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Märtson AG, Barber KE, Crass RL, Hites M, Kloft C, Kuti JL, Nielsen EI, Pai MP, Zeitlinger M, Roberts JA, Tängdén T. The pharmacokinetics of antibiotics in patients with obesity: a systematic review and consensus guidelines for dose adjustments. THE LANCET. INFECTIOUS DISEASES 2025:S1473-3099(25)00155-0. [PMID: 40383125 DOI: 10.1016/s1473-3099(25)00155-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/14/2025] [Accepted: 02/25/2025] [Indexed: 05/20/2025]
Abstract
Obesity can cause physiological changes resulting in antibiotic pharmacokinetic alterations and suboptimal drug exposures. This systematic review aimed to summarise the available evidence on this topic and provide guidance for dose adjustment of antibiotics in adult (age ≥18 years) patients with obesity (BMI >30 kg/m2). We searched PubMed, Embase, and CENTRAL databases to find relevant studies published between database inception and Dec 30, 2023. We initially identified 6113 studies, which became 4654 studies after duplicate removal, and 128 studies were included in the final review. β-lactam antibiotics were most commonly studied (57 studies), followed by the group of glycopeptides, lipoglycopeptides, and oxazolidinones (45 studies). The certainty of evidence was low or very low for all antibiotics and a meta-analysis was not possible due to the heterogeneity of study populations and methods. Obesity modestly alters the pharmacokinetics of β-lactam antibiotics, but evidence does not support routine dose adjustments. For aminoglycosides and glycopeptides, the impact of obesity on pharmacokinetics is evident and weight-based dosing is recommended. Data are sparse for other antibiotic classes and research needs are described. In the absence of robust pharmacokinetic data, therapeutic drug monitoring can be used to guide individualised dosing.
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Affiliation(s)
- Anne-Grete Märtson
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - Katie E Barber
- School of Pharmacy, University of Mississippi, Jackson, MS, USA
| | - Ryan L Crass
- A2-Ai, Ann Arbor, MI, USA; College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Maya Hites
- Clinic of Infectious Diseases, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
| | - Charlotte Kloft
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany
| | - Joseph L Kuti
- Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA
| | | | - Manjunath P Pai
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Markus Zeitlinger
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Jason A Roberts
- University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; Herston Infectious Diseases Institute, Metro North Health, Brisbane, QLD, Australia; Department of Pharmacy and Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; UR UM 103, University of Montpellier, Division of Anesthesia Critical Care and Emergency and Pain Medicine, Nimes University Hospital, Nimes, France
| | - Thomas Tängdén
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Okuwaki T, Kobayashi M, Kikuchi R, Tomoda Y, Ogawa M, Kasugai K, Seto Y, Tomizawa A, Otori K. Vancomycin-associated acute kidney injury in underweight patients: a propensity score matching analysis. Int Urol Nephrol 2025; 57:1329-1336. [PMID: 39652231 DOI: 10.1007/s11255-024-04306-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 11/22/2024] [Indexed: 03/14/2025]
Abstract
PURPOSE To investigate the effect of being underweight on the incidence of vancomycin-associated acute kidney injury (AKI) using propensity score matching analysis. METHODS This study is a retrospective analysis of patients who received vancomycin and had their serum concentration measured at Kitasato University Hospital between January 1, 2016 and December 31, 2020. Patients were divided into underweight and non-underweight groups based on body mass index (BMI), and propensity score matching analysis was used to evaluate whether underweight affected the incidence of acute kidney injury. RESULTS 480 patients met the selection criteria, and 111 patients from each group (BMI < 18.5 and BMI ≥ 18.5) were successfully matched using propensity score matching. After matching, there were no differences in non-physical characteristics between the two groups. The incidence of AKI was 23.4% (26 of 111) in the BMI < 18.5 group and 37.8% (42 of 111) in the BMI ≥ 18.5 group, with the BMI < 18.5 group having a significantly lower incidence. The odds ratio was 0.503 [95% CI 0.281-0.900]. CONCLUSION This study showed that underweight patients (BMI < 18.5) had a significantly lower incidence of vancomycin-associated AKI compared to those with BMI ≥ 18.5. As there have been no previous reports on the association between underweight and vancomycin-associated AKI, this study provides novel insights.
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Affiliation(s)
- Tatsuya Okuwaki
- Department of Pharmacy, Kitasato University Hospital, Sagamihara, Japan
| | - Masahiro Kobayashi
- Department of Pharmacy, Kitasato University Hospital, Sagamihara, Japan.
| | - Rino Kikuchi
- School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Yoshinori Tomoda
- Department of Pharmacy, Kitasato University Hospital, Sagamihara, Japan
- School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Moeka Ogawa
- School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Kumi Kasugai
- Department of Pharmacy, Kitasato University Hospital, Sagamihara, Japan
- School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Yoshinori Seto
- Department of Pharmacy, Kitasato University Hospital, Sagamihara, Japan
| | - Atsushi Tomizawa
- Department of Pharmacy, Kitasato University Hospital, Sagamihara, Japan
- Department of Patient Safety, Kitasato University Hospital, Sagamihara, Japan
| | - Katsuya Otori
- Department of Pharmacy, Kitasato University Hospital, Sagamihara, Japan
- School of Pharmacy, Kitasato University, Tokyo, Japan
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Polášková L, Hartinger JM, Murínová I, Michálek P, Slanař O, Šíma M. Vancomycin loading dose individualization in a population of obese patients undergoing haemodialysis based on population pharmacokinetic model. J Chemother 2025; 37:121-129. [PMID: 38887026 DOI: 10.1080/1120009x.2024.2367937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 05/22/2024] [Accepted: 06/09/2024] [Indexed: 06/20/2024]
Abstract
This study aimed to develop a vancomycin population pharmacokinetic model in obese adult patients treated with intermittent haemodialysis and propose a model-based loading dose strategy ensuring attainment of newly recommended AUC-based PK/PD target. Retrospective cross-sectional analysis was performed among obese haemodialysis dependent adult patients treated with intravenous vancomycin. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were used to identify the optimal loading dose for PK/PD target attainment during the first 48 h of treatment. Therapeutic drug monitoring data from 27 patients with a BMI of 30.2-52.9 kg/m2 were analysed. Among all tested variables, only LBM as a covariate of vancomycin Vd significantly improved the model, while vancomycin CL did not correlate with any of the tested variables. The median (IQR) value from the conditional mean of individual estimates of Vd and CL was 68.4 (56.6-84.2) L and 0.86 (0.79-0.90) L/h, respectively. To ensure optimal vancomycin exposure during the first 48 h of therapy, the vancomycin loading dose of 1500, 1750, 2000, 2250, 2500 and 2750 mg should be administered to obese patients with a lean body mass of ˂50, 50-60, 60-70, 70-80, 80-85 and >85 kg, respectively.
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Affiliation(s)
- Lucie Polášková
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czech Republic
| | - Jan Miroslav Hartinger
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Irena Murínová
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czech Republic
- Department of Applied Pharmacy, Faculty of Pharmacy, Masaryk University, Brno, Czech Republic
| | - Pavel Michálek
- Department of Anaesthesia and Intensive Care, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Ondřej Slanař
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Martin Šíma
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Takada K, Samura M, Igarashi Y, Suzuki A, Ishigo T, Fujii S, Ibe Y, Yoshida H, Tanaka H, Ebihara F, Maruyama T, Hamada Y, Komatsu T, Tomizawa A, Takuma A, Chiba H, Yagi Y, Nishi Y, Enoki Y, Taguchi K, Tanikawa K, Kunishima H, Matsumoto K. Development and validation of a population pharmacokinetic model of vancomycin for patients of advanced age. J Pharm Health Care Sci 2025; 11:18. [PMID: 40075546 PMCID: PMC11900651 DOI: 10.1186/s40780-025-00423-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Population pharmacokinetic (PPK) models of vancomycin (VCM) commonly use creatinine clearance (CLcr) as a covariate for clearance (CL). However, relying on CLcr in patients of advanced age may lead to inaccuracies in estimating VCM clearance. Therefore, this study aimed to develop and validate a new PPK model specifically for patients aged 75 years and older. METHODS PPK analysis was performed based on the blood concentrations of VCM (n = 159 patients). The predictive performance of the developed model was compared with that of previous models using mean absolute error (MAE) and mean squared error (MSE) for another dataset. RESULTS The PPK analysis optimized a two-compartment model using CLcr and the Alb levels as covariates at the central compartment of VCM clearance. The final model was as follows: CL (L/h) = 1.96 × (CLcr/3.09) 0.63 × (Serum albumin (Alb) /2.3) 0.22 × exponential (0.11). Clearance between the central and peripheral compartments (L/h) = 4.86. Central compartment volume of distribution (L) = 31.78. Peripheral compartment volume of distribution (L) = 53.64. The validation study revealed that compared with those of previous models (ranging from 0.67 to 0.79 L/h and from 0.81 to 1.11 (L/h)2, respectively), the final model demonstrated the smallest MAE of 0.60 L/h and MSE of 0.65 (L/h)2 for patients of advanced age with serum creatinine levels of < 0.6 mg/dL. CONCLUSION The PPK model of VCM for patients of advanced age was optimized by adding the Alb levels and CLcr as covariates for CL. The predictive accuracy of the PPK model for patients with an SCr of < 0.6 mg/dL tended to be higher than those of previous models based just on CLcr. Thus, dosage is suggested to be adjusted based on CLcr and Alb levels for patients with an SCr of < 0.6 mg/dL.
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Affiliation(s)
- Keisuke Takada
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan
- Department of Pharmacy, Yokohama General Hospital, 2201-5 Kuroganecho, Aoba-Ku, Yokohama City, Kanagawa, 225-0025, Japan
| | - Masaru Samura
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan.
- Department of Pharmacy, Yokohama General Hospital, 2201-5 Kuroganecho, Aoba-Ku, Yokohama City, Kanagawa, 225-0025, Japan.
- Faculty of Pharmaceutical Sciences, Teikyo Heisei University, 4-21-2 Nakano, Nakano-Ku, Tokyo, 164-8530, Japan.
| | - Yuki Igarashi
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan
- Department of Pharmacy, Yokohama General Hospital, 2201-5 Kuroganecho, Aoba-Ku, Yokohama City, Kanagawa, 225-0025, Japan
| | - Ayako Suzuki
- Department of Pharmacy, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-Ku, Yokohama-Shi, Kanagawa, 227-8501, Japan
- Department of Pharmacy, Showa University Hospital, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, 142-8666, Japan
| | - Tomoyuki Ishigo
- Department of Pharmacy, Sapporo Medical University Hospital, 291 Nishi 16-Chome, Minami 1-Jo, Chuo-Ku, Sapporo-Shi, Hokkaido, 060-8543, Japan
| | - Satoshi Fujii
- Department of Pharmacy, Sapporo Medical University Hospital, 291 Nishi 16-Chome, Minami 1-Jo, Chuo-Ku, Sapporo-Shi, Hokkaido, 060-8543, Japan
| | - Yuta Ibe
- Department of Pharmacy, Sapporo Medical University Hospital, 291 Nishi 16-Chome, Minami 1-Jo, Chuo-Ku, Sapporo-Shi, Hokkaido, 060-8543, Japan
| | - Hiroaki Yoshida
- Department of Pharmacy, Kyorin University Hospital, 6-20-2 Shinkawa, Mitaka-Shi, Tokyo, 181-8611, Japan
| | - Hiroaki Tanaka
- Department of Pharmacy, Kyorin University Hospital, 6-20-2 Shinkawa, Mitaka-Shi, Tokyo, 181-8611, Japan
| | - Fumiya Ebihara
- Department of Pharmacy, Tokyo Women's Medical University Hospital, 8-1 Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
| | - Takumi Maruyama
- Department of Pharmacy, Tokyo Women's Medical University Hospital, 8-1 Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
| | - Yukihiro Hamada
- Department of Pharmacy, Kochi Medical School Hospital, 185-1 Okochokohasu, Nankoku-Shi, Kochi, 783-8505, Japan
| | - Toshiaki Komatsu
- Department of Pharmacy, Kitasato University Hospital, 1-15-1 Kitasato, Minami-Ku, Sagamihara-Shi, Kanagawa, 252-0375, Japan
| | - Atsushi Tomizawa
- Department of Pharmacy, Kitasato University Hospital, 1-15-1 Kitasato, Minami-Ku, Sagamihara-Shi, Kanagawa, 252-0375, Japan
| | - Akitoshi Takuma
- Department of Pharmacy, Showa University Northern Yokohama Hospital, 35-1 Chigasaki-Chuo, Tsuzuki-Ku, Yokohama-Shi, Kanagawa, 224-0032, Japan
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, 142-8555, Japan
| | - Hiroaki Chiba
- Department of Pharmacy, Tohoku Kosai Hospital, 2-3-11 Kokubuncho, Aoba-Ku, Sendai-Shi, Miyagi, 980-0803, Japan
| | - Yusuke Yagi
- Department of Pharmacy, Kochi Medical School Hospital, 185-1 Okochokohasu, Nankoku-Shi, Kochi, 783-8505, Japan
| | - Yoshifumi Nishi
- Center for Pharmacist Education, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-Shi, Chiba, 274-0063, Japan
| | - Yuki Enoki
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan
| | - Kazuaki Taguchi
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan
| | - Koji Tanikawa
- Department of Pharmacy, Yokohama General Hospital, 2201-5 Kuroganecho, Aoba-Ku, Yokohama City, Kanagawa, 225-0025, Japan
| | - Hiroyuki Kunishima
- Department of Infectious Diseases, St. Marianna University School of Medicine Hospital, 2-16-1 Sugao, Miyamae-Ku, Kawasaki City, Kanagawa, 216-8511, Japan
| | - Kazuaki Matsumoto
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan
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Ma P, Ma H, Liu R, Wen H, Li H, Huang Y, Li Y, Xiong L, Xie L, Wang Q. Prediction of vancomycin plasma concentration in elderly patients based on multi-algorithm mining combined with population pharmacokinetics. Sci Rep 2024; 14:27165. [PMID: 39511378 PMCID: PMC11544216 DOI: 10.1038/s41598-024-78558-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/31/2024] [Indexed: 11/15/2024] Open
Abstract
The pharmacokinetics of vancomycin exhibit significant inter-individual variability, particularly among elderly patients. This study aims to develop a predictive model that integrates machine learning with population pharmacokinetics (popPK) to facilitate personalized medication management for this demographic. A retrospective analysis incorporating 33 features, including popPK parameters such as clearance and volume of distribution. A combination of multiple algorithms and Shapley Additive Explanations was utilized for feature selection to identify the most influential factors affecting drug concentrations. The performance of each algorithm with popPK parameters was superior to that without popPK parameters. Our final ensemble model, composed of support vector regression, light gradient boosting machine, and categorical boosting in a 6:3:1 ratio, included 16 optimized features. This model demonstrated superior predictive accuracy compared to models utilizing all features, with testing group metrics including an R2 of 0.656, mean absolute error of 3.458, mean square error of 28.103, absolute accuracy within ± 5 mg/L of 81.82%, and relative accuracy within ± 30% of 76.62%. This study presents a rapid and cost-effective predictive model for estimating vancomycin plasma concentrations in elderly patients. The model offers a valuable tool for clinicians to accurately determine effective plasma concentration ranges and tailor individualized dosing regimens, thereby enhancing therapeutic outcomes and safety.
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Affiliation(s)
- Pan Ma
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China
| | - Huan Ma
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China
| | - Ruixiang Liu
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China
| | - Haini Wen
- Department of Pharmacy, Uppsala University, Husargatan 3, 751 37, Uppsala, Sweden
| | - Haisheng Li
- Institute of Burn Research, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - Yifan Huang
- Medical Big Data and Artificial Intelligence Center, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - Ying Li
- Medical Big Data and Artificial Intelligence Center, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - Lirong Xiong
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China
| | - Linli Xie
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China.
| | - Qian Wang
- Department of Pharmacy, Southwest Hospital, The First Affiliated Hospital of Army Medical University, Gaotanyan Street 30, Chongqing, 400038, China.
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Matsuya S, Kawahata S, Takeda Y. Impact of physical build on serum vancomycin concentrations of patients undergoing hemodialysis: A retrospective cohort study at an acute care hospital. J Infect Chemother 2024; 30:1015-1020. [PMID: 38552840 DOI: 10.1016/j.jiac.2024.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 03/10/2024] [Accepted: 03/26/2024] [Indexed: 04/01/2024]
Abstract
INTRODUCTION Estimating the serum vancomycin (VCM) concentrations of lean and patients with obesity is challenging. Additionally, VCM dosing for Japanese patients undergoing hemodialysis remains particularly unclear. This study aimed to determine the impact of the physical build on serum VCM concentrations of Japanese patients undergoing hemodialysis. METHODS This retrospective cohort study included hospitalized patients undergoing hemodialysis, who received treatment with VCM between May 1, 2019, and December 31, 2021, at Kansai Rosai Hospital, which is a 642-bed acute care hospital in Japan. Patients were divided into the following three groups based on their body mass index (BMI): lean group (≤18.5 kg/m2), normal group (18.5-25 kg/m2), and obese group (≥25 kg/m2). The VCM dose and predialysis serum VCM concentration (PVC) were compared. RESULTS This study included 191 patients. There were 50 patients in the lean group, 85 in the normal group, and 56 in the obese group. The median loading doses per body weight were 24.0, 22.1, and 21.2 mg/kg for the lean, normal, and obese groups, respectively. The VCM dose per body weight decreased significantly with increasing BMI. The median PVCs of the lean and normal groups were approximately 15 mg/L (not significantly different). However, the median PVC of the obese group was 18.3 mg/L, which was significantly higher (P < 0.001). CONCLUSIONS The VCM dose per body weight for Japanese patients undergoing hemodialysis should be adjusted based on the BMI.
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Affiliation(s)
- Shota Matsuya
- Kansai Rosai Hospital, 3-1-69 Inabaso, Amagasaki-shi, Hyogo-ken, 660-0064, Japan.
| | - Shunsuke Kawahata
- Kansai Rosai Hospital, 3-1-69 Inabaso, Amagasaki-shi, Hyogo-ken, 660-0064, Japan
| | - Yoshiaki Takeda
- Kansai Rosai Hospital, 3-1-69 Inabaso, Amagasaki-shi, Hyogo-ken, 660-0064, Japan
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Hsu YC, Liu CH, Wu YC, Lai SJ, Lin CJ, Tseng TS. Combatting Antibiotic-Resistant Staphylococcus aureus: Discovery of TST1N-224, a Potent Inhibitor Targeting Response Regulator VraRC, through Pharmacophore-Based Screening and Molecular Characterizations. J Chem Inf Model 2024; 64:6132-6146. [PMID: 39078379 PMCID: PMC11323011 DOI: 10.1021/acs.jcim.4c01046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 07/31/2024]
Abstract
Staphylococcus aureus (S. aureus) is a major global health concern, causing various infections and presenting challenges due to antibiotic resistance. In particular, methicillin-resistant S. aureus, vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus pose significant obstacles in treating S. aureus infections. Therefore, the critical need for novel drugs to counter these resistant forms is pressing. Two-component systems (TCSs), integral to bacterial regulation, offer promising targets for disruption. In this study, a comprehensive approach, involving pharmacophore-based inhibitor screening, along with biochemical and biophysical analyses were conducted to identify, characterize, and validate potential inhibitors targeting the response regulator VraRC of S. aureus. The constructed pharmacophore model, Phar-VRPR-N3, demonstrated effectiveness in identifying a potent inhibitor, TST1N-224 (IC50 = 60.2 ± 4.0 μM), against the formation of the VraRC-DNA complex. Notably, TST1N-224 exhibited strong binding to VraRC (KD = 23.4 ± 1.2 μM) using a fast-on-fast-off binding mechanism. Additionally, NMR-based molecular modeling revealed that TST1N-224 predominantly interacts with the α9- and α10-helixes of the DNA-binding domain of VraR, where the interactive and functionally essential residues (N165, K180, S184, and R195) act as hotspots for structure-based inhibitor optimization. Furthermore, TST1N-224 evidently enhanced the susceptibility of VISA to both vancomycin and methicillin. Importantly, TST1N-224 distinguished by 1,2,5,6-tetrathiocane with the 3 and 8 positions modified with ethanesulfonates holds significant potential as a lead compound for the development of new antimicrobial agents.
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Affiliation(s)
- Ying-Chu Hsu
- Division
of Neurology, Department of Internal Medicine, Ditmanson Medical Foundation ChiaYi Christian Hospital, Chiayi 600566, Taiwan
| | - Ching-Hui Liu
- Institute
of Molecular Biology, National Chung Hsing University, Taichung 40202, Taiwan
| | - Yi-Chen Wu
- Institute
of Molecular Biology, National Chung Hsing University, Taichung 40202, Taiwan
| | - Shu-Jung Lai
- Graduate
Institute of Biomedical Sciences, China
Medical University, Taichung 404333, Taiwan
- Research
Center for Cancer Biology, China Medical
University, Taichung 404333, Taiwan
| | - Chi-Jan Lin
- Institute
of Molecular Biology, National Chung Hsing University, Taichung 40202, Taiwan
| | - Tien-Sheng Tseng
- Institute
of Molecular Biology, National Chung Hsing University, Taichung 40202, Taiwan
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Shremo Msdi A, Abdul-Mutakabbir JC, Tan KK. Characterizing Day 1 Area Under the Curve Following Vancomycin Loading Dose Administration in Adult Hospitalized Patients Using Non-Trapezoidal Linear Pharmacokinetic Equations: A Retrospective Observational Study. Infect Dis Ther 2024; 13:1807-1819. [PMID: 38922527 PMCID: PMC11266319 DOI: 10.1007/s40121-024-01004-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 06/04/2024] [Indexed: 06/27/2024] Open
Abstract
INTRODUCTION Methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious threat to public health. Vancomycin (VAN) remains the primary treatment for these infections, and achieving the recommended area under the curve (AUC) target has been linked to improved clinical outcomes. The current VAN therapeutic monitoring guidelines recommend a loading dose (LD) of 20-35 mg/kg to rapidly attain targeted VAN exposures within 24 h of therapy. However, there is a paucity of data describing the impact of VAN LD on day 1 area under the curve (AUC0-24). This study aims to employ pharmacokinetic (PK) equations to calculate and describe the AUC0-24 following a VAN LD of 20 mg/kg. METHODS This was a retrospective study of adult patients who were loaded with VAN 20 mg/kg, received ≥ 48 h of treatment, and had two consecutive serum VAN levels collected within 24 h. Linear, non-trapezoidal PK equations and two post-infusion VAN levels were used to calculate AUC0-24. Therapeutic AUC0-24 was defined as 400-600 mg/l*h. RESULTS Among 123 included patients, the median age was 46 years (IQR 36, 62), 54% (67/123) of the patients had a body mass index (BMI) ≥ 30 kg/m2 and 27% (33/123) were admitted to the intensive care unit (ICU). Following a LD of 20 mg/kg, 50% (61/123) of the patients met the therapeutic AUC0-24, while 22% (27/123) of the patients were subtherapeutic, and 28% (35/123) were supratherapeutic. Compared with patients who achieved therapeutic AUC0-24, patients with subtherapeutic AUC0-24 were more likely to be younger (44 vs. 37 years old) and have a BMI ≥ 30 kg/m2 (67 vs. 52%). In contrast, patients with supratherapeutic AUC0-24 were more likely to be older (64 vs. 44 years old) and to have chronic kidney disease diagnosis (23 vs. 7%) when compared to patients who achieved a therapeutic AUC0-24. CONCLUSIONS: Only 50% of patients achieve the target AUC0-24 following a VAN 20 mg/kg LD, with younger, heavier patients underexposed and older patients with renal impairment overexposed, suggesting that different dosing strategies are needed for these populations.
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Affiliation(s)
- Abdulwhab Shremo Msdi
- Department of Pharmacy Practice, Loma Linda University School of Pharmacy, Loma Linda, CA, 92354, USA
- Department of Pharmacy Services, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - Jacinda C Abdul-Mutakabbir
- Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093, USA
- Division of the Black Diaspora and African American Studies, University of California San Diego, La Jolla, CA, 92093, USA
| | - Karen K Tan
- Department of Pharmacy Practice, Loma Linda University School of Pharmacy, Loma Linda, CA, 92354, USA.
- Department of Pharmacy Services, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA.
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9
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Polášková L, Murínová I, Gregorová J, Slanař O, Šíma M. Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients. Front Pharmacol 2024; 15:1364681. [PMID: 38895623 PMCID: PMC11183791 DOI: 10.3389/fphar.2024.1364681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 05/13/2024] [Indexed: 06/21/2024] Open
Abstract
Aim The aim of this study was to develop a vancomycin population pharmacokinetic model in adult obese patients and propose covariate-based dosing individualization in order to maximize the achievement of the newly recommended PK/PD target, according to a revised consensus guideline from 2020. Methods Therapeutic drug monitoring data from initial vancomycin therapy (first 3 days of treatment) in adult obese (BMI ≥ 30 kg/m2) patients from 2013 to 2022 were analyzed using a non-linear mixed-effects modeling method, and Monte Carlo simulations were then used to find the optimal dosage maximizing the PK/PD target attainment. Results A total of 147 vancomycin serum levels obtained from 138 patients were included in the analysis. Based on the covariate model diagnosis among all tested variables, no reliable predictor of vancomycin volume of distribution (Vd) was identified, while clearance (CL) was positively correlated with eGFR and lean body mass. Creatinine-based eGFR predicted vancomycin CL better than cystatin C-based eGFR. The median (interquartile range) value from conditional modes of individual estimates of Vd, CL, and elimination half-life in our population was 74.0 (70.5-75.4) L, 6.65 (4.95-8.42) L/h, and 7.7 (6.0-10.0) h, respectively. Conclusion We proposed dosing individualization based on the covariate found in order to maximize the achievement of the newly recommended PK/PD target of the AUC/MIC ratio of 400-600. Clinical pharmacy/pharmacology interventions may lead to an improvement in vancomycin dosing with a reflection in PK/PD target attainment.
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Affiliation(s)
- Lucie Polášková
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czechia
| | - Irena Murínová
- Department of Clinical Pharmacy, Military University Hospital Prague, Prague, Czechia
- Department of Applied Pharmacy, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Jana Gregorová
- Department of Clinical Pharmacy, Bulovka University Hospital, Prague, Czechia
| | - Ondřej Slanař
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
| | - Martin Šíma
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
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10
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Andreani L, Ipponi E, Varchetta G, Ruinato AD, De-Franco S, Campo FR, D'Arienzo A. Topical Application of Vancomycin Powder to Prevent Infections after Massive Bone Resection and the implantation of Megaprostheses in Orthopaedic Oncology Surgery. Malays Orthop J 2024; 18:125-132. [PMID: 38638658 PMCID: PMC11023351 DOI: 10.5704/moj.2403.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 10/06/2023] [Indexed: 04/20/2024] Open
Abstract
Introduction Periprosthetic joint infection (PJI) represents a serious burden in orthopaedic oncology. Through the years, several local expedients have been proposed to minimise the risk of periprosthetic infection. In this study, we report our outcomes using topical vancomycin powder (VP) with the aim to prevent PJIs. Materials and methods Fifty oncological cases treated with massive bone resection and the implant of a megaprosthesis were included in our study. Among them, 22 [(GGroup A) received one gram of vancomycin powder on the surface of the implant and another gram on the surface of the muscular fascia]. The remaining 28 did not receive such a treatment (Group B). The rest of surgical procedures and the follow-up were the same for the two groups. Patients underwent periodical outpatient visits, radiographs and blood exams' evaluations. Diagnosis of PJIs and adverse reactions to topical vancomycin were recorded. Results None of the cases treated with topical vancomycin developed infections, whereas 6 of the 28 cases (21.4%) who did not receive the powder suffered from PJIs. These outcomes suggest that cases treated with VP had a significantly lower risk of post-operative PJI (p=0.028). None of our cases developed acute kidney failures or any other complication directly or indirectly attributable to the local administration of VP. Conclusions The topical use of vancomycin powder on megaprosthetic surfaces and the overlying fascias, alongside with a correct endovenous antibiotic prophylaxis, can represent a promising approach in order to minimise the risk of periprosthetic infections in orthopaedic oncology surgery.
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Affiliation(s)
- L Andreani
- Department of Orthopedics and Trauma Surgery, University of Pisa, Pisa, Italy
| | - E Ipponi
- Department of Orthopedics and Trauma Surgery, University of Pisa, Pisa, Italy
| | - G Varchetta
- Department of Orthopedics and Trauma Surgery, University of Pisa, Pisa, Italy
| | - A D Ruinato
- Department of Orthopedics and Trauma Surgery, University of Pisa, Pisa, Italy
| | - S De-Franco
- Department of Orthopedics and Trauma Surgery, University of Pisa, Pisa, Italy
| | - F R Campo
- Department of Orthopedics and Trauma Surgery, University of Pisa, Pisa, Italy
| | - A D'Arienzo
- Department of Orthopedics and Trauma Surgery, University of Pisa, Pisa, Italy
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11
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Yamamoto T, Kawada K, Sato C, Tai T, Yamaguchi K, Sumiyoshi K, Tada A, Kurokawa N, Motoki T, Tanaka H, Kosaka S, Abe S. Optimal Blood Sampling Time for Area under the Concentration-Time Curve Estimation of Vancomycin by Assessing the Accuracy of Four Bayesian Software. Biol Pharm Bull 2024; 47:2021-2027. [PMID: 39647905 DOI: 10.1248/bpb.b24-00485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/10/2024]
Abstract
Effective blood sampling times, beyond trough and peak levels, have not been determined for estimating vancomycin's area under the concentration-time curve (AUC) using the Bayesian software. The aim of this study was to evaluate the accuracy of AUC estimation at different blood sampling times during the same dosing interval at steady state utilizing data from a prior phase I trial of vancomycin. Six healthy adult participants were sampled following intravenous administration of 1 g vancomycin for 1.5 h every 12 h. The AUC was estimated using four software packages and four population pharmacokinetic models. Accuracy was assessed using bias (difference between the estimated and reference AUC) and imprecision (absolute percentage difference between the estimated and reference AUC). The accuracy varied with the sampling time. The optimal two-point sampling times were determined to be 2.5 and 5.5 h post-injection using software packages for EasyTDM, Practical AUC-guided therapeutic drug monitoring (TDM), and Anti-MRSA Agents TDM Analysis Software (incorporating Rodvold, Yamamoto, and Yasuhara models). In these estimations, the mean bias (range, -1.7 to 9.5 µg·h/mL) was unbiased and the mean imprecision (range, -3.0% to 5.0%) was precise. The optimal one-point sampling time was 5.5 h post-injection for Anti-MRSA Agents TDM Analysis Software, which incorporated the Yamamoto and Yasuhara models. In conclusion, optimal blood sampling times may vary depending on the software and model used. Our findings suggest that identifying specific sampling times could improve the efficacy of TDM in clinical practice.
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Affiliation(s)
- Takaaki Yamamoto
- Department of Clinical Pharmacy Practice Pedagogy, Tokushima University Graduate School of Biomedical Sciences
| | - Kei Kawada
- Department of Clinical Pharmacy Practice Pedagogy, Tokushima University Graduate School of Biomedical Sciences
- Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences
| | - Chiemi Sato
- Department of Clinical Pharmacy Practice Pedagogy, Tokushima University Graduate School of Biomedical Sciences
| | - Tatsuya Tai
- Department of Pharmacy, Kagawa University Hospital
| | | | | | - Atsushi Tada
- Department of Pharmacy, Kagawa University Hospital
| | | | | | | | | | - Shinji Abe
- Department of Clinical Pharmacy Practice Pedagogy, Tokushima University Graduate School of Biomedical Sciences
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12
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Patterson JT, Slobogean GP, Gary JL, Castillo RC, Firoozabadi R, Carlini AR, Joshi M, Allen LE, Huang Y, Bosse MJ, Obremskey WT, McKinley TO, Reid JS, O'Toole RV, O'Hara NN. The VANCO Trial Findings Are Generalizable to a North American Trauma Registry. J Orthop Trauma 2024; 38:10-17. [PMID: 38093438 DOI: 10.1097/bot.0000000000002704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/11/2023] [Indexed: 12/18/2023]
Abstract
OBJECTIVES To estimate the generalizability of treatment effects observed in the VANCO trial to a broader population of patients with tibial plateau or pilon fractures. METHODS Design and Setting: Clinical trial data from 36 United States trauma centers and Trauma Quality Programs registry data from more than 875 Level I-III trauma centers in the United States and Canada.Patient Selection Criteria: Patients enrolled in the VANCO trial treated with intrawound vancomycin powder from January 2015 to June 2017 and 31,924 VANCO-eligible TQP patients admitted in 2019 with tibial plateau and pilon fractures.Outcome Measure and Comparisons: Deep surgical site infection and gram-positive deep surgical site infection estimated in the TQP sample weighed by the inverse probability of trial participation. RESULTS The 980 patients in the VANCO trial were highly representative of 31,924 TQP VANCO-eligible patients (Tipton generalizability index 0.96). It was estimated that intrawound vancomycin powder reduced the odds of deep surgical infection by odds ratio (OR) = 0.46 (95% confidence interval [CI] 0.25-0.86) and gram-positive deep surgical infection by OR = 0.39 (95% CI, 0.18-0.84) within the TQP sample of VANCO-eligible patients. For reference, the trial average treatment effects for deep surgical infection and gram-positive deep surgical infection were OR = 0.60 (95% CI, 0.37-0.98) and OR = 0.44 (95% CI, 0.23-0.80), respectively. CONCLUSIONS This generalizability analysis found that the inferences of the VANCO trial generalize and might even underestimate the effects of intrawound vancomycin powder when observed in a wider population of patients with tibial plateau and pilon fractures. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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Affiliation(s)
- Joseph T Patterson
- Department of Orthopaedic Surgery, Keck School of Medicine at the University of Southern California, Los Angeles, CA
| | - Gerard P Slobogean
- Department of Orthopaedics, University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD
| | - Joshua L Gary
- Department of Orthopaedic Surgery, Keck School of Medicine at the University of Southern California, Los Angeles, CA
| | - Renan C Castillo
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Reza Firoozabadi
- Department of Orthopedics and Sports Medicine, University of Washington, Harborview Medical Center, Seattle, WA
| | - Anthony R Carlini
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Manjari Joshi
- Department of Medicine, University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD
| | - Lauren E Allen
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Yanjie Huang
- University of Michigan School of Dentistry, Ann Arbor, MI
| | - Michael J Bosse
- Department of Orthopaedic Surgery, Carolinas Medical Center, Charlotte, NC
| | - William T Obremskey
- Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Todd O McKinley
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN; and
| | - J Spence Reid
- Department of Orthopaedic Surgery, Penn State College of Medicine, Hershey, PA
| | - Robert V O'Toole
- Department of Orthopaedics, University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD
| | - Nathan N O'Hara
- Department of Orthopaedics, University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD
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13
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Haag H, Lau A. Correlation of Calculated Vancomycin Trough Concentrations and Exposure: A Monte Carlo Simulation. Ann Pharmacother 2023; 57:1410-1414. [PMID: 36999486 DOI: 10.1177/10600280231160571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2023] Open
Abstract
BACKGROUND Current recommendations are to dose vancomycin to target 24-hour area under the curve (AUC) of 400-600 mg·h/L to optimize efficacy and safety. Limited data support AUC monitoring, and some centers continue to use trough concentrations. A target of 10-20 mg/L has been proposed to reduce nephrotoxicity risk. OBJECTIVE To use previously published pharmacokinetic equations in a Monte Carlo simulation relating AUC exposure to trough concentrations when targeting an AUC between 400 and 600 mg·h/L. METHODS Previously published pharmacokinetic data were used as input parameters for a Monte Carlo simulation using previously published formulae to correlate AUC to simulated trough concentrations. Pharmacokinetic parameters were assumed to occur in a normal distribution pattern. We excluded irrelevant simulated cases. Maintenance doses of 15 mg/kg were rounded to the nearest 250 mg. Calculated trough concentrations for AUCs of both 400 and 600 mg·h/L were evaluated in each simulation. RESULTS A total of 10 000 Monte Carlo simulations were performed. Targeting an AUC of 400 mg·h/L resulted in a mean trough concentration of 10.3 ± 0.8 mg/L. Targeting an AUC of 600 mg·h/L resulted in a mean trough concentration of 15.4 ± 1.2 mg/L. CONCLUSION AND RELEVANCE We demonstrate that a lower trough concentration range may be supported by an AUC of 400-600 mg·h/L, which may reduce risk and rates of nephrotoxicity without compromising previously established efficacious target trough concentrations.
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Affiliation(s)
- Hans Haag
- Vancouver General Hospital, Vancouver, BC, Canada
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada
| | - Anthony Lau
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada
- Emergency Medicine, Vancouver General Hospital, Vancouver, BC, Canada
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14
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Deacon E, Canney M, McCormick B, Ramsay T, Biyani M, Brown PA, Zimmerman D. The Association Between Serum Vancomycin Level and Clinical Outcome in Patients With Peritoneal Dialysis Associated Peritonitis. Kidney Int Rep 2023; 8:2646-2653. [PMID: 38106569 PMCID: PMC10719602 DOI: 10.1016/j.ekir.2023.09.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 08/15/2023] [Accepted: 09/11/2023] [Indexed: 12/19/2023] Open
Abstract
Introduction Intraperitoneal (IP) vancomycin is often first-line empiric therapy and then maintenance therapy for peritoneal dialysis (PD) peritonitis. However, how vancomycin serum levels correlate with clinical outcomes remains unclear. Methods We conducted a retrospective single-center adult cohort study of 98 patients with PD peritonitis treated with IP vancomycin between January 2016 and May 2022. The association between nadir vancomycin level and cure was evaluated in a logistic regression model, first unadjusted and then adjusted for age, sex, weight, glomerular filtration rate (GFR), and total number of days on PD. Vancomycin was assessed both as a continuous exposure (per 1 mg/l increase) and as a categorical exposure (<15 mg/l vs. ≥15 mg/l). A receiver operating characteristic curve (ROC) was created to explore nadir vancomycin level thresholds in an attempt to identify an optimal target level during treatment. Results Of the patients, 81% achieved cure, and patients with nadir vancomycin level ≥15 mg/l were 7.5 times more likely to experience cure compared to those with a nadir level <15 mg/l (odds ratio [OR] 7.58, 95% confidence interval [CI] 1.71-33.57, P = 0.008). Weight, GFR, days on PD, sex, and age were not independently associated with outcome. The vancomycin level with the greatest discriminatory capacity for cure on the ROC analysis was 14.4 mg/l. Conclusion Increasing IP vancomycin serum levels are associated with increased odds of cure; and maintaining vancomycin serum levels above 14-15 mg/l throughout the course of PD peritonitis treatment is likely to improve clinical outcomes.
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Affiliation(s)
- Erin Deacon
- Faculty of Medicine, University of Ottawa, Ontario, Canada
| | - Mark Canney
- Department of Medicine, Ottawa Hospital, Faculty of Medicine, University of Ottawa and the Kidney Research Centre of the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Brendan McCormick
- Department of Medicine, Ottawa Hospital, Faculty of Medicine, University of Ottawa and the Kidney Research Centre of the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Tim Ramsay
- Ottawa Methods Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Mohan Biyani
- Department of Medicine, Ottawa Hospital, Faculty of Medicine, University of Ottawa and the Kidney Research Centre of the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Pierre Antoine Brown
- Department of Medicine, Ottawa Hospital, Faculty of Medicine, University of Ottawa and the Kidney Research Centre of the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Deborah Zimmerman
- Department of Medicine, Ottawa Hospital, Faculty of Medicine, University of Ottawa and the Kidney Research Centre of the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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15
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Coulibaly B, Maire P, Guitton J, Pelletier S, Tangara M, Aulagner G, Goutelle S. Population Pharmacokinetics of Vancomycin in Patients Receiving Hemodialysis in a Malian and a French Center and Simulation of the Optimal Loading Dose. Ther Drug Monit 2023; 45:637-643. [PMID: 36750447 DOI: 10.1097/ftd.0000000000001065] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 09/07/2022] [Indexed: 02/09/2023]
Abstract
PURPOSE Vancomycin dosing remains challenging in patients receiving intermittent hemodialysis, especially in developing countries, where access to therapeutic drug monitoring and model-based dose adjustment services is limited. The objectives of this study were to describe vancomycin population PK in patients receiving hemodialysis in a Malian and French center and examine the optimal loading dose of vancomycin in this setting. METHODS Population pharmacokinetic analysis was conducted using Pmetrics in 31 Malian and 27 French hemodialysis patients, having a total of 309 vancomycin plasma concentrations. Structural and covariate analyses were based on goodness-of-fit criteria. The final model was used to perform simulations of the vancomycin loading dose, targeting a daily area under the concentration-time curve (AUC) of 400-600 mg.h/L or trough concentration of 15-20 mg/L at 48 hours. RESULTS After 48 hours of therapy, 68% of Malian and 63% of French patients exhibited a daily AUC of <400. The final model was a 2-compartment model, with hemodialysis influencing vancomycin elimination and age influencing the vancomycin volume distribution. Younger Malian patients exhibited a lower distribution volume than French patients. Dosing simulation suggested that loading doses of 1500, 2000, and 2500 mg would be required to minimize underexposure in patients aged 30, 50, and 70 years, respectively. CONCLUSIONS In this study, a low AUC was frequently observed in hemodialysis patients in Mali and France after a standard vancomycin loading dose. A larger dose is necessary to achieve the currently recommended AUC target. However, the proposed dosing algorithm requires further clinical evaluation.
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Affiliation(s)
- Balla Coulibaly
- Univ Lyon, Université Claude Bernard Lyon 1, INSA Lyon, CNRS, MATEIS, UMR5510, Lyon, France
- Université des Sciences, des Techniques et des Technologies de Bamako, Bamako, Mali
| | - Pascal Maire
- Univ Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Évolutive, Villeurbanne, France
- Univ Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Sud, Pierre-Bénite, France
| | - Jêrome Guitton
- Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie de Lyon, Lyon, France
- Hospices Civils de Lyon, Groupement Hospitalier Sud, Service de Biochimie et Biologie Moléculaire, UM Pharmacologie-Toxicologie, Lyon, France
| | - Solenne Pelletier
- Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service de Néphrologie, Lyon, France
| | - Moustapha Tangara
- Centre Hospitalo-Universitaire du Point-G de Bamako, Service de Néphrologie, Lyon, France
| | - Gilles Aulagner
- Univ Lyon, Université Claude Bernard Lyon 1, INSA Lyon, CNRS, MATEIS, UMR5510, Lyon, France
- Académie Nationale de Pharmacie, Paris, France; and
| | - Sylvain Goutelle
- Univ Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Évolutive, Villeurbanne, France
- Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie de Lyon, Lyon, France
- Hospices Civils de Lyon, Groupement Hospitalier Nord, Service de Pharmacie, Lyon, France
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16
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Williams P, Cotta MO, Abdul-Aziz MH, Wilks K, Farkas A, Roberts JA. In silico Evaluation of a Vancomycin Dosing Guideline Among Adults with Serious Infections. Ther Drug Monit 2023; 45:631-636. [PMID: 37199397 DOI: 10.1097/ftd.0000000000001102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 03/14/2023] [Indexed: 05/19/2023]
Abstract
BACKGROUND This study aimed to compare the achievement of pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for vancomycin using a newly developed dosing guideline with product-information-based dosing in the treatment of adult patients with serious infections. METHODS In silico product-information- and guideline-based dosing simulations for vancomycin were performed across a range of doses and patient characteristics, including body weight, age, and renal function at 36-48 and 96 hours, using a pharmacokinetic model derived from a seriously ill patient population. The median simulated concentration and area under the 24-hour concentration-time curve (AUC 0-24 ) were used to measure predefined therapeutic, subtherapeutic, and toxicity PK-PD targets. RESULTS Ninety-six dosing simulations were performed. The pooled median trough concentration target with guideline-based dosing at 36 and 96 hours was achieved in 27.1% (13/48) and 8.3% (7/48) of simulations, respectively. The pooled median AUC 0-24 /minimum inhibitory concentration ratio with guideline-based dosing at 48 and 96 hours was attained in 39.6% (19/48) and 27.1% (13/48) of simulations, respectively. Guideline-based dosing simulations yielded improved trough target attainment compared with product-information-based dosing at 36 hours and significantly less subtherapeutic drug exposure. The toxicity threshold was exceeded in 52.1% (25/48) and 0% (0/48) for guideline- and product-information-information-based dosing, respectively ( P < 0.001). CONCLUSIONS A Critical care vancomycin dosing guideline appeared slightly more effective than standard dosing, as per product information, in achieving PK-PD exposure associated with an increased likelihood of effectiveness. In addition, this guideline significantly reduced the risk of subtherapeutic exposure. The risk of exceeding toxicity thresholds, however, was greater with the guideline, and further investigation is suggested to improve dosing accuracy and sensitivity.
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Affiliation(s)
- Paul Williams
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Pharmacy Department, Sunshine Coast University Hospital, Birtinya, Queensland, Australia
| | - Menino Osbert Cotta
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Australia
| | - Mohd H Abdul-Aziz
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Australia
| | - Kathryn Wilks
- Infectious Diseases Department, Sunshine Coast University Hospital, Birtinya, Queensland, Australia
- School of Public Health, The University of Queensland, Brisbane, Queensland, Australia
| | - Andras Farkas
- Department of Pharmacy, Mount Sinai West, New York, New York
- Optimum Dosing Strategies, Bloomingdale, New Jersey
| | - Jason A Roberts
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Australia
- Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
- Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; and
- Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes France
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17
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Patil T, Zysk SN, Akridge ME, McCraven RW, Vasudeva SS. A Quasi-Experimental Evaluation of Single Trough-Based Area Under the Curve Guided Dosing on the Incidence of Vancomycin Associated Nephrotoxicity in Veteran Patients. J Pharm Technol 2023; 39:123-133. [PMID: 37323768 PMCID: PMC10268043 DOI: 10.1177/87551225231172349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023] Open
Abstract
Background: Two common dosing strategies for vancomycin are trough-based and area under the curve (AUC)-based dosing. Objective: To compare the incidence of nephrotoxicity in trough-based dosing group with the single trough-based AUC dosing at the Salem VA Medical Center. Methods: This retrospective study included patients who received trough-based dosing of vancomycin between January 1, 2017, and January 1, 2019 (preimplementation group) and AUC-based dosing (postimplementation) between October 1, 2019, and October 1, 2021, at the Salem VA Medical Center. The primary outcome was nephrotoxicity at 96 hours, 7 days, and entire hospital length of stay (LOS). Secondary outcomes included 30-day readmission and all-cause mortality rates, cumulative doses at 24, 48, and 72 hours, and percentage of patients considered at goal (AUC 400-600 or trough between 10 and 20 mg/L). Propensity score (PS) matching was utilized to adjust for confounding. Results: After PS matching 100 patients were included in preimplementation and 95 patients in the postimplementation group. The average study patient was a 68-year-old white male. There was significant reduction in the risk of nephrotoxicity in postimplementation cohort at 96 hours (adjusted (a)HR: 0.28, 95% CI (0.12-0.66); 7 days (aHR: 0.39, 95% CI (0.18-0.85); and entire hospital LOS (aHR: 0.46, 95% CI (0.22-0.95). Secondary outcomes showed no difference between the groups except significantly higher proportion of patients were considered at therapeutic goal in the postimplementation cohort compared with pre-implementation cohort. Conclusion: This hypothesis generating study shows that AUC-based dosing calculated using single trough concentration may result in reduced rate of nephrotoxicity than trough-based dosing.
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Affiliation(s)
- Tanvi Patil
- Department of Pharmacy, Salem Veterans Affairs Medical Center, Salem Veterans Affairs Health Care System, Salem, VA, USA
| | - Stacey N. Zysk
- Department of Pharmacy, Salem Veterans Affairs Medical Center, Salem Veterans Affairs Health Care System, Salem, VA, USA
| | - Meghan E. Akridge
- Department of Pharmacy, Salem Veterans Affairs Medical Center, Salem Veterans Affairs Health Care System, Salem, VA, USA
| | - Rebecca W. McCraven
- Department of Pharmacy, Salem Veterans Affairs Medical Center, Salem Veterans Affairs Health Care System, Salem, VA, USA
| | - Shikha S. Vasudeva
- Department of Infectious Disease, Salem Veterans Affairs Medical Center, Salem Veterans Affairs Health Care System, Salem, VA, USA
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18
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Arensman Hannan KN, Rivera CG, Fewel N. Vancomycin AUC values estimated with trough-only data: Accuracy in an adult academic medical center population. Am J Health Syst Pharm 2023; 80:452-456. [PMID: 36525590 DOI: 10.1093/ajhp/zxac372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Vancomycin area under the concentration-time curve (AUC) can be calculated using steady-state serum peak and trough concentrations; however, compared to traditional trough-only monitoring, this approach requires an additional blood sample. Recently published data demonstrated vancomycin AUC estimations using trough-only data with a volume of distribution (Vd) model incorporating age and actual body weight were reasonably accurate and precise in a veteran population. This study sought to extend these methods to a Mayo Clinic adult population. METHODS A retrospective, observational cohort of adult patients with documented steady-state vancomycin peak and trough concentrations was evaluated. Vancomycin AUCs were estimated using trough-only data, and 4 Vd models were assessed for accuracy and precision. Estimated AUCs were compared to AUCs calculated using 1-compartment intermittent infusion equations and steady-state peak and trough ("peak-trough") data. RESULTS The study population (N = 95) was 46% female, with a median age of 59 years and a median weight of 97 kg. Using the VancoPK equation Vd = 0.29 (age in y) + 0.33 (actual weight in kg) + 11, the mean peak-trough and estimated trough-only AUC were 533 and 534, respectively, with a correlation of 0.936. The root mean square error was 47.7, meaning about 95% of AUCs were within 95 mg · h/L of peak-trough AUCs. CONCLUSIONS Accuracy and precision of Vancomycin AUC estimations using trough-only data and the described Vd model were demonstrated in a Mayo Clinic cohort. Targeting an estimated AUC of 500 mg · h/L using the VancoPK model would likely result in an actual AUC within 400 to 600 mg · h/L.
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Affiliation(s)
| | | | - Nathan Fewel
- Department of Pharmacy, Central Texas Veterans Health Care System, Temple, TX, USA
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Characteristics and calculations of paired vancomycin measurements for determination of 24-h area-under-curve (AUC). Pract Lab Med 2023; 34:e00310. [PMID: 36798591 PMCID: PMC9926295 DOI: 10.1016/j.plabm.2023.e00310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/12/2023] [Accepted: 01/27/2023] [Indexed: 01/30/2023] Open
Abstract
Background Current pharmacy practice guidelines recommend 24-h area-under-curve (AUC24) targets for use of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA). AUC protocol-specific vancomycin orders were begun recently (2022) at our institution. We reviewed initial AUC protocol-associated data and calculations. Methods AUC24 calculations are derived from timed, paired measurements of vancomycin (V1,V2). We retrieved paired (V1,V2) measurements for a 90-day interval. Calculations to obtain AUC24 were performed according to two accepted methods (A, B) that assume first-order kinetics for vancomycin elimination between V1 and V2. Results 44 (V1,V2) measurement pairs were from among 27 patients. Dosing intervals were 8, 12, or 24 h. The first-order rate constant k was normally distributed (k = 0.096 ± 0.046 1/h); t1/2 ranged from 3 to 30 h. For target AUC24 = 400-600 h × μg/mL, 55% of calculated AUC24 results were within target. Imprecision for calculated k was predicted to be least when V2 is a trough level. Method B results were greater than Method A results by a factor of 1.07. Conclusions 45% of AUC24 results indicated need for change in dosage. Recommendations are that average results from A and B methods of calculation should be used, and that V1 and V2 should be as widely separated as possible.
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20
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Yadav N, Kumar U, Chauhan VS. Conformationally restricted, dipeptide-based, self-assembled nanoparticles for efficient vancomycin delivery. Nanomedicine (Lond) 2022; 17:2023-2035. [PMID: 36645108 DOI: 10.2217/nnm-2022-0144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Aim: Emergence of vancomycin (Van) resistance, and usage of its higher dose and short half-life are posing a serious concern. Slow and sustained release of Van using a nanodelivery system may overcome these problems. Materials & methods: Arginine-α,β-dehydrophenylalanine (RΔF) was synthesized using solution-phase synthesis which self-assembled into nanospheres. Van was entrapped in the nanoparticles (NPs). In vitro and in vivo efficacy of Van-RΔF was determined using broth microdilution and the mouse thigh infection model, respectively. Results & conclusion: Van-RΔF NPs efficiently inhibited bacterial growth (Staphylococcus aureus), while Van alone showed limited growth inhibition in in vitro. Intravenous administration of Van-RΔF in mice with bacterial thigh infection showed enhanced efficacy (double) compared with Van alone, which indicates its high potential for further development.
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Affiliation(s)
- Nitin Yadav
- Molecular Medicine Group, International Centre for Genetic Engineering & Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India
- Delhi Institute of Pharmaceutical Sciences & Research, Mehrauli-Badarpur Road, Sector-3, Pushpvihar, New Delhi, 110017, India
| | - Utkarsh Kumar
- Molecular Medicine Group, International Centre for Genetic Engineering & Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India
| | - Virander Singh Chauhan
- Molecular Medicine Group, International Centre for Genetic Engineering & Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India
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21
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Erstad BL, Matthias KR, Nix DE. Vancomycin dosing in patients with obesity. Am J Health Syst Pharm 2022; 79:2058-2069. [PMID: 35981345 DOI: 10.1093/ajhp/zxac229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
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Affiliation(s)
- Brian L Erstad
- Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, AZ, USA
| | - Kathryn R Matthias
- Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, AZ, USA
| | - David E Nix
- Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, AZ, USA
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22
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Wong S, Reuter SE, Jones GR, Stocker SL. Review and evaluation of vancomycin dosing guidelines for obese individuals. Expert Opin Drug Metab Toxicol 2022; 18:323-335. [PMID: 35815356 DOI: 10.1080/17425255.2022.2098106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Vancomycin dosing decisions are informed by factors such as body weight and renal function. It is important to understand the impact of obesity on vancomycin pharmacokinetics and how this may influence dosing decisions. Vancomycin dosing guidelines use varied descriptors of body weight and renal function. There is uncertainty whether current dosing guidelines result in attainment of therapeutic targets in obese individuals. AREAS COVERED Literature was explored using PubMed, Embase and Google Scholar for articles from January 1980 to July 2021 regarding obesity-driven physiological changes, their influence on vancomycin pharmacokinetics and body size descriptors and renal function calculations in vancomycin dosing. Pharmacokinetic simulations reflective of international vancomycin dosing guidelines were conducted to evaluate the ability of using total, ideal and adjusted body weight, as well as Cockcroft-Gault and CKD-EPI equations to attain an area-under-the-curve to minimum inhibitory concentration ratio (AUC24/MIC) target (400-650) in obese individuals. EXPERT OPINION Vancomycin pharmacokinetics in obese individuals remains debated. Guidelines that determine loading doses using total body weight, and maintenance doses adjusted based on renal function and adjusted body weight, may be most appropriate for obese individuals. Use of ideal body weight leads to subtherapeutic vancomycin exposure and underestimation of renal function.
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Affiliation(s)
- Sherilyn Wong
- UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - Stephanie E Reuter
- UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia
| | - Graham Rd Jones
- St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia.,Department of Chemical Pathology and Clinical Pharmacology, SydPath, St Vincent's Hospital, Darlinghurst, Australia
| | - Sophie L Stocker
- St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia.,Sydney School of Pharmacy, The University of Sydney, Sydney, Australia.,Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital Sydney, Darlinghurst, Australia
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23
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Xu KY, Li D, Hu ZJ, Zhao CC, Bai J, Du WL. Vancomycin dosing in an obese patient with acute renal failure: A case report and review of literature. World J Clin Cases 2022; 10:6218-6226. [PMID: 35949852 PMCID: PMC9254177 DOI: 10.12998/wjcc.v10.i18.6218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/19/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Vancomycin is the most commonly used drug for methicillin-resistant Staphylococcus aureus. The empirical clinical doses of vancomycin based on non-obese patients may not be optimal for obese ones.
CASE SUMMARY This study reports a case of vancomycin dosing adjustment in an obese patient (body mass index 78.4 kg/m2) with necrotizing fasciitis of the scrotum and left lower extremity accompanied with acute renal failure. Dosing adjustment was performed based on literature review and factors that influence pharmacokinetic parameters are analyzed. The results of the blood drug concentration monitoring confirmed the successful application of our dosing adjustment strategy in this obese patient. Total body weight is an important consideration for vancomycin administration in obese patients, which affects the volume of distribution and clearance of vancomycin. The alterations of pharmacokinetic parameters dictate that vancomycin should be dose-adjusted when applied to obese patients. At the same time, the pathophysiological status of patients, such as renal function, which also affects the dose adjustment of the patient, should be considered.
CONCLUSION Monitoring vancomycin blood levels in obese patients is critical to help adjust the dosing regimen to ensure that vancomycin concentrations are within the effective therapeutic range and to reduce the incidence of renal injury.
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Affiliation(s)
- Kun-Yan Xu
- Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Dan Li
- Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Zhen-Jie Hu
- Department of Intensive Care Unit, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Cong-Cong Zhao
- Department of Intensive Care Unit, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Jing Bai
- Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Wen-Li Du
- Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
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Clinical Practice Guidelines for Therapeutic Drug Monitoring of Vancomycin in the Framework of Model-Informed Precision Dosing: A Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. Pharmaceutics 2022; 14:pharmaceutics14030489. [PMID: 35335866 PMCID: PMC8955715 DOI: 10.3390/pharmaceutics14030489] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 01/08/2023] Open
Abstract
Background: To promote model-informed precision dosing (MIPD) for vancomycin (VCM), we developed statements for therapeutic drug monitoring (TDM). Methods: Ten clinical questions were selected. The committee conducted a systematic review and meta-analysis as well as clinical studies to establish recommendations for area under the concentration-time curve (AUC)-guided dosing. Results: AUC-guided dosing tended to more strongly decrease the risk of acute kidney injury (AKI) than trough-guided dosing, and a lower risk of treatment failure was demonstrated for higher AUC/minimum inhibitory concentration (MIC) ratios (cut-off of 400). Higher AUCs (cut-off of 600 μg·h/mL) significantly increased the risk of AKI. Although Bayesian estimation with two-point measurement was recommended, the trough concentration alone may be used in patients with mild infections in whom VCM was administered with q12h. To increase the concentration on days 1–2, the routine use of a loading dose is required. TDM on day 2 before steady state is reached should be considered to optimize the dose in patients with serious infections and a high risk of AKI. Conclusions: These VCM TDM guidelines provide recommendations based on MIPD to increase treatment response while preventing adverse effects.
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Rebold N, Lodise T, Rybak MJ. Panacea or oversimplification: Relating AUC and troughs. Am J Health Syst Pharm 2022; 79:1019-1021. [DOI: 10.1093/ajhp/zxac031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Disclaimer
In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
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Affiliation(s)
- Nicholas Rebold
- Anti-Infective Research Laboratory, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
| | - Thomas Lodise
- Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY, USA
| | - Michael J Rybak
- Anti-Infective Research Laboratory, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, and School of Medicine, Wayne State University, Detroit, MI, USA
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Risk Factors Associated with Suboptimal Tobramycin Levels in the Medical Intensive Care Unit. Eur J Drug Metab Pharmacokinet 2022; 47:271-278. [PMID: 35029839 DOI: 10.1007/s13318-021-00749-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND Optimal aminoglycoside dosing in critically ill patients represents a challenge for practitioners, especially in the medical intensive care unit (MICU). MICU patients exhibit altered pharmacokinetics due to pathophysiological changes the body undergoes in critical illness, leading to possible treatment failure. The literature surrounding optimal dosing and therapeutic drug monitoring strategies of aminoglycosides in MICU patients is scarce and conflicting. Additionally, only a few studies have investigated risk factors for suboptimal pharmacokinetic target obtainment. Currently, no definitive risk factors have been identified to predict suboptimal aminoglycoside target obtainment in MICU patients. OBJECTIVE The objective of this study was to determine risk factors for suboptimal pharmacokinetic target obtainment in patients receiving tobramycin in the MICU. METHODS This single-center, retrospective cohort study included patients 18-89 years old who received at least one 7 mg/kg tobramycin dose in the MICU from January, 1 2015 to September, 30 2020. Patients also had to have at least two detectable drug levels obtained at least one half-life apart following the first tobramycin dose. The primary outcome was to determine the incidence of optimal pharmacokinetic target obtainment, defined as a tobramycin maximum concentration (Cmax) ≥ 10 mcg/ml, and to identify the risk factors for suboptimal (Cmax < 10 mcg/mL) pharmacokinetic target obtainment, in MICU patients. Secondary outcomes were compared between suboptimal and optimal target obtainment in patients with culture confirmed gram-negative infection susceptible to tobramycin. These secondary outcomes included all-cause in-hospital mortality, ICU length of stay (LOS), hospital LOS, and vasopressor duration in those with shock. RESULTS A total of 230 patients were included in this retrospective study. For the primary outcome, 187 (81.3%) patients achieved optimal target obtainment. Through multivariate logistic regression, female sex and serum albumin < 2.5 g/dL were identified as independent risk factors for suboptimal target obtainment; [OR = 2.14; 95% CI (1.05-4.37), p = 0.037], [OR = 2.50; 95% CI (1.21-5.19), p = 0.014], respectively. Fifty-four (23%) patients had culture-confirmed gram-negative infections susceptible to tobramycin and were included in the subgroup analysis. Of these 54 patients, 11 (20.4%) did not achieve optimal target concentrations. In patients with culture-confirmed gram-negative infection, there was no difference between patients with optimal target obtainment and suboptimal target obtainment in ICU LOS, hospital LOS, all-cause mortality, or vasopressor duration in those with shock. CONCLUSIONS Among patients receiving their first dose of tobramycin in the MICU, 81.3% obtained an optimal serum concentration. Female sex and serum albumin < 2.5 g/dL were identified as risk factors for suboptimal target obtainment; however, further research is warranted to assess the utility of using these two covariates as risk factors for more aggressive dosing in critically ill MICU patients.
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Munir MM, Rasheed H, Khokhar MI, Khan RR, Saeed HA, Abbas M, Ali M, Bilal R, Nawaz HA, Khan AM, Qamar S, Anjum SM, Usman M. Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan. Front Pharmacol 2021; 12:721819. [PMID: 34858169 PMCID: PMC8632000 DOI: 10.3389/fphar.2021.721819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 10/12/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan. Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration-time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks. Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively. Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.
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Affiliation(s)
- Muhammad Muaaz Munir
- Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Huma Rasheed
- Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Muhammad Imran Khokhar
- Ameer-ud-Din Medical College, Post-Graduate Medical Institute (PGMI), Lahore General Hospital, Lahore, Pakistan
| | - Rizwan Rasul Khan
- Department of Medicine, Aziz Fatima Medical and Dental College, Faisalabad, Pakistan
| | | | - Mateen Abbas
- Quality Operation Laboratory, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Mohsin Ali
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Govt College University, Faisalabad, Pakistan
| | - Rabiea Bilal
- CMH Lahore Medical College and IOD, NUMS, Lahore, Pakistan
| | - Hafiz Awais Nawaz
- Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Abdul Muqeet Khan
- Quality Operation Laboratory, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Shaista Qamar
- Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Syed Muneeb Anjum
- Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Muhammad Usman
- Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan
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Nix DE, Davis LE, Matthias KR. The relationship of vancomycin 24-hour AUC and trough concentration. Am J Health Syst Pharm 2021; 79:534-539. [PMID: 34849533 DOI: 10.1093/ajhp/zxab457] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
DISCLAIMER In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE Prior to the 2020 release of a joint consensus guideline on monitoring of vancomycin therapy for serious methicillin-resistant Staphylococcus aureus (MRSA) infections, clinicians had escalated vancomycin doses for 2 decades while targeting trough concentrations of 15 to 20 µg/mL, leading to an increased frequency of nephrotoxicity. For MRSA infections, the 2020 guideline recommends adjusting doses to achieve a 24-hour area under the concentration-time curve (AUC) of 400 to 600 µg · h/mL; however, monitoring of trough concentrations has been entrenched for 3 decades. Calculating dose regimens based on AUC will require obtaining an increased number of vancomycin serum concentrations and, possibly, advanced software. The aim of this investigation was to determine the relationship between AUC and trough concentration and the influence of dosing regimen on goal achievement. METHODS The relationship between trough concentration and AUC was explored through derivation of an equation based on a 1-compartment model and simulations. RESULTS 24-hour AUC is related to dosing interval divided by half-life in a nonlinear fashion. The target trough concentration can be individualized to achieve a desired AUC range, and limiting use of large doses (>15-20 mg/kg) can protect against excessive 24-hour AUC with trough-only monitoring. CONCLUSION After initially determining pharmacokinetic parameters, subsequent monitoring of AUC can be accomplished using trough concentrations only. Trough concentration may be used as a surrogate for AUC, although the acceptable target trough concentration will vary depending on dosing interval and elimination rate constant. This work included development of an AUC-trough equation to establish a patient-specific target for steady-state trough concentration.
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Affiliation(s)
- David E Nix
- Department of Pharmacy Practice & Science and Department of Medicine, University of Arizona, Tucson, AZ, USA
| | - Lisa E Davis
- Department of Pharmacy Practice & Science, University of Arizona, Tucson, AZ, USA
| | - Kathryn R Matthias
- Department of Pharmacy Practice & Science, University of Arizona, Tucson, AZ, USA
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Huang J, Wang X, Hao C, Yang W, Zhang W, Liu J, Qu H. Cystatin C and/or creatinine-based estimated glomerular filtration rate for prediction of vancomycin clearance in long-stay critically ill patients with persistent inflammation, immunosuppression and catabolism syndrome (PICS): a population pharmacokinetics analysis. Intern Emerg Med 2021; 16:1883-1893. [PMID: 33728578 DOI: 10.1007/s11739-021-02699-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 03/05/2021] [Indexed: 10/21/2022]
Abstract
Persistent inflammation, immunosuppression and catabolism syndrome (PICS) in critically ill patients are associated with unreliable creatinine (Cr)-based estimated glomerular filtration rate (eGFR) and alteration in vancomycin clearance (CL) due to ongoing muscle wasting and renal dysfunction (RD). Currently, cystatin C (Cys) is of great interest for eGFR due to its muscle independence. Patients receiving intravenous vancomycin with trough concentration monitoring after intensive care unit stay ≥ 14 days were retrospectively enrolled. Those with C-reactive protein > 30.0 mg/L, lymphocytes count < 0.80 × 109, albumin < 30 mg/L and weight loss > 10% were diagnosed with PICS. Impact of PICS on vancomycin trough achievement was analyzed. Plasma Cys and Cr levels with their eGFRs in RD were compared in patients with and without PICS. Furthermore, the performance of eGFRs in predicting vancomycin CL was quantificationally evaluated by population pharmacokinetics (PPK) analysis using the Phoenix NLME software. Of 69 enrolled patients, 32 (46.4%) were PICS. PICS was predictive of Cr-guided vancomycin supratherapeutic trough concentrations (OR = 5.26, P = 0.013). Significant elevation of Cys, not of Cr, was observed in patients with PICS suffering from RD (P = 0.022), causing substantial differences among eGFRs. Fifty-two and 17 patients were enrolled for the modeling group and validation group, respectively. A one-compartment PPK model with first-order elimination adequately described the data of 126 Ctrough. Prediction of vancomycin CL with Cys and Cr-based eGFR (CKD-EPIcys-cr) significantly reduced the interindividual variability of CL (from 75.6 to 28.5%). External validation with 34 Ctrough showed the robustness and accuracy of this model. This study showed the negative impact of PICS on Cr-guided vancomycin trough achievement. PPK model with CKD-EPIcys-cr can be used to optimize vancomycin dosage in patients with PICS.
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Affiliation(s)
- Jingjing Huang
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoli Wang
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 20025, China
| | - Chenxia Hao
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wanhua Yang
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weixia Zhang
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jialin Liu
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 20025, China.
| | - Hongping Qu
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 20025, China.
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Fewel N. Vancomycin area under the curves estimated with pharmacokinetic equations using trough-only data. J Clin Pharm Ther 2021; 46:1426-1432. [PMID: 34169543 PMCID: PMC8518113 DOI: 10.1111/jcpt.13474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/02/2021] [Accepted: 06/09/2021] [Indexed: 01/01/2023]
Abstract
What is known and objective The revised vancomycin monitoring guidelines recommend targeting an area under the curve (AUC) of 400–600 mg*hr/L for serious methicillin‐resistant Staphylococcus aureus (MRSA) infections. An AUC can be measured by checking a peak and trough concentration at steady state; however, this requires obtaining an additional blood sample. The most practical way to perform AUC‐guided dosing is by estimating an AUC from a steady‐state trough. The purpose of this study was to compare AUCs estimated from trough‐only data to AUCs calculated from peak and trough concentrations. Methods Steady‐state peak and trough data were collected from an open‐access clinical calculator VancoPK.com. Patients were included who had (1) peaks drawn ≥60 min after the end of infusion, (2) peak and trough levels drawn ≥4 h apart and (3) troughs drawn ≤4 h early or late. The population was randomized and divided into a model group and test group. A population equation for vancomycin volume of distribution (Vd) was derived and compared to other general adult Vd models. Accuracy and precision of estimated AUCs were measured with bias, root mean square error (RMSE) and Lin's concordance correlation. Results and discussion A total of 2,500 adult patients were included in the model group and 1,843 were included in the test group. The derived Vd equation, Vd (L) = 0.29(age) +0.33(total BW in kg) +11, produced accurate and precise AUC estimates from trough‐only data. The mean actual AUC and estimated AUC were 504 and 503, respectively, with a correlation of 0.926. The RMSE between estimated and actual AUCs was 47.7, meaning that over 95% of estimated AUCs were within 100 points of actual AUCs with the study's Vd model. Other Vd models performed well for certain types of patients, depending on their body weight and age. What is new and conclusion There is limited evidence from large, robust populations regarding how to estimate Vd for general adult patients. Accuracy and precision of estimated AUCs depend on the applied population Vd model. The Vd model from the present study can be used for AUC‐guided dosing with trough‐only data which requires less blood work than peak‐trough monitoring. AUC calculations are practical with the use of open‐access websites.
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Affiliation(s)
- Nathan Fewel
- Independent Researcher, VancoPK, LLC, Temple, TX, USA
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31
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Rybak MJ, Le J, Lodise TP, Levine DP, Bradley JS, Liu C, Mueller BA, Pai MP, Wong-Beringer A, Rotschafer JC, Rodvold KA, Maples HD, Lomaestro BM. 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 2021; 77:835-864. [PMID: 32191793 DOI: 10.1093/ajhp/zxaa036] [Citation(s) in RCA: 713] [Impact Index Per Article: 178.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Michael J Rybak
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI, School of Medicine, Wayne State University, Detroit, MI, and Detroit Receiving Hospital, Detroit, MI
| | - Jennifer Le
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA
| | - Thomas P Lodise
- Albany College of Pharmacy and Health Sciences, Albany, NY, and Stratton VA Medical Center, Albany, NY
| | - Donald P Levine
- School of Medicine, Wayne State University, Detroit, MI, and Detroit Receiving Hospital, Detroit, MI
| | - John S Bradley
- Department of Pediatrics, Division of Infectious Diseases, University of California at San Diego, La Jolla, CA, and Rady Children's Hospital San Diego, San Diego, CA
| | - Catherine Liu
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, and Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | | | | | | | | | - Holly D Maples
- University of Arkansas for Medical Sciences College of Pharmacy & Arkansas Children's Hospital, Little Rock, AR
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Arjangpour S, Sadeghi K, Solduzian M, Mousavi SA. Vancomycin pharmacokinetic parameters in patients undergoing hematopoietic stem cell transplantation. J Oncol Pharm Pract 2021; 28:101-108. [PMID: 33430689 DOI: 10.1177/1078155220985317] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Current guidelines on vancomycin dosing lack specific recommendations about its dosing in hematopoietic stem cell transplant (HSCT) patients, the objective of the current study was to compare vancomycin pharmacokinetic variables in this population with those of general population. METHODS A prospective study was designed and the calculated parameters of vancomycin pharmacokinetic were compared with individualized parameters. Two trough levels before 4th and 5th doses and a peak level after the 4th dose, were taken. All patients received a dose of 15 mg/kg of vancomycin two or three times a day. Pharmacokinetic parameters were calculated using a one compartmental model. The association between different variables and of acute kidney injury (AKI) development and achievement of target levels were also evaluated. RESULTS A significant difference was observed between population Volume of distribution (Vd) and individualized Vd (mean 57.33 L vs 162.86 L, p value 0.019) and trough and peak levels (p values 0.0001 and 0.001; for mean trough and peak levels respectively). The achievement of the recommended trough levels and area under the concentration time curve per minimum inhibitory concentration (AUC24/MIC) was very low (5/71 and 24/71 patients respectively). No significant differences were observed between population and individualized clearance and rate of elimination of vancomycin (p values of 0.092 and 0.55 respectively). Concomitant receipt of cyclosporine was significantly related with development of AKI (p value 0.046). CONCLUSION The dosing methods which use population-based pharmacokinetic variables does not result in desired therapeutic levels in HSCT patients, mainly because of larger vancomycin volume of distribution.
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Affiliation(s)
- Samareh Arjangpour
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Kourosh Sadeghi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Hematology, Oncology, and Hematopoietic Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Solduzian
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz , Iran
| | - Seied Asadollah Mousavi
- Hematology, Oncology, and Hematopoietic Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Evaluation of a trough-only extrapolated area under the curve vancomycin dosing method on clinical outcomes. Int J Clin Pharm 2020; 43:263-269. [PMID: 32964405 DOI: 10.1007/s11096-020-01157-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 09/17/2020] [Indexed: 10/23/2022]
Abstract
Background Vancomycin dosing strategies targeting trough concentrations of 15-20 mg/L are no longer supported due to lack of efficacy evidence and increased risk of nephrotoxicity. Area-under-the-curve (AUC24) nomograms have demonstrated adequate attainment of AUC24 goals ≥ 400 mg h/L with more conservative troughs (10-15 mg/L). Objective The purpose of this study is to clinically validate a vancomycin AUC24 dosing nomogram compared to conventional dosing methods with regards to therapeutic failure and rates of acute kidney injury. Setting This study was conducted at a tertiary, community, teaching hospital in the United States. Method This retrospective, cohort study compared the rates of therapeutic failures between AUC24-extrapolated dosing and conventional dosing methods. Main outcome measure Primary outcome was treatment failure, defined as all-cause mortality within 30 days, persistent positive methicillin-resistant Staphylococcus aureus blood culture, or clinical failure. Rates of acute kidney injury in non-dialysis patients was a secondary endpoint. Results There were 96 participants in the extrapolated-AUC24 cohort and 60 participants in the conventional cohort. Baseline characteristics were similar between cohorts. Failure rates were 11.5% (11/96) in the extrapolated-AUC24 group compared to 18.3% (11/60) in the conventional group (p = 0.245). Reasons for failure were 6 deaths and 5 clinical failures in the extrapolated-AUC24 cohort and 10 deaths and 1 clinical failure in the conventional group. Acute kidney injury rates were 2.7% (2/73) and 16.4% (9/55) in the extrapolated-AUC24 and conventional cohorts, respectively (p = 0.009). Conclusion Extrapolated-AUC24 dosing was associated with less nephrotoxicity without an increase in treatment failures for bloodstream infections compared to conventional dosing. Further investigation is warranted to determine the relationship between extrapolated-AUC24 dosing and clinical failures.
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Laguado SA, Vadiei N, Yenina K. Impact of Recent Methamphetamine Use on Vancomycin Clearance. PSYCHOPHARMACOLOGY BULLETIN 2020; 50:23-35. [PMID: 32733109 PMCID: PMC7377544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
PURPOSE To determine whether recent methamphetamine use increases vancomycin clearance. METHODS This was a multi-center, retrospective, IRB-approved study at two tertiary care medical centers. Adult patients with a urine drug screen, ≥3 consecutive vancomycin doses, and an appropriately drawn vancomycin trough were assessed and classified as amphetamine positive or amphetamine negative. The primary outcome was vancomycin clearance. RESULTS 88 patients were included in the analysis, with 44 patients in each group. Vancomycin clearance was greater in the amphetamine positive group (94.54 vs. 86.84 mL/min, p = 0.042, 95% CI 0.29-15.09). There was no significant difference in goal vancomycin trough achievement between groups (34.1% amphetamine positive vs. 43.2% amphetamine negative; p = 0.512). Per multifactorial logistic regression analysis, older age and male gender were associated with decreased vancomycin clearance, while higher BMI and cocaine positive urine drug screen were associated with increased vancomycin clearance. CONCLUSION Recent methamphetamine use may increase vancomycin clearance. Larger prospective trials with protocolized vancomycin dosing strategies are needed to further elucidate the impact of methamphetamine use on attainment of goal vancomycin troughs in addition to the potential impact on vancomycin clearance.
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Affiliation(s)
- S Andrea Laguado
- S. Andrea Laguado, Pharm.D, Nina Vadiei, Pharm.D, BCPP, Kateryna Yenina, Pharm.D, BCPS, The University of Arizona/Banner University Medical Center South, Tucson, Arizona
| | - Nina Vadiei
- S. Andrea Laguado, Pharm.D, Nina Vadiei, Pharm.D, BCPP, Kateryna Yenina, Pharm.D, BCPS, The University of Arizona/Banner University Medical Center South, Tucson, Arizona
| | - Kateryna Yenina
- S. Andrea Laguado, Pharm.D, Nina Vadiei, Pharm.D, BCPP, Kateryna Yenina, Pharm.D, BCPS, The University of Arizona/Banner University Medical Center South, Tucson, Arizona
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35
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Tsuruyama M, Yamashina T, Tsuruta M, Tsukada H, Fujimoto A, Nagano M, Kawamata Y, Takashima S, Hiraki Y. Vancomycin pharmacokinetics in critically ill patients receiving continuous haemodiafiltration with a polyethyleneimine-coated polyacrylonitrile membrane. J Clin Pharm Ther 2020; 45:1143-1148. [PMID: 32497268 DOI: 10.1111/jcpt.13197] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/01/2020] [Accepted: 05/14/2020] [Indexed: 12/19/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE We investigated the elimination efficiency and pharmacokinetics (PK) parameters of vancomycin (VCM) in patients undergoing continuous haemodiafiltration (CHDF) using a polyethyleneimine-coated polyacrylonitrile membrane (AN69ST) for dosage adjustment. METHODS We conducted a retrospective study of CHDF patients treated with VCM from December 2017 to August 2019. We calculated PK parameters of VCM and determined the 24-hour dose required to maintain the target trough concentration of VCM (VCM_trough ). RESULTS AND DISCUSSION The average (95% CI) volume of distribution and total clearance of VCM were 75.5 L (63.7-87.3 L) and 1.84 L/h (1.38-2.30 L/h), respectively, and the elimination rate constant and half-life were 0.026/h (0.017-0.034/h) and 31.2 h (22.8-39.5 h), respectively. The average AN69ST clearance of VCM (CL_CHDF ) was 0.69 L/h (0.52-0.86 L/h). The estimated average doses required to maintain VCM_trough of 10, 15 and 20 μg/mL were 623.1 mg (379.8-866.4 mg), 934.6 mg (569.7-1299.5 mg) and 1246.2 mg (759.6-1732.8 mg), respectively. WHAT IS NEW AND CONCLUSION The PK of VCM and CL_CHDF of AN69ST were clarified. These results suggest that it is possible to adjust the dose of VCM in using AN69ST, which efficiently removes cytokines, and contributes to improvement of serious infections.
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Affiliation(s)
- Moeko Tsuruyama
- Department of Pharmacy, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Takuya Yamashina
- Department of Pharmacy, National Hospital Organization Beppu Medical Center, Beppu, Japan
| | - Minako Tsuruta
- Department of Pharmacy, National Hospital Organization Beppu Medical Center, Beppu, Japan
| | - Hiroko Tsukada
- Department of Pharmacy, National Hospital Organization Beppu Medical Center, Beppu, Japan
| | - Airi Fujimoto
- Department of Pharmacy, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Masahisa Nagano
- Department of Pharmacy, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Yosei Kawamata
- Department of Pharmacy, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Shinya Takashima
- Department of Pharmacy, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Yoichi Hiraki
- Department of Pharmacy, National Hospital Organization Beppu Medical Center, Beppu, Japan
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Smit C, Wasmann RE, Goulooze SC, Wiezer MJ, van Dongen EPA, Mouton JW, Brüggemann RJM, Knibbe CAJ. Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals. Br J Clin Pharmacol 2020; 86:303-317. [PMID: 31661553 PMCID: PMC7015748 DOI: 10.1111/bcp.14144] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/19/2019] [Accepted: 09/24/2019] [Indexed: 12/11/2022] Open
Abstract
Aims For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (area under the curve 400–700 mg h L−1). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and nonobese individuals, in order to guide vancomycin dosing in the obese. Methods Morbidly obese individuals (n = 20) undergoing bariatric surgery and nonobese healthy volunteers (n = 8; total body weight [TBW] 60.0–234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg−1, maximum 2500 mg; nonobese: 1000 mg) with plasma concentrations measured over 48 h (11–13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n = 10.000 individuals, TBW 60–230 kg) were performed using NONMEM. Results In a 3‐compartment model, peripheral volume of distribution and clearance increased with TBW (both p < 0.001), which was confirmed in the external validation. A dose of 35 mg kg−1 day−1 (maximum 5500 mg/day) resulted in a > 90% target attainment (area under the curve > 400 mg h L−1) in individuals up to 200 kg, with corresponding trough concentrations of 5.7–14.6 mg L−1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for steady state on day 1. Conclusion In this prospective, rich sampling pharmacokinetic study, vancomycin clearance was well predicted using TBW. We recommend that in obese individuals without renal impairment, vancomycin should be dosed as 35 mg kg−1 day−1 (maximized at 5500 mg/day). When given over 2 daily doses, trough concentrations of 5.7–14.6 mg L−1 correspond to the target exposure in obese individuals.
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Affiliation(s)
- Cornelis Smit
- Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.,Department of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Roeland E Wasmann
- Department of Pharmacy, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Sebastiaan C Goulooze
- Department of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Marinus J Wiezer
- Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - Eric P A van Dongen
- Department of Anesthesiology, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - Johan W Mouton
- Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands
| | - Roger J M Brüggemann
- Department of Pharmacy, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Catherijne A J Knibbe
- Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.,Department of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
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Dunn RD, Crass RL, Hong J, Pai MP, Krop LC. Vancomycin volume of distribution estimation in adults with class III obesity. Am J Health Syst Pharm 2019; 76:2013-2018. [PMID: 31630155 DOI: 10.1093/ajhp/zxz241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE To compare methods of estimating vancomycin volume of distribution (V) in adults with class III obesity. METHODS A retrospective, multicenter pharmacokinetic analysis of adults treated with vancomycin and monitored through measurement of peak and trough concentrations was performed. Individual pharmacokinetic parameter estimates were obtained via maximum a posteriori Bayesian analysis. The relationship between V and body weight was assessed using linear regression. Mean bias and root-mean-square error (RMSE) were calculated to assess the precision of multiple methods of estimating V. RESULTS Of 241 patients included in the study sample, 159 (66.0%) had a body mass index (BMI) of 40.0-49.9 kg/m2, and 82 (34.0%) had a BMI of ≥50.0 kg/m2. The median (5th, 95th percentile) weight of patients was 136 (103, 204) kg, and baseline characteristics were similar between BMI groups. The mean ± S.D. V was lower in patients with a BMI of 40.0-49.9 kg/m2 than in those with a BMI of ≥50.0 kg/m2 (72.4 ± 19.6 L versus 79.3 ± 20.6 L, p = 0.009); however, body size poorly predicted V in regression analyses (R2 < 0.20). A fixed estimate of V (75 L) and use of a weight-based value (0.52 L/kg by total body weight [TBW]) yielded similar bias and error in this population. CONCLUSION Results of the largest analysis of vancomycin V in class III obesity to date indicated that use of a fixed V value (75 L) and use of a TBW-based estimate (0.52 L/kg) for estimation of vancomycin V in patients with a BMI of ≥40.0 kg/m2 have similar bias. Two postdistribution vancomycin concentrations are needed to accurately determine patient-specific pharmacokinetic parameters, estimate area under the curve, and improve the precision of vancomycin dosing in this patient population.
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Affiliation(s)
- Ryan D Dunn
- Department of Pharmacy, Morton Plant Hospital, BayCare Health System, Clearwater, FL
| | - Ryan L Crass
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI
| | - Joseph Hong
- Department of Pharmacy, Morton Plant Hospital, BayCare Health System, Clearwater, FL
| | - Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI
| | - Lynne C Krop
- Department of Pharmacy, Morton Plant Hospital, BayCare Health System, Clearwater, FL
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38
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Ortwine JK, Zasowski EJ, Pogue JM, Hanni C, Giuliano C, Casapao AM, Mynatt R, Rybak MJ. Relationship Status between Vancomycin Loading Dose and Treatment Failure in Patients with MRSA Bacteremia: It's Complicated. Infect Dis Ther 2019; 8:627-640. [PMID: 31637596 PMCID: PMC6856471 DOI: 10.1007/s40121-019-00268-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Indexed: 01/29/2023] Open
Abstract
INTRODUCTION A one-time vancomycin loading dose of 25-30 mg/kg is recommended in the current iteration of the vancomycin consensus guidelines in order to more rapidly achieve target serum concentrations and hasten clinical improvement. However, there are few clinical data to support this practice, and the extents of its benefits are largely unknown. METHODS A multicenter, retrospective, cohort study was performed to assess the impact of a vancomycin loading dose (≥ 20 mg/kg) on clinical outcomes and rates of nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. The study matched patients in a 1:1 fashion based on age, Pitt bacteremia score, and bacteremia source. The primary outcome was composite treatment failure (30-day mortality, bacteremia duration ≥ 7 days after vancomycin initiation, persistent signs and symptoms of infection ≥ 7 days after vancomycin initiation, or switch to an alternative antimicrobial agent). Secondary outcomes included duration of bacteremia, length of stay post-bacteremia onset, and nephrotoxicity. RESULTS A total of 316 patients with MRSA bacteremia were included. Median first doses in the loading dose and non-loading dose groups were 23.0 mg/kg and 14.3 mg/kg, respectively (P < 0.001). No difference was found in composite failure rates between the non-loading dose and loading dose groups (40.5% vs. 36.7%; P = 0.488) or in the incidence of nephrotoxicity (12.7% vs. 16.5%; P = 0.347). While multivariable regression modeling showed receipt of a vancomycin loading dose on a mg/kg basis was not significantly associated with composite failure [aOR 0.612, 95% CI (0.368-1.019)]; post hoc analyses demonstrated that initial doses ≥ 1750 mg were independently protective against failure [aOR 0.506, 95% CI (0.284-0.902)] without increasing the risk for nephrotoxicity [aOR 0.909, 95% CI (0.432-1.911)]. CONCLUSION These findings suggest that initial vancomycin doses above a certain threshold may decrease clinical failures without increasing toxicity and that weight-based dosing might not be the optimal strategy.
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Affiliation(s)
- Jessica K Ortwine
- Department of Pharmacy Services, Parkland Health and Hospital System, Dallas, TX, USA
- University of Texas Southwestern Medical School, Dallas, TX, USA
| | - Evan J Zasowski
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
- Department of Clinical Sciences, College of Pharmacy, Touro University California, Vallejo, CA, USA
| | - Jason M Pogue
- Department of Pharmacy Services, Sinai-Grace Hospital, Detroit, MI, USA
- Division of Infectious Diseases, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, USA
| | - Claudia Hanni
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
| | - Chris Giuliano
- Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
- Department of Pharmacy, St. John Hospital and Medical Center, Detroit, MI, USA
| | - Anthony M Casapao
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
- University of Florida College of Pharmacy, Jacksonville, FL, USA
| | - Ryan Mynatt
- Department of Pharmacy Services, Detroit Receiving Hospital, Detroit, MI, USA
| | - Michael J Rybak
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.
- Division of Infectious Diseases, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, USA.
- Department of Pharmacy Services, Detroit Receiving Hospital, Detroit, MI, USA.
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Tuerff D, Nunez M. More Frequent Premature Antibiotic Discontinuations and Acute Kidney Injury in the Outpatient Setting With Vancomycin Compared to Daptomycin. J Clin Pharmacol 2019; 60:384-390. [PMID: 31630403 DOI: 10.1002/jcph.1536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 09/27/2019] [Indexed: 01/27/2023]
Abstract
Vancomycin and daptomycin are often used in outpatient parenteral antimicrobial therapy for gram-positive coverage. Vancomycin's narrow therapeutic window poses challenges. We retrospectively assessed acute kidney injury (AKI) and other adverse drug events in outpatient parenteral antimicrobial therapy patients receiving vancomycin or daptomycin at home after hospital discharge. Among 191 patients included, AKI was the most common adverse drug event. Early antibiotic discontinuation and AKI were more frequent in the vancomycin group. Vancomycin use (odds ratio [OR], 4.57; 95% confidence interval [CI], 1.02-20.51); p = 0.04], female sex (OR, 3.28; 95%CI, 1.41-7.67; P < .01), and longer hospitalization (OR, 1.06; 95%CI, 1.01-1.11; P = .02] independently predicted moderate-to-severe AKI. In the vancomycin group, trough concentrations increased after discharge, and were higher in female compared to male patients, and in those who developed moderate-to-severe AKI compared to those who did not. Female sex (OR, 8.37; 95%CI, 2.35-29.82; P < .01) and higher concentrations (OR, 1.12; 95%CI, 1.05-1.19; P < .01) predicted moderate-to-severe AKI in patients receiving vancomycin. In conclusion, premature antibiotic discontinuations and nephrotoxicity are more frequent in patients treated at home with vancomycin compared to daptomycin. Among patients receiving vancomycin, plasma concentrations increased after hospital discharge and predicted moderate-to-severe AKI. Women had higher vancomycin concentrations and higher risk for AKI.
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Affiliation(s)
- Daniel Tuerff
- Wake Forest School of Medicine, Department of Internal Medicine, Section on Infectious Diseases, Winston-Salem, North Carolina, USA
| | - Marina Nunez
- Wake Forest School of Medicine, Department of Internal Medicine, Section on Infectious Diseases, Winston-Salem, North Carolina, USA
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40
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Hashimoto M, Iketani O, Ichinose N, Enoki Y, Taguchi K, Uno S, Uwamino Y, Hasegawa N, Matsumoto K. Evaluation for optimal dosing of vancomycin in patients with different physical types. J Infect Chemother 2019; 25:735-737. [PMID: 31126752 DOI: 10.1016/j.jiac.2019.04.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/13/2019] [Accepted: 04/20/2019] [Indexed: 10/26/2022]
Abstract
The sufficient dose to obtain an optimal trough concentration of vancomycin (VCM) in patients with non-standard physical types remains controversial. In this study, we examined the relationship between the dose and physical type in patients in whom an optimal trough concentration was obtained among VCM-treated patients. We retrospectively investigated the dose of VCM and physical type in patients treated with VCM between January 2012 and January 2017 at two medical institutions (n = 272). The physical type was classified using the body mass index (BMI). Patients with a BMI of <18.5 kg/m2 were assigned to the lean group, those with a BMI of 18.5-24.9 kg/m2 were assigned to the standard group, and those with a BMI of ≥25 kg/m2 were assigned to the obesity group. The mean doses of VCM per time (mg/kg) to achieve the target trough concentration of VCM, 15-20 μg/mL, were 19.8 ± 4.3, 16.5 ± 3.7, and 13.7 ± 2.7 mg/kg in the lean, standard, and obesity groups, respectively. The dose per time to achieve the target trough concentration decreased significantly in association with an increase of BMI. The upper limit of the recommended dose (15-20 mg/kg) or higher in lean patients, and the lower dose in obese patients than the recommended dose might be appropriate to achieve the target trough concentration when we calculated the dose per time based on actual body weight.
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Affiliation(s)
- Mari Hashimoto
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan; Center for Infectious Diseases and Infection Control, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Osamu Iketani
- Center for Infectious Diseases and Infection Control, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Naoki Ichinose
- Showa General Hospital Pharmaceutical Department, 8-1-1 Hanakoganei, Kodaira-shi, Tokyo, 187-8510, Japan
| | - Yuki Enoki
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
| | - Kazuaki Taguchi
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Shunsuke Uno
- Center for Infectious Diseases and Infection Control, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yoshifumi Uwamino
- Center for Infectious Diseases and Infection Control, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Naoki Hasegawa
- Center for Infectious Diseases and Infection Control, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Kazuaki Matsumoto
- Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
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41
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Heil EL, Claeys KC, Mynatt RP, Hopkins TL, Brade K, Watt I, Rybak MJ, Pogue JM. Making the change to area under the curve–based vancomycin dosing. Am J Health Syst Pharm 2018; 75:1986-1995. [DOI: 10.2146/ajhp180034] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Emily L. Heil
- Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, MD, and Department of Pharmacy, University of Maryland Medical Center, Baltimore MD
| | - Kimberly C. Claeys
- Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, MD, and Department of Pharmacy, University of Maryland Medical Center, Baltimore, MD
| | - Ryan P. Mynatt
- Department of Pharmacy, Detroit Receiving Hospital, Detroit Medical Center, Detroit, MI
| | - Teri L. Hopkins
- Department of Pharmacy, South Texas Veterans Health Care System, San Antonio, TX
| | - Karrine Brade
- Department of Pharmacy, Boston Medical Center, Boston, MA
| | - Ian Watt
- Department of Pharmacy, University of Maryland Medical Center, Baltimore, MD
| | - Michael J. Rybak
- Anti-Infective Research Laboratory, Department of Pharmacy Practice, Wayne State University, Detroit, MI, and Department of Pharmacy, Detroit Receiving Hospital, Detroit Medical Center, Detroit, MI
| | - Jason M. Pogue
- Department of Pharmacy, Sinai Grace Hospital, Detroit Medical Center, Detroit, MI
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Nguyen L, Breen M, Yamaki J, Cadalin G, Lumintaintang L, Shah N. Assessing Vancomycin Dosing Per Pharmacy in Elderly Patients Over the Age of 74 Years. JOURNAL OF CONTEMPORARY PHARMACY PRACTICE 2018. [DOI: 10.37901/jcphp17-00014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Vancomycin has a complex pharmacokinetic profile and carries potential risks for nephrotoxicity and ototoxicity. The pharmacokinetic profile in elderly patients significantly differs from that of younger patients. It is common practice in many institutions for pharmacists to intentionally round serum creatinine levels to 1 mg/dl in elderly patients with levels <1 mg/dl to avoid overestimating clearance and toxicities. This can potentially lead to underestimation of creatinine clearance, and subsequently lead to vancomycin under dosing. The aim of this study was to evaluate vancomycin target trough attainment and the time to trough attainment with vancomycin dosing per pharmacy in elderly patients.
Methods
In this retrospective study, patients 75 years and older who received vancomycin at our institution were evaluated. Subjects were included in the study if they were at least 75 years of age, received intravenous vancomycin therapy, and had a vancomycin trough drawn after the third dose. The study patients were divided into three serum creatinine groups; <0.8 mg/dl (LSCr), 0.8–0.9 mg/dl (MSCr), and ≥1 mg/dl (HSCr). Patients were excluded from the study if they did not meet inclusion criteria, had no trough levels drawn, or were <75 years of age.
Results
Two hundred and four patients 75 years or older were included in the study. The target trough attainment was highest in the HSCr group (n = 37, 80%), which was significantly higher than the LSCr (n=21, 31%; p<0.0001) and MSCr (n=42, 46%; p<0.0001) groups. The time to target trough goals (days, mean ± SD) differed between the three groups, with the LSCr group taking the longest duration: LSCr: 5.14 ± 2.5; MSCr: 3.74 ± 1.1; HSCr: 3.78 ± 1.6, p=0.005.
Conclusion
Adjustments need to be done to improve vancomycin dosing per pharmacy in patients 75 years of age and older. This study shows that LSCr patients (<0.8 mg/dl) had the lowest rates of target trough level attainment. Intentionally rounding serum creatinine to 1 mg/dl if values are less when estimating renal function in this older patient population may not be predictive of true renal function and can decrease the likelihood of target attainment or increase time to target attainment.
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43
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Durand C, Bylo M, Howard B, Belliveau P. Vancomycin Dosing in Obese Patients: Special Considerations and Novel Dosing Strategies. Ann Pharmacother 2017; 52:580-590. [PMID: 29262697 DOI: 10.1177/1060028017750084] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To review the literature regarding vancomycin pharmacokinetics in obese patients and strategies used to improve dosing in this population. DATA SOURCES PubMed, EMBASE (1974 to November 2017), and Google Scholar searches were conducted using the search terms vancomycin, obese, obesity, pharmacokinetics, strategy, and dosing. Additional articles were selected from reference lists of selected studies. STUDY SELECTION AND DATA EXTRACTION Included articles were those published in English with a primary focus on vancomycin pharmacokinetic parameters in obese patients and practical vancomycin dosing strategies, clinical experiences, or challenges of dosing vancomycin in this population. DATA SYNTHESIS Volume of distribution and clearance are the pharmacokinetic parameters that most often affect vancomycin dosing in obese patients; both are increased in this population. Challenges with dosing in obese patients include inconsistent and inadequate dosing, observations that the obese population may not be homogeneous, and reports of an increased likelihood of supratherapeutic trough concentrations. Investigators have revised and developed dosing and monitoring protocols to address these challenges. These approaches improved target trough attainment to varying degrees. CONCLUSIONS Some of the vancomycin dosing approaches provided promising results in obese patients, but there were notable differences in methods used to develop these approaches, and sample sizes were small. Although some approaches can be considered for validation in individual institutions, further research is warranted. This may include validating approaches in larger populations with narrower obesity severity ranges, investigating target attainment in indication-specific target ranges, and evaluating the impact of different dosing weights and methods of creatinine clearance calculation.
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Affiliation(s)
| | - Mary Bylo
- 1 MCPHS University, Manchester, NH, USA
| | - Brian Howard
- 1 MCPHS University, Manchester, NH, USA.,2 Pfizer, Groton, CT, USA
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A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity. Antimicrob Agents Chemother 2017; 61:AAC.01293-17. [PMID: 28923869 DOI: 10.1128/aac.01293-17] [Citation(s) in RCA: 187] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 09/09/2017] [Indexed: 12/11/2022] Open
Abstract
Evidence suggests that maintenance of vancomycin trough concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the concentration-time curve (AUC24) target of ≥400 mg · h/liter. Many patients with trough concentrations in this range have AUC24 values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from trough concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC24 and those monitored by assessment of the trough concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval [CI], 0.34 to 0.80; P = 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P = 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure.
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A Strategy for Dosing Vancomycin to Therapeutic Targets Using Only Trough Concentrations. Clin Pharmacokinet 2017; 56:263-272. [PMID: 27389404 DOI: 10.1007/s40262-016-0435-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Effective treatment of complicated methicillin-resistant Staphylococcus aureus (MRSA) infections with vancomycin requires a 24-h area under the concentration-time curve (AUC24) to minimum inhibitory concentration (MIC) ratio of at least 400. To ensure goal AUC24 has been reached requires either dosing to concentrations strongly associated with nephrotoxicity, measurement of patient-specific pharmacokinetics, or use of Bayesian statistics. In this study, we show a method of determining patient-specific pharmacokinetics and dosing to therapeutic AUC24 while minimizing potentially toxic concentrations, guided by only trough measurements. A Monte-Carlo simulation of 10,000 patients with complicated MRSA infections was prepared from two-compartment pharmacokinetic parameters using patient data extracted from the literature. The proposed method of determining patient-specific pharmacokinetics using consecutive trough concentrations was found to be more accurate than the conventional peak-trough method for peaks measured up to 4 h after infusion. Simulated human error in trough timing was found to reduce accuracy of the consecutive trough method, but an approach to resolve timing errors during a loading sequence or at steady-state using iteration is proposed. Both the simulated minimized concentration strategy and trough-based dosing to 15-20 mg/L had a high probability of achieving AUC24 at least 400 mg·h/L, but conventional trough-based dosing was associated with higher probability of potentially toxic 24-h doses and trough concentrations. The proposed strategy must be validated in real patients, with outcomes assessed before it is used in daily practice, but the theoretical benefits found in the simulation suggest this simple strategy should be considered with other AUC24-based approaches.
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46
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Ariano RE, Zelenitsky SA, Poncsak KR, Davis JC, Vercaigne LM. No role for patient body weight on renal function assessment for drug dosing. J Antimicrob Chemother 2017; 72:1802-1811. [PMID: 28369383 DOI: 10.1093/jac/dkx036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 01/18/2017] [Indexed: 12/23/2022] Open
Abstract
Objectives To evaluate the ability of body-weight-driven renal function assessment (RFA) formulae to predict on-target elimination rate ranges for gentamicin in patients with varying degrees of renal function. Methods A 6 year retrospective pharmacokinetic study was conducted at a university teaching hospital. Results A total of 85 patients met the inclusion criteria and 127 pharmacokinetic files were analysed from patients on medical-surgical wards (53%) and medical-surgical ICUs (13%) receiving intravenous gentamicin for treatment, as well as those for patients receiving it for surgical prophylaxis (34%). Each RFA formula was examined against standard dosing tables for gentamicin. A table of acceptable elimination rates was generated using a traditional peak of 8 mg/L and trough between 0.5 and 2 mg/L associated with each of the dosing interval extensions. The ability of each RFA formula to select on-target elimination rates was evaluated. The RFA formula assuming a normalized body weight of 72 kg and a modified creatinine reagent adjustment factor of 90% provided the most accurate on-target elimination rate selection. This method was superior to dosing interval selection based on the Modification in Diet Renal Disease (MDRD) formula, Sanford's guide method, as well as the Cockcroft-Gault formulae using total body weight, ideal body weight or lean body weight ( P < 0.0001). Conclusions Based on the use of gentamicin as a surrogate guide for renally adjusted drugs, these results support dosing interval selection based on a normalized body weight method and a formula reagent adjustment factor of 90% within the Cockcroft-Gault formula.
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Affiliation(s)
- Robert E Ariano
- Department of Pharmacy, St Boniface General Hospital, 409 Tache Avenue, Winnipeg, Manitoba, Canada.,College of Pharmacy, University of Manitoba, Winnipeg, Canada
| | - Sheryl A Zelenitsky
- Department of Pharmacy, St Boniface General Hospital, 409 Tache Avenue, Winnipeg, Manitoba, Canada.,College of Pharmacy, University of Manitoba, Winnipeg, Canada
| | | | - J Christine Davis
- Department of Pharmacy, St Boniface General Hospital, 409 Tache Avenue, Winnipeg, Manitoba, Canada.,College of Pharmacy, University of Manitoba, Winnipeg, Canada.,Manitoba Renal Program, Winnipeg, Canada
| | - Lavern M Vercaigne
- College of Pharmacy, University of Manitoba, Winnipeg, Canada.,Manitoba Renal Program, Winnipeg, Canada
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47
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Qian X, Du G, Weng C, Zhou H, Zhou X. Evaluation of the variability and safety of serum trough concentrations of vancomycin in patients admitted to the intensive care unit. Int J Infect Dis 2017; 60:17-22. [PMID: 28457752 DOI: 10.1016/j.ijid.2017.04.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 04/06/2017] [Accepted: 04/19/2017] [Indexed: 10/19/2022] Open
Abstract
OBJECTIVE To examine the variability and safety of serum trough concentrations of vancomycin in patients admitted to the intensive care unit (ICU) and to analyze the factors influencing the trough concentration. METHODS Data were collected retrospectively from ICU patients receiving vancomycin treatment at a fixed dose of 2g/day due to unobtainable weight data, at Changzhou No. 2 People's Hospital, between 2012 and 2015. Vancomycin trough concentrations were compared between groups stratified by sex, age, and estimated glomerular filtration rate (eGFR). RESULTS The vancomycin trough concentration varied significantly among ICU patients on a fixed dose of 2g/day. Only 16.9% of ICU patients met the concentration target of 15-20mg/l, while 25% of patients showed supratherapeutic concentrations. A higher proportion of female patients than male patients showed supratherapeutic concentrations (40.4% vs. 15.5%). The trough concentration was positively correlated with age (y=0.279x-2.085; R2=0.186) and negatively correlated with eGFR (y=-0.2x+33.776; R2=0.366). Vancomycin-related nephrotoxicity occurred at an incidence of 5.9%. CONCLUSIONS These results suggest that the fixed-dose regimen is not appropriate for ICU patients in view of the low incidence of target trough concentrations and the high incidence of supratherapeutic concentrations. The dose should be individualized based on weight, age, and renal function to improve outcomes and patient safety.
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Affiliation(s)
- Xiaodan Qian
- Department of Pharmacy, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, 213003, China
| | - Guantao Du
- Department of Pharmacy, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, 213003, China
| | - Chunmei Weng
- Department of Pharmacy, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, 213003, China
| | - Haijun Zhou
- Drug Clinical Trial Institution, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, 213003, China.
| | - Xianju Zhou
- Drug Clinical Trial Institution, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, 213003, China; Laboratory of Neurological Diseases, Department of Neurology, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, 213003, China.
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48
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Gender-based personalized pharmacotherapy: a systematic review. Arch Gynecol Obstet 2017; 295:1305-1317. [PMID: 28378180 DOI: 10.1007/s00404-017-4363-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 03/29/2017] [Indexed: 01/03/2023]
Abstract
PURPOSE In general, male and female are prescribed the same amount of dosage even if most of the cases female required less dosage than male. Physicians are often facing problem on appropriate drug dosing, efficient treatment, and drug safety for a female in general. To identify and synthesize evidence about the effectiveness of gender-based therapy; provide the information to patients, providers, and health system intervention to ensure safety treatment; and minimize adverse effects. METHODS We performed a systematic review to evaluate the effect of gender difference on pharmacotherapy. Published articles from January 1990 to December 2015 were identified using specific term in MEDLINE (PubMed), EMBASE, and the Cochrane library according to search strategies that strengthen the reporting of observational and clinical studies. RESULTS Twenty-six studies fulfilled the inclusion criteria for this systematic review, yielding a total of 6309 subjects. We observed that female generally has a lower the gastric emptying time, gastric PH, lean body mass, and higher plasma volume, BMI, body fat, as well as reduce hepatic clearance, difference in activity of Cytochrome P450 enzyme, and metabolize drugs at different rate compared with male. Other significant factors such as conjugation, protein binding, absorption, and the renal elimination could not be ignored. However, these differences can lead to adverse effects in female especially for the pregnant, post-menopausal, and elderly women. CONCLUSION This systematic review provides an evidence for the effectiveness of dosage difference to ensure safety and efficient treatment. Future studies on the current topic are, therefore, recommended to reduce the adverse effect of therapy.
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49
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Muhl E, Bundesen J, Iven H, Bruch HP. Measurement and Calculation of the Extracorporeal Elimination of Vancomycin During Continuous Venovenous Hemodiafiltration and Continuous Venovenous Hemofiltration in Critically Ill Patients. J Intensive Care Med 2016. [DOI: 10.1177/088506660101600503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Six surgical intensive care patients with continuous renal replacement therapy and therapy with vancomycin entered the prospective clinical study. The first day the patients were treated with continuous venovenous hemodiafiltration (CVVHDF) and the second day with continuous venovenous hemofiltration (CVVH). Three patients received 500 mg and three patients received 1000 mg of vancomycin every 12 hours. Monoclonal fluorescence polarization immunoassay (AxSYM) of vancomycin levels was performed from serum and dialysate/ultrafiltrate (during CVVHDF) or ultrafiltrate (during CVVH). Blood flow was 90 ml/hr, substitution 1 L/hr predilution, dialysate flow 1 L/hr (CVVHDF). The extracorporeal elimination of vancomycin during CVVHDF and CVVH is nearly linear but shows wide interindividual variation. The extracorporeal clearance of vancomycin was 24.2 ± 3.1 ml/min during CVVHDF (total clearance 60.4 ±18.1 ml/min) and 14.5 ± 2.4 ml/min during CVVH (total clearance 50.2 ± 14.9 ml/min). Intraindividual comparison revealed a significantly higher elimination of vancomycin by CVVHDF (p < 0.028). Peak serum vancomycin levels in patients receiving vancomycin 1g/day were 24.7 ± 5.3 μg/ml (CVVH) and 23.1 ± 5.2 μg/ml (CVVHDF), and with 2 g/day were 33.5 ± 2.7 μg/ml (CVVH) and 27.3 ±4.1 μg/ml (CVVHDF). The daily excreted amount of vancomycin during CVVHDF (r2 = 0.950, p = 0.01) and CVVH (r2 = 0.947, p = 0.01) can be calculated from a vancomycin level in the ultrafiltrate/dialysate outlet (CVVHDF) or the ultrafiltrate (CVVH) 8 hours after dosing. The 8-hour concentration of vancomycin in the ultrafiltrate from CVVH (or ultrafiltrate/dialysate from CVVHDF) during continuous renal replacement therapy serves as a basis for predicting extracorporeal elimination within 24 hours for the individual patient. Since critically ill patients show wide interindividual and intraindividual differences in the volume of distribution, clearance, and elimination half-life of vancomycin during therapy, the estimation of serum levels remains a necessity.
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Affiliation(s)
- Elke Muhl
- Departments of Surgery, Luebeck Medical University, Luebeck, Germany
| | - Jens Bundesen
- Departments of Surgery, Luebeck Medical University, Luebeck, Germany
| | - Heiko Iven
- Pharmacology and Toxicology, Luebeck Medical University, Luebeck, Germany
| | - Hans-Peter Bruch
- Departments of Surgery, Luebeck Medical University, Luebeck, Germany
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50
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Barber KE, Bell AM, Stover KR, Wagner JL. Intravenous Vancomycin Dosing in the Elderly: A Focus on Clinical Issues and Practical Application. Drugs Aging 2016; 33:845-854. [PMID: 27878526 PMCID: PMC5122618 DOI: 10.1007/s40266-016-0420-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The elderly population can be divided into three distinct age groups: 65-74 years (young-old), 75-84 years (middle-old), and 85+ years (old-old). Despite evidence of a shift in leading causes for mortality in the elderly from infectious diseases to chronic conditions, infections are still a serious cause of death in this population. These patients are at increased risk due to weakened immune systems, an increased prevalence of underlying comorbidities, and decreased physiologic reserves to fight infection. Additionally, elderly patients, especially adults in institutional settings, are at an increased risk of colonization and subsequent infection with methicillin-resistant Staphylococcus aureus at a rate that is five times higher than in younger individuals, causing an increase in empiric and definitive vancomycin use. Elderly patients have unique characteristics that make dosing vancomycin a challenge for clinicians, such as increased volume of distribution and decreased renal function. Using the best available evidence, it is recommended to initiate lower empiric maintenance doses and monitor vancomycin serum concentrations earlier than steady state to accurately calculate drug elimination and make appropriate dose adjustments.
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Affiliation(s)
- Katie E Barber
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 N. State Street, Jackson, MS, 39216, USA
| | - Allison M Bell
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 N. State Street, Jackson, MS, 39216, USA
| | - Kayla R Stover
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 N. State Street, Jackson, MS, 39216, USA
- Department of Medicine-Infectious Diseases, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
| | - Jamie L Wagner
- Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 N. State Street, Jackson, MS, 39216, USA.
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