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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]

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]

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]

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]

Appropriate prescribing of anti-infectives is a public health challenge. In our hospital, clinical microbiologists (clinical microbiology mobile unit, UMMc) and clinical pharmacists (clinical pharmacy, PHAc) carry out interventions on anti-infective prescriptions to improve practices. Our main objective was to evaluate the acceptance of UMMc and PHAc interventions on anti-infective prescriptions by quantifying the rate of prescription change 24 h after intervention. The secondary objective was to characterize the type of intervention and associate the rate of change for each. All prescriptions are computerized, and interventions traced via DxCare® software, which feeds a local data warehouse (HEGP-CDW). This descriptive, retrospective, single-center, uncontrolled study was conducted from January 2015 to December 2018. The data were extracted over this period from the data warehouse and analyzed using R software. UMMc interventions were accepted 72.2% of the time and PHA interventions 87.3%. The types of interventions found were mostly dose adjustments (61.1% for the UMMc and 54.2% for the PHAc) and proposals to change or stop a drug. Interventions have an impact on anti-infective prescriptions and are generally followed by clinicians. For the category "discontinuation of a molecule", almost half of the advice from the UMMc was refused. The collaboration between the UMMc and PHAc should be reinforced to improve acceptance. [ABSTRACT FROM AUTHOR]

Background In the Netherlands, home treatment with intravenous antimicrobial therapy is a relatively new concept. Although several studies have shown that outpatient parenteral antimicrobial therapy (OPAT) can be administered safely, people receiving antimicrobials at home remain at risk for adverse events, including readmission. Aim The aim of our retrospective study was to identify risk factors for readmission in patients discharged with OPAT. Method Patients who were at least 18 years or older, discharged with OPAT between January 2016–December 2018 were included. Variables that were collected consisted of baseline demographics, complications, readmission within 30 days and treatment failure. Multivariate logistic regression analysis was performed to identify risk factors for readmission. Results A total of 247 patients were included; the most common reason for OPAT was bone and joint infections (17%). Penicillin (37%), cephalosporin (26%) and vancomycin/aminoglycoside (15%) were the most commonly prescribed antimicrobials. Among patients receiving medication subject to therapeutic drug monitoring (i.e. aminoglycosides or vancomycin), 51% (19/37) received weekly therapeutic drug monitoring. Receiving aminoglycosides or vancomycin (adjusted OR 2.05; 95% CI 1.30–3.25, p < 0.05) and infection of prosthetic material (adjusted OR 2.92, 95% CI 1.11–7.65, p < 0.05) were independent risk factors associated with readmission. Conclusion Although patients receiving medication subject to therapeutic drug monitoring are at higher risk of readmission, only half of the patients discharged with aminoglycosides or vancomycin were monitored according to IDSA guidelines. A specialized team in charge of monitoring patients with OPAT is more likely to increase the rate of monitoring to prevent readmissions and complications. [ABSTRACT FROM AUTHOR]

Limited data exists regarding the clinical outcomes of andexanet alfa and four factor prothrombin complex concentrate (4F-PCC) for reversal of apixaban or rivaroxaban in the setting of intracranial hemorrhage (ICH). The objective of this study was to evaluate clinical outcomes of 4F-PCC and andexanet alfa for reversal of ICH associated with oral factor Xa inhibitors. This was a retrospective, single-center, case series evaluating hemostatic efficacy of patients receiving andexanet alfa) or 4F-PCC for reversal of apixaban or rivaroxaban after ICH. Secondary endpoints included in-hospital mortality, thrombotic complications, timing of reversal agents, intensive care unit and hospital length of stay, patient disposition, and 30-day readmission rate. During the study period, 21 patients received andexanet alfa and 35 received 4F-PCC. Hemostatic efficacy occurred in 64.7% of patients receiving andexanet alfa and 54.8% of receiving 4F-PCC. Thirty-day all-cause mortality was 45.2% for 4F-PCC and 30% for andexanet alfa. Thrombotic events were higher with 4F-PCC (31.4%) compared to andexanet alfa (14.3%). Median time from presentation to administration of reversal agent was 2.67 [1.75–4.13] hours with andexanet alfa and 1.73 [1.21–3.55] hours with 4F-PCC. Discharge to skilled nursing facilities and 30-day readmission were similar between groups. In this cohort, reversal with andexanet alfa and 4F-PCC differed in terms ofhemostatic efficacy and thrombotic events after ICH in patients anticoagulated with apixaban or rivaroxaban. [ABSTRACT FROM AUTHOR]

Background: Metformin has been used for the treatment of type 2 diabetes for over 60 years; however, its mechanism of pharmacological action is not fully clear. Different hypotheses exist regarding metformin distribution and redistribution mechanisms between plasma and erythrocytes/red blood cells (RBCs). Objective: We aimed to test the hypothesis that the metformin distribution between plasma and RBC occurs via concentration difference-driven passive transport and estimated transport rate coefficient values based on metformin concentration time series in plasma and RBCs from in vivo studies. Methods: An ordinary differential equation (ODE) system with two compartments was used to describe diffusion-based passive transport between plasma and RBCs. Metformin concentration time series in plasma and RBCs of 35 individuals were used for metformin transport parametrization. Plasma concentration has been approximated by biexponential decline. Results: A single passive transport coefficient, k = 0.044 ± 0.014 (h–1), can be applied, describing the uptake and release transport rate versus the linear equation v = k × (Mpl − MRBC), where Mpl is the metformin concentration in plasma and MRBC is the metformin concentration in RBCs. Conclusions: Our research suggests that passive transport can explain metformin distribution dynamics between plasma and RBCs because transport speed is proportional to the metformin concentration difference and independent of the transport direction. Concentration difference-driven passive transport can explain the mechanism of faster metformin distribution to RBCs the first few hours after administration, and faster release and domination of the redistribution transport rate after metformin concentration in plasma becomes smaller than in RBCs. [ABSTRACT FROM AUTHOR]

Purpose of Review: Antimicrobial stewardship within acute care is common and has been expanding to outpatient areas. Some inpatient antimicrobial stewardship tactics apply to outpatient parenteral antimicrobial therapy (OPAT) and complex outpatient antimicrobial therapy (COpAT) management, but differences do exist. Recent Findings: OPAT/COpAT is a growing area of practice and research with its own unique considerations for antimicrobial stewardship. Potential ideas for antimicrobial stewardship in the OPAT/COpAT setting include redesigning the regimen to COpAT instead of OPAT, ensuring the use of the shortest effective duration of antimicrobial therapy; using antimicrobials dosed less frequently, such as long-acting glycopeptides; optimizing antimicrobial susceptibility testing reporting for common OPAT/COpAT drugs; and establishing routine laboratory and safety monitoring. Future consensus is needed to determine validated OPAT program metrics and outcomes. Summary: As more focus is placed on outpatient antimicrobial stewardship, clinicians practicing in OPAT should publish more data regarding OPAT program methods and outcomes as they relate to antimicrobial stewardship. These can involve patient clinical outcomes, OPAT readmission rates, OPAT therapy completion, and central line-related complications. [ABSTRACT FROM AUTHOR]

Background Correct dosing and therapeutic drug monitoring (TDM) practices are essential when aiming for optimal vancomycin treatment. Objective To assess target attainment after initial dosing and dose adjustments, and to determine compliance to dosing and TDM guidelines. Setting Tertiary care university hospital in Belgium. Method A chart review was performed in 150 patients, ranging from preterm infants to adults, treated intravenously with vancomycin. Patient characteristics, dosing and TDM data were compared to evidence-based hospital guidelines. Main outcome measures Target attainment of vancomycin after initial dosing and dose adjustments. Results Subtherapeutic concentrations were measured in 68% of adults, in 76% of children and in 52% of neonates after treatment initiation. Multiple dose adaptations (median 2, Q1 1–Q3 2) were required for target attainment, whilst more than 20% of children and neonates never reached targeted concentrations. Regarding compliance to the hospital guideline, some points of improvement were identified: omitted dose adjustment in adults with decreased renal function (53%), delayed sampling (16% in adults, 31% in children) and redundant sampling (34% of all samples in adults, 12% in children, 13% in neonates). Conclusion Target attainment for vancomycin with current dosing regimens and TDM is poor in all age groups. Besides, human factors should not be ignored when aiming for optimal treatment. This study reflects an ongoing challenge in clinical practice and highlights the need for optimization of vancomycin dosing strategies and improvement of awareness of all health care professionals involved. [ABSTRACT FROM AUTHOR]

Purpose: Therapeutic drug monitoring guided by the area under the concentration-time curve (AUC-guided TDM) is recommended for vancomycin. However, validated efficient software remains elusive to popularize AUC-guided TDM in Japan. The aim of this study was to validate a newly developed web application, PAT, for AUC estimation. Methods: PAT was developed on the R ver. 3.6.2 platform for use with mobile phones and personal computers. AUC estimated by PAT (AUCPAT) was evaluated against the reference AUC (AUCREF) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUCBM-P) calculated using an evaluated available software with clinical data. Results: Investigating the best sampling points with limited sampling, PAT produced the least bias using two concentrations at 1 h and 11 h after the end of infusion (slope 1.18, intercept −15.57, median AUCPAT/AUCREF 0.93 [range 0.81–1.24]), where only one estimation (6%) was out of the predetermined acceptable range of 0.8–1.2. Employment of only a trough concentration was more biased (AUCPAT/AUCREF range 0.73–1.30 for 11 h, AUCPAT/AUCREF range 0.62–1.40 for 23 h). In comparison with the evaluated software, AUCPAT was not biased against the AUCBM-P (slope 1.04, intercept −15.80, median AUCPAT/AUCBM-P 1.00 [range 0.86–1.10]). Conclusions: The new application using two concentrations was appropriately validated and might be efficient in popularizing the AUC-guided TDM of vancomycin. [ABSTRACT FROM AUTHOR]

Purpose: This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.Methods: Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes.Results: TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients.Conclusion: Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide. [ABSTRACT FROM AUTHOR]

Background: Vancomycin therapeutic drug monitoring (TDM) is based on achieving 24-h area under the concentration–time curve to minimum inhibitory concentration cure breakpoints (AUC24/MIC). Approaches to vancomycin TDM vary, with no head-to-head randomized controlled trial (RCT) comparisons to date. Objectives: We aimed to compare clinical and pharmacokinetic outcomes between peak–trough-based and trough-only-based vancomycin TDM approaches and to determine the relationship between vancomycin AUC24/MIC and cure rates. Methods: A multicentered pragmatic parallel-group RCT was conducted in Hamad Medical Corporation hospitals in Qatar. Adult non-dialysis patients initiated on vancomycin were randomized to peak–trough-based or trough-only-based vancomycin TDM. Primary endpoints included vancomycin AUC24/MIC ratio breakpoint for cure and clinical effectiveness (therapeutic cure vs therapeutic failure). Descriptive, inferential, and classification and regression tree (CART) statistical analyses were applied. NONMEM.v.7.3 was used to conduct population pharmacokinetic analyses and AUC24 calculations. Results: Sixty-five patients were enrolled [trough-only-based-TDM (n = 35) and peak–trough-based-TDM (n = 30)]. Peak–trough-based TDM was significantly associated with higher therapeutic cure rates compared to trough-only-based TDM [76.7% vs 48.6%; p value = 0.02]. No statistically significant differences were observed for all-cause mortality, neutropenia, or nephrotoxicity between the two groups. Compared to trough-only-based TDM, peak–trough-based TDM was associated with less vancomycin total daily doses by 12.05 mg/kg/day (p value = 0.027). CART identified creatinine clearance (CLCR), AUC24/MIC, and TDM approach as significant determinants of therapeutic outcomes. All patients [n = 19,100%] with CLCR ≤ 7.85 L/h, AUC24/MIC ≤ 1256, who received peak–trough-based TDM achieved therapeutic cure. AUC24/MIC > 565 was identified to be correlated with cure in trough-only-based TDM recipients [n = 11,84.6%]. No minimum AUC24/MIC breakpoint was detected by CART in the peak–trough-based group. Conclusion: Maintenance of target vancomycin exposures and implementation of peak–trough-based vancomycin TDM may improve vancomycin-associated cure rates. Larger scale RCTs are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Introduction: Dalbavancin is approved for acute bacterial skin and skin structure infections (ABSSSIs) but offers a potential treatment option for complicated invasive gram-positive infections. Importantly, dalbavancin's real benefits may be in treating complicated infections in vulnerable patient populations, such as persons who inject drugs (PWID). Methods: A multicenter retrospective analysis was performed from March 2014 to April 2017 to assess 30- and 90-day clinical cure and adverse drug events (ADEs) in adult patients who received ≥ 1 dose of dalbavancin for a non-ABSSSI indication. Results: During the study period, 45 patients received dalbavancin, 28 for a non-ABSSSI indication. The predominant infections treated included osteomyelitis (46%), endovascular infection (25%) and uncomplicated bacteremia (14%). Half of the patients had positive Staphylococcus aureus in cultures, 29% methicillin resistant and 21% methicillin susceptible. Most patients were prescribed dalbavancin as sequential treatment with a median of 13.5 days of prior antibiotic therapy. The most common reason for choosing dalbavancin over standard therapy use was PWID (54%). Seven patients were lost to follow-up at day 30. Of the remaining evaluable patients, 30-day clinical cure was achieved in 15/21 (71%) patients. The most common reason for failure was lack of source control (4/6, 67%). At day 90, relapse occurred in two patients. Three patients had a potential dalbavancin-associated ADE: two patients with renal dysfunction and one patient with pruritus. Conclusions: This study demonstrates a possible role for dalbavancin in the treatment of non-ABSSSI invasive gram-positive infections in select vulnerable OPAT patients. [ABSTRACT FROM AUTHOR]

Purpose: This narrative review aims to describe barriers of outpatient parenteral antimicrobial therapy at home (OPAT), potentially compromising general standards of antibiotic stewardship (ABS) and facilitators of OPAT for ABS. Methods: After a literature review, five authors determined the barriers and facilitators to discuss in this review. Results: Sixty-six publications were included in the narrative review and seven barriers and five facilitators are discussed in this article. The impracticability of multiple daily dosing during OPAT, the impact of real-life temperature variations, deviations of the infusion rates of elastomeric devices, access to prolonged intravenous antibiotic therapy, not administering loading doses before the initiation of extended or continuous infusions and the transmural nature of care associated with OPAT, can lead to deviations of recommended treatment regimens and sub-optimal clinical and laboratory follow-up, with a risk of inferior clinical outcomes, adverse events, drug-resistance and higher costs. On the other hand, OPAT provides access to treatments with intravenous antibiotics and simultaneously avoids prolonged hospitalization. Conclusion: Implementing ABS guidelines in OPAT programs, e.g., by using a multidisciplinary team approach and facility-specific protocols for OPAT with patient selection criteria and instructions for selection, storage, preparation and administration of antibiotics, can improve appropriate antibiotic use. Additionally, further research should examine the effectiveness of these interventions on outcomes of OPAT. [ABSTRACT FROM AUTHOR]

Purpose of Review: In the last 50 years, vancomycin has been the agent of choice to treat infections due to methicillin-resistant Staphylococcus aureus (MRSA). However, vancomycin treatment failure is not uncommon, even when MRSA strains are fully susceptible to vancomycin. Treatment with vancomycin requires careful monitoring of drug levels as there is a potential for nephrotoxicity. Resistance to clindamycin is not infrequent, which also limits therapeutic options for treating infections due to MRSA in children. This paper reviews the current data on pharmacokinetics and pharmacodynamics and clinical efficacy of vancomycin in children. Recent Findings: Resistance to vancomycin in MRSA (MIC >2 mg/L) is infrequent; there is increasing evidence in the literature that vancomycin maybe ineffective against increasing proportion of isolates with MICs between 1 and 2 mg/L. Recent studies and meta-analyses have demonstrated that strains with high vancomycin MICs are associated with poor outcomes especially in patients with bacteremia and deep tissue infections due to MRSA. This gradual increase in vancomycin MIC has been reported as MIC creep or vancomycin heteroresistance. Patients infected with MRSA isolates that exhibit MIC creep experience poorer clinical outcomes, including delayed treatment response, increased mortality, increase rate of relapse, and extended hospitalization. There are limited data to guide vancomycin dosing in children with MRSA. Although the vancomycin area under the curve AUC24/MIC ratio > 400 has been shown to predict clinical efficacy in adults, this relationship has not been documented very well for treatment outcomes in MRSA infections in children. Use of higher vancomycin dosages in attempts to achieve higher trough concentrations has been associated with increased nephrotoxicity. Summary: New recently approved antibiotics including ceftaroline, dalbavancin, and tedizolid offer a number of advantages over vancomycin to treat staphylococcal infections: improved antimicrobial activity, superior pharmacokinetics, pharmacodynamics, tolerability, and dosing, including once-daily and weekly regimens, and less need for monitoring drug levels. [ABSTRACT FROM AUTHOR]