of prematurity, PMA and bodyweight. Renal function maturation is slower in preterm neonates.24 Also, reduced protein binding in neonates can influence vancomycin pharmacokinetics. Prior studies demonstrate that the unbound fraction of vancomycin is higher in neonates compared to adults and children.25 reduced protein binding results in increased volume of distribution and is associated with increased renal clearance.26 The main advantage of model-based dosing is that it simultaneously considers all these factors that impact vancomycin pharmacokinetics for more precise dosing. This is particularly important in neonates, in whom multiple factors affect the drugs pharmacokinetics, such as PMA, SCr, weight, and maturity.
Vancomycin 是一種親水性分子，主要經由腎臟排洩。新生兒的腎絲球濾過率隨早產程度、PMA 和體重而改變。早產兒腎功能成熟較慢。 24 此外，新生兒蛋白質結合率降低會影響 Vancomycin 藥物動力學。先前的研究證明，新生兒體內 Vancomycin 的遊離部分比成人和兒童體內較高。 25 蛋白質結合減少造成分佈體積增加，並與腎臟清除率增加有關。 26 根據模式的給藥的主要優點是它同時考慮了影響 Vancomycin 藥物動力學的所有因素，並因此達到更精確的給藥。這對於新生兒尤其重要，因為新生兒的 PMA、SCr、體重和成熟度等多種因素會影響藥物藥物動力學。
24.
Rhodin, M.M. ∙ Anderson, B.J. ∙ Peters, A.M. ...
Human renal function maturation: a quantitative description using weight and postmenstrual age
Pediatr Nephrol. 2009; 24:67-7625.
Smits, A. ∙ Pauwels, S. ∙ Oyaert, M. ...
Factors impacting unbound vancomycin concentrations in neonates and young infants
Eur J Clin Microbiol Infect Dis. 2018; 37:1503-151026.
Roberts, J.A. ∙ Pea, F. ∙ Lipman, J.
The clinical relevance of plasma protein binding changes
Clin Pharmacokinet. 2013; 52:1-8Vancomycin 是一種親水性分子，主要經由腎臟排洩。新生兒的腎絲球濾過率隨早產程度、PMA 和體重而改變。早產兒腎功能成熟較慢。 24
24.
Rhodin, M.M. ∙ Anderson, B.J. ∙ Peters, A.M. ...
Human renal function maturation: a quantitative description using weight and postmenstrual age
Pediatr Nephrol. 2009; 24:67-7625.
Smits, A. ∙ Pauwels, S. ∙ Oyaert, M. ...
Factors impacting unbound vancomycin concentrations in neonates and young infants
Eur J Clin Microbiol Infect Dis. 2018; 37:1503-151026.
Roberts, J.A. ∙ Pea, F. ∙ Lipman, J.
The clinical relevance of plasma protein binding changes
Clin Pharmacokinet. 2013; 52:1-8Two studies on amikacin in neonates have demonstrated similar results. In those studies, model-based dosing improved target attainment27,28 Several other studies have demonstrated the same benefit of model-based dosing for different drugs and populations.29–31 In addition, model-based dosing helps achieve therapeutic targets faster, which is essential to improve clinical outcomes.32,33 Another advantage of model-based dosing would be the indirect cost saving through lowering the number of samples taken from each patient. Usually, patients with concentrations above or below the therapeutic target require multiple sampling. Achieving the therapeutic target early would lower the need for additional samples.
兩項針對新生兒 Amikacin 的研究也顯示了類似的結果。在這些研究中，根據模式的劑量提升了目標達到率 27 28 其他幾項研究也證明了根據模式的劑量對不同藥物和族群具有相同的效益。 29–31 此外，根據模式的給藥有助於較快地達到治療目標，這對於改善臨床結果很重要。 32 33 根據模式的給藥的另一個優點是透過減少從每個病人身上搜集的樣本數量來間接節省成本。通常，濃度高於或低於治療目標的病人需要多次採樣。儘早達到治療目標將降低額外樣本的需求。
27.
An, S.H. ∙ Kim, J.Y. ∙ Gwak, H.S.
Outcomes of a new dosage regimen of amikacin based on pharmacokinetic parameters of Korean neonates
Am J Health Syst Pharm. 2014; 71:122-12728.
Smits, A. ∙ De Cock, R.F. ∙ Allegaert, K. ...
Prospective evaluation of a model-based dosing regimen for amikacin in preterm and term neonates in clinical practice
Antimicrob Agents Chemother. 2015; 59:6344-635129.
Dorajoo, S.R. ∙ Winata, C.L. ∙ Goh, J.H.F. ...
Optimizing vancomycin dosing in chronic kidney disease by deriving and implementing a web-based tool using a population pharmacokinetics analysis
Front Pharmacol. 2019; 10:64130.
Ter Heine, R. ∙ Keizer, R.J. ∙ van Steeg, K. ...
Prospective validation of a model-informed precision dosing tool for vancomycin in intensive care patients
Br J Clin Pharmacol. 2020; 86:2497-250631.
Brown, M.L. ∙ Hutchison, A.M. ∙ McAtee, A.M. ...
Allometric versus consensus guideline dosing in achieving target vancomycin trough concentrations
Am J Health Syst Pharm. 2017; 74:1067-107532.
Casapao, A.M. ∙ Lodise, T.P. ∙ Davis, S.L. ...
Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis
Antimicrob Agents Chemother. 2015; 59:2978-298533.
Lodise, T.P. ∙ Drusano, G.L. ∙ Zasowski, E. ...
Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough?
Clin Infect Dis. 2014; 59:666-675兩項針對新生兒 Amikacin 的研究也顯示了類似的結果。在這些研究中，根據模式的劑量提升了目標達到率 27
27.
An, S.H. ∙ Kim, J.Y. ∙ Gwak, H.S.
Outcomes of a new dosage regimen of amikacin based on pharmacokinetic parameters of Korean neonates
Am J Health Syst Pharm. 2014; 71:122-12728.
Smits, A. ∙ De Cock, R.F. ∙ Allegaert, K. ...
Prospective evaluation of a model-based dosing regimen for amikacin in preterm and term neonates in clinical practice
Antimicrob Agents Chemother. 2015; 59:6344-635129.
Dorajoo, S.R. ∙ Winata, C.L. ∙ Goh, J.H.F. ...
Optimizing vancomycin dosing in chronic kidney disease by deriving and implementing a web-based tool using a population pharmacokinetics analysis
Front Pharmacol. 2019; 10:64130.
Ter Heine, R. ∙ Keizer, R.J. ∙ van Steeg, K. ...
Prospective validation of a model-informed precision dosing tool for vancomycin in intensive care patients
Br J Clin Pharmacol. 2020; 86:2497-250631.
Brown, M.L. ∙ Hutchison, A.M. ∙ McAtee, A.M. ...
Allometric versus consensus guideline dosing in achieving target vancomycin trough concentrations
Am J Health Syst Pharm. 2017; 74:1067-107532.
Casapao, A.M. ∙ Lodise, T.P. ∙ Davis, S.L. ...
Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis
Antimicrob Agents Chemother. 2015; 59:2978-298533.
Lodise, T.P. ∙ Drusano, G.L. ∙ Zasowski, E. ...
Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough?
Clin Infect Dis. 2014; 59:666-675Limitations of this study include its retrospective design and small size. However, all neonatal subgroup populations including term (81; 36%), preterm (119; 53%), and extremely preterm neonates (25; 11%), as well as VLBW neonates (103; 46%), were well represented in the patient population of the present study. This would increase the generalizability of the model-based dosing calculator of the present study. Also, patients with renal impairment (SCr >1.5 mg/dL or urine output <1 mL/kg/h for 24 h) were not included. Therefore, the calculator of the present study does not apply to that patient population. However, because the systemic clearance of vancomycin depends mainly on renal function, it should be dosed very cautiously in this population to avoid accumulation and toxicity. Another limitation is related to the use of Excel calculators for dose calculations, they are prone to error. To help minimize errors in calculations, the excel calculator we developed is locked.34 Also, dosing programs are a useful tool, but clinicians should always be advised to use their clinical judgment to verify the recommended dose. Finally, clinical outcomes, such as nephrotoxicity/efficacy or cost-effectiveness, were not evaluated in this study. Prospective clinical evaluations with larger sample sizes are warranted to assess whether model-based dosing can improve clinical outcomes and/or reduce cost.
本研究的局限性包括回顧性設計和規模較小。然而，所有新生兒次族群族群，包括足月新生兒（81；36%）、早產新生兒（119；53%）、極早產新生兒（25；11%）以及極低出生體重新生兒（103；46%），都在本研究的病人族群中佔有很好的代表性。這將增加本研究根據模式的劑量計算器的通用性。此外，腎功能不全（SCr >1.5 mg/dL 或 24 小時尿量 <1 mL/kg/h）病人也不包括在內。因此，本研究的計算器不適用於該病友。然而，由於 Vancomycin 的全身清除主要取決於腎功能，因此在這個族群中應非常謹慎地使用劑量，以避免蓄積和毒性。另一個限制與使用 Excel 計算器進行劑量計算有關，它們容易出錯。為了幫助儘量減少計算錯誤，我們開發的 Excel 計算器已被鎖定。 34 此外，用法用量是一種有用的工具，但應始終建議臨床醫師使用他們的臨床判斷來驗證建議劑量。最後，本研究未評估腎毒性/功效或成本效益等臨床結果。有必要進行較大規模數的前瞻性臨床評估，以評估根據模式的劑量是否可以改善臨床結果和/或降低成本。
34.
de Wildt, S.N. ∙ Verzijden, R. ∙ van den Anker, J.N. ...
Information technology cannot guarantee patient safety
BMJ. 2007; 334:851-852本研究的局限性包括回顧性設計和規模較小。然而，所有新生兒次族群族群，包括足月新生兒（81；36%）、早產新生兒（119；53%）、極早產新生兒（25；11%）以及極低出生體重新生兒（103；46%），都在本研究的病人族群中佔有很好的代表性。這將增加本研究根據模式的劑量計算器的通用性。此外，腎功能不全（SCr >1.5 mg/dL 或 24 小時尿量 <1 mL/kg/h）病人也不包括在內。因此，本研究的計算器不適用於該病友。然而，由於 Vancomycin 的全身清除主要取決於腎功能，因此在這個族群中應非常謹慎地使用劑量，以避免蓄積和毒性。另一個限制與使用 Excel 計算器進行劑量計算有關，它們容易出錯。為了幫助儘量減少計算錯誤，我們開發的 Excel 計算器已被鎖定。 34
34.
de Wildt, S.N. ∙ Verzijden, R. ∙ van den Anker, J.N. ...
Information technology cannot guarantee patient safety
BMJ. 2007; 334:851-852In conclusion, our personalized pharmacokinetic model-based dosing is easily applicable in routine clinical practice, and they are promising to improve vancomycin exposure and target attainment in neonates.
總之，我們根據個人化藥物動力學模式的給藥很容易使用於常規臨床照護，並且有望改善新生兒的 Vancomycin 暴露和目標達到。
總之，我們根據個人化藥物動力學模式的給藥很容易使用於常規臨床照護，並且有望改善新生兒的 Vancomycin 暴露和目標達到。
Funding
This work was funded by King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia, grant number: KACST 2-17-03-001-0014.
本研究由沙烏地阿拉伯利雅德阿卜杜勒阿齊茲國王科技城 (KACST) 資助，資助編號：KACST 2-17-03-001-0014。
本研究由沙烏地阿拉伯利雅德阿卜杜勒阿齊茲國王科技城 (KACST) 資助，資助編號：KACST 2-17-03-001-0014。
Ethics approval
This study was approved by the institutional review board of the participating institutions. IRB # 2201252 from King Faisal Specialist Hospital and IRB # E-20-5333 from King Saud University Medical City.
本研究已獲得參與機構的機構審查委員會的核可。費薩爾國王專科醫院的 IRB 編號為 2201252，沙烏地國王大學醫學城的 IRB 編號為 E-20-5333。
本研究已獲得參與機構的機構審查委員會的核可。費薩爾國王專科醫院的 IRB 編號為 2201252，沙烏地國王大學醫學城的 IRB 編號為 E-20-5333。
Declaration of competing interest
Manal Abouelkheir, Abdullah Almohaizeie, Abdulrahman Almutairi, Sara Almuhisen, Saeed Alqahtani and Abdullah Alsultan declare that they have no conflicts of interest.
Manal Abouelkheir、Abdullah Almohaizeie、Abdulrahman Almutairi、Sara Almuhisen、Saeed Alqahtani 和 Abdullah Alsultan 說明他們沒有利益衝突。
Manal Abouelkheir、Abdullah Almohaizeie、Abdulrahman Almutairi、Sara Almuhisen、Saeed Alqahtani 和 Abdullah Alsultan 說明他們沒有利益衝突。
Appendix A Supplementary data (1)
The following is the Supplementary data to this article:
以下為本文的補充資料：
以下為本文的補充資料：
Multimedia component 1
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Optimizing vancomycin dosing in chronic kidney disease by deriving and implementing a web-based tool using a population pharmacokinetics analysis
透過使用群體藥物動力學分析計算和實施根據網路的工具來改良慢性腎臟病變中的 Vancomycin 劑量
Front Pharmacol. 2019; 10:641透過使用群體藥物動力學分析計算和實施根據網路的工具來改良慢性腎臟病變中的 Vancomycin 劑量
Ter Heine, R. ∙ Keizer, R.J. ∙ van Steeg, K. ...
海涅 (Ter Heine)，R. ∙ 凱澤 (R.J.) ∙範斯蒂格，K....
海涅 (Ter Heine)，R. ∙ 凱澤 (R.J.) ∙範斯蒂格，K....
Prospective validation of a model-informed precision dosing tool for vancomycin in intensive care patients
根據模式的加護病患 Vancomycin 精準給藥工具的前瞻性驗證
Br J Clin Pharmacol. 2020; 86:2497-2506根據模式的加護病患 Vancomycin 精準給藥工具的前瞻性驗證
Br J Clin Pharmacol. 2020 年； 86：2497-2506
Brown, M.L. ∙ Hutchison, A.M. ∙ McAtee, A.M. ...
布朗，ML ∙ 哈奇森，AM ∙ 麥卡蒂，AM ...
布朗，ML ∙ 哈奇森，AM ∙ 麥卡蒂，AM ...
Allometric versus consensus guideline dosing in achieving target vancomycin trough concentrations
異速給藥與一致指引給藥在達到 Vancomycin 最低目標濃度濃度的比較
Am J Health Syst Pharm. 2017; 74:1067-1075異速給藥與一致指引給藥在達到 Vancomycin 最低目標濃度濃度的比較
Am J Health Syst Pharm. 2017 年； 74：1067-1075
Casapao, A.M. ∙ Lodise, T.P. ∙ Davis, S.L. ...
Casapao，AM ∙ Lodise，TP ∙ Davis，SL ...
Casapao，AM ∙ Lodise，TP ∙ Davis，SL ...
Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis
抗 Methicillin 金黃色葡萄球菌感染性心內膜炎病人 Vancomycin 第 1 天暴露與預後的關係
Antimicrob Agents Chemother. 2015; 59:2978-2985抗 Methicillin 金黃色葡萄球菌感染性心內膜炎病人 Vancomycin 第 1 天暴露與預後的關係
抗生素化療。 2015 年； 59：2978-2985
Lodise, T.P. ∙ Drusano, G.L. ∙ Zasowski, E. ...
Lodise, TP ∙ Drusano, GL ∙ Zasowski, E. ...
Lodise, TP ∙ Drusano, GL ∙ Zasowski, E. ...
Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough?
抗 Methicillin 金黃色葡萄球菌血流感染病人的 Vancomycin 暴露：多少才夠？
Clin Infect Dis. 2014; 59:666-675抗 Methicillin 金黃色葡萄球菌血流感染病人的 Vancomycin 暴露：多少才夠？
de Wildt, S.N. ∙ Verzijden, R. ∙ van den Anker, J.N. ...
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Information technology cannot guarantee patient safety
資訊科技無法保證病人安全
BMJ. 2007; 334:851-852資訊科技無法保證病人安全
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