Background: Vancomycin is an antibiotic known to cause nephrotoxicity, particularly when a vancomycin trough of 15 to 20 mg/L, a surrogate for an area under the curve (AUC) of at least 400 mgh/L, is targeted. Although monitoring vancomycin AUC is more resource intensive, it may especially benefit populations expected to be at higher risk of nephrotoxicity. Objective: To describe the proportion of discordance between vancomycin AUC and trough concentration in targeted high-risk populations. Methods: A prospective observational review was conducted on adults receiving intravenous vancomycin for more than 48 hours from May 9 to June 3, 2022. Patients included were elderly, obese, had renal dysfunction, and/or received 4 grams or more of vancomycin daily with a pending vancomycin trough concentration. A peak concentration was ordered by a project team member to calculate AUC to assess discordance. Results: A total of 47 patients were included with 87 vancomycin minimum concentration (Cmin)/AUC pairs analyzed. Discordance was observed in 52.9% of Cmin/AUC pairs in the entire cohort. The majority (79%) of the 43 Cmin levels <15 mg/L had an associated AUC >400 mgh/L and 57% of 21 Cmin levels within the 15 to 20 mg/L range had an AUC >600 mgh/L. Conclusion: A high degree of discordance between vancomycin Cmin and AUC was present in patients considered to be at high risk of nephrotoxicity. Monitoring vancomycin AUC in these patients may reduce the risk of nephrotoxicity.

The 2020 consensus guidelines for drug monitoring of vancomycin recommended AUC-guided dosing to reduce acute kidney injury (AKI) and improve clinical outcomes in patients with serious methicillin-resistant Staphylococcus aureus (MRSA) infections previously managed with trough concentrations of 15-20 mg/L.

To determine if AUC-guided dosing of vancomycin reduces AKI and improves clinical outcomes including non-invasive infections with S. aureus compared with trough-only dosing broadened to concentrations of 10-20 mg/L.

A retrospective, single-center, cohort study was conducted over 12 months comparing Bayesian software-guided AUC-dosing with trough-only dosing. Information collected included patient demographics, co-morbidities, concurrent nephrotoxins, assessment measures of drug exposure, and patient outcomes. Nominal data were analyzed using the chi-square test, and continuous data using the independent t test.

Based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria, the incidence of AKI was 7.65% and 6.06% (P = 0.56), among 183 patients in the AUC-guided and 165 subjects in the trough-only groups, respectively. Individuals in the trough-only group were younger, had fewer co-morbidities and admissions to the ICU. A lower incidence of AKI findings among trough-only subjects was likely a result of the duration of therapy (mean of 4.2 days), mean trough concentrations <15 mg/L, and fewer concurrent nephrotoxins. AUC-guided dosing significantly reduced the total daily dose, 2.29 vs 2.54 g/day (P = 0.01), but provided no significant reductions in cumulative dose, duration of therapy, length of hospital stays, or overall patient outcomes.

AUC-guided vancomycin dosing did not reduce the incidence of AKI nor impact patient outcomes vs trough-only dosing. Successful clinical outcomes with lower average trough concentrations may have resulted from the treatment of nonbacteremic skin soft tissue infections (SSTI), suggesting an indication for further exploration of vancomycin dosing strategies.

The 2020 vancomycin consensus guidelines recommend AUC-guided dosing over trough-based dosing to decrease nephrotoxicity. This study was performed to add data comparing these dosing methods in the outpatient setting.

This retrospective cohort study compared trough-guided versus AUC-guided dosing in patients receiving vancomycin through two home infusion pharmacies (HIPs). Multivariate analysis was performed to report adjusted relative risks, adjusting for patient demographics and clinical characteristics. Eligible patients were ≥18 years old, had an absolute neutrophil count of ≥1000 cells/mm3, a baseline serum creatinine of <2.0 mg/dL at HIP intake, and ≥7 days of IV vancomycin at home. Primary outcome was rate of acute kidney injury (AKI) events, defined as the number of AKI events per treatment days. Secondary outcomes were rate of 30 day hospital readmission and number of HIP interventions (vancomycin dose changes).

Six hundred and sixty patients were included (303 trough, 357 AUC). The mean number of AKI events was 0.84 per treatment day for trough-guided versus 0.63 for AUC-guided dosing (P = 0.11). In adjusted models, there were no significant associations between the exposure and AKI events [relative risk (RR) = 0.8, 95% CI 0.5-1.2, P = 0.26], 30 day hospital readmissions (RR 1.0, 95% CI 0.8-1.3, P = 0.71) or number of pharmacy interventions (RR = 1.0, 95% CI 0.9-1.2, P = 0.67).

There was no significant difference in AKI rates among patients receiving vancomycin via trough- or AUC-guided monitoring and dosing through a HIP. Further evaluation is needed to determine how to improve AKI rates using AUC-guided monitoring and dosing among patients receiving vancomycin therapy at home.

Background/Objective: Vancomycin, a hydrophilic glycopeptide antibiotic with bactericidal activity against Gram-positive microorganisms, is one of the most commonly used antibiotics un the intensive care unit (ICU). Different efforts have been made to achieve a therapeutically effective plasma concentration of vancomycin by using loading and subsequent maintenance doses on an individual basis, but this remains subject to debate. Our objective was to individualize a dosage regimen in a Chilean ICU to optimize the pharmacological treatment of vancomycin by using a population pharmacokinetic model. Methods: A quantitative descriptive study was carried out in 51 patients at the adult ICU, San Borja Arriarán Clinical Hospital in Santiago, Chile. The dose of vancomycin was calculated by using a population pharmacokinetic software, the Antibiotic Kinetics®, and was subsequently validated with plasma trough levels of the drug through a patient sample. Results: The most commonly prescribed loading dose was 1500 mg and the most commonly used maintenance dose was 1000 mg, three times a day. The measured blood plasma concentrations of each patient (16.98 ± 5.423 μg/mL) were compared with the concentrations calculated through the population pharmacokinetic model (14.33 ± 4.630 μg/mL, p < 0.05). In addition, a correlation was found between the software-calculated trough concentration versus the measured trough concentration for vancomycin, with a positive correlation between both variables established (R2 = 0.65; p < 0.0001). No renal side effects were observed in the treated patient group. Conclusions: In the present study, a vancomycin dosing model for critically ill patients, based on a population pharmacokinetic model, was successfully implemented for routine clinical practice.

Whether risk factors for vancomycin-induced nephrotoxicity (VIN) development reported in recent years are also risk factors in the older population has not yet been fully investigated. This study aimed to investigate the risk factors for VIN development in the older population and to examine factors influencing kidney prognosis after VIN development.

A total of 468 patients aged ≥ 75 years were included in this study. Factors related to VIN onset in older adults were examined through logistic regression analysis.

A total of 40 patients (8.5%) with VIN were identified. Univariate analysis revealed significant differences in body mass index (BMI), combined use of tazobactam/piperacillin (T/P), and intensive care unit admission between the VIN and non-VIN groups (P = 0.042, 0.005, and 0.040, respectively). Multivariate analysis identified the combined use of T/P as a factor related to VIN. In patients aged 85 years or older, the concomitant use of T/P and intensive care unit (ICU) admission were identified as factors related to VIN. Compared with the VIN recovery group, the nonrecovery group had a longer time to VIN onset and a higher proportion of patients on concomitant diuretics.

This study revealed that the combined use of T/P and ICU admission were risk factors for VIN in older individuals. Additionally, the time until VIN onset and the concomitant use of diuretics may affect the kidney prognosis of older patients who develop VIN. When administering vancomycin to older patients, it is necessary to eliminate or be cautious of these factors in relation to VIN development and kidney prognosis.

Background/Objectives: Vancomycin, a glycopeptide antibiotic used for gram-positive infections, is associated with acute kidney injury (AKI). Therapeutic drug monitoring (TDM) is recommended to minimize this risk while ensuring therapeutic efficacy. This study evaluated whether AUC-guided monitoring improved patient safety compared to traditional trough-guided monitoring. Methods: A retrospective observational cohort study was conducted at the University Medical Centre Maribor, Slovenia, involving patients receiving intravenous vancomycin. One cohort was managed using trough-guided monitoring (n = 85), while the other was monitored using the AUC-guided approach (n = 139). The primary outcome was AKI incidence, and secondary outcomes included renal replacement therapy and mortality. Risk factors for AKI were identified, and pharmacokinetic parameters were evaluated at vancomycin therapy initiation and steady state. Results: The incidence of AKI was 20% in the trough-guided group and 18% in the AUC-guided group (p = 0.727). Secondary outcomes were similar in both cohorts. Risk factors for AKI included older age (OR 1.04; p = 0.042), higher steady-state AUC (OR 1.01; p < 0.001), longer duration of concomitant nephrotoxic therapy (OR 1.06; p = 0.019), and concomitant use of loop diuretics (OR 2.46; p = 0.045). Steady-state AUC values and trough levels (AUC0-24ss, AUC24-48ss, AUC0-48ss, and Cmin48ss) were significantly lower in the AUC-guided group, which was further reflected in the lower percentage of patients exceeding the AUC > 600 mg·h/L threshold at steady state. Conclusions: Although AKI incidence was lower in the AUC-guided group, the difference did not reach statistical significance. However, lower AUC values and trough levels in the AUC-guided group at steady state suggest a trend toward reduced vancomycin exposure and toxicity.

Vancomycin is commonly utilized for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Dosing recommendations for vancomycin have shifted in recent years to favor area under the concentration-time curve (AUC) instead of trough-based dosing strategies to decrease vancomycin exposure and rates of acute kidney injury (AKI). However, little data exist on the safety and efficacy of AUC-based dosing in patients with obesity.

This was a single-center retrospective cohort study conducted between 1 January 2014 and 31 December 2022. Adult patients aged ≥18 years were included if they were obese and received vancomycin for treatment of a severe MRSA infection for at least 72 hours. The primary outcome was incidence of AKI based on Kidney Disease: Improving Global Outcomes (KDIGO) criteria.

After initial screening, 398 patients were included, with 230 in the trough group and 168 in the AUC group. Rates of AKI were lower in the AUC group compared to the trough group (11.3% vs 25.2%, P < .001). After adjusting for potential confounders, logistic regression maintained a reduction in AKI with AUC-based dosing for cumulative doses less than the median of 10 250 mg (odds ratio, 0.47 [95% confidence interval, .25-.88]) but not for doses above. Rates of initial target attainment were also higher with AUC-based dosing (50.0% vs 23.9%, P < .001).

Patients with obesity receiving vancomycin for treatment of severe MRSA infections experienced lower rates of AKI when utilizing an AUC- versus trough-based dosing strategy.

Sepsis, a life-threatening disruption, remains a significant global healthcare challenge that urgently needs novel strategies to improve management. This study aimed to develop multifunctional vancomycin-loaded polymersomes (VCM-HA-SIL-Ps) using a novel hyaluronic acid-silybin (HA-SIL) conjugate to target the TLR inflammatory pathway and enhance VCM's efficacy against bacterial sepsis. HA-SIL was synthesized and characterized by FT-IR, UV-Vis spectroscopy, and 1H NMR. The biomimetic properties of HA-SIL were confirmed via in silico (-73.35 kcal/mol) and in vitro (dissociation constant = 2.872 μM) binding affinity studies against TLR2. VCM-HA-SIL-Ps exhibited appropriate physicochemical properties, biocompatibility, and stability. VCM-HA-SIL-Ps sustained VCM release for 48 h, achieving 73.38 % cumulative release. In vitro antibacterial studies showed that VCM-HA-SIL-Ps had superior minimum inhibitory concentration against sensitive and resistant Staphylococcus aureus and faster bacterial killing, compared to free VCM. Additionally, VCM-HA-SIL-Ps demonstrated excellent DPPH radicals scavenging and effective anti-inflammatory activity on bacterial toxin-stimulated cells. Finally, in a mouse model of MRSA-induced sepsis, VCM-HA-SIL-Ps achieved 100 % bacterial eradication, significantly reduced pro-inflammatory markers (IL-6, TNF-α, IL-1β by 2.9-, 1.8-, and 5-fold, respectively), and minimized organ damage. Collectively, these findings demonstrate the potential of HA-SIL as a novel multifunctional adjuvant for effective antibiotic delivery against bacterial sepsis.

Patients with liver disease express multiple pathophysiological variations that alter the pharmacokinetics of numerous drugs. At this time, there is insufficient evidence about the proper dosing of vancomycin in patients with liver disease. This study aimed to assess the risk of acute kidney injury (AKI) during vancomycin therapy and identify predictors of AKI and all-cause mortality among patients with varying degrees of liver dysfunction.

A retrospective cohort study was conducted including patients with chronic liver disease who used vancomycin during hospitalization from January 2016 to January 2024 in two Saudi hospitals. Patients were grouped by the severity of the liver disease (mild liver disease [MLD] or moderate-to-severe liver disease [MSLD] based on the Child-Pugh score). The incidence of AKI, vancomycin mean trough level, and all-cause mortality were compared between the two groups. A multivariable logistic regression model was employed to identify predictors of AKI and mortality.

A total of 110 patients treated with vancomycin were included in this study (28 had MLD and 82 had MSLD). A higher incidence of AKI in patients with MSLD than those with MLD was observed (28% vs. 14.3%, respectively; p = 0.1440), but the difference was statistically insignificant. The vancomycin mean trough levels (12.9 ± 5.2 μmol/L vs. 10.2 ± 4.7 μmol/L, p = 0.0143) and the percentage of patients with vancomycin trough level > 13.8 μmol/L (35.4% vs. 10.7%, p = 0.0131) were significantly higher in the MSLD group compared to the MLD group. Having a Creatinine Clearance (CrCl) between 15.1-29.9 ml/min (adjusted Odds ratio [aOR]: 45.5; 95% Confidence interval [CI] 4.99-414.8), and a vancomycin mean trough level > 13.8 μmol/L (aOR: 7.67; 95%CI 2.49-23.63) were associated with a higher risk of AKI development. Similarly, mortality was significantly higher in the MSLD group than in the MLD (23.2% vs. 3.6%, respectively; p = 0.0203). The risk of mortality was associated with having a body mass index (BMI) between 25-29.9 kg/m2 (sOR 6.69; 95%CI 1.73-25.8), an albumin level < 25 g/L (aOR: 4.33; 95%CI 1.36-13.8), and a vancomycin mean trough level > 13.8 μmol/L (aOR: 6.13; 95%CI 1.82-20.6).

Patients who had MSLD had a higher trough vancomycin levels and mortality than patients who had MLD; and this risk increases as liver disease progresses. Thus, the existence of chronic liver disease should be considered when monitoring toxicity from vancomycin to minimize the risk of adverse outcomes and mortality. Larger studies are needed to closely quantify the risk of vancomycin toxicity among patients with chronic liver disease.

Sepsis, a critical medical emergency, continues to pose a substantial worldwide healthcare challenge that necessitates innovative approaches for enhanced treatment. Hence, this study aimed to develop multifunctional biomimetic vancomycin (VCM)-loaded nanoplexes (VCM-FU-PEP-NPs) utilizing a novel antimicrobial peptide (CC-19 peptide) and Fucoidan (FU) to target the Toll-like receptor (TLR) inflammatory pathway and augment the antibacterial efficacy against bacterial sepsis. The CC-19 peptide (CRPRKWIKIKFRCKSLKFC) was designed utilizing computer-aided drug design tools and subsequently synthesized. The biomimetic properties of FU were assessed through in silico and in vitro binding studies, demonstrating a strong affinity for TLR2. The formulated VCM-FU-PEP-NPs demonstrated appropriate physicochemical characteristics, physical stability, and biocompatibility. Moreover, VCM-FU-PEP-NPs exhibited a 2-fold increase in antibacterial efficacy against sensitive Staphylococcus aureus, superior and sustained antibacterial activity against MRSA over 72 h, 5-fold improvement in MRSA biofilm eradication, faster bacterial-killing kinetics, and significantly greater disruption of MRSA membranes, in comparison to bare VCM. Furthermore, VCM-FU-PEP-NPs exhibited excellent DPPH radical scavenging capacity and significant anti-inflammatory efficacy in cells exposed to bacterial toxins. Accordingly, VCM-FU-PEP-NPs demonstrate promise as a potential innovative, multifunctional antibiotic nanocarrier for advancing the treatment of sepsis.

Background: Vancomycin therapeutic drug monitoring (TDM) has traditionally relied on trough concentrations; however, recent guidelines recommend area under the curve (AUC)-based monitoring due to its potential to improve efficacy and safety. Limited studies have evaluated the impact of AUC-based dosing on clinical outcomes, particularly in South Korea. Methods: This single-center retrospective cohort study compared the incidence of acute kidney injury (AKI) and total vancomycin usage between patients receiving TDM based on AUC versus trough concentrations. Propensity score matching was applied to balance baseline characteristics, including age, sex, body weight, renal function, and concomitant nephrotoxic medication use. The study analyzed data from adult patients with normal renal function treated between 2021 and 2023. Results: After propensity score matching, AKI incidence was significantly lower in the AUC-based group (1.20%) compared to the trough-based group (5.08%) (odds ratio 0.23, 95% CI: 0.09-0.59, p = 0.0021). Although no significant differences were observed in treatment duration or dose adjustments, the total administered vancomycin dose was significantly reduced in the AUC-based group. This reduction likely contributed to lower AKI rates and decreased unnecessary drug exposure. Conclusions: Compared to trough-based dosing, AUC-based vancomycin dosing significantly reduced AKI incidence and total drug usage in adult patients with normal renal function. These findings underscore the importance of adopting AUC-based TDM in clinical practice to enhance patient safety and optimize vancomycin therapy. Further studies are needed to evaluate the broader implementation of AUC-based monitoring in diverse clinical settings.

Vancomycin is an effective first-line therapy primarily in methicillin-resistant Staphylococcus aureus (MRSA) infection and Clostridium difficile, however, it has been shown that its effectiveness and the reduction of nephrotoxicity depend on maintaining adequate therapeutic levels. Population pharmacokinetic (PopPk) models attempt to parameterize the behavior of plasma concentrations in different target populations and scenarios such as renal replacement therapy, to successful therapeutic outcome and avoid these side effects.

A scoping review was conducted following the guidelines of Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR), through a search in PubMed, LILACS, OVID Medline, Scopus, Web of Science, SAGE Journals, Google Scholar and previous known registers of PopPk models in non-critically ill adult patients, published between 1998 and 2024.

A total of 190 papers were fully screened, of which were included 36 studies conducted in different populations; 12 in general population, 23 in special populations (surgical, with impaired renal function, obese, elderly, with cancer and cystic fibrosis), and 1 in mixed population (general and with cancer). The main parameters in the models were renal clearance and volume of distribution. The principal covariables that affected the models were creatinine clearance and weight. All studies used internal evaluation and 4 of them used an external group.

The technology for the development and implementation of PopPk models requires experts in clinical pharmacology and is limited to university and research centers. The software is mostly expensive and, in most cases, the pharmacokinetic models and the heterogeneity in the parameters and evaluation methods depend on which compartmental model, parameters, covariates and software have been used.

These models require validation in the clinical context and conducting experiments to adapt them for precision dosing in different subpopulations.

Therapeutic drug monitoring is standard of care for vancomycin because of the known efficacy and safety exposure window (ie, area under the concentration-time curve [AUC] of 400-600 mg × 24 hours/L). Despite guideline recommendations, AUCs are infrequently calculated because of the perceived adequacy of trough (Cmin) concentrations. Yet, the percentage of real-world patients with goal measured vancomycin trough concentrations that achieve target vancomycin AUC remains unknown.

A large cohort of internationally represented adult patients treated with vancomycin in 2021 and 2022 and therapeutic drug monitoring performed had data anonymized via an electronic clearinghouse at DoseMe. Unique patients, dosing events, and measured Cmin were identified. Patient-individualized AUC was calculated using a Bayesian method with 4 validated models. For each dosing event, Cmin and AUC pairs were compared and categorized as "low," "target," and "high" using the therapeutic ranges for Cmin of 15-20 mg/L and AUC of 400-600 mg × 24 hours/L.

In 2022, 17,711 adult patients from the European Union (4.9%), Australia (4.0%), and the United States (91.1%) had 26 769 measured trough levels obtained. Categorical disagreement between Cmin and AUC was 34.3%, with most disagreement (7959 Cmin levels, 30%) occurring with low Cmin but target AUC. Only 23% of paired Cmin and AUC were within range. AUC was variable for all trough categories (ie, low, target, and high).

These findings support AUC therapeutic drug monitoring and challenge Cmin as an adequate vancomycin AUC proxy. Because no trough concentration or range was sufficiently precise to ensure AUC targets, we suggest direct calculation of AUC.

Albumin is recommended in the management of patients with spontaneous bacterial peritonitis (SBP) to reduce rates of renal injury and mortality. Current guideline recommendations suggest an intravenous albumin dosing regimen of 1.5 g/kg on day 1 and 1 g/kg on day 3, although a maximum dosing strategy is not well-defined.

The purpose of this study was to evaluate differences in renal injury for patients with SBP treated with a capped dose less than or equal to 100 g vs a weight-based dose greater than 100 g.

A retrospective analysis was conducted at a single academic medical center for patients with a diagnosis of cirrhosis treated with albumin for SBP. The primary outcome examined rates of acute renal injury at 5 days between patients treated with capped dose vs weight-based doses of intravenous albumin. Secondary outcomes included resolution of SBP by day 5, death by day 5, death by day 30, and change in serum creatinine from day 0 to day 5.

In total, 258 patient encounters were analyzed, with 154 included in this study. There were 70 encounters encompassing the capped dose and 84 in the non-capped. Acute renal injury at day 5 was observed in 10% (n = 7) of the capped dosed group and 6% (n = 5) of the non-capped group (P = 0.381).

This study did not show a significant difference in outcomes associated with a capped albumin dose at 100 g for SBP. Application of these data may aid in reducing health system and patient costs.

Vancomycin (VCM) induces nephrotoxicity in a dose-dependent manner, and patients with risk factors for nephrotoxicity have been reported to develop nephrotoxicity even within the effective concentration range. In the present study, we investigated measures to set an appropriate AUCss for each case by assessing the risk of developing nephrotoxicity using logistic regression curves, separating patients into a High-risk group with risk factors associated with nephrotoxicity when VCM is used and a Low-risk group without risk factors.

A multivariate logistic regression analysis was used to identify risk factors for nephrotoxicity. The AUCss threshold was selected by a CART analysis and ROC curves, and a logistic regression analysis was used to examine the relationship between AUCss and the probability of developing nephrotoxicity.

The incidence of nephrotoxicity was 31.7% (33/104) in the High-risk group and 13.0% (14/108) in the Low-risk group, and was significantly higher in the former (p = 0.001). The AUCss threshold was set at 575 mg·h/L for the High-risk group and 650 mg·h/L for the Low-risk group. The probability of developing nephrotoxicity in the High-risk group (104 patients) was high: AUCss 400 mg·h/L (16.8%), 500 mg·h/L (23.3%), and 575 mg·h/L (29.3%). The target concentration range was newly set at 400 ≤ AUCss < 500, suggesting that the target AUCss needs to be considered for each patient based on the balance between therapeutic efficacy and the prevention of adverse effects. The probability of developing nephrotoxicity in the Low-risk group (108 patients) was AUCss 500 mg·h/L (4.7%), 575 mg·h/L (8.4%), and 650 mg·h/L (14.6%). Since the Low-risk group has a high safety profile, the target concentration range was newly set at 400 ≤ AUCss < 650, suggesting the safe administration of the drug up to AUCss 650 mg·h/L while aiming for AUCss 600 mg·h/L from the initial dose design.

In the present study, the risk of nephrotoxicity for each AUCss was quantitatively analyzed using logistic regression curves for the High- and Low-risk groups. This allowed for the proposal of strategic individual target concentrations based on the balance between risk and benefit.

Osteoarticular infections pose a challenge for therapeutic drug monitoring of vancomycin because they often require prolonged treatment. Given the extensive renal elimination of vancomycin, its pharmacokinetic properties are difficult to predict in the later stages of treatment because the risk of nephrotoxicity increases with the duration of treatment. In this study, published longitudinal population pharmacokinetic (popPK) models were externally evaluated in a cohort of patients with osteoarticular infections.

A literature search was performed in PubMed/EMBASE and published reviews. The predictive performance of the selected models was assessed through prediction- and simulation-based diagnostics using NONMEM software. Data were collected during both the retrospective and prospective phases, during which prospectively recruited patients provided additional vancomycin concentrations.

The external validation dataset comprised 525 vancomycin concentrations obtained from 73 patients treated for osteoarticular infections at Montréal General Hospital. Two published popPK models that provided different approaches for integrating a longitudinal structure were identified. Both failed to meet the clinically acceptable threshold of imprecision in population predictions. The weighted median absolute prediction error ranged from 34.9% to 48.3% before re-estimation of model parameters and from 33.5% to 35.2% after re-estimation. The re-estimated models tended to underpredict vancomycin concentrations in the later stages of treatment.

The 2 evaluated models showed poor predictive performance in our local study population. Further studies should explore new strategies to incorporate a longitudinal component and consider other relevant clinical covariates to develop improved longitudinal popPK models for vancomycin.

Current guidelines recommend dosing vancomycin based on the area under the concentration time curve (AUC) to maximise efficacy and minimise the risk of nephrotoxicity. The preferred approach to AUC-guided therapy is to apply model-informed precision dosing (MIPD). However, the adoption in clinical practice has been slow.

We aimed to develop an intervention, including a standardised MIPD workflow and an implementation plan for vancomycin AUC-guided dosing, in a Swedish tertiary hospital.

The intervention was developed in a framework-guided process. The design phase included stakeholder feedback (nurses, pharmacists, physicians), local data collection and feasibility testing of intervention components with parallel consideration of implementation aspects. The hypothesised relationships between the different components, implementation strategies and the mechanism of action resulting in expected outcomes were represented by a logic model.

The final intervention consisted of a workflow for MIPD, with defined roles and responsibilities, as well as processes for data and information transfer. Details were provided in supportive documents; an instruction on therapeutic drug monitoring (TDM) sampling and documentation for nurses, and a detailed dosing software instruction for MIPD consultants and clinical pharmacists. Activities to facilitate implementation included the development of a local clinical routine for vancomycin dosing, staff training and recurring MIPD rounds.

An intervention for MIPD, with an implementation plan for AUC-guided dosing of vancomycin, was developed for a tertiary hospital setting. The process can be used as guidance for other institutions with similar context wishing to initiate MIPD.

Children with acute hematogenous osteomyelitis (AHO) from methicillin-resistant Staphylococcus aureus (MRSA) are treated with vancomycin despite the risk of acute kidney injury (AKI). This study evaluates the rate of AKI and resource utilization for children with or without AKI when vancomycin is used in this setting.

Children with MRSA AHO treated with vancomycin were retrospectively studied. AKI was assessed by clinical diagnosis and Kidney Disease Improving Global Outcomes (KDIGO) criteria. Cohorts of children with or without AKI were compared for differences in treatment, resource utilization, and outcomes. Multivariate logistic regression analysis assessed factors associated with risk for AKI. Cost analysis was performed using the Pediatric Health Information System and Healthcare Cost and Utilization Project databases.

Among 85 children studied, 14 (16.5%) had chart-diagnosed AKI and 24 (28.2%) met KDIGO criteria. Children with AKI had more febrile days and higher thrombosis rates. They had longer vancomycin treatment (8 vs 5 d), higher troughs (27.8 vs 17.5 mg/L), and prolonged hospitalization (19.9 vs 11.1 d). Multivariate analysis found a maximum vancomycin trough level (odds ratio: 1.05, P = 0.003) with a cutoff of 21.7 mg/L predicted AKI.Only 2 of 20 (10%) children who had MRSA isolates with a minimum inhibitory concentration of 2 achieved therapeutic vancomycin levels. Pediatric Health Information System data of 3133 children with AHO treated with vancomycin identified 75 (2.4%) with AKI who had significantly longer lengths of stay (13 vs 7 d) and higher billed charges ($117K vs $51K) than children without AKI.

Chart documentation of AKI (16.5%) grossly underestimated KDIGO-defined occurrence (28.2%). This study showed that vancomycin-associated AKI required substantially greater resource utilization and higher health care costs. Lowering the targeted trough range, shortening the duration of vancomycin therapy, and considering alternative antibiotics when minimum inhibitory concentration ≥2 will reduce the risk and cost of AKI among children with MRSA AHO.

Level III-retrospective comparative therapeutic study.

Individualized medication with peptide antibiotics, guided by therapeutic drug monitoring, is essential to treat infections caused by multidrug-resistant bacteria. Peptide antibiotics exhibit an "on-off" elution mechanism on a C18 column, leading to adsorption at the column inlet in all-aqueous conditions. Unlike small molecules, column length minimally influences their retention, with longer columns simply broadening peptide antibiotic peaks due to unnecessary post-column volume. Our theory suggests short columns can achieve comparable separation quality and enable faster analysis. Consequently, we developed a rapid LC-MS/MS method using an ultra-short (4 × 2.0 mm) column to quantify five peptide antibiotics in human plasma simultaneously. Calibration curves demonstrated strong linear regression (R2 > 0.996). The inter- and intra-accuracy at the three QC levels ranged from 86.7 % to 109.1 %, and at the LLOQ, it was between 87.6 % and 116.0 %. The precision for QCs and LLOQ was consistently below 11.7 % and 18.5 %, respectively. This method, characterized by simplicity and universality, was undoubtedly useful in clinically tailoring peptide antibiotic medication for individual patients.

Patients with suspected bacterial infection frequently receive empiric, broad-spectrum antibiotics prior to pathogen identification due to the time required for bacteria to grow in culture. Direct-from-blood diagnostics identifying the presence or absence of bacteria and/or resistance genes from whole blood samples within hours of collection could enable earlier antibiotic optimisation for patients suspected to have bacterial infections. However, few randomised trials have evaluated the effect of using direct-from-blood bacterial testing on antibiotic administration and clinical outcomes. This manuscript describes the protocol and statistical analysis plan for a randomised trial designed to evaluate the effect of blood cultures plus direct-from-blood bacterial testing results compared with blood culture results alone on antibiotic administration and clinical outcomes.

We are conducting a prospective, single-centre, parallel-group, non-blinded, pragmatic, randomised trial. The trial will enrol 500 adult patients presenting to the emergency department at Vanderbilt University Medical Center with suspected bacterial infection who have been initiated on empiric intravenous vancomycin. Eligible patients are randomised 1:1 to receive Food and Drug Administration-approved direct-from-blood bacterial testing in addition to blood cultures or blood cultures alone. The primary outcome is the time to the last dose of intravenous vancomycin within 14 days of randomisation. The secondary outcome is the time to the last dose of systemic antipseudomonal beta-lactam antibiotics within 14 days of randomisation. Additional outcomes include highest stage of acute kidney injury, lowest platelet count and receipt of kidney replacement therapy within 14 days of randomisation, as well as hospital-free days, intensive care unit-free-days and all-cause, in-hospital mortality within 28 days of randomisation. Enrolment began on 13 December 2023.

The trial involves human participants and was approved by the Vanderbilt University Medical Center institutional review board with a waiver of informed consent (IRB#231229). Results will be submitted in a peer-reviewed journal and presented at scientific conferences.

NCT06069206.

Among people with cystic fibrosis (PwCF), methicillin-resistant Staphylococcus aureus (MRSA)-associated acute pulmonary exacerbations (APEs) have been increasing in prevalence and can cause rapid declines in lung function and increased mortality. Fortunately, since 2019, incidence has started to decline.

The purpose of this study was to evaluate if doxycycline has comparable efficacy to vancomycin for the treatment of APEs in PwCF. Given the potential toxicities and intolerances associated with vancomycin, evaluating alternative therapies such as doxycycline is warranted.

A multicenter retrospective cohort study was conducted in adult and pediatric PwCF who received greater than 48 hours of either vancomycin or doxycycline to treat MRSA-associated APEs between May 1, 2014, and August 31, 2021. The primary outcome was the number of PwCF with a return to ≥90% of baseline forced expiratory volume in the first second (FEV1).

There were 229 PwCF encounters screened, of which 89 met inclusion criteria (n = 26, vancomycin; n = 63, doxycycline). There were no differences between vancomycin and doxycycline for the primary outcome: 18/26 (69.2%) in the vancomycin group vs 51/63 (81.0%) in the doxycycline group (P = 0.23). Secondary outcomes were similar between groups, including no difference in incidence of acute kidney injury (AKI), although a significantly higher incidence of adverse events occurred in the vancomycin arm.

The findings of this study suggest doxycycline may be a reasonable alternative to vancomycin for MRSA-associated APEs, particularly in PwCF who may not tolerate vancomycin or who require concomitant nephrotoxins such as intravenous (IV) aminoglycosides.

Vancomycin, an antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA), is frequently included in empiric treatment for community-acquired pneumonia (CAP) despite the fact that MRSA is rarely implicated in CAP. Conducting polymerase chain reaction (PCR) testing on nasal swabs to identify the presence of MRSA colonization has been proposed as an antimicrobial stewardship intervention to reduce the use of vancomycin. Observational studies have shown reductions in vancomycin use after implementation of MRSA colonization testing, and this approach has been adopted by CAP guidelines. However, the ability of this intervention to safely reduce vancomycin use has yet to be tested in a randomized controlled trial.

STOP-Vanc is a pragmatic, prospective, single center, non-blinded randomized trial. The objective of this study is to test whether the use of MRSA PCR testing can safely reduce inappropriate vancomycin use in an intensive care setting. Adult patients with suspicion for CAP who are receiving vancomycin and admitted to the Medical Intensive Care Unit at Vanderbilt University Medical Center will be screened for eligibility. Eligible patients will be enrolled and randomized in a 1:1 ratio to either receive MRSA nasal swab PCR testing in addition to usual care (intervention group), or usual care alone (control group). PCR testing results will be transmitted through the electronic health record to the treating clinicians. Primary providers of intervention group patients with negative swab results will also receive a page providing clinical guidance recommending discontinuation of vancomycin. The primary outcome will be vancomycin-free hours alive, defined as the expected number of hours alive and free of the use of vancomycin within the first 7 days following trial enrollment estimated using a proportional odds ratio model. Secondary outcomes include 30-day all-cause mortality and time alive off vancomycin.

STOP-Vanc will provide the first randomized controlled trial data regarding the use of MRSA nasal swab PCR testing to guide antibiotic de-escalation. This study will provide important information regarding the effect of MRSA PCR testing and antimicrobial stewardship guidance on clinical outcomes in an intensive care unit setting.

ClinicalTrials.gov NCT06272994. Registered on February 22, 2024.

Increasing evidence indicates an association between microbiome composition and respiratory homeostasis and disease, particularly disordered breathing, such as obstructive sleep apnea. Previous work showing respiratory disruption is limited by the methodology employed to disrupt, eliminate, or remove the microbiome by antibiotic depletion. Our work utilized germ-free mice born without a microbiome and described respiratory alterations. We used whole-body flow through barometric plethysmography to assay conscious and unrestrained C57BL/6J germ-free (GF, n = 24) and specific-pathogen-free (SPF, n = 28) adult mice (with an intact microbiome) in normoxic (21% O2,79% N2) conditions and during challenges in hypercapnic (5% CO2, 21% O2, 74% N2) and hypoxic (10% O2, 90% N2) environments. Following initial plethysmography analysis, we performed fecal transplants to test the ability of gut microbiome establishment to rescue any observed phenotypes. Data were comprehensively analyzed using our newly published respiratory analysis software, Breathe Easy, to identify alterations in respiratory parameters, including ventilatory frequency, tidal volume, ventilation, apnea frequency, and sigh frequency. We also considered possible metabolic changes by analyzing oxygen consumption, carbon dioxide production, and ventilatory equivalents of oxygen. We also assayed GF and SPF neonates in an autoresuscitation assay to understand the effects of the microbiome on cardiorespiratory stressors in early development. We found several differences in baseline and recovery cardiorespiratory parameters in the neonates and differences in body weight at both ages studied. However, there was no difference in the overall survival of the neonates, and in contrast to prior studies utilizing gut microbial depletion, we found no consequential respiratory alterations in GF versus SPF adult mice at baseline or following fecal transplant in any groups. Interestingly, we did see alterations in oxygen consumption in the GF adult mice, which suggests an altered metabolic demand. Results from this study suggest that microbiome alteration in mice may not play as large a role in respiratory outcomes when a less severe methodology to eliminate the microbiome is utilized.

Due to a narrow therapeutic window, side-effects, toxicities, and individual pharmacokinetics (PK) variability, WHO classifies vancomycin (VCM) as a "watch antibiotic" whose use should be monitored to improve clinical effectiveness. Availability and ease of use have made the immunoassay technique the basic tool for the therapeutic drug monitoring (TDM) of VCM concentrations.

The present study describes the development of a TDM tool for VCM based on anti-eremomycin (ERM) antibody enzyme-linked immunosorbent assay (ELISA).

The optimized assay format based on coating a BSA-VCM conjugate allowed for the equal recognition of both VCM and ERM (100 and 104%) and was not influenced by concomitant antibiotics. Among the sample pretreatments studied, acetonitrile deproteinization was preferred to effectively remove the most likely matrix interferences and to provide 75-96% VCM recovery in the range of 3-30 mg/L, ensuring reliable determination of the key PK parameter, Ctrough. Higher peak concentrations were measured in more diluted samples. Several inflammatory indices, biochemical markers, and key proteins significantly different from normal in critically ill patients were investigated as assay interferers and were found not to interfere with VCM analysis. Serum samples (n = 108) from patients (n = 4) with extensive burn injuries treated with combined antibiotic therapy were analyzed for VCM using the developed assay and confirmed by LC-MS/MS, demonstrating good agreement.

The approach used shows that the same analytical instrument is suitable for measuring structurally related analytes and is fully adequate for their therapeutic monitoring. Suboptimal exposure based on Ctrough values obtained with standard dosing regimens supports the use of TDM in these patients.

The incidence and mortality of severe Gram-positive cocci infections are particularly high in intensive care units (ICUs). Vancomycin remains the treatment of choice for severe infections caused by Gram-positive cocci, particularly methicillin-resistant Staphylococcus aureus (MRSA). Some guidelines recommend therapeutic drug monitoring (TDM) for critically ill patients treated with vancomycin; however, there is currently a lack of evidence to support that TDM improves the mortality rates of these patients. Therefore, we designed this cohort study to compare the impact of monitoring vancomycin blood concentrations on mortality rates in critically ill patients and to provide evidence to support this routine clinical practice.

Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database for a retrospective cohort analysis of critically ill patients receiving intravenous vancomycin treatment. The primary outcome was the 28 day mortality rate. The propensity score matching (PSM) method was used to match the baseline characteristics between patients in the TDM group and the non-TDM group. The relationship between 28 day mortality and vancomycin TDM in the critically ill cohort was evaluated using Cox proportional hazards regression analysis and Kaplan-Meier survival curves. Validation of the primary outcomes was conducted by comparing the PSM model and the Cox proportional hazards regression model. The robustness of the conclusion was subsequently verified by subgroup and sensitivity analyses.

Data for 18,056 critically ill patients who met the study criteria were collected from the MIMIC-IV database. Of these, 7,451 patients had at least one record of vancomycin blood concentration monitoring, which we defined as the TDM group. The TDM group exhibited a 28 day mortality rate of 25.7% (1,912/7,451) compared to 16.2% in the non-TDM group (1,723/10,605). After PSM, 4,264 patients were included in each of the TDM and non-TDM groups, with a 28 day mortality rate of 20.0% (1,022/4,264) in the TDM group and 26.4% (1,126/4,264) in the non-TDM group. Multivariate Cox proportional hazards analysis revealed a significantly lower 28 day mortality risk in the TDM group when compared to the non-TDM group (adjusted hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.79, 0.93; p < 0.001). Further PSM analyses (adjusted HR: 0.91; 95% CI: 0.84, 0.99; p = 0.033) confirmed the lower risk of mortality in the TDM group. Kaplan-Meier survival analysis revealed a significantly higher survival rate at 28 days for the TDM group (log-rank test, p < 0.001). Subgroup analysis results indicated that patients with sepsis, septic shock, estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2, undergoing renal replacement therapy, using vasoactive drugs, on mechanical ventilation, and those with higher severity scores (Acute Physiology Score III ≥40, Oxford Acute Severity of Illness Score ≥30, Simplified Acute Physiology Score II ≥ 30) significantly benefited from monitoring vancomycin blood concentrations. The results remained unchanged excluding patients staying in ICU for less than 48 h or those infected with MRSA.

This cohort study showed that monitoring vancomycin blood concentrations is associated with a significantly lower 28 day mortality rate in critically ill patients, highlighting the importance of routinely performing vancomycin TDM in these patients.

Background: Dalbavancin is a long-acting lipoglycopeptide, approved for treatment of skin and skin structure infections. Its PK/PD profile and safety allow for short hospital stays even in the case of difficult-to-treat infections requiring long courses of therapy, e.g., osteomyelitis, cardiovascular, and prosthetic infections. Objectives: We aimed to evaluate the safety and efficacy of dalbavancin in real life settings for both in-label and off-label indications. Methods: retrospective evaluation of all consecutive patients treated with dalbavancin at our site between May 2017 and September 2021. Results: A total of 100 patients treated with dalbavancin and followed up for 6 months after treatment (58% male; median age 63.5 years, median Charlson Comorbidity Index CCI = 2.7, 28% inpatients) were included with the following indications: acute bacterial skin and skin structure infections (22%), bone and prosthetic infections (57%), and cardiovascular infections (19%). Infections were caused by MSSA (30%), MRSA (5%), MR-CoNS (20%), and Streptococcus spp. (8%). In 32 cases, no isolate was obtained. The average number of infusions was 5 (s.d. = 3). Neither ensuing alteration of renal function nor neutropenia or thrombocytopenia were observed during treatment and follow-up. Two self-limiting skin rashes occurred. The overall clinical success rate was 84%-91% for registered and 82% for unregistered indications. The prescription of higher loading doses was the only predictor independently associated with better outcomes in multivariate models (OR: 5.2, 95%CI: 1.5-17.9, p < 0.01). Conclusions: Dalbavancin proved to be effective for skin and skin structure infections, as well as for difficult-to-treat infections in highly comorbid patients. Regarding tolerability, our results support the use of dalbavancin for long-lasting treatments of deep-seated infections.

Current vancomycin monitoring guidelines recommend monitoring 24-hour area under the concentration-time curve (AUC) to minimum inhibitory concentration ratios for patients with serious methicillin-resistant Staphylococcus aureus infections. However, there are sparse data on the safety, feasibility, and efficacy of vancomycin AUC monitoring for outpatients. Traditional AUC pharmacokinetic calculations require 2 concentrations, while bayesian software allows for single-concentration AUC estimations.

We conducted a single-center, quasi-experimental, interrupted time series study of patients enrolled in the outpatient parenteral antimicrobial therapy program at our institution for vancomycin management. Our institution implemented a pharmacist-driven vancomycin AUC monitoring program from September 2019 to February 2020, and again from September 2022 to March 2023. Patients enrolled underwent vancomycin monitoring using an AUC goal of 400-600 mg⋅h/L, estimated through bayesian modeling. Patients enrolled in the outpatient parenteral antimicrobial therapy program from July 2021 through August 2022 for trough-based monitoring were used for comparison. The primary outcome was nephrotoxicity incidence, defined as a serum creatinine increase by ≥0.5 mg/dL or ≥50% during outpatient vancomycin therapy.

We enrolled 63 patients in the AUC group and 60 patients in the trough-based group. Nephrotoxicity was significantly lower in the AUC cohort (6.3% vs 23.3%; P = .01). The number of unusable vancomycin concentrations was also significantly lower in the AUC cohort (0% vs 6%; P < .01). There was no difference in composite 90-day all-cause mortality or readmission (33.3% vs 38.3%; P = .56).

Following implementation of a pharmacist-driven AUC monitoring program, patients were less likely to develop nephrotoxicity during outpatient vancomycin therapy.

Vancomycin, a crucial antibiotic for Gram-positive bacterial infections, requires therapeutic drug monitoring (TDM). Contemporary guidelines advocate for AUC-based monitoring; however, using Bayesian programs for AUC estimation poses challenges. We aimed to develop and evaluate a simplified AUC estimation equation using a steady-state trough concentration (Ctrough) value. Utilizing 1,034 TDM records from 580 general hospitalized patients at a university-affiliated hospital in Ulsan, we created an equation named SSTA that calculates the AUC by applying Ctrough, body weight, and single dose as input variables. External validation included 326 records from 163 patients at a university-affiliated hospital in Seoul (EWUSH) and literature data from 20 patients at a university-affiliated hospital in Bangkok (MUSI). It was compared with other AUC estimation models based on the Ctrough, including a linear regression model (LR), a sophisticated model based on the first-order equation (VancoPK), and a Bayesian model (BSCt). Evaluation metrics, such as median absolute percentage error (MdAPE) and the percentage of observations within ±20% error (P20), were calculated. External validation using the EWUSH data set showed that SSTA, LR, VancoPK, and BSCt had MdAPE values of 6.4, 10.1, 6.6, and 7.5% and P20 values of 87.1, 82.5, 87.7, and 83.4%, respectively. External validation using the MUSI data set showed that SSTA, LR, and VancoPK had MdAPEs of 5.2, 9.4, and 7.2%, and P20 of 95, 90, and 95%, respectively. Owing to its decent AUC prediction performance, simplicity, and convenience for automated calculation and reporting, SSTA could be used as an adjunctive tool for the AUC-based TDM.

The Infectious Disease Society of America guidelines recommend vancomycin trough levels of 15-20 mg/L for severe methicillin-resistant Staphylococcus aureus. However, recent consensus guidelines of four infectious disease organizations no longer recommend vancomycin dosing using minimum serum trough concentrations. Therefore, this study aimed to evaluate the impact of low (< 15 mg/L) vs. high (≥ 15 mg/L) vancomycin trough levels on clinical outcomes in adult patients with sepsis or gram-positive bacterial infections.

A systematic literature review from inception to December 2022 was conducted using four online databases, followed by a meta-analysis. The outcomes of interest included clinical response/efficacy, microbial clearance, length of ICU stay, treatment failure, nephrotoxicity, and mortality.

Fourteen cohort studies met the inclusion criteria from which vancomycin trough concentration data were available for 5,228 participants. Our analysis found no association between vancomycin trough levels and clinical response [OR = 1.06 (95%CI 0.41-2.72], p = 0.91], microbial clearance [OR = 0.47 (95% CI 0.23-0.96), p = 0.04], ICU length of stay [MD=-1.01 (95%CI -5.73-3.71), p = 0.68], or nephrotoxicity [OR = 0.57 (95% CI 0.31-1.06), p = 0.07]. However, low trough levels were associated with a non-significant trend towards a lower risk of treatment failure [OR = 0.89 (95% CI 0.73-1.10), p = 0.28] and were significantly associated with reduced risk of all-cause mortality [OR = 0.74 (95% CI 0.62-0.90), p = 0.002].

Except for a lower risk of treatment failure and all-cause mortality at low vancomycin trough levels, this meta-analysis found no significant association between vancomycin trough levels and clinical outcomes in adult patients with sepsis or gram-positive bacterial infections.

Vancomycin trough concentration is closely associated with clinical efficacy and toxicity. Predicting vancomycin trough concentrations in pediatric patients is challenging due to significant inter-individual variability and rapid physiological changes during maturation.

This study aimed to develop a machine learning model to predict vancomycin trough concentrations and determine optimal dosing regimens for pediatric patients < 4 years of age using ML algorithms.

A single-center retrospective observational study was conducted from January 2017 to March 2020. Pediatric patients who received intravenous vancomycin and underwent therapeutic drug monitoring were enrolled. Seven ML models [linear regression, gradient boosted decision trees, support vector machine, decision tree, random forest, Bagging, and extreme gradient boosting (XGBoost)] were developed using 31 variables. Performance metrics including R-squared (R2), mean square error (MSE), root mean square error (RMSE), and mean absolute error (MAE) were compared, and important features were ranked.

The study included 120 eligible trough concentration measurements from 112 patients. Of these, 84 measurements were used for training and 36 for testing. Among the seven algorithms tested, XGBoost showed the best performance, with a low prediction error and high goodness of fit (MAE = 2.55, RMSE = 4.13, MSE = 17.12, and R2 = 0.59). Blood urea nitrogen, serum creatinine, and creatinine clearance rate were identified as the most important predictors of vancomycin trough concentration.

An XGBoost ML model was developed to predict vancomycin trough concentrations and aid in drug treatment predictions as a decision-support technology.

Area under the concentration-time curve (AUC)-guided dosing of vancomycin was introduced in a clinical setting; however, the target range of non-steady-state AUCs, such as Day 1 AUC and Day 2 AUC, remains controversial. Therefore, we sought to determine pharmacokinetic parameter thresholds and identify independent risk factors associated with acute kidney injury (AKI) to establish a safe initial dosing design for vancomycin administration.

A single-centre, retrospective, cohort study of hospitalized patients treated with vancomycin was conducted to determine the threshold of both non-steady-state AUCs (Day 1 and 2 AUCs) and trough levels at the first blood sampling point (therapeutic drug monitoring, TDM). In addition, independent risk factors associated with AKI were evaluated using univariate and multivariate logistic regression analyses.

The thresholds for predicting AKI were estimated as 456.6 mg·h/L for AUC0-24h, 554.8 mg·h/L for AUC24-48h, 1080.8 mg·h/L for AUC0-48h and 14.0 μg/mL for measured trough levels, respectively. In a multivariate analysis, Day 2 AUC ≥ 554.8 mg·h/L [adjusted odds ratio (OR), 57.16; 95% confidence interval (CI), 11.95-504.05], piperacillin/tazobactam (adjusted OR, 15.84; 95% CI, 2.73-127.70) and diuretics (adjusted OR, 4.72; 95% CI, 1.13-21.01) were identified as risk factors for AKI.

We identified thresholds for both AUCs in the non-steady-state and trough levels at the first TDM. Our results highlight the importance of monitoring not only the AUC but also trough levels during vancomycin treatment to reduce the likelihood of AKI.

Higher doses of vancomycin are currently prescribed due to the emergence of bacterial tolerance and resistance. This study aimed to evaluate the efficacy and safety of the currently adopted vancomycin dosing guide in pediatric cardiology.

This was a single-center prospective cohort study with pediatric cardiac patients, younger than 14 years, from June 2020 to March 2021. The patients received intravenous vancomycin (40 mg/kg/day divided every 6-8 h) according to the department's vancomycin medication administration guide (MAG) for at least three days.

In total, 88 cardiac patients were included, with a median age of 0.82 years (IQR: 0.25-2.9), and 51 (58%) received cardiopulmonary bypass surgery (CPB). The majority (71.6%, n = 61) achieved a serum vancomycin level within the therapeutic range (7-20 mg/L). Infants, young children, and children exposed to CPB surgery had an increased incidence of subtherapeutic vancomycin levels, [7 (29.2%); P = 0.033], [13 (54.2%); P = 0.01], and [21 (87.5%); P = 0.009] respectively. After the treatment, 8 (10%) patients had an elevated Serum creatinine (SCr) and 2 (2.5%) developed acute kidney injury (AKI). However, no significant difference was found between the patients developing AKI or an elevated SCr and the group who did not, in terms of clinical, therapeutic, and demographic characteristics, except for the decreased incidence of SCr elevation in patients receiving an ACE inhibitor, [4 (36.4%); P = 0.036].

Our institution followed MAG recommendations; however, subtherapeutic serum concentrations were evident in infants, young children, and CPB patients. Strategies to prevent AKI should be investigated, as the possible causes have not been identified in this study.

Vancomycin continuous infusion (CI) has suggested benefits over intermittent infusion: reduced nephrotoxicity, higher target attainment, and simpler therapeutic drug monitoring (TDM). Empiric dosing regimens range from 30-60 mg/kg/day and it is unclear which regimen results in optimal exposure. This study evaluates whether a dosing regimen of 45 mg/kg/day after a 20 mg/kg loading dose for patients with estimated glomerular filtration rate (eGFR) ≥ 50 mL/min results in adequate exposure. We retrospectively analyzed plasma concentrations from patients treated with vancomycin CI as routine clinical care between February and October 2021. Patients under 18 years old, with renal replacement therapy, reduced creatinine clearance (Chronic Kidney Disease Epidemiology Collaboration < 50 mL min/1.73 m2) or outpatient antibiotic therapy were excluded. Dose, renal function, and blood draw procedures were assessed for each measured vancomycin sample. Initially, 121 samples were included. Subsequently, 7 samples, 6 of which with concentrations ≥ 40 mg/L, were verified to be incorrectly drawn and excluded. With doses of 40-50 mg/kg/day concentrations ranged from 18.4-61.0 mg/L. Only 25% were within the target window of 17-25 mg/L and 15% were ≥ 40 mg/L. Supratherapeutic concentrations were observed in 89% of samples from patients dosed 40-60 mg/kg/day with eGFR 50-80 mL/min. Concluding, an empiric dosing regimen of 45 mg/kg results in too high vancomycin exposure and thus we recommend lower doses and differentiation according to renal function. Additionally, when measuring concentrations over 40 mg/L incorrect sampling must be excluded before dose adjustment and the large variability in exposure between patients, warrants the need for swift TDM.

Background: The combination of vancomycin and piperacillin-tazobactam (VPT) has been associated with acute kidney injury (AKI) in hospitalized patients when compared to similar combinations. Additional studies examining this nephrotoxic risk in critically ill patients have not consistently demonstrated the aforementioned association. Furthermore, patients with baseline renal dysfunction have been excluded from almost all of these studies, creating a need to examine the risk in this patient population. Methods: This was a retrospective cohort analysis of critically ill adults with baseline chronic kidney disease (CKD) who received vancomycin plus an anti-pseudomonal beta-lactam at Emory University Hospital. The primary outcome was incidence of AKI. Secondary outcomes included stage of AKI, time to development of AKI, time to return to baseline renal function, new requirement for renal replacement therapy, intensive care unit and hospital length of stay, and in-hospital mortality. Results: A total of 109 patients were included. There was no difference observed in the primary outcome between the VPT (50%) and comparator (58%) group (P = .4), stage 2 or 3 AKI (15.9% vs 6%; P = .98), time to AKI development (1.7 vs 2 days; P = .5), time to return to baseline renal function (4 vs 3 days; P = .2), new requirement for RRT (4.5% vs 1.5%; P = .3), ICU length of stay (7.3 vs 7.4 days; P = .9), hospital length of stay (19.3 vs 20.1 days; P = .87), or in-hospital mortality (15.9% vs 10.8%; P = .4). A significant difference was observed in the duration of antibiotic exposure (3.32 vs 2.62 days; P = .045 days). Conclusion: VPT was not associated with an increased risk of AKI or adverse renal outcomes. Our findings suggest that the use of this antibiotic combination should not be avoided in this patient population. More robust prospective studies are warranted to confirm these findings.

Vancomycin-associated acute kidney injury (AKI) leads to underestimated morbidity in the intensive care unit (ICU). It is significantly important to predict its occurrence in advance. However, risk factors and nomograms to predict this AKI are limited.

This was a retrospective analysis of two databases. A total of 1,959 patients diagnosed with AKI and treated with vancomycin were enrolled from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. According to the 7:3 ratio, the training set (n = 1,372) and the internal validation set (n = 587) were randomly allocated. The external validation set included 211 patients from the eICU Collaborative Research Database (eICU). Next, to screen potential variables, the least absolute shrinkage and selection operator (LASSO) regression was utilized. Subsequently, the nomogram was developed by the variables of the selected results in the multivariable logistic regression. Finally, discrimination, calibration, and clinical utility were evaluated to validate the nomogram.

The constructed nomogram showed fine discrimination in the training set (area under the receiver operator characteristic curve [AUC] = 0.791; 95% confidence interval [CI]: 0.758-0.823), internal validation set (AUC = 0.793; 95% CI: 0.742-0.844), and external validation set (AUC = 0.755; 95% CI: 0.663-0.847). Moreover, it also well demonstrated calibration and clinical utility. The significant improvement (P < 0.001) in net reclassification improvement (NRI) and integrated differentiation improvement (IDI) confirmed that the predictive model outperformed others.

This established nomogram indicated promising performance in determining individual AKI risk of vancomycin-treated critical care patients, which will be beneficial in making clinical decisions.

Vancomycin-induced acute kidney injury (VI-AKI) is one of its serious adverse reactions. The purpose of this study is to discuss the risk factors for VI-AKI in overweight patients and construct a clinical prediction model based on the results of the analysis.

Multivariable logistic regression analysis was used to identify risk factors for VI-AKI and constructed nomogram models. The performance of the nomogram was evaluated based on the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCA).

Cancer (OR 4.186, 95% CI 1.473-11.896), vancomycin trough concentration >20.0 μg/mL (OR 6.251, 95% CI 2.275-17.180), concomitant furosemide (OR 2.722, 95% CI 1.071-6.919) and vasoactive agent (OR 2.824, 95% CI 1.086-7.340) were independent risk factors for VI-AKI. The AUC of the nomogram validation cohorts were 0.807 (95% CI 0.785-0.846). The calibration curve revealed that the predicted outcome was in agreement with the actual observations. Finally, the DCA curves showed that the nomogram had a good clinical applicability value.

There are four independent risk factors for the occurrence of VI-AKI in overweight patients, and the nomogram prediction model has good predictive ability, which can provide reference for clinical decision-making.

Vancomycin, a first-line drug for treating methicillin-resistant Staphylococcus aureus infections, is associated with acute kidney injury (AKI). This study involved an evaluation of biomarkers for AKI detection and their comparison with traditional serum creatinine (SCr). We prospectively enrolled patients scheduled to receive intravenous vancomycin for methicillin-resistant S aureus infection. Blood samples for pharmacokinetic assessment and SCr and cystatin C (CysC) measurements were collected at baseline and on days 3, 7, and 10 from the initiation of vancomycin administration (day 1). Urinary biomarkers, including kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin, and clusterin, were collected from days 1 to 7 and adjusted for urinary creatinine levels. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Of the 42 patients, 6 experienced vancomycin-induced AKI. On day 7, the change from baseline eGFR using CysC (ΔeGFRCysC) showed a stronger correlation with vancomycin area under the curve (r = -0.634, P < .001) than that using SCr (ΔeGFRSCr; r = -0.437, P = .020). ΔeGFRSCr showed no significant correlation with vancomycin pharmacokinetic in patients with body mass index ≥23. The median (interquartile range) level of KIM-1 (μg/mg) was significantly higher in the AKI group (0.006 [0.005-0.008]) than in the non-AKI group (0.004 [0.001-0.005]) (P = .039, Mann-Whitney U test), with area under the receiver operating characteristic curve (95% confidence interval) of 0.788 (0.587-0.990). Serum CysC, particularly in overweight individuals or those with obesity, along with urinary KIM-1 are important predictors of vancomycin-induced AKI. These results may aid in selecting better biomarkers than traditional SCr for detecting vancomycin-induced AKI.

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.

Vancomycin is a renally eliminated, nephrotoxic, glycopeptide antibiotic with a narrow therapeutic window, widely used in intensive care units (ICU). We aimed to predict the risk of inappropriate vancomycin trough levels and appropriate dosing for each ICU patient.

Observed vancomycin trough levels were categorized into sub-therapeutic, therapeutic, and supra-therapeutic levels to train and compare different classification models. We included adult ICU patients (≥ 18 years) with at least one vancomycin concentration measurement during hospitalization at Mayo Clinic, Rochester, MN, from January 2007 to December 2017.

The final cohort consisted of 5337 vancomycin courses. The XGBoost models outperformed other machine learning models with the AUC-ROC of 0.85 and 0.83, specificity of 53% and 47%, and sensitivity of 94% and 94% for sub- and supra-therapeutic categories, respectively. Kinetic estimated glomerular filtration rate and other creatinine-based measurements, vancomycin regimen (dose and interval), comorbidities, body mass index, age, sex, and blood pressure were among the most important variables in the models.

We developed models to assess the risk of sub- and supra-therapeutic vancomycin trough levels to improve the accuracy of drug dosing in critically ill patients.