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Study Objective: To compare rates of nephrotoxicity, time to nephrotoxicity onset, and clinical failure among patients who received continuous infusion (C-I) or intermittent infusion (I-I) vancomycin in an outpatient parenteral antimicrobial therapy (OPAT) program. Nephrotoxicity was defined as an increase in serum creatinine greater than 0.5 mg/dl or a 50% increase from baseline for two consecutive measurements while receiving vancomycin during OPAT. Clinical failure was defined as unplanned readmission, extension of therapy, or change in antibiotics., Design: Single-center propensity score-matched retrospective cohort study., Setting: OPAT clinic affiliated with two nearby hospitals., Patients: We identified 300 patients who received C-I or I-I vancomycin for at least 1 week in the OPAT program between October 1, 2017, and March 31, 2019. Propensity score matching based on age, sex, and infection was performed to minimize differences in patient characteristics between groups., Measurements and Main Results: After propensity score matching and exclusion criteria, 74 patients were included in each cohort. Continuous infusion vancomycin was associated with a 3.22-fold decrease in nephrotoxicity risk (C-I 6.8% [5/74 patients] vs I-I 18.9% [14/74 patients]; odds ratio 3.22, 95% confidence interval 1.10-9.46, p=0.027) and a significantly slower onset to nephrotoxicity compared with I-I (p=0.035). No statistically significant difference in clinical failure rates was observed between the C-I and I-I groups (13.5% [10/74 patients] vs 23.0% [17/74 patients], p=0.147)., Conclusion: In an OPAT setting, C-I vancomycin was associated with a lower risk of and slower onset to nephrotoxicity than I-I vancomycin; however, no statistically significant difference in clinical failure rates was observed with C-I versus I-I vancomycin., (© 2020 Pharmacotherapy Publications, Inc.)

An area‐under‐the‐curve (AUC24)‐based approach is recommended to guide vancomycin therapeutic drug monitoring (TDM), yet trough concentrations are still commonly used despite associated risks. A definitive toxicity target is lacking, which is important for hematology patients who have a higher risk of nephrotoxicity. The aims were to (1) assess the impact of trough‐based TDM on acute kidney injury (AKI) incidence, (2) establish a vancomycin nephrotoxicity threshold, and (3) evaluate the proportion of hematology patients achieving vancomycin therapeutic targets. Retrospective data was collected from 100 adult patients with a hematological malignancy or aplastic anemia who received vancomycin between April 2020 and January 2021. AKI occurrence was determined based on serum creatinine concentrations, and individual pharmacokinetic parameters were estimated using a Bayesian approach. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of pharmacokinetic indices to predict AKI occurrence. The proportion of patients who achieved target vancomycin exposure was evaluated based on an AUC24/MIC ≥400 and the determined toxicity threshold. The incidence of AKI was 37%. ROC curve analysis indicated a maximum AUC24 of 644 mg.h/L over the treatment period was an important predictor of AKI. By Day 4 of treatment, 29% of treatment courses had supratherapeutic vancomycin exposure, with only 62% of courses achieving AUC24 targets. The identified toxicity threshold supports an AUC24 target range of 400–650 mg.h/L, assuming an MIC of 1 mg/L, to optimize vancomycin efficacy and minimize toxicity. This study highlights high rates of AKI in this population and emphasizes the importance of transitioning from trough‐based TDM to an AUC‐based approach to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Aims: Evidence on the optimal targets of vancomycin for treating other Gram-positive infections apart from methicillin-resistant Staphylococcus aureus (MRSA) is lacking. This review aims to identify the recommended vancomycin therapeutic level for favourable clinical outcomes among patients infected with vancomycin-sensitive enterococcal infections., Methods: Analytical studies describing the vancomycin levels of vancomycin-sensitive enterococcal infections among adult population were searched. The primary outcome was 30-day all-cause mortality, and the secondary outcomes were clinical failure and nephrotoxicity. Study characteristics were extracted and pooled using random-effects meta-analysis. The study quality was assessed using the Joanna Briggs Institute critical appraisal tool., Results: A total of nine retrospective cohorts studies involving 1013 patients with vancomycin-sensitive enterococci were included. The meta-analysis found that high area under the curve to minimum inhibitory concentration ratio (AUC/MIC) of vancomycin ≥ 389 mg*h/L significantly lowered the 30-day mortality (odds ratio [OR], 0.44, 95% confidence interval [CI], 0.26-0.75). Analysis of the target AUC/MIC showed that high vancomycin AUC/MIC (≥ 389-400 mg*h/L) significantly reduced clinical failure rate (OR 0.59, 95% CI 0.37-0.94). The mortality and treatment failure rates did not differ significantly between those with high or low trough levels. Higher vancomycin AUC/MIC and trough levels were significantly associated with increased nephrotoxicity (OR 3.11, 95% CI 1.65-5.89; OR 2.95, 95% CI 1.60-5.44, respectively)., Conclusions: The use of a higher vancomycin AUC/MIC concentration can be effective to reduce 30-day mortality and clinical failure but this needs to take into consideration the risk of nephrotoxicity. Well-conducted prospective studies are warranted due to the scarcity of evidence., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The 2023 ACCP Research Affairs Committee was charged with developing a commentary to address best practices in pharmacy resident research and quality improvement projects and to consider methods to overcome the challenges encountered in conducting these projects. Literature regarding best practices was evaluated, and approaches were recommended that might help (1) advance the value of the projects to stakeholders; (2) overcome limited preparation for research by residents and mentors, including writing skills and dissemination experience; (3) overcome challenges related to resources (e.g., time and mentors); and (4) avoid burnout among residents and mentors. Although there are many challenges to completing projects and disseminating the results, studies have provided useful recommendations to help circumvent the barriers. [ABSTRACT FROM AUTHOR]

Study Objective: The aim of this study was to compare the achievement of therapeutic pharmacokinetic–pharmacodynamic (PK‐PD) exposure targets for beta‐lactam antibiotics using product information dosing or guideline‐based dosing for the treatment of serious infections. Design: In silico study. Data Source: ID‐ODSTM (Individually Designed Optimum Dosing Strategies). Patients and Intervention: None. Measurements and Main Results: In silico product information and guideline‐based dosing simulations for cefepime, ceftazidime, flucloxacillin, meropenem, and piperacillin/tazobactam were performed using pharmacokinetic models from seriously ill patient populations. The median simulated concentration at 48 and 96 h was used to measure the probability of target attainment (PTA) to achieve predefined therapeutic and toxicity PK‐PD targets. A multiple linear regression model was constructed to identify the effect of guideline‐based dosing covariates on achieving pre‐defined therapeutic targets. In total, 480 dosing simulations were performed. The PTA percentage with guideline‐based dosing at 48 and 96 h was 80% and 68%, respectively, yielding significantly higher results when compared to product information dosing (48.45% and 49%, respectively), p < 0.001 at both time points. At 48 h, predefined toxicity thresholds were exceeded in 4.7% and 0% of simulations for guideline‐based and product information‐based dosing, respectively (p = 0.002). eGFR was significantly associated with the % PTA by guideline‐based dosing, with eGFR values of 20 and 50 ml/min both statistically significant in leading to an increase in PTA. Conclusions: Our study demonstrated that achievement of PK‐PD exposures associated with an increased likelihood of effectiveness was more likely to occur with guideline‐based dosing; especially at 48 h. [ABSTRACT FROM AUTHOR]

Beta‐lactam therapeutic drug monitoring (TDM) can improve precision dosing and clinical outcomes in critically ill patients, but has not been implemented widely in the United States. Mayo Clinic recently implemented a beta‐lactam TDM program. This single‐center experience forms the basis of the manuscript which outlines practical considerations involved with beta‐lactam TDM implementation, including the pharmacist's role as a leader. Our implementation effort focused on three primary domains. First, we aimed to ensure a supportive organizational infrastructure. Early leadership engagement by the pharmacist‐led core team facilitated advocacy for the clinical need, allocation of resources, and assay development. Second, core clinical workflows were developed that addressed the preferred patient population for use, desirable pharmacokinetic and pharmacodynamic targets, and the preferred sampling strategy. Clinical tools to guide pharmacists in interpreting the results (e.g., pharmacokinetics calculator) and documenting decisions were developed. Third, stakeholders were offered repeated exposure to evidence and expertise to facilitate understanding and application of the new practice. This act of 'individual internalization' seems to be uniquely important to beta‐lactam TDM implementation compared with the implementation of other antimicrobial TDM programs. Educational strategies and supportive materials that were developed were focused on providing substantive and varied information tailored to the stakeholders' role in the process. For pharmacists, this included both clinical and operational considerations. A continuous improvement plan to support management of the process was instituted to address necessary updates and changes that inevitably emerged. In summary, the described approach to implementation of a pharmacist‐led beta‐lactam TDM program could be used as a roadmap to aid other institutions that aim to develop such a program. [ABSTRACT FROM AUTHOR]

Dose‐prediction software is recommended to enable area under the curve over 24 h (AUC24)‐guided dosing of the antibiotic vancomycin. However, uncertainty remains about how best to implement software in the clinic. We describe the activity, over 18 months, of a consultative therapeutic drug monitoring Advisory Service (the Service) for vancomycin that used dose‐prediction software alongside clinical expertise, identifying factors that influence attainment of therapeutic targets. Of the 408 vancomycin dose reports provided for 182 courses of therapy, most (57%) recommended a dose change. The majority (82.8%, 193/233) of recommended dose adjustments were accepted by treating teams. A dose report was not published for 125 courses of therapy, with reasons including patient in intensive care unit or service error. An estimated 26.6 h of staff time was allocated to Service activities each month. Publication of a dose report facilitated attainment of therapeutic targets (P =.002). Software integration could improve Service outcomes, avoiding errors and reducing staff workload. [ABSTRACT FROM AUTHOR]

Previous meta-analyses assessed andexanet alfa (AA) or prothrombin complex concentrate (PCC) products for the treatment of Factor Xa inhibitor (FXaI)-associated major bleeding. However, they did not include recent studies or assess the impact of the risk of bias. We conducted a systematic review with meta-analysis on the effectiveness of AA versus PCC products for FXaI-associated major bleeding, inclusive of the studies' risk of bias. PubMed and Embase were searched for comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. We used the Methodological Index for NOn-Randomized Studies (MINORS) checklist and one question from the Joanna Briggs Institute (JBI) Critical Appraisal of Case Series tool to assess the risk of bias. Random-effects meta-analyses were performed to provide a pooled estimate for the effect of AA versus PCC products on hemostatic efficacy, in-hospital mortality, 30-day mortality, and thrombotic events. Low-moderate risk of bias studies were meta-analyzed separately, as well as combined with high risk of bias studies. Eighteen comparative evaluations of AA versus PCC were identified. Twenty-eight percent of the studies (n = 5) had low-moderate risk and 72% (n = 13) had a high risk of bias. Studies with low-moderate risk of bias suggested improvements in hemostatic efficacy [Odds Ratio (OR) 2.72 (95% Confidence Interval (CI): 1.15-6.44); one study], lower in-hospital mortality [OR 0.48 (95% CI: 0.38-0.61); three studies], and reduced 30-day mortality [OR 0.49 (95% CI: 0.30-0.80); two studies] when AA was used versus PCC products. When studies were included regardless of the risk of bias, pooled effects showed improvements in hemostatic efficacy [OR 1.36 (95% CI: 1.01-1.84); 12 studies] and reductions in 30-day mortality [OR 0.53 (95% CI: 0.37-0.76); six studies] for AA versus PCC. The difference in thrombotic events with AA versus PCC was not statistically significant in the low-moderate, high, or combined risk of bias groups. The evidence from low-moderate quality real-world studies suggests that AA is superior to PCC in enhancing hemostatic efficacy and reducing in-hospital and 30-day mortality. When studies are assessed regardless of the risk of bias, the pooled hemostatic efficacy and 30-day mortality risk remain significantly better with AA versus PCC., (© 2024 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Background: The physical intravenous Y‐site compatibility of 15 different medications with highly concentrated neonatal and pediatric parenteral nutrition (PN) compounds is described, using existing and novel methods. Methods: PN formulations were developed based on common prescribing practices in a 400+‐bed freestanding children's hospital. Medications at commonly used pediatric concentrations were mixed in a 1:1 ratio with both pediatric and neonatal PN formulations and incubated at room temperature for 4 h to simulate Y‐site administration. Samples were then analyzed using the light obscuration (LO) technique, as recommended by United States Pharmacopeia (USP) chapter <788>, in addition to novel flow imaging (FI) microscopy and backgrounded membrane imaging (BMI). Physical compatibility was determined using USP <788> particle count limits for all techniques. Results: Most combinations were found to be compatible per USP <788> thresholds. Pediatric PN was incompatible by at least two methods with cisatracurium 2 mg/ml, sildenafil 0.8 mg/ml, furosemide 10 mg/ml, and ketamine 10 mg/ml. Neonatal PN was incompatible by at least two methods with cisatracurium 2 mg/ml and furosemide 10 mg/ml. Overall, results for 20 of the 30 combinations (66%) agreed across all three methods. FI and BMI results agreed for 22 of 30 combinations. LO agreed with FI in 25 of 30 combinations, and BMI and LO results agreed in 23 of 30 combinations. Conclusion: Most combinations tested were found to be compatible across all methods. Novel methods of FI and BMI seem useful to further evaluate LO findings and improve accuracy of particle counts when assessing PN‐medication combinations. [ABSTRACT FROM AUTHOR]

The current recommendation for therapeutic monitoring of vancomycin has recently suggested AUC-guided dosing in patients with serious methicillin-resistant Staphylococcus aureus infections. The study objective was to evaluate mathematical equations and trapezoidal methods for calculating the 24h area under the plasma vancomycin concentration-time curve (AUC24). The analysis of plasma vancomycin concentrations was performed in 20 adult patients treated with intravenous vancomycin. For each patient, AUC24 was estimated using two methods including, equation and trapezoidal calculation. The AUC24 from two methods was analyzed for correlation. The correlation between the equation and trapezoidal methods was strong. The coefficient of determination (R²) values was greater than .99. The two plasma vancomycin concentrations to achieve the highest correlation were concentration at 2.5 to 3 h after starting the infusion and concentration at 1 h before the next dose. Moreover, the AUC24 calculation from trapezoidal and equation methods showed that 19 out of 20 patients (95%) had AUC24 of more than 400mg-h/L, and more than 50% in this group had AUC24/MIC greater than 600. Of those patients with AUC-trapezoidal >600, 15.38% of patients had trough under 15mg/L, 15.38% of patients had trough in the range 15 to 20mg/L and 69.23% of patients had trough more than 20mg/L. The results of AUC-equation were similar to those of the AUC-trapezoidal method. Our study confirmed that the AUC monitoring is more appropriate than the trough vancomycin concentration. Given these considerations, the AUC-equation method is better and more practical to use in part of a point-of-care treatment, especially in the part of the Bayesian program is not available. The best sampling time point of the peak concentration was 0.5-1 h after 2-h infusion. [ABSTRACT FROM AUTHOR]

Study Objective: The preferred antibiotic salvage regimen for persistent methicillin‐resistant Staphylococcus aureus bacteremia (MRSAB) is unclear. We sought to evaluate the effectiveness and safety of vancomycin plus ceftaroline for persistent MRSAB. The primary outcome was time to MRSAB clearance post‐ceftaroline initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90‐day readmission for MRSAB, 90‐day all‐cause mortality, MRSAB‐related mortality, and incidence of antibiotic‐associated adverse effects. Design: Single‐center, retrospective cohort study between January 1, 2016, and December 31, 2021. Setting: State University of New York Upstate University Hospital, a 748‐bed tertiary care, academic medical center in Syracuse, NY. Patients Adult patients were included if they had blood cultures positive for MRSA ≥72 h, received vancomycin monotherapy initially, and received vancomycin plus ceftaroline for ≥24 h. Patients were excluded if they received other anti‐MRSA antibiotics, were pregnant, or were incarcerated. Of the 178 patients identified, 30 unique patients were evaluated. Measurements and Main Results: Patients were medically complex with a median Pitt bacteremia score of 3, 63.3% (19/30) were admitted to the intensive care unit, and 66.7% (20/30) had infective endocarditis. Vancomycin‐associated acute kidney injury was observed in 10% (3/30) of patients, which resulted in dose adjustments. No patients experienced ceftaroline‐associated neutropenia or Clostridioides difficile infection, but 6.7% (2/30) developed a rash attributed to ceftaroline. Median time to MRSAB clearance post‐ceftaroline initiation was 2.6 days. Microbiologic cure occurred in nearly all patients 96.7% (29/30). Median hospital length of stay was 19.5 days, and 6.7% (2/30) of patients had 90‐day readmission for MRSAB. 90‐day all‐cause mortality and MRSAB‐related mortality occurred in 26.7% (8/30) and 13.3% (4/30) of patients, respectively. Conclusions: Vancomycin plus ceftaroline may represent an effective and well‐tolerated salvage regimen option for persistent MRSAB. [ABSTRACT FROM AUTHOR]

The most recent consensus guidelines for dosing and monitoring vancomycin recommended the use of area‐under‐the‐curve with Bayesian estimation for therapeutic monitoring. As this is a modern concept in the practice of clinical pharmacy, the main objective of this review is to introduce the fundamentals of Bayesian estimation and its mathematical application as it relates to vancomycin therapeutic drug monitoring. In addition, we aim to identify pharmacokinetic (PK) software programs that incorporate Bayesian estimation for vancomycin dosing and to describe the PK models utilized in those software programs for the adult population. Twelve software programs that utilize Bayesian estimation were identified, which included: Adult and Pediatric Kinetics, Best Dose, ClinCalc, DoseMeRx, ID‐ODS, InsightRx, MwPharm++, NextDose, PrecisePK, TDMx, Tucuxi, and VancoCalc. The software programs varied in the population PK models used as the Bayesian a priori. With the presence of various vancomycin Bayesian software programs, it is important to choose those that utilize PK models reflective of the specific patient population. [ABSTRACT FROM AUTHOR]

What Is Known and Objective: Current vancomycin monitoring guidelines recommend the use of area under the concentration‐time curve (AUC24) monitoring in patients with serious Methicillin‐Resistant Staphylococcus aureus (MRSA) infections by utilizing either a Bayesian approach or first‐order analytic equations. Several open‐access websites exist that allow estimation of vancomycin AUC24 with the use of a single steady‐state concentration. It is uncertain how these open‐access calculators perform against guideline‐recommended methods. The objective was to compare AUC24 estimates from two online, open‐access, single‐concentration vancomycin calculators compared with the two‐point pharmacokinetic (2PK) method. Methods: AUC24 estimates were made using the 2PK reference method and the single‐concentration vancomycin calculators, ClinCalc and VancoPK. The AUC24 estimates from the 2PK reference method were compared to the online calculators by assessing bias (median AUC24 difference) and precision (AUC24 difference ± 100 mg*h/L). Clinical precision was also assessed by characterizing the frequency that the 2PK reference method and the online calculators showed clinical disagreement based on the following AUC24 categories: (1) AUC24 < 400 mg*h/L; (2) AUC24 400–600 mg*h/L and (3) AUC24 > 600 mg*h/L. Results and Discussion: A total of 253 patients were included in the study. The AUC24 estimates from the ClinCalc and VancoPK single‐concentration vancomycin calculators showed some bias and imprecision, though VancoPK appeared to have less. Clinical disagreement versus the 2PK reference method occurred in 31.2% and 19.4% of AUC24 estimates from the ClinCalc and VancoPK single‐concentration vancomycin calculators, suggesting clinical imprecision. What Is New and Conclusion: The AUC24 estimates from single‐concentration, online vancomycin calculators showed some bias and imprecision in comparison to the 2PK method. Institutions should validate these online, trough‐only calculators relative to a 2PK method in their patient populations prior to adoption as standard‐of‐care. [ABSTRACT FROM AUTHOR]

Background: Outcomes following andexanet alfa reversal of factor Xa inhibitors in patients requiring urgent or emergent invasive procedures are lacking. This study aimed to describe efficacy and safety outcomes following andexanet alfa administration within 24 h of an invasive procedure. Methods: This single‐center, observational, retrospective study included patients who received andexanet alfa within 24 h of an invasive or surgical procedure. The primary outcome was hemostatic efficacy graded as excellent, good, or poor using similar definitions to the ANNEXA‐4 criteria. Secondary outcomes included hospital discharge disposition, intensive care unit (ICU) and hospital length of stay, 30‐day mortality, 30‐day thromboischemic event rates, and serum coagulation assay changes pre‐ and postreversal. Results: Forty‐four patients met inclusion criteria; of these, 27 (62.8%) received apixaban and 16 (37.2%) were treated with rivaroxaban prior to admission. The indications for reversal were categorized as intracranial (n = 20 [45.5%]) or extracranial (n = 24 [54.5%]) sites. Majority of patients required emergent operative procedures (18 [40.9%]), followed by invasive device placement (10 [22.7%]) or arterial embolization (9 [20.5%]). Thirty‐eight (86.4%) patients were able to be adequately graded for hemostatic efficacy. Overall, 30 (78.9%) patients achieved excellent or good hemostasis within 24 h after periprocedural administration of andexanet alfa (19 [82.6%] apixaban vs. 11 [78.6%] rivaroxaban; 12 [80.0%] intracranial events vs. 18 [78.3%] extracranial events). Discharge disposition was most often to a short‐ or long‐term care facilities (27 [61.4%]). Thirty‐day mortality and thromboischemic complications occurred in 15 (34.1%) and 12 (27.3%) patients, respectively. Prothrombin time and antifactor Xa assay results were significantly decreased after andexanet alfa administration (p < 0.05) while thromboelastogram assay values (reaction time, kinetic time, and activated clotting time) showed nonsignificant changes pre‐ versus postreversal. Conclusion: Andexanet alfa may be used for urgent or emergent reversal of apixaban and rivaroxaban peri‐procedurally with promising hemostatic outcomes. Further prospective, comparative clinical research is warranted. [ABSTRACT FROM AUTHOR]

Several natural antimicrobial peptides (AMPs), including the novel semisynthetic lipoglycopeptide antibiotics telavancin, dalbavancin, and oritavancin, have been approved for clinical use to address the growing problem of multiple antibiotic‐resistant Gram‐positive bacterial infections. Nevertheless, the efficacy of these antibiotics has already been compromised. The SARS‐CoV‐2 pandemic led to the increased clinical use of all antibiotics, further promoting the development of bacterial resistance. Therefore, it is critical to gain a deeper understanding of the role of resistance mechanisms to minimize the consequential risks of long‐term antibiotic use and misuse. Here, we summarize for the first time the current knowledge of resistance mechanisms that have been shown to cause resistance to clinically used AMPs, with particular focus on membrane proteins that have been reported to interfere with the activity of AMPs by affecting the binding of AMPs to bacteria. [ABSTRACT FROM AUTHOR]

The recently released revised vancomycin consensus guideline endorsed area under the concentration‐time curve (AUC) guided monitoring. Means to AUC‐guided monitoring include pharmacokinetic (PK) equations and Bayesian software programs, with the latter approach being preferable. We aimed to evaluate the predictive performance of these two methods when monitoring using troughs or peaks and troughs at varying single or mixed dosing intervals (DIs), and evaluate the significance of satisfying underlying assumptions of steady‐state and model transferability. Methods included developing a vancomycin population PK model and conducting model‐informed precision dosing clinical trial simulations. A one‐compartment PK model with linear elimination, exponential between‐subject variability, and mixed (additive and proportional) residual error model resulted in the best model fit. Conducted simulations demonstrated that Bayesian‐guided AUC can, potentially, outperform that of equation‐based AUC predictions depending on the quality of model diagnostics and met assumptions. Ideally, Bayesian‐guided AUC predictive performance using a trough from the first DI was equivalent to that of PK equations using two measurements (peak and trough) from the fifth DI. Model transferability diagnostics can guide the selection of Bayesian priors but are not strong indicators of predictive performance. Mixed versus single fourth and/or fifth DI sampling seems indifferent. This study illustrated cases associated with the most reliable AUC predictions and showed that only proper Bayesian‐guided monitoring is always faster and more reliable than equations‐guided monitoring in pre‐steady‐state DIs in the absence of a loading dose. This supports rapid Bayesian monitoring using data as sparse and early as a trough at the first DI. [ABSTRACT FROM AUTHOR]

The updated vancomycin guideline and recent studies suggested that trough concentrations may result in underestimation of the actual area under the curve (AUC), leading to excessive dosing and nephrotoxicity. With limited data available on critically ill cancer patients, this study aimed to compare the two methods in this patient population. This was a 5‐year retrospective study on patients treated with vancomycin in the intensive care unit (ICU) of a comprehensive cancer center. The measured trough concentration was compared to Bayesian‐derived AUC/minimum‐inhibitory‐concentration (MIC), considering MIC as 1. Trough concentrations of 15–20 mg/L and AUC of 400–600 mg h/L were considered the targeted goal. Multivariate analysis was performed to identify factors associated with an AUC below the targeted goal. During the study period, 316 patients were included. The mean age was 54 years ±16 (SD); most patients had solid tumors (75%), and 11% had neutropenia. A targeted goal AUC and trough were recorded in 128 (41%) patients and in 64 (20%) patients, respectively. Of the 128 patients with targeted goal AUC, 31 (24%) had targeted goal trough concentrations and 91 (71%) had trough concentrations below 15 mg/L. Furthermore, among the patients with targeted goal trough concentration (n = 64), 33 (52%) had higher than targeted goal AUC. Augmented renal clearance (ARC), defined as a calculated creatinine‐clearance ≥130 ml/min, was associated with an AUC below the targeted goal. In a cohort of critically ill patients with cancer, over two‐thirds of the patients with a targeted goal Bayesian AUC/MIC had trough concentrations below the targeted goal. ARC was associated with AUC below the targeted goal. [ABSTRACT FROM AUTHOR]

Published vancomycin dosing recommendations for patients receiving maintenance hemodialysis were not designed to meet newly recommended 24‐hour area under the curve/minimum inhibitory concentration (AUC24h/MIC) pharmacokinetic/pharmacodynamic targets. The aims of this study were to predict pharmacokinetic/pharmacodynamic target attainment rates with a commonly used vancomycin regimen and to design a new dosing scheme incorporating therapeutic drug monitoring (TDM) to maximize target attainment in patients receiving vancomycin and hemodialysis with high‐ or low‐flux hemodialyzers. Vancomycin pharmacokinetic‐ and dialysis‐specific parameters were incorporated into Monte Carlo simulations (MCS). A commonly used vancomycin regimen was modeled to determine its likelihood of attaining AUC24h/MIC targets for 1 week of thrice‐weekly hemodialysis treatments. MCS was then used to develop optimal initial vancomycin dosing for patients receiving intradialytic or postdialytic vancomycin administration with either high‐ or low‐flux hemodialyzers. Finally, a new MCS model incorporating TDM was built to further optimize the probability of pharmacokinetic/pharmacodynamic target attainment. Traditional vancomycin dosing methods are unlikely to meet AUC24h/MIC targets. Vancomycin doses necessary to attain AUC24h/MIC targets are significantly influenced by hemodialyzer permeability and whether vancomycin is administered intradialytically or after hemodialysis. Depending on dialyzer type and whether vancomycin is administered during or after hemodialysis, loading doses of 25 to 35 mg/kg followed by maintenance doses of 7.5 to 15 mg/kg are necessary to reach minimum AUC24h/MIC targets in 90% of virtual patients. For a 3‐day interdialytic period, a 30% higher maintenance dose is required to maintain target attainment. Dosing based on a single vancomycin serum concentration obtained prior to the second dialysis session greatly enhances the probability of target attainment. [ABSTRACT FROM AUTHOR]

What is known and objective: The influence of venovenous extracorporeal membrane oxygenation (VV‐ECMO) on the population pharmacokinetics (PPK) of vancomycin in recipients after lung transplantation (LTx) is unknown. We investigated whether VV‐ECMO influences vancomycin PPK and determined optimal recommended dosage for patients after LTx. Methods: We tested vancomycin serum concentration and calculated PPK parameters using NONMEM. To check for any potential influence of ECMO on vancomycin PK, we compared ECMO patients with a non‐ECMO patient control group, and patients before and after ECMO weaning as self‐control to analysed changes in vancomycin PK. Monte Carlo dosing simulation was conducted to explore vancomycin dosing regimens. Results: Nineteen ECMO and 6 non‐ECMO lung transplant recipients were enrolled. Vancomycin serum concentrations did not significantly differ between patients with and without ECMO support. Comparison of separate vancomycin population pharmacokinetic models showed that ECMO patients had smaller peripheral compartment volume of distribution (V2) [Estimate (relative standard error, RSE, %) 19.7 (12) vs. 22 (17) L, P =.003] than non‐ECMO patients. For treatment of methicillin‐resistant Staphylococcus aureus (MRSA) infections with MIC ≤ 0.5 µg/mL, venous infusion of 400 mg vancomycin every 8 hours was recommended. For MRSA infection with MIC ≤ 1 µg/mL, the proposed dosage was 600 mg every 8 hours. What is new and conclusion: Venovenous extracorporeal membrane oxygenation slightly alters vancomycin PK but does not significantly impact vancomycin serum concentration in patients after LTx. Dose adjustment is not necessary for VV‐ECMO support. Specific vancomycin dosing regimens with lower nephrotoxicity may benefit LTx recipients with VV‐ECMO. [ABSTRACT FROM AUTHOR]

Background: Deoxycholic acid (DCA) was developed by the pharmaceutical industry for aesthetical use in submental fat reduction. It represents the first lipolytic substance approved by the Food and Drug Administration (FDA) for fat reduction in that area. Aims: This study presents an update of properties and the use of DCA, as well as adverse events and possible complications. Methods: A search in MEDLINE/PubMed, Cochrane, and Bireme/LILACS databases was performed using the terms: "deoxycholic acid" OR "ATX‐101" AND "injection" NOT "amphotericin" NOT "biliary" NOT "bile." Experimental studies developed in animals, clinical trials, literature reviews, case reports, and letters to the editor that included the DCA mechanism of action, dose, manner of use, adverse effects, and complications were selected. Results: The most frequent adverse events are edema, local pain, bruise, and numbness, which usually spontaneously regress. However, complications, including, skin necrosis, nerve injury, alopecia, and vascular events, can occur, demanding complex management without specific protocols. Conclusion: Although DCA is beneficial for lysis of adipose tissue, clinicians should be aware about the adverse effects and risks involved with the use of this substance. The knowledge of local anatomy, properties, and adverse effects are fundamental to treatment with DCA. [ABSTRACT FROM AUTHOR]

Medication management in children and adolescents with obesity is challenging because both developmental and pathophysiological changes may impact drug disposition and response. Evidence to date indicates an effect of obesity on drug disposition for certain drugs used in this population. This work identified published studies evaluating drug dosing, pharmacokinetics (PK), and effect in pediatric patients with obesity, focusing on 70 common medications used in a pediatric network of 42 US medical centers. A PubMed search revealed 33 studies providing PK and/or effectiveness data for 23% (16 of 70) of medications, 44% of which have just one study and can be considered exploratory. This work appraising 4 decades of literature shows several promising approaches: greater use of PK models applied to prospective clinical studies, dosing recommendations derived from both PK and safety, and multiyear effectiveness data on drugs for chronic conditions (e.g., asthma). Most studies make dose recommendations but are weakened by retrospective study design, small study populations, and no controls or historic controls. Dosing decisions continue to rely on extrapolating knowledge, including targeting systemic drug exposure typically achieved in adults. Optimal weight-based dosing strategies vary by drug and warrant prospective, controlled studies incorporating PK and modeling and simulation to complement clinical assessment. [ABSTRACT FROM AUTHOR]

The 24‐hour vancomycin area under the serum concentration‐time curve (AUC24) divided by the minimum inhibitory concentration (MIC) (AUC24/MIC) is more closely related to patient outcomes than serum trough concentrations (Ctrough). Two‐point simplified equations for calculating AUC based on serum peak concentrations (Cpeak) and Ctrough, named equation A (EqA) and equation B (EqB), have recently been adopted into clinical use for adult pediatric patients. We aimed to find the agreement between predicted AUC24 using the reference method (ref) relative to EqA and EqB and the correlation between Ctrough and AUC24. From June to December 2018, 43 pediatric patients with normal renal function, receiving 15 mg/kg of vancomycin intravenously every 6 hours, were enrolled. The pediatric patients' median age was 2.2 years (range 0.1‐15.3). At steady state, vancomycin Cpeak and Ctrough were measured at 2 hours after infusion completion and within 30 minutes before the next dosing, respectively. AUC24 was estimated using ref, EqA, and EqB. From Bland‐Altman analysis, the 2 AUC24s estimated by ref and EqA showed less bias than those estimated by ref and EqB (bias 1.3 and –72.1 mg⋅h/L, respectively). Ctrough and AUC24 using either ref or EqA were correlated more closely (r2 = 0.94) than with EqB (r2 = 0.86). Assuming a vancomycin MIC of 1 mg/L, an AUC24 ≥400 mg⋅h/L was targeted. Regardless of the method used, AUC24 ≥400 mg⋅h/L was never seen with Ctrough <8 mg/L but was always seen with Ctrough >10 mg/L. In conclusion, EqA based on the 2 measured serum concentrations was sufficiently accurate for AUC24 estimation. Ctrough >10 mg/L correlated highly to AUC24 ≥400 mg⋅h/L. [ABSTRACT FROM AUTHOR]

Study Objective: The optimal pharmacodynamic parameter for the prediction of efficacy of vancomycin is the area under the concentration–time curve (AUC), and current published data indicate that dosing based on vancomycin trough concentrations is an inaccurate substitute. In this study, our objective was to compare the achievement of therapeutic target attainment after switching from a trough‐based to an AUC‐based dosing strategy as a part of our institution's vancomycin‐per‐pharmacy protocol. Design: Prospective observational quality assurance study. Setting: Academic medical center. Patients: A total of 296 hospitalized adults who received vancomycin and monitoring under our institution's vancomycin‐per‐pharmacy protocol were included in the analysis. The preimplementation retrospective comparison group consisted of 179 patients in whom vancomycin was initiated using a trough‐based dosing strategy between November 22, 2017, and January 22, 2018. The postimplementation group included 117 patients in whom vancomycin was initiated using an AUC‐based dosing strategy using two‐point sampling between June 19, 2018, and July 19, 2018, after hospital‐wide implementation of this protocol on June 19, 2018. Measurements and Main Results: AUC values were calculated from two vancomycin concentrations (peak and trough). The primary outcome was achievement of therapeutic AUC values (400–800 mg·hr/L) in the postimplementation group or therapeutic trough level values (10–20 mg/L) in the preimplementation group. Only 98 (55%) of 179 initial trough values were therapeutic in the preimplementation group (trough‐only dosing method) versus 86 (73.5%) of 117 initial AUC values in the postimplementation group (AUC‐based dosing method) (p=0.0014). A lower proportion of supratherapeutic AUC values was observed in the postimplementation group compared with supratherapeutic trough concentrations in the preimplementation group (1.7% vs 18%, p<0.0001). Overall, 62% of patients with initially therapeutic AUC values had subsequent trough value increases of 25% or greater, occurring at a median of 6 days of vancomycin therapy. Nephrotoxicity occurred in 11% of patients in the preimplementation versus 9.4% in the postimplementation group (p=0.70). Conclusion: Compared with a trough concentration–based dosing strategy, AUC‐based dosing using two‐point sampling improved therapeutic target attainment. Implementation is feasible at any hospital that performs vancomycin peak concentration testing and is a workable alternative to using Bayesian software for estimating AUC. This approach should also be directly compared with AUC‐based dosing using Bayesian software. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum (PG) is a rare ulcerative skin disease that presents a therapeutic challenge. Tumour necrosis factor alpha (TNFα) inhibitors have been reported to successfully control PG. Our aim was to systematically evaluate and compare the clinical effectiveness of TNFα inhibitors in adults with PG. A literature search including databases such as PubMed, Embase, Scopus, and Web of Science was conducted, using search terms related to PG and TNFα inhibitors. Studies and case reports were included if patients were diagnosed with PG, over the age of 18 and administered TNFα inhibitor. A total of 3212 unique citations were identified resulting in 222 articles describing 356 patients being included in our study. The study we report found an 87% (95% CI: 83%‐90%) response rate and a 67% (95% CI: 62%‐72%) complete response rate to TNFα inhibitors. No statistically significant differences in the response rates (P = 0.6159) or complete response rates (P = 0.0773) to infliximab, adalimumab, and etanercept were found. In our study TNFα inhibitors demonstrated significant effectiveness with response and complete response rates supporting the use of TNFα inhibitors to treat PG in adults. Our study suggests that there is no significant difference in effectiveness among infliximab, adalimumab, and etanercept. [ABSTRACT FROM AUTHOR]

Aims: The 2019 update to the US consensus guideline for vancomycin therapeutic monitoring advocates using Bayesian-guided personalised dosing to maximise efficacy and minimise toxicity of vancomycin. We conducted an observational cohort study of the implementation of bed-side Bayesian-guided vancomycin dosing in vascular surgery patients., Methods: Over a 9-month prospective study period, vascular surgery patients were dosed vancomycin using Bayesian-guided dosing decision tool (DoseMeRx) and compared retrospectively with a control group admitted to the same ward in the 14 months prior to the study and dosed using a standard algorithmic approach. Primary endpoints were proportion of patients achieving mean area under the curve in 24 hours (AUC 24 ) in the acceptable range 350-450 mg/L• h and percentage time in acceptable range (%TTR). Secondary endpoints focused on clinical outcomes including incidence of acute kidney injury., Results: A significantly higher proportion of DoseMeRx patients achieved mean AUC 24 values in the acceptable range compared to the control group; 71/104 (68.3%) vs 58/139 (41.7%), P < .005. The median %TTR was also greater in DoseMeRx patients compared to the control group (57.1 vs 30.0%, P < .00001). Patients in the DoseMeRx group missed an average of 0.23 doses per course compared to 1.04 doses in the control group (P < .00001). No difference was observed in secondary (clinical) outcomes between the 2 groups., Conclusion: Bedside Bayesian-guided personalised dosing of vancomycin increases the proportion of patients achieving target AUC 24 and the %TTR., (© 2020 The British Pharmacological Society.)

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the epidemiology, diagnosis, prevention, and management of methicillin‐resistant Staphylococcus aureus (MRSA) infections in solid organ transplantation. Despite an increasing armamentarium of antimicrobials active against MRSA, improved diagnostic tools, and overall declining rates of infection, MRSA infections remain a substantial cause of morbidity and mortality in solid organ transplant recipients. Pre‐ and post‐transplant MRSA colonization is a significant risk factor for post‐transplant MRSA infection. The preferred initial treatment of MRSA bacteremia remains vancomycin. Hand hygiene, chlorhexidine bathing in the ICU, central‐line bundles that focus on reducing unnecessary catheter use, disinfection of patient equipment, and the environment along with antimicrobial stewardship are all aspects of an infection prevention approach to prevent MRSA transmission and decrease healthcare‐associated infections. [ABSTRACT FROM AUTHOR]