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Objective: Andexanet alfa is approved for the reversal of life-threatening or uncontrolled bleeding due to factor-Xa inhibitors. Data are limited on outcomes for patients who receive both andexanet alfa and 4-factor prothrombin complex concentrate (4F-PCC). The aim of this case series is to evaluate the safety and efficacy outcomes in patients receiving the two agents in combination. Methods: Electronic medical records of patients who received both 4F-PCC and andexanet alfa for nontraumatic intracranial hemorrhage from January 2019 to March 2022 were retrospectively reviewed. Hemostatic efficacy and complications related to concurrent use of 4F-PCC with andexanet alfa were documented. Results: Nine patients received 4F-PCC and andexanet alfa for reversal of factor Xa inhibitor-associated intracranial bleeding, eight of whom required reversal of apixaban. Of these nine patients, five patients died within 28 days for a 56% incidence of mortality. The average time from 4F-PCC administration to andexanet alfa administration was 3 hours and 9 minutes. Most doses of andexanet alfa were given for concern for bleed expansion after 4F-PCC administration. Hemostatic efficacy based on stability of repeat computed tomography scans post-administration of both agents was found in six patients (66.67%), with a 55.56% n incidence of thromboembolism, including two pulmonary embolisms, two deep vein thromboses, and one renal artery thrombosis. Conclusion : Risks and benefits should be weighed to determine if there is benefit to adding andexanet alfa to 4F-PCC in patients with incomplete hemostasis and life-threatening hemorrhage. The combination of andexanet alfa and 4F-PCC may increase the risk of thrombotic complications without improving mortality. [ABSTRACT FROM AUTHOR]

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious threat to public health. Vancomycin (VAN) remains the primary treatment for these infections, and achieving the recommended area under the curve (AUC) target has been linked to improved clinical outcomes. The current VAN therapeutic monitoring guidelines recommend a loading dose (LD) of 20–35 mg/kg to rapidly attain targeted VAN exposures within 24 h of therapy. However, there is a paucity of data describing the impact of VAN LD on day 1 area under the curve (AUC0–24). This study aims to employ pharmacokinetic (PK) equations to calculate and describe the AUC0–24 following a VAN LD of 20 mg/kg. Methods: This was a retrospective study of adult patients who were loaded with VAN 20 mg/kg, received ≥ 48 h of treatment, and had two consecutive serum VAN levels collected within 24 h. Linear, non-trapezoidal PK equations and two post-infusion VAN levels were used to calculate AUC0–24. Therapeutic AUC0–24 was defined as 400–600 mg/l*h. Results: Among 123 included patients, the median age was 46 years (IQR 36, 62), 54% (67/123) of the patients had a body mass index (BMI) ≥ 30 kg/m2 and 27% (33/123) were admitted to the intensive care unit (ICU). Following a LD of 20 mg/kg, 50% (61/123) of the patients met the therapeutic AUC0–24, while 22% (27/123) of the patients were subtherapeutic, and 28% (35/123) were supratherapeutic. Compared with patients who achieved therapeutic AUC0–24, patients with subtherapeutic AUC0–24 were more likely to be younger (44 vs. 37 years old) and have a BMI ≥ 30 kg/m2 (67 vs. 52%). In contrast, patients with supratherapeutic AUC0–24 were more likely to be older (64 vs. 44 years old) and to have chronic kidney disease diagnosis (23 vs. 7%) when compared to patients who achieved a therapeutic AUC0–24. Conclusions: Only 50% of patients achieve the target AUC0-24 following a VAN 20 mg/kg LD, with younger, heavier patients underexposed and older patients with renal impairment overexposed, suggesting that different dosing strategies are needed for these populations. [ABSTRACT FROM AUTHOR]

Background: There is currently a lack of evidence for the comparative effectiveness of Andexanet alpha and four-factor prothrombin complex concentrate (4F-PCC) in anticoagulation reversal of direct oral anticoagulants (DOACs). The primary aim of our systematic review was to verify which drug is more effective in reducing short-term all-cause mortality. The secondary aim was to determine which of the two reverting strategies is less affected by thromboembolic events. Methods: A systematic review and meta-analysis was performed. Results: Twenty-two studies were analysed in the systematic review and quantitative synthesis. In all-cause short-term mortality, Andexanet alpha showed a risk ratio (RR) of 0.71(95% CI 0.37–1.34) in RCTs and PSMs, compared to 4F-PCC (I2 = 81%). Considering the retrospective studies, the pooled RR resulted in 0.84 (95% CI 0.69–1.01) for the common effects model and 0.82 (95% CI 0.63–1.07) for the random effects model (I2 = 34.2%). Regarding the incidence of thromboembolic events, for RCTs and PSMs, the common and the random effects model exhibited a RR of 1.74 (95% CI 1.09–2.77), and 1.71 (95% CI 1.01–2.89), respectively, for Andexanet alpha compared to 4F-PCC (I2 = 0%). Considering the retrospective studies, the pooled RR resulted in 1.21 (95% CI 0.87–1.69) for the common effects model and 1.18 (95% CI 0.86–1.62) for the random effects model (I2 = 0%). Conclusion: Considering a large group of both retrospective and controlled studies, Andexanet alpha did not show a statistically significant advantage over 4F-PCC in terms of mortality. In the analysis of the controlled studies alone, Andexanet alpha is associated with an increased risk of thromboembolic events. Clinical trial registration: PROSPERO: International prospective register of systematic reviews, 2024, CRD42024548768. [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 goal of this commentary is to provide recent pharmacy school graduates and student pharmacists completing APPEs the essential background for correct vancomycin therapeutic drug monitoring (TDM) in the inpatient setting. [ABSTRACT FROM AUTHOR]

Glyphosate is a widely used herbicide worldwide. Research on human health effects has been limited and the toxicokinetics of glyphosate have not been widely examined. This research aimed to study the excretion profile and half-life of glyphosate in farmers and residents who use glyphosate to control weeds in their agricultural fields and near their households, respectively. Multiple spot urine samples per day were collected from the participants for 3 consecutive days after spraying glyphosate. The participants were interviewed about general characteristics, planting activities, glyphosate use, and their health problems related to glyphosate use. Glyphosate concentrations in urine samples were determined by HPLC with a fluorescence detector. The average age of residents (56.4 years) was significantly higher than that of farmers (45.5 years). The glyphosate excretion profile of most participants showed a gradual decline in glyphosate concentrations, but with or without additional exposures some of the profiles showed a jagged pattern of decline. The average urinary half-life of glyphosate in all participants was 24.58 h (95% CI: 18.43–30.73) and 20.95 h (95%CI: 16.85–25.05) for creatinine adjusted and non-adjusted measurements, respectively. The urinary glyphosate half-life measurements among the residents and farmers were not significantly different. [ABSTRACT FROM AUTHOR]

Introduction: Long-acting lipoglycopeptides such as dalbavancin may have utility in patients with Gram-positive bloodstream infections (BSI), particularly in those with barriers to discharge or who require prolonged parenteral antibiotic courses. A retrospective cohort study was performed to provide further multicenter real-world evidence on dalbavancin use as a sequential therapy for Gram-positive BSI. Methods: One hundred fifteen patients received dalbavancin with Gram-positive BSI, defined as any positive blood culture or diagnosed with infective endocarditis, from 13 centers geographically spread across the United States between July 2015 and July 2021. Results: Patients had a mean (SD) age of 48.5 (17.5) years, the majority were male (54%), with many who injected drugs (40%). The most common infection sources (non-exclusive) were primary BSI (89%), skin and soft tissue infection (SSTI) (25%), infective endocarditis (19%), and bone and joint infection (17%). Staphylococcus aureus accounted for 72% of index cultures, coagulase-negative Staphylococcus accounted for 18%, and Streptococcus species in 16%. Dalbavancin started a median (Q1–Q3) of 10 (6–19) days after index culture collection. The most common regimen administered was dalbavancin 1500 mg as one dose for 50% of cases. The primary outcome of composite clinical failure occurred at 12.2%, with 90-day mortality at 7.0% and 90-day BSI recurrence at 3.5%. Conclusions: Dalbavancin may serve as a useful tool in facilitating hospital discharge in patients with Gram-positive BSI. Randomized controlled trials are anticipated to validate dalbavancin as a surrogate to current treatment standards. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Direct oral anticoagulants (DOACs) exert anticoagulation effect by directly inhibiting Factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Though DOACs are characterized by fixed-dose prescribing and generally do not require routine laboratory drug-level monitoring (DLM), circumstances may arise where the DLM may aid in clinical decision-making, including DOAC dose adjustment, anticoagulant class change, or decisions to withhold or administer reversal agents. We review the current literature that describes high-risk patient groups in which DLM may be beneficial for improved patient anticoagulation management and stewardship. The review also summarizes the limitations of conventional coagulation testing and discuss the emerging utility of quantitative methods for routine and rapid emergent evaluation of DOAC drug levels—in particular, the Anti-Xa activity to detect Factor Xa Inhibitors (rivaroxaban, apixaban, and edoxaban). Both technical and regulatory barriers to widespread DLM implementation are limiting factors to further clinical research that must be overcome, in order to propose universal DOAC DLM strategies and provide clinical-laboratory correlation to formally classify high-risk patient groups. [ABSTRACT FROM AUTHOR]

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]

Background: Stroke is a neurological disease and a leading cause of mortality worldwide. Strokes mainly consist of two types: hemorrhage and ischemia. Stroke patients are being administered multiple drug therapy and are at risk of drug-related problems. Aim: To estimate drug-related problems (DRPs) and clinical end outcomes in hospitalized stroke patients. Methods: Current study was a multicenter, cross-sectional prospective observational study including 250 stroke patients admitted to tertiary care hospitals in Karachi, Pakistan. The study included all clinical subtypes of stroke patients i.e. Stroke, Ischemic stroke, Hemorrhagic stroke, CVA, and TIA. Associations among patient-clinical end outcomes and drug therapy-related variables like DRPs, mortality, and morbidity rates were estimated using Pearson's chi-squared test. Statistical analysis was done by using SPSS software, version 25. Results: A total of 250 patients participated in this study suffering from different clinical subtypes of stroke i.e. Ischemic stroke, hemorrhagic stroke, TIA, and CVA, including 46% male and 54% female patients. The majority of patients' stay at the hospital was between 1–10 days. The overall mortality rate in stroke patients was 51%. HAIs were observed in 70% of patients, HAIs faced by patients were SAP, CAP, UTI, sepsis, and VAP. Drugs were assessed according to NEML i.e. access group antibiotics, watch group antibiotics, reserve group antibiotics, statins, antiepileptics, and proton pump inhibitors. Majorly ceftriaxone was administered to 79% of patients, piperacillin-tazobactam to 52%, and cefixime to 48%, whereas meropenem was administered to 42% of patients along with vancomycin to 39% of total patients. A high mortality rate was observed in the case of Klebsiella pneumoniae and Staphylococcus aureus i.e. 78% and in the case of streptococcus pneumoniae 61% mortality rate was observed. Due to the presence of DRPs and various other clinical factors like comorbidities, DDIs, HAIs, administration of potentially nephrotoxic drugs, and administration of antibiotics without having CST, hospitalized stroke patients faced many problems. Conclusion: This study helped determine DRPs along with various clinical factors affecting the clinical end outcomes of patients suffering from any clinical subtype of stroke. Due to the enhancement in the evidence of the incidence of DRPs in tertiary care hospitals, pharmacist-led drug therapy review by interfering with doctors and other medical professionals at the patient bed site is needed and should be done to avoid any negative end outcomes and serious issues related to DRPs. [ABSTRACT FROM AUTHOR]

Background: Antibiotic use related problems lead to the emergence of resistance, failure of therapy, morbidity, mortality, and unnecessary healthcare expenditure. However, little is known about antimicrobial use related problems in our setting particularly in hospitalized surgical patients. Objective: The purpose of this study was to investigate antibiotic use related problems and their determinants among hospitalized surgical patients. Methodology: A prospective observational study was conducted from December 2018 to April 2019 at the surgical ward of the Ayder comprehensive specialized hospital, located in Northern Ethiopia. We included patients admitted to the surgical ward who were on antibiotic therapy or were candidates for antibiotic therapy/prophylaxis. The patients were recruited during admission and were followed daily until discharge. Data were collected through patient interviews and expert reviews of medical and medication records. The appropriateness of antibiotic use was evaluated according to the Infectious Disease Society of America, American Society of Health System Pharmacists, and World Health Organization guidelines. Subsequently, antibiotic use related problems were identified and classified based on Cipolle's method followed by consensus review with experts. Binary logistic regression was performed to identify the determinants of antibiotic use related problems. Statistical significance was set at p <0.05. Results: Among 272 patients, 167(61.4%) experienced antibiotics use related problems. A total of 235 antibiotics use related problems were identified equating 0.86±0.82 problems per patient. The commonly identified antibiotic use related problems were the need for additional drug therapy (29.4%), unnecessary drug therapy (15%), and dosage too high (12.1%). Cephalosporin (47.02%) was the most commonly implicated class of antibiotics in these drug related problems, followed by penicillin (18.45%) and metronidazole (16.02%). Prolonged hospitalization (AOR: 3.57, 95% CI: 1.91–6.70), number of medications≥5 (AOR: 2.08, 95%CI: 1.10–3.94), and lower qualifications of practitioners [general practitioners (AOR: 10.27, 95%CI: 4.13–25.58) and surgical residents (AOR: 2.28, 95%CI: 1.12–4.63)] were predictors of antibiotic use related problems. Conclusion: Antibiotic use related problems were common among the hospitalized surgical patients. Prolonged hospitalizations, number of medications, and lower qualifications of practitioners were predictors of antibiotic use related problems. Therefore, more emphasis should be given for patients with prolonged hospitalization and multiple medications. Moreover, practitioners with higher qualifications including surgical specialists need to be involved in patient evaluations. [ABSTRACT FROM AUTHOR]

Drug-induced kidney disease (DIKD) accounts for about one-fourth of all cases of acute kidney injury (AKI) in hospitalized patients, especially in critically ill setting. There is no standard definition or classification system of DIKD. To address this, a phenotype definition of DIKD using expert consensus was introduced in 2015. Recently, a novel framework for DIKD classification was proposed that incorporated functional change and tissue damage biomarkers. Medications were stratified into four categories, including "dysfunction without damage," "damage without dysfunction," "both dysfunction and damage," and "neither dysfunction nor damage" using this novel framework along with predominant mechanism(s) of nephrotoxicity for drugs and drug classes. Here, we briefly describe mechanisms and provide examples of drugs/drug classes related to the categories in the proposed framework. In addition, the possible movement of a patient's kidney disease between certain categories in specific conditions is considered. Finally, opportunities and barriers to adoption of this framework for DIKD classification in real clinical practice are discussed. This new classification system allows congruencies for DIKD with the proposed categorization of AKI, offering clarity as well as consistency for clinicians and researchers. [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]

Infective endocarditis (IE) during pregnancy is a rare condition that is associated with a high level of morbidity and mortality. The epidemiology, diagnosis, treatment, and prognosis have changed significantly in the last two decades. The declining incidence of rheumatic heart disease, improved life expectancy with congenital heart disease, advances in cardiac surgery and cardiac devices, rise in resistant microorganisms, complications of the opioid epidemic, and increasing maternal age are some of the many factors contributing to these changes. This article explores existing literature on the topic including case reports, case series, registry data, and clinical guidelines. The focus of this article is the evolving epidemiology, predisposing factors and preventative measures, clinical presentation, investigation, management, and potential complications of IE in pregnancy. Robust prospective data on the management of IE in pregnancy is lacking, and obtaining these data will be very challenging. It is imperative that international registries are used to provide data on best clinical practices and inform future clinical guidelines. Multimodal imaging should be incorporated in the investigation of complicated cases. A multidisciplinary approach to the management of this rare and life-threatening condition is essential to ensure the best outcomes for both the mother and the fetus. [ABSTRACT FROM AUTHOR]

Purpose: Anti-Xa peak level monitoring is recommended during LMWH treatment in renal impairment or obesity. The trough level has been proposed as marker for bleeding. We studied the influence of renal impairment and obesity on anti-Xa levels. Methods: Peak and trough levels were collected during therapeutic nadroparin treatment in patients with renal impairment, obese patients, and controls. 27 patients (n = 68 samples) were evaluated and combined with published data (n = 319 samples from 35 patients) using population pharmacokinetic (popPK) modelling. Results: Median peak level was 0.44 and 0.95 IU/mL in renal impairment with and without dose reduction and 0.60 and 0.43 IU/mL in obesity and controls, respectively. Trough levels were < 0.5 IU/mL in all patients with renal impairment with dose reduction and in 5/6 control patients. In the popPK model, total body weight and eGFR were covariates for clearance and lean body weight for distribution volume. Model-based evaluations demonstrated peak levels below the therapeutic window in controls and increased levels in renal impairment. Dose reductions resulted in a different effect on peak and trough levels. Obese patients (BMI up to 32 kg/m2) had similar levels upon weight-based dosing. Conclusion: In renal impairment, anti-Xa peak levels after dose reduction are comparable to those in controls. Weight-based dosing is suitable for obese patients. Aiming for peak levels between 0.6 and 1.0 IU/mL in these patients would result in overexposure compared to controls. Considering the association of trough levels and bleeding risk and our findings, trough monitoring seems to be a suitable parameter to identify nadroparin accumulation. [ABSTRACT FROM AUTHOR]

Factor Xa inhibitors (FXaI) are increasingly used for anticoagulation therapy, yet their association with intracranial hemorrhage poses a significant challenge. Although andexanet alfa (AA) and four-factor prothrombin complex concentrate (4F-PCC) have shown promise in reversing FXaI effects, their comparative efficacy and safety remain uncertain. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a literature search on electronic databases to obtain the relevant studies until May 16, 2024. Our primary outcomes were successful anticoagulation reversal, overall mortality (including 30-day and in-hospital mortality), and thromboembolic events. Secondary outcomes were length of hospital and intensive care unit stay and hematoma volume expansion. Data were pooled using a random-effects model. We included 16 eligible studies with a total of 2,977 patients. A statistically significant improvement in hemostatic efficacy rates was in favor of the AA group (risk ratio [RR] 1.10, 95% confidence interval [CI] 1.01-1.20, P = 0.02). Lower overall mortality rates were found in the AA group (RR 0.67, 95% CI 0.51-0.88, P = 0.004). However, no difference was found in 30-day mortality rates (RR 0.82, 95% CI 0.58-1.16, P = 0.26). In terms of thromboembolic events, more events were found in the AA group (RR 1.47, 95% CI 1.01-2.15, P = 0.046). AA was associated with a longer duration of hospital stay compared to 4F-PCC (mean difference [MD] 0.64, 95% CI 0.07-1.22, P = 0.03). Neither a significant difference in length of intensive care unit stay (MD 0.25, 95% CI - 0.36 to 0.86, P = 0.41) nor a significant difference in hematoma volume expansion was reported (MD - 0.89, 95% CI - 3.11 to 1.34, P = 0.435). Our results suggest that AA is superior to 4F-PCC in enhancing the hemostatic efficacy and reducing the overall and in-hospital mortality rates. More thromboembolic events are thought to be associated with the use of AA. However, more studies are required to validate whether the better results of AA in improving hemostatic efficacy are enough to make up for their higher cost and their possible risk of thromboembolic events., (© 2024. The Author(s).)

Introduction: Older adults face a higher risk of vancomycin-related toxicity given their (patho)-physiological changes, making early management of supratherapeutic exposure crucial. Yet, data on vancomycin exposure in older adults is scarce. This study aims to compare vancomycin concentrations between older and younger patients, emphasizing supratherapeutic concentrations and the effect of patient characteristics., Methods: This observational retrospective study was conducted in the University Hospital of Leuven (EC Research S65213). We analyzed early (first) vancomycin concentrations between older (≥ 75 years) and younger patients. Multivariable analyses were conducted to evaluate the association between baseline patient characteristics with supratherapeutic exposure (logistic regression), and dose-normalized concentrations (linear regression)., Results: We included 449 patients aged ≥ 75 years (median 80) and 1609 aged < 75 years (median 61). In univariable analysis, the first-measured vancomycin concentrations were significantly higher in older adults (p < 0.001), who more frequently reached supratherapeutic concentrations (30.7% versus 21%; p < 0.001). In multivariable analysis, factors associated with supratherapeutic concentrations were decreased the estimated glomerular filtration rate calculated by using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR CKD-EPI ) [odds ratio (OR) of 0.98, confidence interval (CI) 0.97-0.98]. Supratherapeutic concentrations had inverse association with giving lower loading dose (OR of 0.59, CI 0.39-0.90), and lower maintenance dose (OR of 0.45, CI 0.26-0.77). Factors that predicted increased dose-normalized concentrations included decreased eGFR CKD-EPI (coefficient of -0.05, CI -0.06 to -0.04), lower body weight (coefficient of -0.04, CI -0.05 to -0.03), increased blood urea nitrogen (coefficient of 0.02, CI 0.01-0.03), and delayed time to therapeutic drug monitoring (TDM) sampling (coefficient of 0.08, CI 0.06-0.09)., Conclusions: The absence of age as a significant factor in the multivariable analysis suggests that eGFR CKD-EPI mediated the relationship between age and vancomycin exposure. Older adults may benefit more from vancomycin TDM., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This study was condcuted to examine the association of area under the curve (AUC)/minimum inhibitory concentration (MIC) and trough concentration (C trough ) of vancomycin with treatment outcome and nephrotoxicity in infections caused by Enterococcus spp. and coagulase-negative Staphylococci (CoNS). Peak and trough concentrations were used to calculate AUC in 89 patients receiving vancomycin for infections with Enterococcus spp. (n = 65) or CoNS (n = 24). Correlations between C trough , AUC/MIC, early clinical response (ECR), and nephrotoxicity were assessed and cutoff values were determined. Sixty-three (70.8%) patients showed improvement in ECR and 10 (11.2%) experienced nephrotoxicity. Enterococcus spp. infections displayed correlations between AUC/MIC and ECR for AUC 0-24 h /MIC (r 2 = 0.27, P ≤ .05) and AUC 24-48 h /MIC (r 2 = 0.28, P ≤ .05), but not for C trough (r 2 = 0.21, P > .05). There were no correlations between C trough (r 2 = 0.26, P > .05), AUC 0-24 h /MIC (r 2 = -0.12, P > .05), AUC 24-48 h /MIC (r 2 = 0.01, P > .05) and ECR for CoNS. In the CoNS group, a moderate correlation was found between ECR and C trough at a cutoff value of 6.9 μg/mL. In addition, nephrotoxicity is also moderately associated with AUC 0-24 h and AUC 24-48 h at 505.7 and 667.1 μg•h/mL, respectively. A strong correlation between nephrotoxicity and C trough was observed when the cutoff value was 18.9 μg/mL. AUC/MIC during the first 48 h was a determinant of vancomycin efficacy in Enterococcus infections but not for CoNS. C trough was not correlated with clinical outcome. Nephrotoxicity could be predicted using C trough and AUC for infections with both pathogens., (© 2024, The American College of Clinical Pharmacology.)

Antimicrobials are commonly prescribed and often misunderstood. With more than 50% of hospitalized patients receiving an antimicrobial agent at any point in time, judicious and optimal use of these drugs is paramount to advancing patient care. This narrative will focus on myths relevant to nuanced consultation from infectious diseases specialists, particularly surrounding specific considerations for a variety of antibiotics. [ABSTRACT FROM AUTHOR]

Meningitis is an important cause of morbidity and mortality in children and adults. Its treatment strategy varies with age and gender. To assess potential drug-related problems (PDRP) and clinical outcomes in bacterial meningitis patients, a multicenter, clinical, descriptive, cross-sectional prospective observational study in 120 patients admitted to different tertiary care hospitals in Karachi was conducted. It includes both males 48% and females 52% belonging from all age groups i.e. peadiatrics (01 to 12 years), adults (18 to 65 years), and geriatrics (66 to 75 years). Out of these 72 patients were admitted in the public sector and 48 patients were admitted in private sector hospitals. Nosocomial infections were developed in 41% of patients during their stay at the hospital. Potentially nephrotoxic drugs were administered to all BM patients, these drugs should be administered carefully. Majorly Ceftriaxone was administered to 86% of patients, Vancomycin 71%, and meropenem 73% whereas 68% of patients were administered piperacillin-tazobactam. Organisms involved as causative agents in the majority of patients are Neisseria meningitides, Pseudomonas aeruginosa and, Streptococcus pneumoniae. DRPs impacted patient clinical outcomes in presence of many other factors like comorbidities, DDIs, Nis, administration of potentially nephrotoxic drugs, and administration of watch group and reserve group antibiotics without having culture sensitivity test, even after having CST no principles of de-escalation for antibiotics were done, which is a very important factor for hospitalized patients having IV antibiotics. The mortality rate among BM patients was 66%. The majority of patients (87%) stay at the hospital was 1–10 days. The present study helped in the identification of DRPs along with some other factors affecting the clinical outcomes in patients suffering from bacterial meningitis. Healthcare professionals should receive awareness and education on the importance of CST before initiating antibiotic therapy. Pharmacist-led medication review is necessary and should be followed to avoid negative outcomes and serious consequences related to DRPs. [ABSTRACT FROM AUTHOR]

To compare the clinical outcomes of linezolid and vancomycin regimens combined with one-stage surgery in treating traumatic osteomyelitis of the limbs caused by methicillin-resistant Staphylococcus aureus (MRSA) infection. A retrospective study was performed to analyze patients with traumatic osteomyelitis of the limbs attributable to MRSA infection. All of these patients received one-stage surgery to debride their wounds, with subsequent implantation of a vancomycin-loaded calcium sulfate artificial bone. Patients received either intravenous linezolid (study group) or vancomycin (control group) during the perioperative period. The postoperative inflammatory markers, renal function, duration of drainage catheter placement, duration of antibiotic administration, length of hospital stay, adverse events, and recurrence of osteomyelitis in these two groups were compared. The study group had a shorter duration of antibiotic administration and length of hospital stay (p < 0.05). There was a significant difference in the incidences of adverse events between the two groups (5.88% and 17.65% in the study and control groups, respectively, p < 0.05). There was no recurrence in either group during the three-year follow-up period. As of year, five after the surgery, one patient in the control group had a recurrence of osteomyelitis. The linezolid regimen should be preferred to the vancomycin regimen in patients with traumatic osteomyelitis of the extremities caused by MRSA infection because the linezolid regimen showed fewer adverse events, shorter periods of antibiotic use, and shorter hospital stay. However, both treatment regimens achieved satisfactory outcomes and warranted further investigations. [ABSTRACT FROM AUTHOR]

Background: There are no randomized trials comparing andexanet alfa and 4 factor prothrombin complex concentrate (4F-PCC) for the treatment of factor Xa inhibitor (FXa-I)-associated bleeds, and observational studies lack important patient characteristics. We pursued this study to demonstrate the feasibility of acquiring relevant patient characteristics from electronic health records. Secondarily, we explored outcomes in patients with life-threatening FXa-I associated bleeds after adjusting for these variables. Methods: We conducted a multicenter, chart review of 100 consecutive adult patients with FXa-I associated intracerebral hemorrhage (50) or gastrointestinal bleeding (50) treated with andexanet alfa or 4F-PCC. We collected demographic, clinical, laboratory, and imaging data including time from last factor FXa-I dose and bleed onset. Results: Mean (SD) age was 75 (12) years; 34% were female. Estimated time from last FXa-I dose to bleed onset was present in most cases (76%), and patients treated with andexanet alfa and 4F-PCC were similar in baseline characteristics. Hemostatic efficacy was excellent/good in 88% and 76% of patients treated with andexanet alfa and 4F-PCC, respectively (P = 0.29). Rates of thrombotic events within 90 days were 14% and 16% in andexanet alfa and 4F-PCC patients, respectively (P = 0.80). Survival to hospital discharge was 92% and 76% in andexanet alfa and 4F-PCC patients, respectively (P = 0.25). Inclusion of an exploratory propensity score and treatment in a logistic regression model resulted in an odds ratio in favor of andexanet alfa of 2.01 (95% confidence interval 0.67-6.06) for excellent/good hemostatic efficacy, although the difference was not statistically significant. Conclusion: Important patient characteristics are often documented supporting the feasibility of a large observational study comparing real-life outcomes in patients with FXa-I-associated bleeds treated with andexanet alfa or 4F-PCC. The small sample size in the current study precluded definitive conclusions regarding the safety and efficacy of andexanet alfa or 4F-PCC in FXa-I-associated bleeds. [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]

Background: Andexanet alfa (andexanet) is the only FDA-approved medication for reversal of apixaban and rivaroxaban anticoagulation for life-threatening or uncontrolled bleeding. Infusion modifications may be required in surgical patients undergoing prolonged operative intervention but have not previously been described. Case Report: A 78-year-old woman on rivaroxaban for atrial fibrillation was admitted to the trauma service for a mechanical fall, sustaining a T4 burst fracture with severe canal stenosis and spinal cord edema resulting in loss of strength and sensation in her legs. Clinically relevant rivaroxaban activity was verified with an elevated low molecular weight heparin anti-factor Xa assay, and laboratory confirmed coagulopathy was demonstrated by a prolonged prothrombin time, thromboelastography (TEG) R-time, and activated clotting time (ACT). The patient required urgent surgical intervention for spinal fixation. Given the expected prolonged duration of the procedure, standard dose andexanet was initiated with a prolonged infusion at half the standard rate during the operation. The procedure was successful and intraoperative TEGs demonstrated normalization of R-time and ACT throughout the procedure. The patient did not experience any complications postoperatively and successfully discharged to inpatient rehabilitation. Conclusion: Modifications to the andexanet infusion may be required in surgical patients requiring rivaroxaban reversal for a prolonged procedure. Further data are needed to determine the optimal approach to infusion modification. [ABSTRACT FROM AUTHOR]

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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]

After receiving a monitored first-dose antimicrobial infusion at an infusion center, 6 of 93 (6%) patients enrolled in outpatient parenteral antimicrobial therapy services experienced an immediate reaction, none of which were consistent with immunoglobulin E-mediated reactions. These findings suggest it would be reasonable to forgo monitoring for most patients receiving first-dose intravenous antimicrobials outpatient. [ABSTRACT FROM AUTHOR]

Andexanet alfa (AA) is a recombinant factor Xa competing for binding with factor Xa inhibitors, thereby reversing their anticoagulation effects. Since 2019, it has been approved for individuals under apixaban or rivaroxaban therapy suffering from life-threatening or uncontrolled bleeding. Apart from the pivotal trial, real-world data on the use of AA in daily clinics are scarce. We reviewed the current literature on patients with intracranial hemorrhage (ICH) and summarized the available evidence regarding several outcome parameters. On the basis of this evidence, we provide a standard operating procedure (SOP) for routine AA application. We searched PubMed and additional databases through 18 January 2023 for case reports, case series, studies, reviews, and guidelines. Data on hemostatic efficacy, in-hospital mortality, and thrombotic events were pooled and compared with the pivotal trial data. While hemostatic efficacy in world-wide clinical routine seems to be comparable to the pivotal trial, thrombotic events and in-hospital mortality appear to be substantially higher. Various confounding factors responsible for this finding such as exclusion and inclusion criteria resulting in a highly selected patient cohort within the controlled clinical trial have to be considered. The SOP provided should support physicians in patient selection for AA treatment as well as facilitate routine use and dosing. This review underlines the urgent need for more data from randomized trials to appreciate the benefit and safety profile of AA. Meanwhile, this SOP should help to improve frequency and quality of AA use in patients suffering from ICH while on apixaban or rivaroxaban treatment. [ABSTRACT FROM AUTHOR]

Over the past 20 years, there has been a shift from vitamin K antagonists to direct oral anticoagulants (DOACs), which include the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban. Although DOACs are associated with less serious bleeding than vitamin K antagonists, bleeding still occurs with DOACs, particularly in the elderly and in those with comorbidities. Reversal of the anticoagulant effects of the DOACs may be needed in patients with serious bleeding and in those requiring urgent surgery or intervention. Reversal can be effected with specific agents, such as idarucizumab for dabigatran and andexanet alfa for apixaban, edoxaban, and rivaroxaban, or with non-specific agents, such as prothrombin complex concentrates, activated prothrombin complex concentrate, and recombinant activated factor VII. This paper (i) provides an update on when and how to reverse the DOACs, (ii) describes new reversal agents under development, and (iii) provides a strategic framework for the reversal of the factor XI inhibitors currently under investigation in phase three clinical trials. [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. Ischemic stroke incidence is increasing amongst elderly patients in China; this is closely associated with drug-related problems (DRPs). Objectives. To evaluate the influencing factors of DRPs among elderly patients with a history of ischemic stroke in the Chinese community and the role clinical pharmacists play in providing solutions. Materials and methods. This study was conducted in 2 community health service centers in Putuo District, Shanghai, China, between December 2018 and June 2019. Demographics and clinical characteristics of the 130 selected patients were collected. Drug-related problems were classified using the Pharmaceutical Care Network Europe (PCNE)-DRP V8.03 classification system. The number, types, causes, interventions, and status of DRPs were then analyzed. Results. The average number of DRPs per patient was 1.3, corresponding to 256 causes. "Treatment effectiveness P1" was identified as the most common problem (75.0%). The main causes were "drug selection C1" (33.2%) and "patient-related C7" (30.9%). Antihypertensive drugs, statins, aspirin, and Chinese patent medicines were the top 4 drugs for DRPs. Age, unintentional medication discrepancy and medication compliance were independent predictors of DRPs. Pharmacists provided 339 interventions, mainly "at drug level I3" (38.9%) and "at patient level I2" (30.7%). Most of the interventions (85.5%) were accepted by the patients and 65.9% of the problems were solved. Conclusions. The number, types and etiology of DRPs in elderly patients with ischemic stroke in our community are diverse and treatment effectiveness is the main cause of their occurrence. Clinical pharmacists play an important role in providing interventions for major causes of DRPs. [ABSTRACT FROM AUTHOR]

Acute bacterial skin and skin structure infections (ABSSSIs) are a subtype of skin and soft tissue infections (SSTI), usually sustained by Gram-positive bacteria, whose incidence is high among children. ABSSSIs are responsible for a considerable number of hospitalizations. Moreover, as multidrug resistant (MDR) pathogens become widespread, the pediatric category seems burdened with an increased risk of resistance and treatment failure. To obtain a view on the status of the field, we describe the clinical, epidemiological, and microbiological aspects of ABSSSI in children. Old and new treatment options were critically revised with a focus on the pharmacological characteristics of dalbavancin. Evidence on the use of dalbavancin in children was collected, analyzed, and summarized. Many of the therapeutic options available at the moment are characterized by the need for hospitalization or repeated intravenous infusions, safety issues, possible drug–drug interactions, and reduced efficacy on MDRs. Dalbavancin, the first long-acting molecule with strong activity against methicillin-resistant and also many vancomycin-resistant pathogens represents a game changer for adult ABSSSI. In pediatric settings, the available literature is still limited, but a growing body of evidence supports dalbavancin use in children with ABSSSI, demonstrating this drug to be safe and highly efficacious. [ABSTRACT FROM AUTHOR]

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]

Background: Severe trauma represents a major global public health burden and the management of post-traumatic bleeding continues to challenge healthcare systems around the world. Post-traumatic bleeding and associated traumatic coagulopathy remain leading causes of potentially preventable multiorgan failure and death if not diagnosed and managed in an appropriate and timely manner. This sixth edition of the European guideline on the management of major bleeding and coagulopathy following traumatic injury aims to advise clinicians who care for the bleeding trauma patient during the initial diagnostic and therapeutic phases of patient management. Methods: The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma included representatives from six European professional societies and convened to assess and update the previous version of this guideline using a structured, evidence-based consensus approach. Structured literature searches covered the period since the last edition of the guideline, but considered evidence cited previously. The format of this edition has been adjusted to reflect the trend towards concise guideline documents that cite only the highest-quality studies and most relevant literature rather than attempting to provide a comprehensive literature review to accompany each recommendation. Results: This guideline comprises 39 clinical practice recommendations that follow an approximate temporal path for management of the bleeding trauma patient, with recommendations grouped behind key decision points. While approximately one-third of patients who have experienced severe trauma arrive in hospital in a coagulopathic state, a systematic diagnostic and therapeutic approach has been shown to reduce the number of preventable deaths attributable to traumatic injury. Conclusion: A multidisciplinary approach and adherence to evidence-based guidelines are pillars of best practice in the management of severely injured trauma patients. Further improvement in outcomes will be achieved by optimising and standardising trauma care in line with the available evidence across Europe and beyond. Key messages: Immediate detection and management of traumatic coagulopathy improves outcomes of severely injured patients. This guideline follows management of the severe trauma patient in chronological order, with a focus on prevention of possible exsanguination. These structured recommendations support measures that prioritise the optimisation of resources for the benefit of bleeding control based on scientific evidence. Empirical management should not be implemented unless no method of monitoring bleeding and coagulation is available. Optimal organisation of the resuscitation team for the bleeding trauma patient includes implementation of these guidelines. [ABSTRACT FROM AUTHOR]