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Endo A, Hanawa K, Asakawa D, Ishibe T, Nakane Y, Matsumoto K, Hamada Y. Potential risk factors for early acute kidney injury in patients treated with vancomycin. J Infect Chemother 2024; 30:989-994. [PMID: 38490480 DOI: 10.1016/j.jiac.2024.03.010] [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: 12/09/2023] [Revised: 03/01/2024] [Accepted: 03/12/2024] [Indexed: 03/17/2024]
Abstract
PURPOSE The acute kidney injury (AKI) onset owing to vancomycin (VCM) is reported that depend on the area under the blood concentration-time curve (AUC) and occur comparison early phase (early AKI). This study aimed to investigate the occurrence of early AKI in patients treated with VCM and new indicators to avoid early AKI. METHODS Adult patients who received VCM treatment for more than 4 days and whose trough values measured at least once on or after day 4 and serum creatinine before day 7 from the initiation of VCM administration between August 2021 and September 2022 at the Yamanashi Prefectural Central Hospital were enrolled. Early AKI (defined as AKI occurring within day 7 from VCM administration) and the association between each AUC (0-24, 24-48, 48-72, 0-48, 24-72, 0-72) were investigated. Furthermore, each AUC cut-off value for early AKI was calculated. RESULT In total, 164 patients were enrolled; early AKI developed in 21 patients and most frequently occurred on day 4. All stratified AUC were associated with early AKI development. The AUC cut-off values were AUC0-24: 470.8 μg/mL⋅h; AUC24-48: 473.0 μg/mL⋅h; AUC48-72: 489.7 μg/mL⋅h; AUC0-48: 910.2 μg/mL⋅h; AUC24-72: 1039.2 μg/mL⋅h; and AUC0-72: 1544.0 μg/mL⋅h. CONCLUSION The possibility of AKI development owing to the AUC accumulation of VCM was observed (accumulation toxicity). Concentration control through early-phase blood concentration measurements and a transition to AUC0-48 <910.2 μg/mL⋅h may reduce the early-phase AKI onset.
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Affiliation(s)
- Aiju Endo
- Department of Pharmacy, Yamanashi Prefectural Central Hospital, Kofu, 400-8506, Yamanashi, Japan.
| | - Kazumi Hanawa
- Department of Pharmacy, Kameda Medical Center, Kamogawa, 296-8602, Chiba, Japan.
| | - Daiki Asakawa
- Department of Pharmacy, Yamanashi Prefectural Central Hospital, Kofu, 400-8506, Yamanashi, Japan.
| | - Taiki Ishibe
- Department of Pharmacy, Yamanashi Prefectural Central Hospital, Kofu, 400-8506, Yamanashi, Japan.
| | - Yu Nakane
- Department of Pharmacy, Yamanashi Prefectural Central Hospital, Kofu, 400-8506, Yamanashi, Japan.
| | - Kaori Matsumoto
- Department of Pharmacy, Yamanashi Prefectural Central Hospital, Kofu, 400-8506, Yamanashi, Japan.
| | - Yukihiro Hamada
- Department of Pharmacy, Kochi Medical School University, 185-1 Kohasu, Oko-cho, Nankoku, 783-8505, Kochi, Japan.
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Hanai Y, Hashi H, Hanawa K, Endo A, Miyazaki T, Yamaguchi T, Harada S, Yokoo T, Uekusa S, Namiki T, Yokoyama Y, Asakawa D, Isoda R, Enoki Y, Taguchi K, Matsumoto K, Matsuo K. Predictive Value of Vancomycin AUC 24/MIC Ratio for 30-day Mortality in Patients with Severe or Complicated Methicillin-Resistant Staphylococcus aureus Infections: A Multicenter Retrospective Study. Pharm Res 2024; 41:1381-1389. [PMID: 38886259 DOI: 10.1007/s11095-024-03728-9] [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: 03/13/2024] [Accepted: 06/09/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC24/MIC ratio associated with treatment outcomes of infections treated with vancomycin. METHODS This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC24/MIC and outcomes. RESULTS This study included 82 patients. ROC identified a target AUC24/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC24/MIC cutoff (34.1%) than for above AUC24/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC24/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335-18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups. CONCLUSIONS In treating severe/complicated MRSA infections, vancomycin AUC24/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC24/MIC ratios.
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Affiliation(s)
- Yuki Hanai
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
| | - Hideki Hashi
- Department of Pharmacy, Tokyo Bay Urayasu Ichikawa Medical Center, Chiba, Japan
| | - Kazumi Hanawa
- Department of Pharmacy, Kameda Medical Center, Chiba, Japan
| | - Aiju Endo
- Department of Pharmacy, Yamanashi Prefectural Central Hospital, Yamanashi, Japan
| | - Taito Miyazaki
- Department of General Medicine and Emergency Care (Infectious Diseases), Toho University Omori Medical Center, Tokyo, Japan
| | - Tetsuo Yamaguchi
- Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan
| | - Sohei Harada
- Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan
| | - Takuya Yokoo
- Department of Pharmacy, Toho University Omori Medical Centre, Tokyo, Japan
| | - Shusuke Uekusa
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
| | - Takaya Namiki
- Department of Pharmacy, Tokyo Bay Urayasu Ichikawa Medical Center, Chiba, Japan
| | | | - Daiki Asakawa
- Department of Pharmacy, Yamanashi Prefectural Central Hospital, Yamanashi, Japan
| | - Ryo Isoda
- Department of Pharmacy, Toho University Omori Medical Centre, Tokyo, Japan
| | - Yuki Enoki
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Kazuaki Taguchi
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Kazuaki Matsumoto
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Kazuhiro Matsuo
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
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Yang W, Zhang K, Chen Y, Fan Y, Zhang J. Is It Still Beneficial to Monitor the Trough Concentration of Vancomycin? A Quantitative Meta-Analysis of Nephrotoxicity and Efficacy. Antibiotics (Basel) 2024; 13:497. [PMID: 38927164 PMCID: PMC11200798 DOI: 10.3390/antibiotics13060497] [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: 04/24/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
This study conducted a quantitative meta-analysis to investigate the association of vancomycin indicators, particularly area under the curve over 24 h (AUC24) and trough concentrations (Ctrough), and their relationship with both nephrotoxicity and efficacy. Literature research was performed in PubMed and Web of Science on vancomycin nephrotoxicity and efficacy in adult inpatients. Vancomycin Ctrough, AUC24, AUC24/minimum inhibitory concentration (MIC), nephrotoxicity evaluation and treatment outcomes were extracted. Logistic regression and Emax models were conducted, stratified by evaluation criterion for nephrotoxicity and primary outcomes for efficacy. Among 100 publications on nephrotoxicity, 29 focused on AUC24 and 97 on Ctrough, while of 74 publications on efficacy, 27 reported AUC24/MIC and 68 reported Ctrough. The logistic regression analysis indicated a significant association between nephrotoxicity and vancomycin Ctrough (odds ratio = 2.193; 95% CI 1.582-3.442, p < 0.001). The receiver operating characteristic curve had an area of 0.90, with a cut-off point of 14.55 mg/L. Additionally, 92.3% of the groups with a mean AUC24 within 400-600 mg·h/L showed a mean Ctrough of 10-20 mg/L. However, a subtle, non-statistically significant association was observed between the AUC24 and nephrotoxicity, as well as between AUC24/MIC and Ctrough concerning treatment outcomes. Our findings suggest that monitoring vancomycin Ctrough remains a beneficial and valuable approach to proactively identifying patients at risk of nephrotoxicity, particularly when Ctrough exceeds 15 mg/L. Ctrough can serve as a surrogate for AUC24 to some extent. However, no definitive cut-off values were identified for AUC24 concerning nephrotoxicity or for Ctrough and AUC24/MIC regarding efficacy.
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Affiliation(s)
- Wanqiu Yang
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai 200040, China; (W.Y.); (K.Z.)
- Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai 200040, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Kaiting Zhang
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai 200040, China; (W.Y.); (K.Z.)
- Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai 200040, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yuancheng Chen
- Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai 200040, China;
| | - Yaxin Fan
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai 200040, China; (W.Y.); (K.Z.)
- Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai 200040, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Zhang
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai 200040, China; (W.Y.); (K.Z.)
- Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai 200040, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
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Knight JM, Iso T, Perez KK, Swan JT, Janak CE, Ikwuagwu JO, Musick WL. Risk of Acute Kidney Injury Based on Vancomycin Target Trough Attainment Strategy: Area-Under-the-Curve-Guided Bayesian Software, Nomogram, or Trough-Guided Dosing. Ann Pharmacother 2024; 58:110-117. [PMID: 37144736 DOI: 10.1177/10600280231171373] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Guidelines support area-under-the-curve (AUC) monitoring for vancomycin dosing which may lower overall doses and reduce acute kidney injury (AKI). OBJECTIVE The aim of this study was to compare incidence of AKI across 3 vancomycin dosing modalities: AUC-targeted Bayesian pharmacokinetic software, AUC-targeted empiric dosing nomogram, and trough-guided dosing using clinical pharmacists' judgment. METHODS This retrospective study included adult patients with a pharmacy dosing consult who received ≥1 dose of vancomycin and ≥1 serum vancomycin level documented between January 1, 2018, and December 31, 2019. Patients with baseline serum creatinine ≥2 mg/dL, weight ≥100 kg, receiving renal replacement therapy, AKI prior to vancomycin therapy, or vancomycin ordered only for surgical prophylaxis were excluded. The primary analysis was incidence of AKI adjusted for baseline serum creatinine, age, and intensive care unit admission. A secondary outcome was adjusted incidence of an abnormal trough value (<10 or >20 μg/mL). RESULTS The study included 3459 encounters. Incidence of AKI was 21% for Bayesian software (n = 659), 22% for the nomogram (n = 303), and 32% for trough-guided dosing (n = 2497). Compared with trough-guided dosing, incidence of AKI was lower in the Bayesian (adjusted odds ratio [OR] = 0.72, 95% confidence interval [CI]: 0.58-0.89) and the nomogram (adjusted OR = 0.71, 95% CI: 0.53-0.95) groups. Compared with trough-guided dosing, abnormal trough values were less common in the Bayesian group (adjusted OR = 0.83, 95% CI: 0.69-0.98). CONCLUSION AND RELEVANCE Study results suggest that use of AUC-guided Bayesian software reduces the incidence of AKI and abnormal trough values compared with trough-guided dosing.
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Affiliation(s)
| | - Tomona Iso
- Department of Pharmacy, Houston Methodist, Houston, TX, USA
- Department of Surgery, Houston Methodist, Houston, TX, USA
- Department of Pharmacy Practice, Loma Linda University School of Pharmacy, Loma Linda, CA, USA
| | | | - Joshua T Swan
- Department of Pharmacy, Houston Methodist, Houston, TX, USA
- Department of Surgery, Houston Methodist, Houston, TX, USA
- Center for Outcomes Research, Houston Methodist, Houston, TX, USA
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The Bayesian-Based Area under the Curve of Vancomycin by Using a Single Trough Level: An Evaluation of Accuracy and Discordance at Tertiary Care Hospital in KSA. Healthcare (Basel) 2023; 11:healthcare11030362. [PMID: 36766937 PMCID: PMC9914540 DOI: 10.3390/healthcare11030362] [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: 11/25/2022] [Revised: 01/20/2023] [Accepted: 01/23/2023] [Indexed: 02/01/2023] Open
Abstract
The AUC0-24 is the most accurate way to track the vancomycin level while the Cmin is not an accurate surrogate. Most hospitals in Saudi Arabia are under-practicing the AUC-guided vancomycin dosing and monitoring. No previous work has been conducted to evaluate such practice in the whole kingdom. The current study objective is to calculate the AUC0-24 using the Bayesian dosing software (PrecisePK), identify the probability of patients who receive the optimum dose of vancomycin, and evaluate the accuracy and precision of the Bayesian platform. This retrospective study was conducted at King Abdulaziz medical city, Jeddah. All adult patients treated with vancomycin were included. Pediatric patients, critically ill patients requiring ICU admission, patients with acute renal failure or undergoing dialysis, and febrile neutropenic patients were excluded. The AUC0-24 was predicted using the PrecisePK platform based on the Bayesian principle. The two-compartmental model by Rodvold et al. in this platform and patients' dose data were utilized to calculate the AUC0-24 and trough level. Among 342 patients included in the present study, the mean of the estimated vancomycin AUC0-24 by the posterior model of PrecisePK was 573 ± 199.6 mg, and the model had a bias of 16.8%, whereas the precision was 2.85 mg/L. The target AUC0-24 (400 to 600 mg·h/L) and measured trough (10 to 20 mg/L) were documented in 127 (37.1%) and 185 (54%), respectively. Furthermore, the result demonstrated an increase in odds of AUC0-24 > 600 mg·h/L among trough level 15-20 mg/L group (OR = 13.2, p < 0.05) as compared with trough level 10-14.9 mg/L group. In conclusion, the discordance in the AUC0-24 ratio and measured trough concentration may jeopardize patient safety, and implantation of the Bayesian approach as a workable alternative to the traditional trough method should be considered.
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Dilworth TJ, Schulz LT, Micek ST, Kollef MH, Rose WE. β-Lactam Therapeutic Drug Monitoring in Critically Ill Patients: Weighing the Challenges and Opportunities to Assess Clinical Value. Crit Care Explor 2022; 4:e0726. [PMID: 35815181 PMCID: PMC9259115 DOI: 10.1097/cce.0000000000000726] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE β-lactams are the cornerstone of empiric and targeted antibiotic therapy for critically ill patients. Recently, there have been calls to use β-lactam therapeutic drug monitoring (TDM) within 24-48 hours after the initiation of therapy in critically ill patients. In this article, we review the dynamic physiology of critically ill patients, β-lactam dose response in critically ill patients, the impact of pathogen minimum inhibitory concentration (MIC) on β-lactam TDM, and pharmacokinetics in critically ill patients. Additionally, we highlight available clinical data to better inform β-lactam TDM for critically ill patients. DATA SOURCES We retrospectively analyzed patients admitted for sepsis or septic shock at a single academic medical center who were treated with β-lactam antibiotics. STUDY SELECTION Indexed studies in PubMed in English language were selected for review on topics relative to critical care physiology, β-lactams, pharmacokinetics/pharmacodynamics, TDM, and antibiotic susceptibility. DATA EXTRACTION We reviewed potentially related studies on β-lactams and TDM and summarized their design, patients, and results. This is a synthetic, nonsystematic, review. DATA SYNTHESIS In the retrospective analysis of patients treated with β-lactam antibiotics, approximately one-third of patients received less than 48 hours of β-lactam therapy. Of those who continued beyond 48 hours, only 13.7% had patient-specific factors (augmented renal clearance, fluid overload, morbid obesity, and/or surgical drain), suggesting a potential benefit of β-lactam TDM. CONCLUSIONS These data indicate that a strategy of comprehensive β-lactam TDM for critically ill patients is unwarranted as it has not been shown yet to improve patient-oriented outcomes. This review demonstrates that β-lactam TDM in the ICU, while laudable, layers ambiguous β-lactam exposure thresholds upon uncertain/unknown MIC data within a dynamic, unpredictable patient population for whom TDM results will not be available fast enough to significantly affect care. Judicious, targeted TDM for those with risk factors for β-lactam over- or underexposure is a better approach but requires further study. Clinically, choosing the correct antibiotic and dosing β-lactams aggressively, which have a wide therapeutic index, to overcome critical illness factors appears to give critically ill patients the best likelihood of survival.
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Affiliation(s)
- Thomas J Dilworth
- Department of Pharmacy Services, Advocate Aurora Health, Milwaukee, WI
| | | | - Scott T Micek
- Center for Health Outcomes Research and Education, University of Health Sciences and Pharmacy, St. Louis, MO
- Department of Pharmacy, Barnes-Jewish Hospital, St. Louis, MO
| | - Marin H Kollef
- Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO
| | - Warren E Rose
- School of Pharmacy, University of Wisconsin-Madison, Madison, WI
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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: 78] [Impact Index Per Article: 26.0] [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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Abdul-Aziz MH, Brady K, Cotta MO, Roberts JA. Therapeutic Drug Monitoring of Antibiotics: Defining the Therapeutic Range. Ther Drug Monit 2022; 44:19-31. [PMID: 34750338 DOI: 10.1097/ftd.0000000000000940] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/30/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE In the present narrative review, the authors aimed to discuss the relationship between the pharmacokinetic/pharmacodynamic (PK/PD) of antibiotics and clinical response (including efficacy and toxicity). In addition, this review describes how this relationship can be applied to define the therapeutic range of a particular antibiotic (or antibiotic class) for therapeutic drug monitoring (TDM). METHODS Relevant clinical studies that examined the relationship between PK/PD of antibiotics and clinical response (efficacy and response) were reviewed. The review (performed for studies published in English up to September 2021) assessed only commonly used antibiotics (or antibiotic classes), including aminoglycosides, beta-lactam antibiotics, daptomycin, fluoroquinolones, glycopeptides (teicoplanin and vancomycin), and linezolid. The best currently available evidence was used to define the therapeutic range for these antibiotics. RESULTS The therapeutic range associated with maximal clinical efficacy and minimal toxicity is available for commonly used antibiotics, and these values can be implemented when TDM for antibiotics is performed. Additional data are needed to clarify the relationship between PK/PD indices and the development of antibiotic resistance. CONCLUSIONS TDM should only be regarded as a means to achieve the main goal of providing safe and effective antibiotic therapy for all patients. The next critical step is to define exposures that can prevent the development of antibiotic resistance and include these exposures as therapeutic drug monitoring targets.
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Affiliation(s)
- Mohd H Abdul-Aziz
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Kara Brady
- Adult Intensive Care Unit and Pharmacy, The Prince Charles Hospital, Brisbane, Australia
| | - Menino Osbert Cotta
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Jason A Roberts
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Departments of Intensive Care Medicine and Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, Australia; and
- Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
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A personalised approach to antibiotic pharmacokinetics and pharmacodynamics in critically ill patients. Anaesth Crit Care Pain Med 2021; 40:100970. [PMID: 34728411 DOI: 10.1016/j.accpm.2021.100970] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/26/2021] [Accepted: 08/14/2021] [Indexed: 01/01/2023]
Abstract
Critically ill patients admitted to intensive care unit (ICU) with severe infections, or those who develop nosocomial infections, have poor outcomes with substantial morbidity and mortality. Such patients commonly have suboptimal antibiotic exposures at routinely used antibiotic doses related to an increased volume of distribution and altered clearance due to their underlying altered physiology. Furthermore, the use of extracorporeal devices such as renal replacement therapy and extracorporeal membrane oxygenation in these group of patients also has the potential to alter in vivo drug concentrations. Moreover, ICU patients are likely to be infected with less-susceptible pathogens. Therefore, one potential contributing cause to the poor outcomes observed in critically ill patients may be related to subtherapeutic antibiotic exposures. Newer concepts include the clinician considering optimised dosing based on a blood antibiotic exposure defined by pharmacokinetic modelling and therapeutic drug monitoring, combined with a knowledge of the antibiotic penetration into the site of infection, thereby achieving optimal bacterial killing. Such optimised dosing is likely to improve patient outcomes. The aim of this review is to highlight key aspects of antibiotic pharmacokinetics and pharmacodynamics (PK/PD) in critically ill patients and provide a PK/PD approach to tailor antibiotic dosing to the individual patient.
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10
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Effectiveness of a vancomycin dosing protocol guided by area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) with multidisciplinary team support to improve hospital-wide adherence to a vancomycin dosing protocol: A pilot study. Infect Control Hosp Epidemiol 2021; 43:1043-1048. [PMID: 34247663 DOI: 10.1017/ice.2021.296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Limited data are available on the implementation of an area under the concentration-time curve (AUC)-based dosing protocol with multidisciplinary team (MT) support to improve adherence with vancomycin dosing protocol. OBJECTIVE To evaluate the effectiveness of an AUC-based dosing protocol with MT support intervention with adherence to a hospital-wide vancomycin dosing protocol at Thammasat University Hospital. METHOD We conducted a quasi-experimental study in patients who were prescribed intravenous vancomycin. The study was divided into 2 periods; (1) the preintervention period when the vancomycin dosing protocol was already applied in routine practice and (2) the post-intervention period when the implementation of an AUC-based dosing protocol with MT support was added to the existing vancomycin dosing protocol. The primary outcome was the rate of adherence, and the secondary outcomes included acute kidney injury events, vancomycin-related adverse events, and 30-day mortality rate. RESULTS In total, 240 patients were enrolled. The most common infections were skin and soft-tissue infections (24.6%) and bacteremia (24.6%). The most common pathogens were coagulase-negative staphylococci (19.6%) and Enterococcus spp (15.4%). Adherence with the vancomycin dosing protocol was significantly higher in the postintervention period (90.8% vs 55%; P ≤ .001). By multivariate analysis, an AUC-based dosing protocol with MT support was the sole predictor for adherence with the vancomycin dosing protocol (adjusted odds ratio, 10.31; 95% confidence interval, 4.54-23.45; P ≤ .001). The 30-day mortality rate was significantly lower during the postintervention period (8.3% vs 20%; P = .015). CONCLUSIONS AUC-based dosing protocol with MT support significantly improved adherence with vancomycin dosing protocol and was associated with a lower 30-day mortality rate.
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Optimizing Antimicrobial Drug Dosing in Critically Ill Patients. Microorganisms 2021; 9:microorganisms9071401. [PMID: 34203510 PMCID: PMC8305961 DOI: 10.3390/microorganisms9071401] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/25/2021] [Accepted: 06/25/2021] [Indexed: 12/23/2022] Open
Abstract
A fundamental step in the successful management of sepsis and septic shock is early empiric antimicrobial therapy. However, for this to be effective, several decisions must be addressed simultaneously: (1) antimicrobial choices should be adequate, covering the most probable pathogens; (2) they should be administered in the appropriate dose, (3) by the correct route, and (4) using the correct mode of administration to achieve successful concentration at the infection site. In critically ill patients, antimicrobial dosing is a common challenge and a frequent source of errors, since these patients present deranged pharmacokinetics, namely increased volume of distribution and altered drug clearance, which either increased or decreased. Moreover, the clinical condition of these patients changes markedly over time, either improving or deteriorating. The consequent impact on drug pharmacokinetics further complicates the selection of correct drug schedules and dosing during the course of therapy. In recent years, the knowledge of pharmacokinetics and pharmacodynamics, drug dosing, therapeutic drug monitoring, and antimicrobial resistance in the critically ill patients has greatly improved, fostering strategies to optimize therapeutic efficacy and to reduce toxicity and adverse events. Nonetheless, delivering adequate and appropriate antimicrobial therapy is still a challenge, since pathogen resistance continues to rise, and new therapeutic agents remain scarce. We aim to review the available literature to assess the challenges, impact, and tools to optimize individualization of antimicrobial dosing to maximize exposure and effectiveness in critically ill patients.
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Hughes DM, Goswami S, Keizer RJ, Hughes MSA, Faldasz JD. Bayesian clinical decision support-guided versus clinician-guided vancomycin dosing in attainment of targeted pharmacokinetic parameters in a paediatric population. J Antimicrob Chemother 2021; 75:434-437. [PMID: 31670812 DOI: 10.1093/jac/dkz444] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 09/30/2019] [Accepted: 10/01/2019] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES To compare a Bayesian clinical decision support (CDS) dose-optimizing software program with clinician judgement in individualizing vancomycin dosing regimens to achieve vancomycin pharmacokinetic (PK)/pharmacodynamic (PD) targets in a paediatric population. METHODS A retrospective review combined with a model-based simulation of vancomycin dosing was performed on children aged 1 year to 18 years at the University of California, San Francisco Benioff Children's Hospital Mission Bay. Dosing regimens recommended by the clinical pharmacists, 'clinician-guided', were compared with alternative 'CDS-guided' dosing regimens. The primary outcome was the percentage of occasions predicted to achieve steady-state trough levels within the target range of 10-15 mg/L, with a secondary outcome of predicted attainment of AUC24 ≥400 mg·h/L. Statistical comparison between approaches was performed using a standard t-test. RESULTS A total of n=144 patient occasions were included. CDS-guided regimens were predicted to achieve vancomycin steady-state troughs in the target range on 70.8% (102/144) of occasions, as compared with 37.5% (54/144) in the clinician-guided arm (P<0.0001). An AUC24 of ≥400 mg·h/L was achieved on 93% (112/121) of occasions in the CDS-guided arm versus 72% (87/121) of occasions in the clinician-guided arm (P<0.0001). CONCLUSIONS In a simulated analysis, the use of a Bayesian CDS tool was better than clinician judgement in recommending vancomycin dosing regimens in which PK/PD targets would be attained in children.
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Affiliation(s)
- David M Hughes
- Boston Medical Center, Boston, MA, USA.,University of California, San Francisco Medical Center, San Francisco, CA, USA
| | | | | | | | - Jonathan D Faldasz
- University of California, San Francisco Medical Center, San Francisco, CA, USA.,InsightRX, San Francisco, CA, USA
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13
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Poston-Blahnik A, Moenster R. Association Between Vancomycin Area Under the Curve and Nephrotoxicity: a single center, retrospective cohort study in a veteran population. Open Forum Infect Dis 2021; 8:ofab094. [PMID: 34046514 DOI: 10.1093/ofid/ofab094] [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] [Received: 02/01/2021] [Accepted: 03/11/2021] [Indexed: 11/13/2022] Open
Abstract
Background It is unclear which vancomycin area under the curve (AUC) values are most associated with risk for acute kidney injury (AKI). Methods This retrospective cohort study was undertaken to determine if vancomycin AUC >550 is associated with a higher rate of AKI than an AUC <550. Patients treated with vancomycin for at least 4 days at the VA St. Louis Health Care System from 1/1/2016 to 9/31/2018 were included. The primary outcome was AKI (defined as an increase in serum creatinine by 0.3 mg/dL or 50% from baseline). Secondary outcomes included length of stay, readmission in 30 days, and mortality in 30 days. A bivariate analysis was used to determine other potential factors affecting AKI rate, with significant variables (P < .2) to be included in the multivariate logistic regression analysis to determine independent risk for AKI. Results Two hundred patients were included in the analysis; 100 patients with an AUC ≥550 and 100 with an AUC <550. Only mean vancomycin dose (1722.50 mg vs 2361.25 mg; P < .05), mean AUC (465.88 vs 696.45; P < .05), and peak SCr (1.22 mg/dL vs 1.48 mg/dL; P = .015) were significantly different between groups (AUC <550 vs AUC ≥550, respectively). AKI occurred in 42% (42/100) of patients with AUC ≥550 compared with 2% (2/100) of patients with AUC <550 (P < .05). Secondary outcomes were not different between the groups. In the bivariate analysis, age ≥70, CrCl <50 mL/min, and AUC ≥550 (odds ratio, 49.5; 95% CI, 10.1-242.3; P < .05) were found to be independently associated with risk for developing AKI. Conclusions Patients with a vancomycin AUC ≥550 were found to have a significantly higher rate of AKI compared with those with an AUC <550.
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Affiliation(s)
- Anna Poston-Blahnik
- Pharmacy Department, VA St. Louis Health Care System, St. Louis, Missouri, USA
| | - Ryan Moenster
- Pharmacy Department, VA St. Louis Health Care System, St. Louis, Missouri, USA.,Department of Pharmacy Practice, St. Louis College of Pharmacy, St. Louis, Missouri, USA
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14
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Jorgensen SCJ, Dersch-Mills D, Timberlake K, Stewart JJ, Gin A, Dresser LD, Dalton BR. AUCs and 123s: a critical appraisal of vancomycin therapeutic drug monitoring in paediatrics. J Antimicrob Chemother 2021; 76:2237-2251. [PMID: 33675656 DOI: 10.1093/jac/dkab048] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The revised vancomycin guidelines recommend implementing AUC24-based therapeutic drug monitoring (TDM) using Bayesian methods in both adults and paediatrics. The motivation for this change was accumulating evidence showing aggressive dosing to achieve high troughs, as recommended in the first guidelines for adults and extrapolated to paediatrics, is associated with increased nephrotoxicity without improving clinical outcomes. AUC24-based TDM requires substantial resources that may need to be diverted from other valuable interventions. It can therefore be justified only after certain assumptions are shown to be true: (i) there is a clear relationship between vancomycin efficacy and/or toxicity and the proposed therapeutic range; and (ii) maintaining exposure within the target range with AUC24-based TDM improves clinical outcomes and/or decreases toxicity. In this review, we critically appraise the scientific basis for these assumptions. We find studies evaluating the relationship between vancomycin AUC24/MIC and efficacy in adults and children do not offer strong support for the recommended lower limit of the proposed therapeutic range (i.e. AUC24/MIC ≥400). Nephrotoxicity in children increases in a stepwise manner along the vancomycin exposure continuum but it is unclear if one parameter (AUC24 versus trough) is a superior predictor. Overall, evidence in children suggests good-to-excellent correlation between AUC24 and trough. Most importantly, there is no convincing evidence that the method of vancomycin TDM has a causal role in improving efficacy or reducing toxicity. These findings question the need to transition to resource-intensive AUC24-based TDM over retaining trough-based TDM with lower targets to minimize nephrotoxicity in paediatrics.
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Affiliation(s)
| | | | - Kathryn Timberlake
- Department of Pharmacy, The Hospital for Sick Children, Toronto, ON, Canada
| | - Jackson J Stewart
- Pharmacy Services, University of Alberta Hospital, Edmonton, AB, Canada
| | - Alfred Gin
- Department of Pharmacy, Winnipeg Regional Health Authority, Winnipeg, MB, Canada.,Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Linda D Dresser
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.,Antimicrobial Stewardship Program, University Health Network, Toronto, ON, Canada
| | - Bruce R Dalton
- Pharmacy Services, Alberta Health Services, Calgary, AB, Canada
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15
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The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing. BMC Infect Dis 2021; 21:153. [PMID: 33549035 PMCID: PMC7866743 DOI: 10.1186/s12879-021-05858-6] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 01/31/2021] [Indexed: 12/18/2022] Open
Abstract
Background This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety. Methods We conducted our analysis using the MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials electronic databases searched on August 9, 2020. We calculated odds ratios (ORs) and 95% confidence intervals (CIs). Results Adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia with VCM trough concentrations ≥15 μg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47–0.85). The incidence of acute kidney injury (AKI) increased with increased trough concentrations and was significantly higher for trough concentrations ≥20 μg/mL compared to those at 15–20 μg/mL (OR 2.39, 95% CI 1.78–3.20). Analysis of the target area under the curve/minimum inhibitory concentration ratios (AUC/MIC) showed significantly lower treatment failure rates for high AUC/MIC (cut-off 400 ± 15%) (OR 0.28, 95% CI 0.18–0.45). The safety analysis revealed that high AUC value (cut-off 600 ± 15%) significantly increased the risk of AKI (OR 2.10, 95% CI 1.13–3.89). Our meta-analysis of differences in monitoring strategies included four studies. The incidence of AKI tended to be lower in AUC-guided monitoring than in trough-guided monitoring (OR 0.54, 95% CI 0.28–1.01); however, it was not significant in the analysis of mortality. Conclusions We identified VCM trough concentrations and AUC values that correlated with effectiveness and safety. Furthermore, compared to trough-guided monitoring, AUC-guided monitoring showed potential for decreasing nephrotoxicity. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-021-05858-6.
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16
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Shingde RV, Reuter SE, Graham GG, Carland JE, Williams KM, Day RO, Stocker SL. Assessing the accuracy of two Bayesian forecasting programs in estimating vancomycin drug exposure. J Antimicrob Chemother 2020; 75:3293-3302. [DOI: 10.1093/jac/dkaa320] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 06/28/2020] [Indexed: 11/14/2022] Open
Abstract
Abstract
Background
Current guidelines for intravenous vancomycin identify drug exposure (as indicated by the AUC) as the best pharmacokinetic (PK) indicator of therapeutic outcome.
Objectives
To assess the accuracy of two Bayesian forecasting programs in estimating vancomycin AUC0–∞ in adults with limited blood concentration sampling.
Methods
The application of seven vancomycin population PK models in two Bayesian forecasting programs was examined in non-obese adults (n = 22) with stable renal function. Patients were intensively sampled following a single (1000 mg or 15 mg/kg) dose. For each patient, AUC was calculated by fitting all vancomycin concentrations to a two-compartment model (defined as AUCTRUE). AUCTRUE was then compared with the Bayesian-estimated AUC0–∞ values using a single vancomycin concentration sampled at various times post-infusion.
Results
Optimal sampling times varied across different models. AUCTRUE was generally overestimated at earlier sampling times and underestimated at sampling times after 4 h post-infusion. The models by Goti et al. (Ther Drug Monit 2018;
40
212–21) and Thomson et al. (J Antimicrob Chemother 2009;
63
1050–7) had precise and unbiased sampling times (defined as mean imprecision <25% and <38 mg·h/L, with 95% CI for mean bias containing zero) between 1.5 and 6 h and between 0.75 and 2 h post-infusion, respectively. Precise but biased sampling times for Thomson et al. were between 4 and 6 h post-infusion.
Conclusions
When using a single vancomycin concentration for Bayesian estimation of vancomycin drug exposure (AUC), the predictive performance was generally most accurate with sample collection between 1.5 and 6 h after infusion, though optimal sampling times varied across different population PK models.
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Affiliation(s)
- Rashmi V Shingde
- Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Darlinghurst, NSW, Australia
| | - Stephanie E Reuter
- School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, SA, Australia
| | - Garry G Graham
- Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Darlinghurst, NSW, Australia
- School of Medical Science, University of New South Wales, Kensington, NSW, Australia
| | - Jane E Carland
- Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, University of New South Wales, Kensington, NSW, Australia
| | - Kenneth M Williams
- Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Darlinghurst, NSW, Australia
- School of Medical Science, University of New South Wales, Kensington, NSW, Australia
| | - Richard O Day
- Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Darlinghurst, NSW, Australia
- School of Medical Science, University of New South Wales, Kensington, NSW, Australia
- St Vincent’s Clinical School, University of New South Wales, Kensington, NSW, Australia
| | - Sophie L Stocker
- Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, University of New South Wales, Kensington, NSW, Australia
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17
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Alosaimy S, Sabagha NL, Lagnf AM, Zasowski EJ, Morrisette T, Jorgensen SCJ, Trinh TD, Mynatt RP, Rybak MJ. Monotherapy with Vancomycin or Daptomycin versus Combination Therapy with β-Lactams in the Treatment of Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections: A Retrospective Cohort Analysis. Infect Dis Ther 2020; 9:325-339. [PMID: 32248513 PMCID: PMC7237588 DOI: 10.1007/s40121-020-00292-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with high morbidity and mortality. More in vitro, in vivo, and clinical data suggest that vancomycin (VAN) or daptomycin (DAP) combination therapy with β-lactams (BL) improves outcomes of MRSA infections. We hypothesize that BL combination with VAN or DAP would reduce the odds of clinical failure compared to VAN or DAP monotherapy. METHODS A retrospective cohort study of adult patients ≥ 18 years treated with VAN or DAP for MRSA BSI from 2006 to 2019 at Detroit Medical Center. Combination therapy (CT) was defined as VAN or DAP plus any BL for ≥ 24 h within 72 h of index culture. Monotherapy (MT) was defined as ≥ 72 h VAN or DAP within 72 h of index culture and no BL for ≥ 24 h up to 7 days following VAN/DAP initiation. Primary outcome was composite endpoint of clinical failure defined as: (1) 30-day mortality, (2) 60-day recurrence, or (3) persistent bacteremia (PB). PB was defined as bacteremia > 5 days. Multivariable logistic regression was used to evaluate the association between CT and the primary outcome. RESULTS Overall, 597 patients were included in this analysis, 153 in the MT group and 444 in the CT group. CT was independently associated with reduced odds of clinical failure (adjusted odds ratio, 0.523; 95% confidence interval, 0.348-0.787). The composite endpoint was driven by 60-day recurrence and PB but not 30-day mortality. There were no difference in adverse events including nephrotoxicity between the two study arms. CONCLUSIONS In hospitalized adults with MRSA BSI, CT with any BL was independently associated with improved clinical outcomes and may ultimately be selected as preferred therapy.
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Affiliation(s)
- Sara Alosaimy
- Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
| | - Noor L Sabagha
- Department of Pharmacy, Henry Ford Hospital, Detroit, MI, USA
| | - Abdalhamid M Lagnf
- Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
| | - Evan J Zasowski
- Department of Clinical Sciences, Touro University California College of Pharmacy, Vallejo, CA, USA
| | - Taylor Morrisette
- Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
| | | | - Trang D Trinh
- Department of Clinical Pharmacy, San Francisco School of Pharmacy, University of California, San Francisco, CA, USA
| | - Ryan P Mynatt
- University of Kentucky Healthcare, Lexington, KY, UK
| | - Michael J Rybak
- Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.
- Department of Pharmacy, Detroit Medical Center, Detroit, MI, USA.
- School of Medicine, Wayne State University, Detroit, MI, USA.
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18
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Abdul-Aziz MH, Alffenaar JWC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, Neely MN, Paiva JA, Pea F, Sjovall F, Timsit JF, Udy AA, Wicha SG, Zeitlinger M, De Waele JJ, Roberts JA. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper .. Intensive Care Med 2020; 46:1127-1153. [PMID: 32383061 PMCID: PMC7223855 DOI: 10.1007/s00134-020-06050-1] [Citation(s) in RCA: 618] [Impact Index Per Article: 123.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/10/2020] [Indexed: 12/12/2022]
Abstract
Purpose This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.
Methods Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes. Results TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients. Conclusion Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide. Electronic supplementary material The online version of this article (10.1007/s00134-020-06050-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mohd H Abdul-Aziz
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia
| | - Jan-Willem C Alffenaar
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.,Westmead Hospital, Westmead, NSW, Australia.,Marie Bashir Institute of Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia
| | - Matteo Bassetti
- Infectious Diseases Clinic, Department of Health Sciences, University of Genoa, Genoa and Hospital Policlinico San Martino - IRCCS, Genoa, Italy
| | - Hendrik Bracht
- Department of Anaesthesiology, University Ulm, Ulm, Germany
| | - George Dimopoulos
- Department of Critical Care, University Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece
| | - Deborah Marriott
- Department of Microbiology and Infectious Diseases, St. Vincent's Hospital, Sydney, NSW, Australia
| | - Michael N Neely
- Department of Paediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.,Division of Infectious Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Jose-Artur Paiva
- Department of Medicine, Faculty of Medicine of Porto, Porto, Portugal.,Department of Emergency and Intensive Care Medicine, Centro Hospitalar Universitario de São João, Porto, Portugal
| | - Federico Pea
- Institute of Clinical Pharmacology, SM Misericordia University Hospital, ASUFC, Udine, Italy
| | - Fredrik Sjovall
- Department of Perioperative Medicine, Skåne University Hospital, Malmö, Sweden
| | - Jean F Timsit
- Department of Intensive Care Medicine and Infectious Diseases, Bichat-Claude Bernard University Hospital, AP-HP, Paris, France.,Infection, Antimicrobials, Modelling, Evolution (IAME), Paris Diderot University, Paris, France
| | - Andrew A Udy
- Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.,Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia
| | - Sebastian G Wicha
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany
| | - Markus Zeitlinger
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Jan J De Waele
- Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium
| | - Jason A Roberts
- University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia. .,Department of Intensive Care Medicine and Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. .,Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia. .,Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.
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19
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Dalton BR, Rajakumar I, Langevin A, Ondro C, Sabuda D, Griener TP, Dersch-Mills D, Rennert-May E. Vancomycin area under the curve to minimum inhibitory concentration ratio predicting clinical outcome: a systematic review and meta-analysis with pooled sensitivity and specificity. Clin Microbiol Infect 2019; 26:436-446. [PMID: 31756451 DOI: 10.1016/j.cmi.2019.10.029] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/27/2019] [Accepted: 10/29/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND Vancomycin is a first-line antibiotic for methicillin-resistant Staphylococcus aureus infections or other Gram-positive infections. The area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio is proposed as a therapeutic drug-monitoring parameter. How well clinical efficacy is predicted by this measure has not been established. OBJECTIVE Determine the test performance characteristics (TPC) of AUC:MIC of vancomycin for prediction of positive outcome. DATA SOURCES PubMed and Ovid Medline (1946 to 2018) and EMBASE (1974 to 2018). Study Eligibility Criteria and Participants: Studies of patients treated with vancomycin for any type of infection in peer reviewed publications. All patient populations were included. INTERVENTIONS Vancomycin AUC:MIC or AUC was related to patient clinical outcome. METHODS Searches of medical databases using relevant terms were performed. Screening, study reviewing, data extracting and assessing data quality was performed independently by two reviewers. Studies were stratified by type of primary outcome for calculation of pooled sensitivity, specificity and construction of hierarchical summary receiver operating characteristic (HSROC) curves. RESULTS Nineteen studies including 1699 patients were meta-analysed. Pooled sensitivity and specificity were 0.77 (95% CI 0.67-0.84) and 0.62 (95% CI 0.53-0.71) respectively for the seven studies with primary outcome of mortality and 0.65 (95% CI 0.53-0.75), 0.58 (95% CI 0.48-0.67) for studies with composite or clinical cure outcome (n = 12). HSROC curves suggested considerable heterogeneity. An additional 11 studies were described but could not be included for meta-analysis because data were not available. The majority of these studies (9/11) failed to demonstrate a relationship between AUC:MIC and positive clinical outcome. CONCLUSIONS Vancomycin AUC:MIC performance was modest and inconsistent. Analysis was limited by studies without sufficient data; therefore, meta-analytic results may overestimate TPC values. Given this, as well as the lack of standardization of methods, widespread adoption of AUC:MIC as the preferred vancomycin monitoring parameter may be premature.
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Affiliation(s)
- B R Dalton
- Pharmacy Services, Alberta Health Services, Calgary, Alberta, Canada.
| | - I Rajakumar
- Pharmacy Services, Alberta Health Services, Calgary, Alberta, Canada
| | - A Langevin
- Pharmacy Services, Alberta Health Services, Calgary, Alberta, Canada
| | - C Ondro
- Pharmacy Services, Alberta Health Services, Calgary, Alberta, Canada
| | - D Sabuda
- Pharmacy Services, Alberta Health Services, Calgary, Alberta, Canada
| | - T P Griener
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Canada
| | - D Dersch-Mills
- Pharmacy Services, Alberta Health Services, Calgary, Alberta, Canada
| | - E Rennert-May
- Section of Infectious Diseases, Department of Medicine, University of Calgary, Calgary, Canada
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20
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Selby AR, Hall RG. Utilizing the Patient Care Process to Minimize the Risk of Vancomycin-Associated Nephrotoxicity. J Clin Med 2019; 8:E781. [PMID: 31159415 PMCID: PMC6616424 DOI: 10.3390/jcm8060781] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 12/28/2022] Open
Abstract
Vancomycin-associated acute kidney injury (AKI) is a popular topic in the medical literature with few clear answers. While many studies evaluate the risk of AKI associated with vancomycin, few data are high quality and/or long in duration of follow-up. This review takes the clinician through an approach to evaluate a patient for risk of AKI. This evaluation should include patient assessment, antibiotic prescription, duration, and monitoring. Patient assessment involves evaluating severity of illness, baseline renal function, hypotension/vasopressor use, and concomitant nephrotoxins. Evaluation of antibiotic prescription includes evaluating the need for methicillin-resistant Staphylococcus aureus (MRSA) coverage and/or vancomycin use. Duration of therapy has been shown to increase the risk of AKI. Efforts to de-escalate vancomycin from the antimicrobial regimen, including MRSA nasal swabs and rapid diagnostics, should be used to lessen the likelihood of AKI. Adequate monitoring includes therapeutic drug monitoring, ongoing fluid status evaluations, and a continual reassessment of AKI risk. The issues with serum creatinine make the timely evaluation of renal function and diagnosis of the cause of AKI problematic. Most notably, concomitant piperacillin-tazobactam can increase serum creatinine via tubular secretion, resulting in higher rates of AKI being reported. The few studies evaluating the long-term prognosis of AKI in patients receiving vancomycin have found that few patients require renal replacement therapy and that the long-term risk of death is unaffected for patients surviving after the initial 28-day period.
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Affiliation(s)
- Ashley R Selby
- Department of Pharmacy Practice, Texas Tech University Health Sciences Center Jerry H. Hodge School of Pharmacy, Dallas, TX 75235, USA.
- VA North Texas Health Care System, Dallas, TX 75216, USA.
| | - Ronald G Hall
- Department of Pharmacy Practice, Texas Tech University Health Sciences Center Jerry H. Hodge School of Pharmacy, Dallas, TX 75235, USA.
- VA North Texas Health Care System, Dallas, TX 75216, USA.
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
- Dose Optimization and Outcomes Research (DOOR) Program, Dallas, TX 75235, USA.
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21
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Hassan D, Omolo CA, Gannimani R, Waddad AY, Mocktar C, Rambharose S, Agrawal N, Govender T. Delivery of novel vancomycin nanoplexes for combating methicillin resistant Staphylococcus aureus (MRSA) infections. Int J Pharm 2019; 558:143-156. [PMID: 30641177 DOI: 10.1016/j.ijpharm.2019.01.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 12/31/2018] [Accepted: 01/03/2019] [Indexed: 01/01/2023]
Abstract
The development of novel antibiotic systems is needed to address the methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of the study was to explore the novel nanoplex delivery method for vancomycin (VCM) against MRSA using dextran sulfate sodium salt (DXT) as a polyelectrolyte complexing agent. Nanoplexes were formulated by the self-assembling amphiphile polyelectrolyte complexation method and characterized. The size, polydispersity index (PDI), and zeta potential (ZP) of the optimized VCM nanoplexes were 84.6 ± 4.248 nm, 0.449 ± 0.024 and -33.0 ± 4.87 mV respectively, with 90.4 ± 0.77% complexation efficiency (CE %) and 62.3 ± 0.23% drug loading. The in vitro (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)tetrazolium (MTT) studies of the nanoplexes were found to be non-toxic against different mammalian cell lines tested and may confirm its biosafety. While the in vitro drug release studies demonstrated sustained slower release. The in silico study confirmed the spontaneous interaction of VCM with DXT in the presence of sodium chloride. A 6.24-fold enhancement was observed for VCM nanoplexes via in vitro antibacterial studies. Flow-cytometric analysis showed effective cell killing of 67% from VCM nanoplexes compared to 32.98% from the bare vancomycin at the minimum inhibitory concentration (MIC) of 1.25 μg/mL. The in vivo studies using BALB/c mouse skin infection model revealed that nanoplexes reduced MRSA burden by 2.3-folds compared to bare VCM. The novel nanoplexes have potential to be a promising delivery system to combat MRSA infections for improved treatment of bacterial infections.
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Affiliation(s)
- Daniel Hassan
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa
| | - Calvin A Omolo
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa
| | - Ramesh Gannimani
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa
| | - Ayman Y Waddad
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa
| | - Chunderika Mocktar
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa
| | - Sanjeev Rambharose
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa; Division of Emergency Medicine, Department of Surgery, University of Cape Town, Cape Town, South Africa
| | - Nikhil Agrawal
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa
| | - Thirumala Govender
- Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa.
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22
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The dosing and monitoring of vancomycin: what is the best way forward? Int J Antimicrob Agents 2018; 53:401-407. [PMID: 30599240 DOI: 10.1016/j.ijantimicag.2018.12.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 12/19/2018] [Accepted: 12/22/2018] [Indexed: 11/22/2022]
Abstract
We have evaluated the literature to review optimal dosing and monitoring of intravenous vancomycin in adults, in response to evolving understanding of targets associated with efficacy and toxicity. The area under the total concentration-time curve (0-24 h) divided by the minimum inhibitory concentration (AUC24/MIC) is the most commonly accepted index to guide vancomycin dosing for the treatment of Staphylococcus aureus infections, with a value of 400 h a widely recommended target for efficacy. Upper limits of AUC24 exposure of around 700 (mg/L).h have been proposed, based on the hypothesis that higher exposures of vancomycin are associated with an unacceptable risk of nephrotoxicity. If AUC24/MIC targets are used, sources of variability in the assessment of both AUC24 and MIC need to be considered. Current consensus guidelines recommend measuring trough vancomycin concentrations during intermittent dosing as a surrogate for the AUC24. Trough concentrations are a misleading surrogate for AUC24 and a poor end-point in themselves. AUC24 estimation using log-linear pharmacokinetic methods based on two plasma concentrations, or Bayesian methods are superior. Alternatively, a single concentration measured during continuous infusion allows simple AUC24 estimation and dose-adjustment. All of these methods have logistical challenges which must be overcome if they are to be adopted successfully.
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23
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Morales-Cartagena A, Fernández-Ruiz M, Lalueza A, Lora-Tamayo J, San Juan R, López-Medrano F, Origüen J, Chaves F, Aguado JM. Impact on mortality of adherence to evidence-based interventions in patients with catheter-related bloodstream infection due to methicillin-sensitive Staphylococcus aureus. Infect Dis (Lond) 2018; 50:837-846. [PMID: 30325676 DOI: 10.1080/23744235.2018.1501513] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
Abstract
BACKGROUND Recent studies have demonstrated improved survival when the management of Staphylococcus aureus bloodstream infection (BSI) is compliant with evidence-based therapeutic interventions. Whether this effect extends to low-risk sources, such as catheter-related BSI, remains unclear. METHODS We retrospectively included 225 episodes of methicillin-sensitive S. aureus catheter-related BSI diagnosed in our centre during two non-consecutive periods: 2002-2004 (first period (101 episodes)) and 2009-2013 (second period (124 episodes)). We evaluated the adherence (percentage of compliance = (no. of interventions performed/no. of interventions recommended) × 100) to the following bundle: early catheter removal (≤72 hours), early initiation of appropriate antibiotic therapy, adequate sampling of follow-up blood cultures, transthoracic echocardiography (TTE) during hospitalization and adequate duration of therapy. RESULTS Patients in the second period had a higher burden of comorbidities and more severe underlying conditions. All-cause 30-day mortality was 9.3%, with a significant difference between the first and second periods (13.9% versus 5.6%; p value = .035). Bundle adherence was significantly higher in the second period, particularly for follow-up blood cultures (26.7% versus 48.4%; p value = .001), performance of TTE (45.5% versus 84.7%; p value < .001) and appropriate duration of therapy (34.7% versus 50.0%; p value = .022). Bundle adherence ≥ 55% was associated with lower 30-day mortality (hazard ratio: 0.31; 95% confidence interval: 0.13-0.76). This effect remained significant across propensity score-based models adjusted for septic shock, study period and underlying conditions. CONCLUSIONS There was a survival benefit in adhering to a bundle of evidence-based interventions in the specific setting of catheter-related BSI due to methicillin-sensitive S. aureus.
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Affiliation(s)
- Alejandra Morales-Cartagena
- a School of Medicine , Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Universidad Complutense , Madrid , Spain
| | - Mario Fernández-Ruiz
- a School of Medicine , Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Universidad Complutense , Madrid , Spain
| | - Antonio Lalueza
- a School of Medicine , Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Universidad Complutense , Madrid , Spain
| | - Jaime Lora-Tamayo
- a School of Medicine , Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Universidad Complutense , Madrid , Spain
| | - Rafael San Juan
- a School of Medicine , Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Universidad Complutense , Madrid , Spain
| | - Francisco López-Medrano
- a School of Medicine , Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Universidad Complutense , Madrid , Spain
| | - Julia Origüen
- a School of Medicine , Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Universidad Complutense , Madrid , Spain
| | - Fernando Chaves
- b Department of Microbiology, School of Medicine , Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Universidad Complutense , Madrid , Spain
| | - José María Aguado
- a School of Medicine , Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Universidad Complutense , Madrid , Spain
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24
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Rawson TM, Charani E, Moore LSP, Gilchrist M, Georgiou P, Hope W, Holmes AH. Exploring the Use of C-Reactive Protein to Estimate the Pharmacodynamics of Vancomycin. Ther Drug Monit 2018; 40:315-321. [PMID: 29561305 PMCID: PMC6485622 DOI: 10.1097/ftd.0000000000000507] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND C-reactive protein (CRP) pharmacodynamic (PD) models have the potential to provide adjunctive methods for predicting the individual exposure response to antimicrobial therapy. We investigated CRP PD linked to a vancomycin pharmacokinetic (PK) model using routinely collected data from noncritical care adults in secondary care. METHODS Patients receiving intermittent intravenous vancomycin therapy in secondary care were identified. A 2-compartment vancomycin PK model was linked to a previously described PD model describing CRP response. PK and PD parameters were estimated using a Non-Parametric Adaptive Grid technique. Exposure-response relationships were explored with vancomycin area-under-the-concentration-time-curve (AUC) and EC50 (concentration of drug that causes a half maximal effect) using the index, AUC:EC50, fitted to CRP data using a sigmoidal Emax model. RESULTS Twenty-nine individuals were included. Median age was 62 (21-97) years. Fifteen (52%) patients were microbiology confirmed. PK and PD models were adequately fitted (r 0.83 and 0.82, respectively). There was a wide variation observed in individual Bayesian posterior EC50 estimates (6.95-48.55 mg/L), with mean (SD) AUC:EC50 of 31.46 (29.22). AUC:EC50 was fitted to terminal CRP with AUC:EC50 >19 associated with lower CRP value at 96-120 hours of therapy (100 mg/L versus 44 mg/L; P < 0.01). CONCLUSIONS The use of AUC:EC50 has the potential to provide in vivo organism and host response data as an adjunct for in vitro minimum inhibitory concentration data, which is currently used as the gold standard PD index for vancomycin therapy. This index can be estimated using routinely collected clinical data. Future work must investigate the role of AUC:EC50 in a prospective cohort and explore linkage with direct patient outcomes.
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Affiliation(s)
- Timothy M Rawson
- National Institute for Health Research Health Protection Research
Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial
College London, Hammersmith Campus, Du Cane Road, London. W12 0NN. United
Kingdom
| | - Esmita Charani
- National Institute for Health Research Health Protection Research
Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial
College London, Hammersmith Campus, Du Cane Road, London. W12 0NN. United
Kingdom
| | - Luke SP Moore
- National Institute for Health Research Health Protection Research
Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial
College London, Hammersmith Campus, Du Cane Road, London. W12 0NN. United
Kingdom
- Imperial College Healthcare NHS Trust, Du Cane Road, London.W12 0HS.
United Kingdom
| | - Mark Gilchrist
- Imperial College Healthcare NHS Trust, Du Cane Road, London.W12 0HS.
United Kingdom
| | - Pantelis Georgiou
- Department of Electrical and Electronic Engineering, Imperial
College London, South Kensington Campus, London, SW7 2AZ, United Kingdom
| | - William Hope
- Department of Molecular and Clinical Pharmacology, University of
Liverpool, Liverpool, L69 3GE, United Kingdom
| | - Alison H Holmes
- National Institute for Health Research Health Protection Research
Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial
College London, Hammersmith Campus, Du Cane Road, London. W12 0NN. United
Kingdom
- Imperial College Healthcare NHS Trust, Du Cane Road, London.W12 0HS.
United Kingdom
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25
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Stoessel AM, Hale CM, Seabury RW, Miller CD, Steele JM. The Impact of AUC-Based Monitoring on Pharmacist-Directed Vancomycin Dose Adjustments in Complicated Methicillin-Resistant Staphylococcus aureus Infection. J Pharm Pract 2018; 32:442-446. [PMID: 29554847 DOI: 10.1177/0897190018764564] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE This study aimed to assess the impact of area under the curve (AUC)-based vancomycin monitoring on pharmacist-initiated dose adjustments after transitioning from a trough-only to an AUC-based monitoring method at our institution. METHODS A retrospective cohort study of patients treated with vancomycin for complicated methicillin-resistant Staphylococcus aureus (MRSA) infection between November 2013 and December 2016 was conducted. The frequency of pharmacist-initiated dose adjustments was assessed for patients monitored via trough-only and AUC-based approaches for trough ranges: 10 to 14.9 mg/L and 15 to 20 mg/L. RESULTS Fifty patients were included: 36 in the trough-based monitoring and 14 in the AUC-based-monitoring group. The vancomycin dose was increased in 71.4% of patients when troughs were 10 to 14.9 mg/L when a trough-only approach was used and in only 25% of patients when using AUC estimation (P = .048). In the AUC group, the dose was increased only when AUC/minimum inhibitory concentration (MIC) <400; unchanged regimens had an estimated AUC/MIC ≥400. The AUC-based monitoring did not significantly increase the frequency of dose reductions when trough concentrations were 15 to 20 mg/L (AUC: 33.3% vs trough: 4.6%; P = .107). CONCLUSIONS The AUC-based monitoring resulted in fewer patients with dose adjustments when trough levels were 10 to 14.9 mg/L. The AUC-based monitoring has the potential to reduce unnecessary vancomycin exposure and warrants further investigation.
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Affiliation(s)
- Andrew M Stoessel
- 1 Department of Pharmacy, Upstate University Hospital, Syracuse, New York, NY, USA
| | - Cory M Hale
- 2 Department of Pharmacy, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Robert W Seabury
- 1 Department of Pharmacy, Upstate University Hospital, Syracuse, New York, NY, USA
| | - Christopher D Miller
- 1 Department of Pharmacy, Upstate University Hospital, Syracuse, New York, NY, USA.,3 Department of Medicine, Upstate Medical University, Syracuse, New York, NY, USA
| | - Jeffrey M Steele
- 1 Department of Pharmacy, Upstate University Hospital, Syracuse, New York, NY, USA.,3 Department of Medicine, Upstate Medical University, Syracuse, New York, NY, USA
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26
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Filippone EJ, Kraft WK, Farber JL. The Nephrotoxicity of Vancomycin. Clin Pharmacol Ther 2017; 102:459-469. [PMID: 28474732 PMCID: PMC5579760 DOI: 10.1002/cpt.726] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/07/2017] [Accepted: 04/28/2017] [Indexed: 12/13/2022]
Abstract
Vancomycin use is often associated with nephrotoxicity. It remains uncertain, however, to what extent vancomycin is directly responsible, as numerous potential risk factors for acute kidney injury frequently coexist. Herein, we critically examine available data in adult patients pertinent to this question. We review the pharmacokinetics/pharmacodynamics of vancomycin metabolism. Efficacy and safety data are discussed. The pathophysiology of vancomycin nephrotoxicity is considered. Risk factors for nephrotoxicity are enumerated, including the potential synergistic nephrotoxicity of vancomycin and piperacillin‐tazobactam. Suggestions for clinical practice and future research are given.
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Affiliation(s)
- E J Filippone
- Department of Medicine, Sydney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,Division of Nephrology, Sydney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - W K Kraft
- Department of Pharmacology and Experimental Therapeutics, Sydney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - J L Farber
- Department of Pathology, Sydney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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27
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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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28
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Establishment of an AUC 0-24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother 2017; 61:AAC.02535-16. [PMID: 28242672 DOI: 10.1128/aac.02535-16] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/16/2017] [Indexed: 12/16/2022] Open
Abstract
Unlike vancomycin trough concentrations, data on the utility of vancomycin pharmacokinetic (PK) parameters, namely, the area under the concentration-time curve from 0 to 24 h (AUC0-24), in predicting acute kidney injury (AKI) are limited. Our aim was to investigate this relationship in patients receiving vancomycin therapy for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B). A single-center retrospective observational cohort study involving 127 consecutive MRSA-B patients was conducted to examine the incidence of AKI (defined as serum creatinine of ≥0.5 mg/liter and a 50% increase from baseline) and vancomycin exposure parameters associated with nephrotoxicity. Bayesian estimation was used to predict individual vancomycin AUC0-24 All patients received vancomycin monotherapy for a minimum of 14 days following the diagnosis of MRSA-B. AKI was observed in 15.7% of patients (20/127). Clinical characteristics were similar between patients with and without AKI. At steady state, higher vancomycin trough concentrations were associated with AKI (17.2 mg/liter versus 13.1 mg/liter; P = 0.003). A vancomycin AUC0-24 threshold for AKI of >563 mg · h/liter was detected by classification and regression tree (CART) analysis; patients with exposures above this threshold were significantly more likely to experience AKI than patients with lower vancomycin exposures (40% [8/20] versus 11.2% [12/107]; P = 0.002). This parameter remained an independent predictor of AKI on multivariate logistic regression (odds ratio [OR], 5.07; 95% confidence interval [CI], 1.57 to 16.29; P = 0.006) and was a better predictor of nephrotoxicity than vancomycin trough concentrations. Overall, AKI is associated with higher vancomycin exposure as measured by AUC0-24 These results suggest that individualized patient dosing may be possible with dose modifications directed toward established pharmacodynamic targets while balancing AKI risks.
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29
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Hirano R, Sakamoto Y, Kitazawa J, Yamamoto S, Tachibana N. Pharmacist-managed dose adjustment feedback using therapeutic drug monitoring of vancomycin was useful for patients with methicillin-resistant Staphylococcus aureus infections: a single institution experience. Infect Drug Resist 2016; 9:243-252. [PMID: 27789965 PMCID: PMC5072573 DOI: 10.2147/idr.s109485] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Vancomycin (VCM) requires dose adjustment based on therapeutic drug monitoring. At Aomori Prefectural Central Hospital, physicians carried out VCM therapeutic drug monitoring based on their experience, because pharmacists did not participate in the dose adjustment. We evaluated the impact of an Antimicrobial Stewardship Program (ASP) on attaining target VCM trough concentrations and pharmacokinetics (PK)/pharmacodynamics (PD) parameters in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. Materials and methods The ASP was introduced in April 2012. We implemented a prospective audit of prescribed VCM dosages and provided feedback based on measured VCM trough concentrations. In a retrospective pre- and postcomparison study from April 2007 to December 2011 (preimplementation) and from April 2012 to December 2014 (postimplementation), 79 patients were treated for MRSA infection with VCM, and trough concentrations were monitored (pre, n=28; post, n=51). In 65 patients (pre, n=15; post, n=50), 24-hour area under the concentration–time curve (AUC 0–24 h)/minimum inhibitory concentration (MIC) ratios were calculated. Results Pharmacist feedback, which included recommendations for changing dose or using alternative anti-MRSA antibiotics, was highly accepted during postimplementation (88%, 29/33). The number of patients with serum VCM concentrations within the therapeutic range (10–20 μg/mL) was significantly higher during postimplementation (84%, 43/51) than during preimplementation (39%, 11/28) (P<0.01). The percentage of patients who attained target PK/PD parameters (AUC 0–24 h/MIC >400) was significantly higher during postimplementation (84%, 42/50) than during preimplementation (53%, 8/15; P=0.013). There were no significant differences in nephrotoxicity or mortality rate. Conclusion Our ASP increased the percentage of patients that attained optimal VCM trough concentrations and PK/PD parameters, which contributed to the appropriate use of VCM in patients with MRSA infections.
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Affiliation(s)
| | - Yuichi Sakamoto
- Laboratory Medicine and Blood Transfusion, Aomori Prefectural Central Hospital, Aomori-shi, Japan
| | - Junichi Kitazawa
- Laboratory Medicine and Blood Transfusion, Aomori Prefectural Central Hospital, Aomori-shi, Japan
| | | | - Naoki Tachibana
- Laboratory Medicine and Blood Transfusion, Aomori Prefectural Central Hospital, Aomori-shi, Japan
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30
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Hale CM, Seabury RW, Steele JM, Darko W, Miller CD. Are Vancomycin Trough Concentrations of 15 to 20 mg/L Associated With Increased Attainment of an AUC/MIC ≥ 400 in Patients With Presumed MRSA Infection? J Pharm Pract 2016; 30:329-335. [PMID: 27074786 DOI: 10.1177/0897190016642692] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE To determine whether there is an association between higher vancomycin trough concentrations and attainment of a calculated area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) ≥400. METHODS A retrospective analysis was conducted among vancomycin-treated adult patients with a positive methicillin-resistant Staphylococcus aureus (MRSA) culture. Attainment of a calculated AUC/MIC ≥400 was compared between patients with troughs in the reference range of 15 to 20 mg/L and those with troughs in the following ranges: <10, 10 to 14.9, and >20 mg/L. Nephrotoxicity was assessed as a secondary outcome based on corrected average vancomycin troughs over 10 days of treatment. RESULTS Overall, 226 patients were reviewed and 100 included. Relative to troughs ≥10, patients with vancomycin troughs <10 mg/L were 73% less likely to attain an AUC/MIC ≥400 (odds ratio [OR] 0.27, 95% confidence interval [CI]: 0.01-0.75). No difference was found in the attainment of an AUC/MIC ≥400 in patients with troughs of 10 to 14.9 mg/L and >20 mg/L when compared to patients with troughs of 15 to 20 mg/L. The mean corrected average vancomycin trough was higher in patients developing nephrotoxicity compared to those who did not (19.5 vs 14.5 mg/L, P < .001). CONCLUSION Achieving vancomycin serum trough concentrations of 15 to 20 mg/L did not result in an increased attainment of the AUC/MIC target relative to troughs of 10 to 14.9 mg/L but may increase nephrotoxicity risk.
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Affiliation(s)
- Cory M Hale
- 1 Department of Pharmacy, Upstate University Hospital, Syracuse, New York, NY, USA
| | - Robert W Seabury
- 1 Department of Pharmacy, Upstate University Hospital, Syracuse, New York, NY, USA
| | - Jeffrey M Steele
- 1 Department of Pharmacy, Upstate University Hospital, Syracuse, New York, NY, USA.,2 Department of Medicine, Upstate Medical University, Syracuse, New York, NY, USA
| | - William Darko
- 1 Department of Pharmacy, Upstate University Hospital, Syracuse, New York, NY, USA.,2 Department of Medicine, Upstate Medical University, Syracuse, New York, NY, USA
| | - Christopher D Miller
- 1 Department of Pharmacy, Upstate University Hospital, Syracuse, New York, NY, USA.,2 Department of Medicine, Upstate Medical University, Syracuse, New York, NY, USA
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31
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Association between the AUC0-24/MIC Ratio of Vancomycin and Its Clinical Effectiveness: A Systematic Review and Meta-Analysis. PLoS One 2016. [PMID: 26731739 DOI: 10.1371/journal.pone.0146224.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND A target AUC0-24/MIC ratio of 400 has been associated with its clinical success when treating Staphylococcus aureus infections but is not currently supported by state-of-the-art evidence-based research. OBJECTIVE This current systematic review aimed to evaluate the available evidence for the association between the AUC0-24/MIC ratio of vancomycin and its clinical effectiveness on hospitalized patients and to confirm the existing target value of 400. METHODS PubMed, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, CBM) were systematically searched. Manual searching was also applied. Both RCTs and observational studies comparing the clinical outcomes of high AUC0-24/MIC groups versus low AUC0-24/MIC groups were eligible. Two reviewers independently extracted the data. The primary outcomes were mortality and infection treatment failure. Risk ratios (RRs) with 95% confidence intervals (95%CIs) were calculated. RESULTS No RCTs were retrieved. Nine cohort studies were included in the meta-analysis. Mortality rates were significantly lower in high AUC0-24/MIC groups (RR = 0.47, 95%CI = 0.31-0.70, p<0.001). The rates of infection treatment failure were also significantly lower in high AUC/MIC groups and were consistent after correcting for heterogeneity (RR = 0.39, 95%CI = 0.28-0.55, p = 0.001). Subgroup analyses showed that results were consistent whether MIC values were determined by broth microdilution (BMD) method or Etest method. In studies using the BMD method, breakpoints of AUC0-24/MIC all fell within 85% to 115% of 400. CONCLUSIONS This meta-analysis demonstrated that achieving a high AUC0-24/MIC of vancomycin could significantly decrease mortality rates by 53% and rates of infection treatment failure by 61%, with 400 being a reasonable target.
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Men P, Li HB, Zhai SD, Zhao RS. Association between the AUC0-24/MIC Ratio of Vancomycin and Its Clinical Effectiveness: A Systematic Review and Meta-Analysis. PLoS One 2016; 11:e0146224. [PMID: 26731739 PMCID: PMC4701440 DOI: 10.1371/journal.pone.0146224] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 12/15/2015] [Indexed: 01/21/2023] Open
Abstract
Background A target AUC0-24/MIC ratio of 400 has been associated with its clinical success when treating Staphylococcus aureus infections but is not currently supported by state-of-the-art evidence-based research. Objective This current systematic review aimed to evaluate the available evidence for the association between the AUC0-24/MIC ratio of vancomycin and its clinical effectiveness on hospitalized patients and to confirm the existing target value of 400. Methods PubMed, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, CBM) were systematically searched. Manual searching was also applied. Both RCTs and observational studies comparing the clinical outcomes of high AUC0-24/MIC groups versus low AUC0-24/MIC groups were eligible. Two reviewers independently extracted the data. The primary outcomes were mortality and infection treatment failure. Risk ratios (RRs) with 95% confidence intervals (95%CIs) were calculated. Results No RCTs were retrieved. Nine cohort studies were included in the meta-analysis. Mortality rates were significantly lower in high AUC0-24/MIC groups (RR = 0.47, 95%CI = 0.31–0.70, p<0.001). The rates of infection treatment failure were also significantly lower in high AUC/MIC groups and were consistent after correcting for heterogeneity (RR = 0.39, 95%CI = 0.28–0.55, p = 0.001). Subgroup analyses showed that results were consistent whether MIC values were determined by broth microdilution (BMD) method or Etest method. In studies using the BMD method, breakpoints of AUC0-24/MIC all fell within 85% to 115% of 400. Conclusions This meta-analysis demonstrated that achieving a high AUC0-24/MIC of vancomycin could significantly decrease mortality rates by 53% and rates of infection treatment failure by 61%, with 400 being a reasonable target.
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Affiliation(s)
- Peng Men
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Hui-Bo Li
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Suo-Di Zhai
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- * E-mail:
| | - Rong-Sheng Zhao
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
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Prybylski JP. Vancomycin Trough Concentration as a Predictor of Clinical Outcomes in Patients withStaphylococcus aureusBacteremia: A Meta-analysis of Observational Studies. Pharmacotherapy 2015; 35:889-98. [DOI: 10.1002/phar.1638] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Impact of area under the concentration-time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia. Int J Antimicrob Agents 2015; 46:689-95. [PMID: 26555059 DOI: 10.1016/j.ijantimicag.2015.09.010] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 09/15/2015] [Accepted: 09/18/2015] [Indexed: 12/20/2022]
Abstract
There have been few clinical studies on the association between the vancomycin 24-h area under the concentration-time curve (AUC24) to minimum inhibitory concentration (MIC) ratio and vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus (MRSA) infections. To examine this association and to establish a suitable cut-off value for AUC24/MIC, a multicentre prospective observational study was conducted in patients with MRSA bacteraemia. Data were collected on all patients aged ≥18 years with MRSA bacteraemia treated with vancomycin for ≥72 h without dialysis. The MIC was determined by broth microdilution (BMD) and Etest. Treatment failure was defined as (i) 30-day mortality, (ii) persistent bacteraemia (≥7 days) and (iii) recurrence (≤30 days after completion of therapy). AUC24 was estimated by a Bayesian approach based on individual vancomycin concentrations. The AUC24/MIC cut-off value for differentiating treatment success and failure was calculated by Classification and Regression Tree (CART) analysis. In total, 117 patients were enrolled, among which vancomycin treatment failure occurred in 38 (32.5%). In univariate analysis, high vancomycin MIC and low trough levels were unrelated to treatment outcomes. In the CART analysis, low vancomycin AUC24/MIC [<392.7 (BMD) and <397.2 (Etest)] was associated with treatment failure. In multivariate analysis, low AUC24/MIC was a risk factor for treatment failure [adjusted odds ratio (aOR)=3.50, 95% confidence interval (CI) 1.39-8.82 by BMD; aOR=5.61, 95% CI 2.07-15.24 by Etest]. AUC24/MIC is associated with vancomycin treatment outcomes in MRSA bacteraemia, and seeking individualised AUC24/MIC ratios above target (>400) may improve treatment outcomes.
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Shoji H, Maeda M, Shirakura T, Takuma T, Ugajin K, Fukuchi K, Ishino K, Niki Y. More accurate measurement of vancomycin minimum inhibitory concentration indicates poor outcomes in meticillin-resistant Staphylococcus aureus bacteraemia. Int J Antimicrob Agents 2015; 46:532-7. [PMID: 26364848 DOI: 10.1016/j.ijantimicag.2015.07.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 07/14/2015] [Accepted: 07/19/2015] [Indexed: 02/04/2023]
Abstract
Meticillin-resistant Staphylococcus aureus (MRSA) is an important pathogen associated with community-acquired and nosocomial infections. The aim of this study was to validate the vancomycin (VAN) minimum inhibitory concentration (MIC) and administration of VAN that may affect the prognosis of patients with MRSA bacteraemia. In total, 140 clinical MRSA strains from blood cultures were collected from January 2009 to December 2013 at a university hospital in Tokyo (Japan). Patient background, their clinical situation and the susceptibility of isolates to anti-MRSA agents in all cases were reviewed, and factors contributing to 30-day mortality were analysed. Susceptibility to anti-MRSA agents was measured by a microdilution susceptibility testing method. The VAN MIC was further evaluated at 0.25 μg/mL intervals from 0.5 μg/mL to 2.0 μg/mL. Multiple logistic regression analysis revealed a 4-fold increase in mortality of patients with a VAN MIC ≥1.5 μg/mL [odds ratio (OR)=3.952, 95% confidence interval (CI) 1.471-10.614; P=0.006]. A one-score increase in the Charlson co-morbidity index resulted in a 1.2-fold increase in the risk of death (OR=1.199, 95% CI 1.054-1.364; P=0.006). However, no significant difference was found in the ratio of the VAN 24-h area under the concentration-time curve to MIC between VAN MIC ≥1.5 μg/mL and <1.5 μg/mL. A significant increase in the MICs of teicoplanin and daptomycin was observed in strains with high VAN MICs. For patients with high VAN MICs, administration of these anti-MRSA antibiotics may have a poor outcome owing to cross-resistance.
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Affiliation(s)
- Hisashi Shoji
- Division of Clinical Infectious Diseases, Department of Medicine, School of Medicine, Showa University, 1-4-5 Hatanodai, Shinagawa, Tokyo 142-0064, Japan.
| | - Masayuki Maeda
- Division of Infection Control Sciences, Department of Pharmacotherapeutics, School of Pharmacy, Showa University, 1-4-5 Hatanodai, Shinagawa, Tokyo, Japan
| | - Tetsuro Shirakura
- Department of Microbiology, School of Medicine, Showa University, 1-4-5 Hatanodai, Shinagawa, Tokyo, Japan
| | - Takahiro Takuma
- Division of Clinical Infectious Diseases, Department of Medicine, School of Medicine, Showa University, 1-4-5 Hatanodai, Shinagawa, Tokyo 142-0064, Japan
| | - Kazuhisa Ugajin
- Showa University Hospital, 1-4-5 Hatanodai, Shinagawa, Tokyo, Japan
| | - Kunihiko Fukuchi
- Showa University, Graduate School, 1-4-5 Hatanodai, Shinagawa, Tokyo, Japan
| | - Keiko Ishino
- Division of Infection Control Sciences, Department of Pharmacotherapeutics, School of Pharmacy, Showa University, 1-4-5 Hatanodai, Shinagawa, Tokyo, Japan
| | - Yoshihito Niki
- Division of Clinical Infectious Diseases, Department of Medicine, School of Medicine, Showa University, 1-4-5 Hatanodai, Shinagawa, Tokyo 142-0064, Japan
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Morales-Cartagena A, Lalueza A, López-Medrano F, Juan RS, Aguado JM. Treatment of methicillin-resistant Staphylococcus aureus infections: Importance of high vancomycin minumum inhibitory concentrations. World J Clin Infect Dis 2015; 5:14-29. [DOI: 10.5495/wjcid.v5.i2.14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 10/30/2014] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
Staphylococcus aureus (SA) infections remain a major cause of morbidity and mortality despite the availability of numerous effective anti-staphylococcal antibiotics. This organism is responsible for both nosocomial and community-acquired infections ranging from relatively minor skin and soft tissue infections to life-threatening systemic infections. The increasing incidence of methicillin-resistant strains has granted an increasing use of vancomycin causing a covert progressive increase of its minimum inhibitory concentration (MIC) (dubbed the MIC “creep”). In this way, the emergence of vancomycin-intermediate SA (VISA) strains and heteroresistant-VISA has raised concern for the scarcity of alternative treatment options. Equally alarming, though fortunately less frequent, is the emergence of vancomycin-resistant SA. These strains show different mechanisms of resistance but have similar problems in terms of therapeutic approach. Ultimately, various debate issues have arisen regarding the emergence of SA strains with a minimum inhibitory concentration sitting on the superior limit of the sensitivity range (i.e., MIC = 2 μg/mL). These strains have shown certain resilience to vancomycin and a different clinical behaviour regardless of vancomycin use, both in methicillin-resistant SA and in methicillin-sensitive SA. The aim of this text is to revise the clinical impact and consequences of the emergence of reduced vancomycin susceptibility SA strains, and the different optimal treatment options known.
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Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis. Antimicrob Agents Chemother 2015; 59:2978-85. [PMID: 25753631 DOI: 10.1128/aac.03970-14] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 03/01/2015] [Indexed: 11/20/2022] Open
Abstract
Given the critical importance of early appropriate therapy, a retrospective cohort (2002 to 2013) was performed at the Detroit Medical Center to evaluate the association between the day 1 vancomycin exposure profile and outcomes among patients with MRSA infective endocarditis (IE). The day 1 vancomycin area under the concentration-time curve (AUC0-24) and the minimum concentration at 24 h (Cmin 24) was estimated for each patient using the Bayesian procedure in ADAPT 5, an approach shown to accurately predict the vancomycin exposure with low bias and high precision with limited pharmacokinetic sampling. Initial MRSA isolates were collected and vancomycin MIC was determined by broth microdilution (BMD) and Etest. The primary outcome was failure, defined as persistent bacteremia (≥7 days) or 30-day attributable mortality. Classification and regression tree analysis (CART) was used to determine the vancomycin exposure variables associated with an increased probability of failure. In total, 139 patients met study criteria; 76.3% had right-sided IE, 16.5% had left-sided IE, and 7.2% had both left and right-sided IE. A total of 89/139 (64%) experienced failure by composite definition. In the CART analysis, failure was more pronounced in patients with an AUC0-24/MIC as determined by BMD of ≤600 relative to those with AUC0-24/MIC as determined by BMD of >600 (69.8% versus 54.7%, respectively, P = 0.073). In the logistic regression analysis, an AUC/MIC as determined by BMD of ≤600 (adjusted odds ratio, 2.3; 95% confidence interval, 1.01 to 5.37; P = 0.047) was independently associated with failure. Given the retrospective nature of the present study, further prospective studies are required but these data suggest that patients with an AUC0-24/MIC as determined by BMD of ≤600 present an increased risk of failure.
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