It is hypothesized that systemically administered antibiotics penetrate wound sites more effectively during negative pressure wound therapy (NPWT). However, there is a lack of clinical data from patients who receive NPWT for deep sternal wound infection (DSWI) after open-heart surgery. Here, we evaluated vancomycin penetration into exudate in this patient group.

For this prospective observational study, we enrolled 10 consecutive patients treated with NPWT for post-sternotomy DSWI. On the first sampling day, serum and exudate samples were synchronously collected at 0 (pre-dose), 0.5, 1, 2, 3 and 6 h after vancomycin administration. On the following three consecutive days, additional samples were collected, only before vancomycin administration.

The ratio of average vancomycin concentration in wound exudate to in serum was higher for free (unbound) (1.51 ± 0.53) than for total (bound + unbound) (0.91 ± 0.29) concentration (p = 0.049). The percentage of free vancomycin was higher in wound exudate than serum (0.79 ± 0.19 vs. 0.46 ± 0.16; p = 0.04). Good vancomycin wound penetration was maintained on the following three days (vancomycin trough exudate-to-serum concentration ratio > 1). The total hospital stay was significantly longer in patients with DSWI (46 ± 11.6 days) versus without DSWI (14 ± 11.7 days) (p < 0.001). There was no in-hospital or 90-day mortality. Two patients experienced late DSWI recurrence. All-cause mortality was 4.8% during a median follow-up of 2.5 years.

Vancomycin effectively penetrates wound exudate in patients receiving NPWT for DSWI after open-heart surgery.The protocol for this study was registered at ClinicalTrials.gov on July 16, 2024 (NCT06506032).

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.

Optimizing vancomycin dosing in neonates is a critical yet complex goal. Traditional trough concentration-based dosing strategies correlate poorly with therapeutic efficacy and often fail to account for the significant renal function variability and drug clearance in neonates. The 24-hour area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) ≥ 400 mg h/L has emerged as a superior pharmacodynamic target. Population pharmacokinetics (PopPK) models allow optimized dosing by incorporating neonatal-specific factors such as postmenstrual age (PMA), gestational age (GA), serum creatinine (SCr), and weight.

To develop optimized vancomycin dosing regimens for neonates that achieve an 80% probability of target attainment (PTA) for an AUC24/MIC ≥ 400 mg h/L across diverse clinical cohorts and simulated neonatal populations.

Real-world data from three international centers (Belgium, New Zealand, USA), including 610 individuals and 2399 vancomycin concentrations, were used to externally evaluate a previously published PopPK model (NONMEM®). Missing data, including body weight, were imputed using Amelia II version 1.7.3 for R, while Zelig for R integrated multiple imputed datasets. A virtual population of 10,000 neonates was independently generated using MATLAB to simulate clinical scenarios considering covariates such as PMA, GA, SCr, body weight, and imputed body length.

Simulations showed that PMA and SCr were key covariates that significantly improved PTA, particularly in preterm neonates. Preterm neonates achieved PTAs of 80% with daily doses of 30 or 40 mg/kg/day, while term neonates required 15 mg/kg every 8 hours or 20 mg/kg every 12 hours. The simulations demonstrated that these optimized dosing strategies achieved an 80% PTA for AUC24/MIC ≥ 400 mg h/L in the virtual neonatal population. For neonates with PMA < 29 weeks and SCr > 0.6 mg/dL, including SCr as a covariate increased the likelihood of achieving the target from 65% to 87%.

Incorporating developmental factors like PMA and SCr into vancomycin dosing strategies achieved robust and clinically relevant outcomes. The optimized regimens achieved an 80% PTA for the AUC24/MIC target for preterm and term neonates. These findings offer a scalable framework for improving neonatal vancomycin pharmacotherapy across diverse populations and clinical settings.

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.

Periprosthetic joint infection (PJI) remains a feared complication after total knee arthroplasty (TKA). This study reports updated outcomes of the incidence of PJI, adverse reactions, and complications of our cohort with increased clinical follow-up of our previous study reported in 2021.

A retrospective review of 1,923 knees that received either IV or IO vancomycin during primary TKA between May 2016 and May 2023 with a minimum 90-day follow-up (mean 913 ± 611 days). There were 564 cases in the IV group and 1,359 in the IO group. The IV group received a weight-based dose of vancomycin before incision, and the IO group received 500 mg of vancomycin in the proximal tibia after tourniquet inflation. All patients received a weight-based dose of IV cefazolin perioperatively. The 2018 International Consensus Meeting criteria were used to diagnose PJI. Acute kidney injury (AKI) was defined as a creatinine increase of 0.3 mg/dL.

The IO group demonstrated a significantly lower incidence of PJI compared to the IV group at 90-day (0.5 versus 1.6%, P = 0.018), 1-year (0.7 versus 1.8%, P = 0.048), and 2-year (0.9 versus 2.4%, P = 0.032) follow-up. Additionally, there was a lower incidence of non-operative wound complications requiring oral antibiotics in the IO group at 30-day (2.3 versus 4.3%, P = 0.023) and at 90-day (2.5 versus 5.4%, P = 0.003) follow-up. There was a lower incidence of AKI in the IO group (1.6 versus 3.2%, P = 0.078), but this did not reach statistical significance. There was no difference in the incidence of deep vein thrombosis, pulmonary embolism, or operative wound complications.

Intraosseous vancomycin demonstrated superior clinical outcomes over IV vancomycin with a reduced incidence of PJI at 90-day, 1- and 2-year follow-up after primary TKA. Additional benefits of IO vancomycin were a reduction in non-operative wound complications through 90-day follow-up and a non-statistically significant reduction in the incidence of AKI.

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/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.

Staphylococcus aureus (SA) pneumonia is a leading cause of neonatal morbidity and mortality, particularly with methicillin-resistant Staphylococcus aureus (MRSA). Despite its prevalence, limited studies have focused on clinical presentation, antimicrobial resistance patterns, and outcomes of SA pneumonia in neonates. This study aimed to explore the clinical features, laboratory findings, and outcomes of neonates with SA pneumonia at the National Children's Hospital, Vietnam.

We conducted a retrospective observational study on 31 neonates diagnosed with SA pneumonia from January 2022 to June 2023. Clinical data, including demographic details, symptoms, white blood cell (WBC) count, C-reactive protein (CRP) levels, antimicrobial susceptibility, and radiological findings, were collected. We analyzed the antibiotic resistance patterns of SA and evaluated factors associated with vancomycin treatment failure.

Of the 31 neonates, 96.8 % were diagnosed with MRSA pneumonia. The main clinical symptoms were fever (77.4 %), tachypnea (83.9 %), and chest retraction (80.6 %). SA was primarily isolated from endotracheal fluid (71.0 %), pleural fluid (41.9 %), and both combined (51.6 %) with positive blood cultures. Complications were common, with pleural effusion in 54.8 %, pneumothorax in 48.4 %, necrotizing pneumonia in 25.8 %, and lung abscess in 29.0 % of cases. Vancomycin was the primary antibiotic administered, though treatment failure occurred in 38.7 % of cases, necessitating alternative antibiotics, particularly in patients with severe illness requiring mechanical ventilation, vasopressor support, and elevated CRP levels (>15 mg/L). Most strains were resistant to beta-lactam antibiotics but sensitive to vancomycin, linezolid, ciprofloxacin, and levofloxacin. The average hospital stay was 24.4 ± 12.6 days, with a mortality rate of 12.9 %, mainly due to severe respiratory failure and septic shock.

These findings highlight the critical importance of early diagnosis, optimized antibiotic therapy, and careful monitoring to reduce complications and improve survival outcomes in neonates with SA pneumonia.

Off-target effects, which arise from drug interactions in nontarget tissues, can lead to unfavored side effects. The treatment efficacy of vancomycin (Vanco) in Gram-positive bacterial infections is often compromised by the frequent occurrence of Vanco-induced vascular injury. However, the potential targets and underlying molecular mechanisms of this phenomenon remain unclear. Here, we developed multidimensional two-photon imaging for dynamic tracking of fluorescently labeled Vanco in vivo, characterizing the molecular behavior of Vanco in situ after administration and providing the first direct evidence of its interactions with vascular wall. Morphological analysis combined with colocalization imaging identified elastin within the vascular wall as the molecular target. After binding, Vanco underwent self-assembly into forming irregular nanoaggregates, primarily driven by electrostatic and hydrophobic forces. This persistent binding and self-assembly on the elastic lamina resulted in significant endothelial cytotoxicity and subsequent apoptosis, suggesting a mechanistic link to the vascular injury observed in clinical settings. Taken together, our findings revealed off-target molecular interactions between Vanco and vascular elastin in situ, highlighting the importance of considering unintended drug-vascular interactions.

Staphylococcus aureus (S. aureus) is a Gram positive opportunistic pathogen and a major cause for bacterial septic arthritis. Vancomycin is the preferred antibiotic for the treatment of methicillin resistance S. aureus septic arthritis. Patients undergoing vancomycin treatment need to be hospitalized and their serum vancomycin level should be monitored, as increase in vancomycin concentration in serum may lead to hepatotoxicity. To overcome vancomycin mediated cytotoxicity, we have prepared a local injectable delivery system by incorporating vancomycin into hyaluronic acid (HA)-chitosan (van-HA-chitosan) hydrogel. The prepared van-HA-chitosan hydrogel was characterized using Fourier Transform Infrared Spectroscopy (FTIR) and rheometer. The van-HA-chitosan hydrogel is injectable, has shear thinning behaviour; and is hemo- and cyto-compatible. In vitro drug release assay showed that 95 % of vancomycin was released from the hydrogel in 8 days. Under in vitro conditions the load of S. aureus decreased from 6.4 Log10 CFU/ml to 3.5 Log10 CFU/ml when treated with van-HA-chitosan hydrogel for 6 h. Significant decrease in bacterial counts was observed when S. aureus infected synovial fluid and bone samples were treated with van-HA-chitosan hydrogel. Our results suggest that the prepared van-HA-chitosan could be used for the treatment of septic arthritis caused by S. aureus.

To develop and validate a novel artificial intelligence model for predicting the initial empiric dose of vancomycin, with the aim of achieving an area under the concentration-time curve (AUC) of 400-600 mg∙h/L, using individual clinical data.

Machine learning models were developed and validated internally and externally using data from adult patients who received intravenous vancomycin treatment between November 2020 and June 2023, using records from July to September 2023, sourced from two hospitals. This study included 205, 44, and 35 patients in the training, internal validation, and external validation sets, respectively. The Random Forest, XGBoost, and Ensemble models were evaluated based on the mean squared error, root mean squared error, R-squared value, and accuracy (±20 % of the actual dose).

In internal validation, the Random Forest model achieved the highest 20% Accuracy at 56.8%, while the XGBoost model achieved 56.8% and Voting Ensemble models attained 54.5% accuracy. In external validation, the XGBoost model achieved the highest 20% Accuracy at 74.3%, followed by Random Forest and Voting Ensemble, both also achieving 74.3% accuracy. The estimated glomerular filtration rate was the most significant predictor in all models, with body weight, serum creatinine, height, and age also prominently influencing the XGBoost model's predictions.

The proposed model is capable of accurately predicting the optimal dose of vancomycin, which could aid physicians in making more informed treatment decisions regarding early therapy, particularly when AUC estimation systems are not accessible or readily available in routine clinical practice.

Evidence on the optimal targets of vancomycin for treating other Gram-positive infections apart from methicillin-resistant Staphylococcus aureus (MRSA) is lacking. This review aims to identify the recommended vancomycin therapeutic level for favourable clinical outcomes among patients infected with vancomycin-sensitive enterococcal infections.

Analytical studies describing the vancomycin levels of vancomycin-sensitive enterococcal infections among adult population were searched. The primary outcome was 30-day all-cause mortality, and the secondary outcomes were clinical failure and nephrotoxicity. Study characteristics were extracted and pooled using random-effects meta-analysis. The study quality was assessed using the Joanna Briggs Institute critical appraisal tool.

A total of nine retrospective cohorts studies involving 1013 patients with vancomycin-sensitive enterococci were included. The meta-analysis found that high area under the curve to minimum inhibitory concentration ratio (AUC/MIC) of vancomycin ≥ 389 mg*h/L significantly lowered the 30-day mortality (odds ratio [OR], 0.44, 95% confidence interval [CI], 0.26-0.75). Analysis of the target AUC/MIC showed that high vancomycin AUC/MIC (≥ 389-400 mg*h/L) significantly reduced clinical failure rate (OR 0.59, 95% CI 0.37-0.94). The mortality and treatment failure rates did not differ significantly between those with high or low trough levels. Higher vancomycin AUC/MIC and trough levels were significantly associated with increased nephrotoxicity (OR 3.11, 95% CI 1.65-5.89; OR 2.95, 95% CI 1.60-5.44, respectively).

The use of a higher vancomycin AUC/MIC concentration can be effective to reduce 30-day mortality and clinical failure but this needs to take into consideration the risk of nephrotoxicity. Well-conducted prospective studies are warranted due to the scarcity of evidence.

Vancomycin is commonly dosed using standard weight-based methods before dose adjustments are made through therapeutic drug monitoring (TDM). However, variability in initial dosing can lead to suboptimal therapeutic outcomes. A predictive model that personalizes initial dosing based on patient-specific pharmacokinetic factors prior to administration may enhance target attainment and minimize the need for subsequent dose adjustments.

This study aimed to develop and evaluate a machine learning (ML)-based algorithm to predict whether an initial vancomycin dose falls within the therapeutic range of the 24-hour area under the curve to minimum inhibitory concentration, thereby optimizing the initial vancomycin dosage.

A retrospective cohort study was conducted using hospitalized patients who received intravenous vancomycin and underwent pharmacokinetic TDM consultation (n=415). The cohort was randomly divided into training and testing datasets in a 7:3 ratio, and multiple ML techniques were used to develop an algorithm for optimizing initial vancomycin dosing. The optimal algorithm, referred to as the OPTIVAN algorithm, was selected and validated using an external cohort (n=268). We evaluated the performance of 4 ML models: gradient boosting machine, random forest (RF), support vector machine (SVM), and eXtreme gradient boosting (XGB). Additionally, a web-based clinical support tool was developed to facilitate real-time vancomycin TDM application in clinical practice.

The SVM algorithm demonstrated the best predictive performance, achieving an area under the receiver operating characteristic curve (AUROC) of 0.832 (95% CI 0.753-0.900) for the training dataset and 0.720 (95% CI 0.654-0.783) for the external validation dataset. The gradient boosting machine followed closely with AUROC scores of 0.802 (95% CI 0.667-0.857) for the training dataset and 0.689 (95% CI 0.596-0.733) for the validation dataset. In contrast, both XGB and RF exhibited relatively lower performance. XGB achieved AUROC values of 0.769 (95% CI 0.671-0.853) for the training set and 0.707 (95% CI 0.644-0.772) for the validation set, while RF recorded AUROC scores of 0.759 (95% CI 0.656-0.846) for the test dataset and 0.693 (95% CI 0.625-0.757) for the external validation set. The SVM model incorporated 7 covariates: age, BMI, glucose, blood urea nitrogen, estimated glomerular filtration rate, hematocrit, and daily dose per body weight. Subgroup analyses demonstrated consistent performance across different patient categories, such as renal function, sex, and BMI. A web-based TDM analysis tool was developed using the OPTIVAN algorithm.

The OPTIVAN algorithm represents a significant advancement in personalized initial vancomycin dosing, addressing the limitations of current TDM practices. By optimizing the initial dose, this algorithm may reduce the need for subsequent dosage adjustments. The algorithm's web-based app is easy to use, making it a practical tool for clinicians. This study highlights the potential of ML to enhance the effectiveness of vancomycin treatment.

AUC-based dosing with validated Bayesian software is recommended as a good approach to guide bedside vancomycin dosing.

To compare treatment and vancomycin-associated acute kidney injury (AKI) costs between Bayesian AUC-based dosing and conventional therapeutic drug monitoring (TDM) using steady-state plasma concentrations of vancomycin administered as continuous infusion in hospitalized non-critically ill patients with severe Gram-positive infection.

A cost-benefit analysis presented as a return on investment (ROI) analysis from a hospital perspective was conducted using a decision tree model (TDM versus AUC-based dosing) to simulate treatment cost (personnel, serum sampling and drug cost), vancomycin-associated AKI risk and cost up to 14 days. ROI was calculated against AUC-based software cost. One-way and probabilistic sensitivity analyses (respectively OWSA and PSA) were performed to check for robustness.

In base case, an overall cost per patient of €621.0 with TDM and €543.6 with AUC-based dosing resulted in a treatment saving of €77.4 per patient when applying AUC-based dosing. This saving against the software cost (€26.9/patient) generated an ROI per patient of €1.9 per invested € in software [€1.9 (95% CI 1.6-2.2) in PSA]. Enrolling 900 AUC-based dosed patients annually translated to a net saving of €45 469. Software break-even was reached after 313 patients. In OWSA, a higher AKI risk with TDM strongly contributed to a positive ROI.

AUC-based dosing appeared a cost-saving strategy compared with conventional TDM when applying base-case settings of vancomycin-associated AKI risk, treatment and AKI 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.

It has been reported that the protein binding rate of vancomycin (VCM) varies among individual patients. So, the authors investigated relevant factors that may affect free VCM concentration and target attainment of free area under the concentration-time curve (fAUC).

Thirty-nine patients were included. Multiple regression analysis was performed to determine the valuable factors in the free VCM concentration, and the target attainment of area under the concentration-time curve (AUC) 400-600 mg・h/L and fAUC200-300 mg・h/L was calculated.

We found total protein was significant covariate for free VCM. Among 18 patients who were investigated for AUC and fAUC estimation, 9 patients (50.0%) and 12 patients (66.7%) reached AUC > 600 mg・h/L, and fAUC > 300 mg・h/L (p = 0.310), respectively.

Total protein is a significant predictor for free VCM estimation. And the fAUC-guided TDM for VCM TDM may contribute to more strict dosing than the AUC-guided TDM in hyper- or hypo-proteinemic population.

Retrospectively registered.

Little is known about the frequency, hospital-level variation, predictors, and outcomes of antibiotic de-escalation in suspected sepsis.

We retrospectively analyzed adults admitted to 236 US hospitals from 2017-2021 with suspected sepsis (defined by blood culture draw, lactate measurement, and intravenous antibiotic administration) who were initially treated with ≥2 days of anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-pseudomonal antibiotics but had no resistant organisms that required these agents identified through hospital day 4. De-escalation was defined as stopping anti-MRSA and anti-pseudomonal antibiotics or switching to narrower antibiotics by day 4. We created a propensity score for de-escalation using 82 hospital and clinical variables; matched de-escalated to non-de-escalated patients; and assessed associations between de-escalation and outcomes.

Among 124 577 patients, antibiotics were de-escalated in 36 806 (29.5%): narrowing in 27 177 (21.8%), cessation in 9629 (7.7%). De-escalation rates varied between hospitals (median, 29.4%; interquartile range, 21.3%-38.0%). Predictors of de-escalation included less severe disease on day 3-4, positive cultures for nonresistant organisms, and negative/absent MRSA nasal swabs. De-escalation was more common in medium, large, and teaching hospitals in the Northeast and Midwest. De-escalation was associated with lower adjusted risks for acute kidney injury (AKI) (odds ratio [OR], 0.80; 95% confidence interval [CI], .76-.84), intensive-care unit (ICU) admission after day 4 (OR, 0.59; 95% CI, .52-.66), and in-hospital mortality (OR, 0.92; 95% CI, .86-.996).

Antibiotic de-escalation in suspected sepsis is infrequent, variable across hospitals, linked with clinical and microbiologic factors, and associated with lower risk for AKI, ICU admission, and in-hospital mortality.

Therapeutic drug monitoring (TDM) is recommended during vancomycin (VCM) administration to adjust the dosage such that the area under the curve (AUC) remains between 400 and 600 µg·h/mL (minimum inhibitory concentration = 1 µg/mL). However, measuring the AUC requires frequent blood sampling, which increases the burden of added time and cost for testing on both patients and healthcare personnel. Therefore, we aimed to address these issues by developing a simple and rapid method for measuring urinary VCM levels using solid-phase extraction and fluorescence spectrometry. The developed method had a quantification range of 100-2,000 µg/mL, with an accuracy of 100.0%-108.5% for concentrations of 200, 1,000, and 2,000 µg/mL. The intra- and inter-day relative standard deviations were below 3.39% and 4.48%, respectively. Furthermore, to predict the AUC from urinary VCM concentrations, we calculated the slope of the urinary concentrations at 7-12 h post-VCM administration in six patients. The slope for one patient differed significantly from that for the others, and the AUC was obtained using practical AUC-guided TDM for vancomycin (PAT) ver. 3.0c for the patient whose value deviated from the recommended range. A negative correlation was observed between the slope and AUC, with a correlation coefficient of 0.65, suggesting the potential for predicting AUC from urinary concentration trends. The use of urine samples, which can be easily obtained, for VCM dose adjustment is expected to contribute to providing more appropriate drug therapy to patients and reduce the burden on healthcare professionals.

This study aimed to develop a suitable osteomyelitis model for pharmacokinetic/pharmacodynamic (PK/PD) evaluation and to investigate the target PK/PD values of vancomycin and tedizolid against methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis.

An osteomyelitis model was established by implanting an MRSA-exposed sterilized suture in the tibia of normal mice and mice with cyclophosphamide-induced neutropenia. The suitability of the osteomyelitis mouse model for PK/PD evaluation was assessed using vancomycin as an indicator. The target PK/PD values for tedizolid were determined using this model.

In neutropenic mice, to achieve a static effect and 1 log10 kill against MRSA, the ratios of the area under the free drug concentration-time curve for 24 h to the minimum inhibitory concentration (fAUC24/MIC) of vancomycin were 91.29 and 430.03, respectively, confirming the validity of the osteomyelitis model for PK/PD evaluation. In immunocompetent mice, the target fAUC24/MIC values of tedizolid for achieving a static effect and 1 log10 kill against MRSA were 2.40 and 49.20, respectively. Additionally, only a 0.28 log10 kill was achieved in neutropenic mice with 20 times the human equivalent dose of tedizolid.

In patients with restored immunity, tedizolid can potentially be used as an alternative to intravenous vancomycin therapy.

Acute kidney injury (AKI) is a complication associated with vancomycin use. There is evidence that this was related to the presence of supratherapeutic vancomycin levels rather than the drug itself. The area under the curve over 24 h to minimum inhibitory concentration (AUC/MIC) dosing for vancomycin has replaced trough-based dosing, but the impact of this change on AKI rates remains unclear. A retrospective cohort study was conducted in a tertiary care teaching hospital. Patients from the trough cohort were recruited from January 1, 2019, to June 30, 2019, and the AUC/MIC cohort from July 1, 2021, to January 1, 2022. Sociodemographics, clinical characteristics, and concomitant medications were obtained. AKI was defined by The Kidney Disease Improving Global Outcomes. A total of 1056 patients were included, 509 in the trough cohort and 547 in the AUC/MIC cohort. The baseline rates of chronic kidney disease were 15.4% and 9.9%, respectively. The AKI rates were 15.9% and 11.9% for trough and AUC/MIC cohorts, respectively (P-value .045). The most frequent nephrotoxins were piperacillin/tazobactam (TZP), diuretics, and IV contrast for both groups. The rates of supratherapeutic levels were higher in the trough cohort (20.7%) than in the AUC/MIC cohort (6.6%). The multivariate logistic regression analysis showed that trough dosing was not associated with increased rates of AKI (OR = 0.96 CI 0.64-1.44). Supratherapeutic levels (OR = 4.64), diuretics (OR = 1.62), TZP (OR = 2.01), and ICU admission (OR = 1.72) were associated with AKI. Vancomycin AUC/MIC dosing strategy was associated with decreased rates of supratherapeutic levels of this drug compared to trough dosing, with a trend toward lower rates of AKI.

Donor-derived fecal microbiota treatments are efficacious in preventing recurrent Clostridioides difficile infection (rCDI), but they have inherently variable quality attributes, are difficult to scale and harbor the risk of pathogen transfer. In contrast, VE303 is a defined consortium of eight purified, clonal bacterial strains developed for prevention of rCDI. In the phase 2 CONSORTIUM study, high-dose VE303 was well tolerated and reduced the odds of rCDI by more than 80% compared to placebo. VE303 organisms robustly colonized the gut in the high-dose group and were among the top taxa associated with non-recurrence. Multi-omic modeling identified antibiotic history, baseline stool metabolites and serum cytokines as predictors of both on-study CDI recurrence and VE303 colonization. VE303 potentiated early recovery of the host microbiome and metabolites with increases in short-chain fatty acids, secondary bile acids and bile salt hydrolase genes after antibiotic treatment for CDI, which is considered important to prevent CDI recurrences. These results support the idea that VE303 promotes efficacy in rCDI through multiple mechanisms.

Intubated patients with methicillin-resistant Staphylococcus aureus pneumonia, fail optimized treatment with intravenous (IV) vancomycin (serum trough 15-20 μg/mL) in 38-79% of cases. Airway blood flow is diminished compared to alveoli and we hypothesized that vancomycin concentrations achieved in airway secretions are suboptimal and nonbactericidal. Targeted therapy by inhalation may overcome this deficit.

Airway pharmacokinetics of optimized IV and inhaled vancomycin in infected clinically stable prolonged mechanically ventilated patients were measured. First, IV vancomycin was given until optimized concentrations were achieved (15-20 μg/mL), and, at the same time point, sputum vancomycin concentrations were measured. Then, sputum concentrations were re-assessed after 4 treatments of inhaled vancomycin (120 mg/2 mL) via a previously characterized nebulizing system that deposited 18 ± 2 mg in the lungs. Vancomycin post-distribution phase serum peak and trough concentrations were also obtained. Serum albumin was measured to assess binding to vancomycin.

Mean serum trough concentration was 18.4 ± 6.5 μg/mL. Sputum concentrations were affected by serum albumin. Only patients with severe hypoalbuminaemia had penetration of drug leading to therapeutic (15.7-17 μg/mL) sputum concentrations. Following inhaled vancomycin, sputum concentrations increased significantly to 199 ± 37.0 μg/mL (P = .002) exceeding minimum inhibitory concentration by 2 orders of magnitude.

Despite optimized serum concentrations, patients with albumin near normal had suboptimal concentrations of vancomycin in their sputum. Inhaled therapy may be clinically important for successful treatment of ventilator-associated methicillin-resistant Staphylococcus aureus infection. Further studies of inhaled therapy are needed to define their role as adjunctive therapy in ventilator-associated pneumonia and as single therapy in tracheobronchitis.

Vancomycin is an antibiotic used for severe infections. To ensure microbiological efficacy, a ratio of AUC/MIC ≥400 is recommended. However, there is significant interindividual variability in its pharmacokinetic parameters, necessitating therapeutic drug monitoring to adjust dosing regimens and ensure efficacy while avoiding toxicity. Population pharmacokinetic (PopPK) models enable dose personalization, but the challenge lies in the choice of the model to use among the multitude of models in the literature. We compared 18 PopPK models created from populations with the same sociodemographic and clinicobiological characteristics. Simulations were performed for a 47 years old man, weighing 70 kg, with an albumin level of 35.5 g/L, a creatinine clearance of 100 mL/min, an eGFR of 106 mL/min/1.73 m2, and receiving an intravenous infusion of 1 g × 2/day of VCM over 1 h for 48 h. Simulations of time-concentration profiles revealed differences, leading us to determine the probability of achieving microbiological efficacy (AUC/MIC ≥ 400) with each model. Depending on some models, a dose of 1 g × 2/day is required to ensure microbiological efficacy in over 90% of the population, while with the same dose other models do not exceed 10% of the population. To ensure that 90% of the patients are correctly exposed, a dose of vancomycin ranging from 0.9 g × 2/day to 2.2 g × 2/day is necessary a priori depending on the chosen model. These differences raise an issue in choosing a model for performing therapeutic drug monitoring using a PopPK model with or without Bayesian approach. Thus, it is fundamental to evaluate the impact of these differences on both efficacy/toxicity.

Vancomycin, a glycopeptide antibiotic has antibacterial activity against Gram-positive bacteria and is frequently used in the intensive care unit (ICU). Inappropriate therapeutic drug monitoring (TDM) of vancomycin is a common problem encountered in hospital daily practice. The aim of this study was to evaluate the appropriateness of vancomycin trough-guided TDM in patients treated in the ICU using a clinical pharmacy approach.

The study was conducted retrospectively in patients over 18 years old who had at least one vancomycin trough level and who had received intravenous (IV) vancomycin for ≥3 days between 1 November 2020 and 1 April 2022. The study included 137 patients. Patient demographics and relevant vancomycin TDM data were collected from medical records. The appropriateness of TDM was evaluated according to the criteria established based on the monitoring recommendations specified in consensus guidelines for therapeutic drug monitoring of vancomycin published by the American Society of Health-System Pharmacists (ASHP) in 2009 and 2020.

Of a total of 238 vancomycin trough levels measured in patients, 32.4% were collected at an inappropriate time. When patients were evaluated in terms of TDM appropriateness according to vancomycin level ranges (<10 µg/mL, 10-20 µg/mL and >20 µg/mL), we found the appropriate TDM was significantly higher in the therapeutic range (10-20 µg/mL) (p <0.001). Of the total 238 vancomycin trough concentrations taken from patients, 77 (32.4%) were measured at an inappropriate time. This caused dose withholding, wrong adjustments and therapy failure. The total TDM appropriateness of vancomycin was significantly higher in the therapeutic range defined as 10-20 µg/mL when evaluated based on 'TDM appropriateness criteria' (p <0.001).

Our study shows that appropriate vancomycin TDM increases the likelihood of achieving target trough concentrations. Involvement of clinical pharmacists in TDM management may prevent the development of adverse reactions by ensuring appropriate sampling time and appropriate interpretation of vancomycin levels.

To monitor total trough concentration (Cmin_total) and unbound trough concentration (Cmin_free) of vancomycin in clinical samples and analyze the factors influencing them, and to assess their correlation with clinical efficacy and acute kidney injury (AKI).

Plasma samples were processed by protein precipitation, followed by hollow-fiber centrifugal ultrafiltration to separate unbound vancomycin from plasma. Thereafter, Cmin_total and Cmin_free were determined using high-performance liquid chromatography. Clinical data of patients were collected. Factors affecting vancomycin Cmin_total, Cmin_free, and their correlation with clinical efficacy and nephrotoxicity were investigated.

A total of 146 samples from 105 included patients were collected. Cmin_total and Cmin_free of vancomycin ranged from 0.62 to 56.08 mcg·mL-1 and 0.61-38.51 mcg·mL-1, respectively. Cmin_total and Cmin_free were correlated (r = 0.8899), influenced by basal creatinine and cystatin C. Higher level of Cmin_free (˃8.6 mcg·mL-1) and nephrotoxic drugs concomitant were risk factors of vancomycin-associated AKI (P < 0.05); Cmin_total and Cmin_free thresholds of vancomycin-associated AKI were 15.35 and 6.83 mcg·mL-1, respectively.

vancomycin Cmin_total and Cmin_free, higher Cmin_total and Cmin_free were correlated and higher concentrations of both may increase the risk of AKI.

Background: The objective of this study was to compare infection rates, pathogen species detection and antimicrobial susceptibility testing in patients with total hip arthroplasty (THA) and total knee arthroplasty (TKA) following post-traumatic osteoarthritis (PTOA) and primary osteoarthritis (POA). Results: Patients undergoing both THA and TKA were significantly more likely to have a PJI after PTOA than after POA (THA: 2.5% vs. 10.2%, p = 0.003; TKA: 3.2% vs. 10.3%, p = 0.028). The most frequently detected pathogen in both THA and TKA was Staphylococcus spp. Among patients with a PJI in THA, Staphylococcus spp. was detected in 47% after POA and 60% after PTOA. Among patients with a PJI in TKA, Staphylococcus spp. was isolated in 59% after POA and 80% after PTOA. The remaining pathogens were mainly Enterococcus spp., Enterobacterales and anaerobic bacteria. After THA, beta-lactam-resistant staphylococcal isolates were detected more frequently in PTOA patients than in POA patients (13% vs. 100%, p = 0.024). There was no difference in the beta-lactam staphylococcal resistance rate in patients after TKA (20% vs. 25%, p = 0.945). Furthermore, an analysis of susceptibility testing from all groups showed that significantly more pathogens were susceptible to vancomycin than to cefuroxime (76% vs. 45%, p < 0.001) or clindamycin (76% vs. 52%, p = 0.007). Methods: A retrospective analysis was performed using clinic-owned data during the period January 2016-December 2020. A total of 1485 patients following primary implantation of THA or TKA due to PTOA or POA were included. Early-onset periprosthetic joint infection (PJI), defined according to the 2018 Definition of Periprosthetic Hip and Knee Infection Criteria, was evaluated. Conclusions: Therefore, the use of vancomycin as a perioperative prophylaxis should be discussed under benefit/risk consideration in further studies.

Therapeutic drug monitoring (TDM), which involves measuring drug levels in patients' body fluids, is an important procedure in clinical practice. However, the analysis technique currently used, i.e. liquid chromatography-tandem mass spectrometry (LC-MS/MS), is laboratory-based, so does not offer the short response time that is often required by clinicians. We suggest that techniques based on Fourier transform infrared spectroscopy (FTIR) offer a promising alternative for TDM. FTIR is rapid, highly specific and can be miniaturized for near-patient applications. The challenge, however, is that FTIR for TDM is limited by the strong mid-IR absorption of endogenous serum constituents. Here, we address this issue and introduce a versatile approach for removing the background of serum lipids, proteins and small water-soluble substances. Using phenytoin, an antiepileptic drug, as an example, we show that our approach enables FTIR to precisely quantify drug molecules in human serum at clinically relevant levels (10 μg/mL), providing an efficient analysis method for TDM. Beyond mid-IR spectroscopy, our study is applicable to other drug sensing techniques that suffer from the large background of serum samples.

Guidelines for vancomycin therapeutic monitoring recommend using a Bayesian approach with a population pharmacokinetic model to estimate the 24 h area under the concentration-time curve over first-order equations. Thus, we performed an external evaluation of population pharmacokinetic models of vancomycin in neonates and compared Bayesian results with those observed in clinical practice via pharmacokinetic equations to improve therapeutic monitoring by proposing optimized initial dosing nomograms and assessing the feasibility of reduced blood sampling strategies using the most predictive models.

Models were identified from the literature and evaluated via an external neonatal population. A priori predictive performance was first assessed by prediction-based diagnostics, then by simulation-based diagnostics and a posteriori analyses only if deemed satisfactory; model-informed vancomycin exposure was also compared with reference first-order pharmacokinetic equations. The best-performing models were ultimately subjected to Monte Carlo simulations to develop new initial dosing nomograms offering the highest probability of achieving therapeutic target.

A total of 28 population pharmacokinetic models were evaluated in the external dataset, which includes 72 neonates and 380 vancomycin concentrations. Eleven models had an adequate predictive performance with bias ≤ ± 15% and imprecision ≤ 30%, while the Bayesian approach yielded over 75% agreement with reference exposure values in most cases. Nonetheless, Capparelli et al. and Mehrotra et al. models performed the best overall, showing the lowest imprecisions of 16.8% and 16.9%, respectively; both models recommended higher dosage regimens than the theoretical nomogram currently applied to favor therapeutic target attainment.

We externally evaluated numerous neonatal population pharmacokinetic models of vancomycin and used the most predictive ones to advocate new initial dosing nomograms. Clinical implementation of the Bayesian approach could reduce the time needed to reach therapeutic target and limit the number of blood samples in newborns compared with traditional pharmacokinetic equations.

Vancomycin is a glycopeptide antibiotic that requires close therapeutic monitoring. Prolonged exposure to elevated concentrations increases risk for serious adverse effects such as nephrotoxicity. However, subtherapeutic concentrations may lead to bacterial resistance and clinical failure or death. The most recent Infectious Diseases Society of America publication regarding therapeutic monitoring of vancomycin recommends using area under the curve (AUC)-based monitoring to maximize clinical success. Despite the guideline recommendation for AUC-guided dosing, many institutions still use trough-only monitoring in their practices, including those caring for patients with acute burn injuries. Following burn injury, patients are at a higher risk for infections, multiorgan failure, and pharmacokinetic alterations. The primary objective of this multicenter retrospective study is to determine optimal therapeutic monitoring of vancomycin by comparing clinical success between AUC and trough-based monitoring in patients with burns. MONITOR was a multicenter, retrospective study of patients with thermal or inhalation injury admitted to one of 13 burn centers from January 1, 2017 to August 31, 2022 who received vancomycin. Demographic and clinical course data, including acute kidney injury (AKI) incidence and clinical success, were obtained. Patients were evaluated for clinical success and grouped according to method of monitoring and adjusting doses: AUC vs trough-based monitoring. Clinical success was a composite definition and lack of meeting any 1 of 5 criteria: (1) persistent infection, (2) relapse, (3) antibiotic failure (clinical worsening), (4) AKI, and (5) death. A total of 517 vancomycin courses were assessed from 485 patients. There was no difference in the rate of clinical success between AUC monitored and the trough-only monitored groups. Incidence of AKI was higher in the trough-only group; however, it was not statistically significant after controlling for renal function on admission, past medical history of chronic kidney disease, and concomitant nephrotoxins.

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.

An increase in Staphylococcus aureus infections has been reported in pediatric patients with cystic fibrosis (CF) over the last few years. This pathogen is commonly treated with vancomycin, an antibiotic for which therapeutic drug monitoring (TDM) is recommended. Updated guidelines were recently published regarding new targets of exposure for the TDM of vancomycin through a Bayesian approach, using population pharmacokinetic (popPK) models.

This study aims to assess the predictive performance of vancomycin popPK models in pediatric patients with CF and to recommend optimal initial dosing regimens based on simulations.

Patient data were collected from two centers in Canada, and a literature review was conducted to identify all published vancomycin popPK models for pediatric CF patients. External evaluation and simulations were performed according to patient and occasion of treatment.

A total of 53 vancomycin concentrations were collected from six pediatric CF patients. Only two popPK models of vancomycin for pediatric CF patients were identified through the literature review. The external evaluation results for both centers combined revealed a population bias of 28.1% and an imprecision of 33.7%. A re-estimation of parameters was performed to improve predictive performance. The optimal initial dosing regimen was 15 mg/kg/dose administered every 6 hours according to the per occasion remodel.

The predictive performance and identified optimal initial dosing regimens associated with the model were different depending on the data used, showing external evaluation's importance before implementing a model in clinical practice.

Current methods for therapeutic drug monitoring (TDM) have a long turnaround time as they involve collecting patients' blood samples followed by transferring the samples to medical laboratories where sample processing and analysis are performed. To enable real-time and minimally invasive TDM, a microneedle (MN) biosensor to monitor the levels of two important antibiotics, vancomycin (VAN) and gentamicin (GEN) is developed. The MN biosensor is composed of a hydrogel MN (HMN), and an aptamer-functionalized flexible (Flex) electrode, named HMN-Flex. The HMN extracts dermal interstitial fluid (ISF) and transfers it to the Flex electrode where sensing of the target antibiotics happens. The HMN-Flex performance is validated ex vivo using skin models as well as in vivo in live rat animal models. Data is leveraged from the HMN-Flex system to construct pharmacokinetic profiles for VAN and GEN and compare these profiles with conventional blood-based measurements. Additionally, to track pH and monitor patient's response during antibiotic treatment, an HMN is developed that employs a colorimetric method to detect changes in the pH, named HMN-pH assay, whose performance has been validated both in vitro and in vivo. Further, multiplexed antibiotic and pH detection is achieved by simultaneously employing the HMN-pH and HMN-Flex on live animals.

Mechanical debridement supplemented with antibacterial agents effectively eradicates subgingival biofilms formed in the periodontal pockets of severe periodontitis patients. However, the available antimicrobial agents have limited penetrating ability to kill the bacteria encased in the deep layers of biofilms. This study aimed to fabricate a novel magnetic nanoparticle (MNP) loaded with rhamnolipid (RL) and vancomycin (Vanc, Vanc/RL-Ag@Fe3O4) to combat subgingival biofilms.

The multispecies subgingival biofilm was formed by periodontal pathogens, including Streptococcus oralis (S. oralis), Streptococcus sanguinis (S. sanguinis), Actinomyces naeslundii (A. naeslundii), Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum). Scanning electron microscope (SEM), confocal laser scanning microscopy (CLSM), and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine the anti-biofilm efficacy of Vanc/RL-Ag@Fe3O4 with or without a magnetic field on multispecies subgingival biofilms.

The minimal inhibitory concentration (MIC) values of Vanc/RL-Ag@Fe3O4 on S. oralis, S. sanguinis, A. naeslundii, P. gingivalis, and F. nucleatum were 25, 50, 100, 50, and 25 μg/mL, respectively. Vanc/RL-Ag@Fe3O4 (200 μg/mL) reduced the 7-d biofilm thickness from 22 to 13 µm by degrading extracellular polymeric substance (EPS) and killing most bacteria except for tolerant F. nucleatum. A magnetic field enhanced the anti-biofilm effect of Vanc/RL-Ag@Fe3O4 by facilitating its penetration into the bottom layers of biofilms and killing tolerant F. nucleatum.

Vanc/RL-Ag@Fe3O4 MNPs can release RL, Vanc, and Ag and eradicate subgingival biofilms by disrupting EPS and killing bacteria. Vanc/RL-Ag@Fe3O4 combined with a magnetic force is a promising approach for combating periodontal infection.

An ultra-high performance liquid chromatography tandem mass spectrometry cubed (UHPLC/MS3) assay coupled with protein precipitation and counter-extraction for detection of tricyclic glycopeptide vancomycin in human plasma was established and validated in this study. After protein precipitation and counter-extraction with dichloromethane, chromatographic separation of vancomycin and norvancomycin were performed on a reversed phase column (XBridge Peptide BEH C18 column, 2.1 × 100 mm I.D, 3.5 μm). The transition (parent ions → fragment ions → further fragment ions) at m/z 725.3 → 144.1 → 100.1 was used for quantification of vancomycin. The transition (parent ions → fragment ions) at m/z 718.3 → 144.2 was used for detection of norvancomycin. The linear range of the developed analytical method for quantification of vancomycin was 0.5-100 µg/mL (r = 0.9989). The range of intra- and inter-day precisions of the assay among low, medium and high concentrations is between 1.88 % and 6.33 %. The sensitivity of the analytical method was significantly improved by using MS3 technique as monitoring mode and counter-extraction with dichloromethane followed by protein precipitation as sample processing assay. The developed UHPLC/MS3 assay was successfully applied for clinical therapeutic drug monitoring (TDM) of vancomycin in 45 human plasma samples.

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.

Antimicrobial peptides take a specific position in the field of antibiotics (ATBs), however, from a large number of available molecules only a few of them were approved and are used in clinics. These therapeutic modalities play a crucial role in the management of diseases caused by multidrug-resistant bacterial pathogens and represent the last-line therapy for bacterial infections. Therefore, there is a demand for a rationale use of such ATBs based on optimization of the dosing strategy to minimize the risk of resistance and ensure the sustainable efficacy of the drug in real clinical practice. Therapeutic drug monitoring, as a measurement of drug concentration in the body fluids or tissues, results in the optimization of the patient´s medication and therapy outcome. This strategy is beneficial and could result in tailored therapy for different types of infection and the prolongation of the use and efficacy of ATBs in hospitals. This review paper provides an actual overview of approved antimicrobial peptides used in clinical practice and covers current trends in their analysis by convenient and advanced methodologies used for their identification and/or quantitation in biological matrices for therapeutic drug monitoring purposes. Special emphasis is given to the methods with perspective clinical outcomes.

Obesity can significantly influence the pharmacokinetics of several medications, including vancomycin. Consequently, specialized dosing strategies may be required to ensure efficacy and safety in patients with obesity (PwO) requiring treatment with vancomycin. This single-center, prospective study evaluated two vancomycin loading dose regimens in PwO, comparing serum vancomycin concentrations, adverse events, and the impact on renal function.

Adult patients weighing over 100 kg were randomized into two study groups. A 20 mg/kg loading dose of vancomycin was administered to both groups, with one group restricted to a maximum dose of 2000 mg (n=33) and the other group receiving up to 4000 mg (n=34).

Patients receiving the 4000 mg maximal dose achieved significantly higher median vancomycin concentrations at the initial trough (9.1 mg/L vs. 11.3 mg/L, p=0.0497), mean concentrations at the 7.5-hour interval trough (14.4 mg/L vs. 17.1 mg/L, p=0.0151), and mean concentrations at the post-load peak (23.9 mg/L vs. 30.9 mg/L, p=0.0023), without a corresponding increase in adverse renal outcomes, hospital length of stay, or mortality as compared with the 2000 mg maximum dose group.

The study's findings demonstrate that higher vancomycin doses in PwO are safely tolerated and do not result in short-term adverse effects on renal function. This study helps us better understand vancomycin pharmacotherapy in PwO, supporting the need for further research to refine dosing guidelines for these patients.

Both parametric and nonparametric methods have been proposed to support model-informed precision dosing (MIPD). However, which approach leads to better models remains uncertain. Using open-source software, these 2 statistical approaches for model development were compared using the pharmacokinetics of vancomycin in a challenging subpopulation of class 3 obesity.

Patients on vancomycin at the University of Vermont Medical Center from November 1, 2021, to February 14, 2023, were entered into the MIPD software. The inclusion criteria were body mass index (BMI) of at least 40 kg/m 2 and 1 or more vancomycin levels. A parametric model was created using nlmixr2/NONMEM, and a nonparametric model was created using Pmetrics. Then, a priori and a posteriori predictions were evaluated using the normalized root mean squared error (nRMSE) for precision and the mean percentage error (MPE) for bias. The parametric model was evaluated in a simulated MIPD context using an external validation dataset.

In total, 83 patients were included in the model development, with a median age of 56.6 years (range: 24-89 years), and a median BMI of 46.3 kg/m 2 (range: 40-70.3 kg/m 2 ). Both parametric and nonparametric models were 2-compartmental, with creatinine clearance and fat-free mass as covariates to clearance and volume parameters, respectively. The a priori MPE and nRMSE for the parametric versus nonparametric models were -6.3% versus 2.69% and 27.2% versus 30.7%, respectively. The a posteriori MPE and RMSE were 0.16% and 0.84%, and 13.8% and 13.1%. The parametric model matched or outperformed previously published models on an external validation dataset (n = 576 patients).

Minimal differences were found in the model structure and predictive error between the parametric and nonparametric approaches for modeling vancomycin class 3 obesity. However, the parametric model outperformed several other models, suggesting that institution-specific models may improve pharmacokinetics management.