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In this randomized trial of fidaxomicin as compared with vancomycin in 629 patients, oral fidaxomicin was shown to be noninferior to oral vancomycin in the treatment of C. difficile infection and was associated with lower rates of recurrence. Clostridium difficile infection generally occurs after exposure to broad-spectrum antibiotics. The incidence and severity of C. difficile infection are increasing. The increases have been ascribed to the emergence of a hypervirulent C. difficile strain, known variously as North American Pulsed Field type 1 (NAP1), restriction-endonuclease analysis (REA) type BI, or polymerase-chain-reaction ribotype 027 (referred to collectively as the NAP1/BI/027 strain). 1 – 4 Furthermore, the rates of death associated with C. difficile infection are rising, 5 – 7 and the infection is occurring in populations that were previously considered to be at low risk, such as young, healthy persons living in the community and . . .

The pharmacokinetics and pharmacodynamics (PK/PD) of vancomycin change during HD, increasing the risk of subtherapeutic concentrations. The aim of this study was to evaluate during and after the conventional and prolonged hemodialysis sessions to identify the possible risk of the patient remaining without adequate antimicrobial coverage during therapy. Randomized, non-blind clinical trial, including critically ill adults with septic AKI on conventional (4 h) and prolonged HD (6 and 10 h) and using vancomycin for at least 72 h. Sessions were analyzed and randomized into three groups (G): control (C), dose of 15 mg/kg after session), intervention (I) 2 h (dose of 7.5 mg/kg in the second hour and 7.5 mg/kg after) and IG continuous infusion (dose of 30 mg/kg in 24 h). Of the 316 patients recruited, 87 were randomized, and 174 HD sessions were monitored. For the analysis, 28 sessions belonged to the CG, 47 to the 2-hour IG, and 31 to the continuous IG. The groups were similar in age, weight, severity scores, use of nephrotoxins, sérum albumin, Kt/V, HD modality, ultrafiltration, and intradialytic intercurrences. The intervention groups showed a higher therapeutic concentration frequency than the control group ( p  < 0.002). The initial concentration was identified as a risk factor (OR 1.16, p  = 0.001) for a non-therapeutic vancomycin concentration in the logistic regression. In contrast, the 2-hour IG was identified as a protective factor (OR 0.24, p  = 0.04). Administration of vancomycin during dialysis proved to be a protective factor against concentrations outside the therapeutic target. Further studies are needed to suggest more appropriate doses of vancomycin for patients with AKI on dialysis therapy and to assess the impact of these results on clinical outcomes.

Background This study aimed to elucidate the safety and intra-articular elution profiles of vancomycin and gentamicin bone cement in patients undergoing primary total knee arthroplasty (TKA), with a focus on serum safety thresholds and therapeutic efficacy. Methods Consecutive patients who underwent unilateral primary TKA were prospectively enrolled. The implants were fixed using gentamicin-impregnated bone cement, and after arthrotomy closure, 1000 mg of vancomycin suspended in 25 mL of normal saline was directly injected into the joint. Peripheral venous blood and drain fluid samples were collected 2, 8, and 24 h postoperatively. The serum and intra-articular concentrations of vancomycin and gentamicin were analyzed using liquid chromatography-tandem mass spectrometry within 24 h. Results Clinical data reflecting renal and liver function were recorded preoperatively, and at 24 and 72 h postoperatively. A total of 100 patients were included. At 2, 8, and 24 h postoperatively, the serum vancomycin concentration was 7.0 ± 2.0, 5.7 ± 1.8, and 3.6 ± 1.4 µg/mL, respectively, while the intra-articular concentration was 468.5 (interquartile range [IQR] 286.0 to 774.8), 139.5 (IQR 52.0 to 295.3), and 34.4 (IQR 22.2 to 56.8) µg/mL, respectively; 33.2 (IQR 19.5 to 80.5) mg vancomycin was lost in drainage fluid at 24 h postoperatively. For gentamicin, the overall intra-articular concentration was 70.4 (IQR 35.4 to 109.2), 33.8 (IQR 17.8 to 73.9), and 21.1 (IQR 12.2 to 36.0) µg/mL at 2, 8, and 24 h postoperatively, respectively, with an undetectable serum concentration. No cases of acute renal injury, liver injury, ototoxicity, or anaphylaxis were observed. Conclusions Intra-articular injection of 1000 mg vancomycin after arthrotomy closure combined with gentamicin-impregnated bone cement provided a therapeutic intra-articular concentration while avoiding systemic toxicity over the initial 24 h after primary TKA. Therefore, intra-articular vancomycin administration may offer a safer alternative to intravenous antibiotics, reducing systemic toxicity; however, further large-scale studies are necessary. Trial registration ClinicalTrials. Gov (registration number: NCT05338021).

Target-controlled infusion (TCI) could provide a patient-tailored approach for vancomycin dosing. This study aimed to externally evaluate the predictive performance of a previously constructed pharmacokinetic model of vancomycin (Choi model) specifically optimized for TCI administration of vancomycin differing from the existing model, and to assess the feasibility of administering vancomycin via TCI in clinical practice. Additionally, clinical outcomes were exploratively compared between the TCI and intermittent infusion (standard) methods for vancomycin administration. Clinically ill patients were randomly assigned in a 1:1 ratio to either the TCI or standard group. In the TCI group, vancomycin was administered using the Choi model, targeting an initial concentration of 25 mg/L, adjusted to maintain therapeutic levels (20-30 mg/L). The standard group received a loading dose of 25 mg/kg, then 15 mg/kg every 12 hours. Vancomycin concentrations for analysis were obtained from three blood samples per patient at set times, along with routine therapeutic drug monitoring data. Predictive performance was assessed using four parameters: inaccuracy, divergence, bias, and wobble. The occurrence of acute kidney injury (AKI) during and up to 7 days after vancomycin was investigated. The study was terminated early due to challenges in enrolling subjects (TCI: n=12, standard: n=13). Thirty-seven serum concentration measurements from the TCI group were analyzed. Pooled median bias and inaccuracy (95% confidence interval) were -2.7 (-7.3 to 1.9) and 17.0 (13.9 to 20.2), respectively. AKI incidence was similar between groups (TCI: n=0, standard: n=1) in this exploratory analysis, but caution is warranted in interpreting these outcomes as the planned sample size was not met. The predictive performance of the TCI system integrated with the Choi model was suitable for clinical use. Further studies with a large cohort should be performed to determine the clinical effectiveness of vancomycin administered via the TCI method. This study was registered at the Clinical Research Information Service of the Korean National Institute of Health (CRIS, http://cris.nih.go.kr), with registration number KCT0003462, on January 31, 2019).

This study is a multicenter, randomized controlled prospective trial aimed at evaluating the effects of two vancomycin pharmacokinetics/pharmacodynamics (PK/PD) parameters on clinical outcomes in children with different severe infections: trough concentration (Cmin) and the area under the curve (AUC0‐24/MIC). From January 2023 to December 2024, 472 pediatric patients from seven hospitals in Southwest China were included in the present study. These patients were randomly assigned to the AUC0‐24/MIC group or the Cmin group. After excluding 75 patients with renal function impairment caused by the primary disease, three patients with incomplete data, and one patient who received vancomycin for less than 48 h, 393 patients were finally enrolled for the present study. Then, the vancomycin treatment for children was evaluated using two PK/PD parameters, to guide clinical efficacy and monitor the incidence of adverse reactions: AUC0‐24/MIC, with a target value of 400–600 mg·h/L; trough concentration (Cmin), with a target value of 5–15 mg/L. The results indicated that there were no significant differences between the two groups in terms of daily dose, clinical efficacy, and adverse reactions. However, patients in the Cmin group had significantly shorter pediatric intensive care unit (PICU) stays (Z = −2.05, p = 0.04), and patients in the 28‐day to 1‐year‐old subgroup had shorter mechanical ventilation times (Z = −2.25, p = 0.024). Both Cmin and AUC0‐24/MIC were effective in guiding the vancomycin treatment for children with severe infections. However, patients in the Cmin group presented with advantages in PICU stay and ventilation duration. Trial Registration: China Clinical Trial Registry: ChiCTR2300067373

Background Vancomycin is a commonly prescribed antibiotic to treat serious Gram-positive infections in children. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration–time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. In most countries, steady-state plasma concentrations are used as a surrogate parameter for this target AUC/MIC, but this practice has some drawbacks. Hence, AUC-based dosing using model-informed precision dosing (MIPD) tools has been proposed for increasing the target attainment rate and reducing vancomycin-related nephrotoxicity. Solid scientific evidence for these claimed benefits is lacking in children. This randomized controlled trial aims to investigate the large-scale utility of MIPD dosing of vancomycin in critically ill children. Methods Participants from 14 neonatal intensive care, pediatric intensive care, and pediatric hemo-oncology ward units from 7 hospitals are randomly allocated to the intervention or standard-of-care comparator group. In the intervention group, a MIPD dosing calculator is used for AUC-based dosing, in combination with extra sampling for therapeutic drug monitoring in the first hours of treatment, as compared to standard-of-care. An AUC24h between 400 and 600 is targeted, assuming an MIC of 1 mg/L. Patients in the comparator group receive standard-of-care dosing and monitoring according to institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400–600 between 24 and 48 h after the start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury during vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400–600 between 48 and 72 h after the start of vancomycin treatment, time to clinical cure, ward unit length-of-stay, hospital length-of-stay, and 30-day all-cause mortality. Discussion This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment in critically ill children. Trial registration Eudract number: 2019–004538-40. Registered on 2020–09-08 ClinicalTrials.gov NCT046666948. Registered on 2020–11-28

Background The pharmacokinetics of vancomycin, a drug used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), varies between paediatric and adult patients. Objective The objective of this study was to assess the pharmacokinetics of vancomycin in preterm neonates and determine the optimum dose regimen. Methods This was a randomised double-blind study of preterm neonates admitted to neonatal intensive care units. They all received vancomycin 15 mg/kg every 12 h. Blood was sampled just before administration of the third, sixth and ninth vancomycin dose. Pharmacokinetic parameters were estimated using a Bayesian approach implemented in Monolix 2018R2 software. Covariates assessed included postmenstrual age, current weight, creatinine clearance, albumin, gestational age, body surface area and current age. We used Monte Carlo simulations for dose regimen optimisation targeting area under the concentration–time curve up to 24 h (AUC 0–24h ) of ≥ 400 mg × h/L. Results In total, 19 preterm neonates were enrolled in the study with a median age of 14 (3–58) days. A one-compartment model with linear elimination best described the pharmacokinetics of vancomycin. Volume of distribution and clearance was 0.88 L and 0.1 L/h, respectively, for a typical neonate weighing 1.48 kg. Simulation of the current dose regimen showed that 27.5% of the neonates would achieve the target AUC 0–24h of ≥ 400 mg × h/L, and 70.7% of the neonates would achieve it with 12 mg/kg every 8 h. Conclusion The majority of the neonates were under dosed. Vancomycin 12 mg/kg should be administered every 8 h over 1 h infusion to improve the likelihood of achieving the AUC 0–24h target of ≥ 400 mg × h/L. This target is considered optimal for MRSA infections, where the vancomycin minimum inhibitory concentration is ≤ 1 µg/mL.

Background Oral vancomycin (125 mg qid) is recommended as treatment of severe Clostridium difficile infection (CDI). Higher doses (250 or 500 mg qid) are sometimes recommended for patients with very severe CDI, without supporting clinical evidence. We wished to determine to what extent faecal levels of vancomycin vary according to diarrhoea severity and dosage, and whether it is rational to administer high-dose vancomycin to selected patients. Methods We recruited hospitalized adults suspected to have CDI for whom oral vancomycin (125, 250 or 500 mg qid) had been initiated. Faeces were collected up to 3 times/day and levels were measured with the AxSYM fluorescence polarization immunoassay. Results Fifteen patients (9 with confirmed CDI) were treated with oral vancomycin. Patients with ≥4 stools daily presented lower faecal vancomycin levels than those with a lower frequency. Higher doses of oral vancomycin (250 mg or 500 mg qid) led to consistently higher faecal levels (> 2000 mg/L), which were 3 orders of magnitude higher than the MIC 90 of vancomycin against C. difficile . One patient receiving 125 mg qid had levels below 50 mg/L during the first day of treatment. Conclusions Faecal levels of vancomycin are proportional to the dosage administered and, even in patients with increased stool frequency, much higher than the MIC 90 . Patients given the standard 125 mg qid dosage might have low faecal levels during the first day of treatment. A loading dose of 250 mg or 500 mg qid during the first 24-48 hours followed by the standard dosage should be evaluated in larger studies, since it might be less disruptive to the colonic flora and save unnecessary costs.

Medium cut-off membrane (MCO) dialysers have been shown to remove a range of middle molecules, which are associated with adverse outcomes in haemodialysis (HD) patients, more effectively than high-flux HD. Vancomycin is widely used in HD patients for treating a variety of infections. To avoid subtherapeutic trough concentrations, it is important to understand vancomycin clearance in patients undergoing HD with the MCO membrane. This open label single centre, cross-over clinical study compared the vancomycin pharmacokinetics in chronic HD patients using MCO membrane (Theranova) and high-flux membrane (Revaclear). Five patients established on chronic HD who were due to receive vancomycin were enrolled. The study used alternating Theranova and Revaclear dialysis membranes over six consecutive sessions. Vancomycin was administered over the last one to two hours of each HD session. The maintenance dose was adjusted based on pre-HD serum concentrations. Over the 210 study samples, vancomycin clearance was higher with MCO-HD compared to high-flux HD but not statistically significant. Median percentage of vancomycin removal at 120 min by MCO membrane was 39% (20.6–51.5%) compared with 34.1% (21.3–48.4%) with high-flux HD. MCO-HD removes a slightly higher percentage of vancomycin at 120 min into dialysis compared to high-flux membrane dialysis in HD patients with infections. Application of vancomycin during the last one to two hours of each dialysis is required to maintain therapeutic concentrations to minimise loss through the dialyser and maintain therapeutic levels.

Background Vancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late-onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin’s continued efficacy. Methods NeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excluding Staphylococcus aureus ) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation. The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA. The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h. Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy. Discussion Based on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS. Trial registration ClinicalTrials.gov, NCT02790996 . Registered on 7 April 2016. EudraCT, 2015–000203-89. Entered on 18 July 2016.