Optimisation of vancomycin regimen in neutropenic haematological patients with normal renal function. Multiple daily doses may be preferable

Objective: To assess the appropriateness, on a pharmacokinetic basis, of a twice-daily regimen of vancomycin 1 g in neutropenic patients with normal renal function, a regimen frequently used in the empirical treatment of this patient group. The study also used a Bayesian pharmacokinetic approach to predict vancomycin concentrations in order to determine the optimal dosage frequency of the drug (two or four daily doses) in this population. Patients and Methods: Data were collected retrospectively as part of routine therapeutic drug monitoring (TDM) of vancomycin in 16 adult neutropenic patients. TDM of vancomycin peak (C(max)) and trough (C(min)) serum concentrations was performed after twice daily administration of vancomycin 1 g as a 1-hour intravenous infusion for 48 hours. According to TDM results (C(min) 65 7 or MIC, an important determinant of vancomycin efficacy. However, because of interpatient variability, TDM of vancomycin is strongly recommended to individualise therapy in this subpopulation

Optimisation of vancomycin regimen in neutropenic haematological patients with normal renal function. Multiple daily doses may be preferable

Objective: To assess the appropriateness, on a pharmacokinetic basis, of a twice-daily regimen of vancomycin 1 g in neutropenic patients with normal renal function, a regimen frequently used in the empirical treatment of this patient group. The study also used a Bayesian pharmacokinetic approach to predict vancomycin concentrations in order to determine the optimal dosage frequency of the drug (two or four daily doses) in this population. Patients and Methods: Data were collected retrospectively as part of routine therapeutic drug monitoring (TDM) of vancomycin in 16 adult neutropenic patients. TDM of vancomycin peak (C(max)) and trough (C(min)) serum concentrations was performed after twice daily administration of vancomycin 1 g as a 1-hour intravenous infusion for 48 hours. According to TDM results (C(min) 65 7 or < 7 mg/L), the vancomycin regimen was individualised (total daily dose split into two or four divided doses) by means of a Bayesian-based pharmacokinetic computer programme. TDM was then repeated on day 7. Optimal C(min) were defined as with the range of 7 to 10 mg/L. Results: On day 3 of therapy, nine patients had subtherapeutic C(min) (3.97 \ub1 0.59 mg/L; range 2.98 to 4.95 mg/L) according to a high estimated creatinine clearance (CL(CR) 1.79 \ub1 0.49 ml/kg/min; range 1.39 to 2.79 ml/kg/min), and another three patients had C(min) < 7 mg/L. On day 7, higher vancomycin C(min) were achieved (8.92 \ub1 2.87 mg/L) in the 12 patients in whom their total daily dose was split into four (C(min) were optimal in nine and supratherapeutic in three patients), despite no major differences in the total daily dosage of vancomycin (29.77 \ub1 5.89 vs 30.85 \ub1 6.68 mg/kg; p = 0.79) and CL(CR)(1.63 \ub1 0.43 vs 1.90 \ub1 0.45 ml/kg/min; p = 0.19) versus day 3. Dose-normalised results suggested large interindividual pharmacokinetic variability. Conclusion: Since the volume of distribution and/or clearance of vancomycin can be increased in patients with haematological malignancies and normal renal function, increasing the number of daily doses from two to four (with the same total daily dose) may increase t > MIC, an important determinant of vancomycin efficacy. However, because of interpatient variability, TDM of vancomycin is strongly recommended to individualise therapy in this subpopulation

Which reliable pharmacodynamic breakpoint should be advised for ciprofloxacin monotherapy in the hospital setting? A TDM-based retrospective perspective

OBJECTIVES: To define in critically ill patients receiving intravenous (iv) ciprofloxacin (200 mg or 400 mg twice daily) and undergoing routine therapeutic drug monitoring (TDM) the interindividual pharmacokinetic variability and the reliable pharmacodynamic breakpoint enabled by these fixed dosing regimens according to the PK/PD principles and to the pattern of susceptibility to this antibiotic. METHODS: Ciprofloxacin plasma concentrations [trough (Cmin) and 30 min post-dose peak (Cmax) levels] were analysed by means of an HPLC method. Optimal pharmacodynamic exposure was assessed by estimating the theoretical pharmacodynamic breakpoints (PD BP) for either Cmax or AUC. RESULTS: The final database included 177 sets of Cmin and Cmax performed in 89 patients (200 mg twice daily group, n=68; 400 mg twice daily group, n=21). A very wide interindividual scatter of results was observed for both the 200 mg group and the 400 mg group. Interestingly, for both groups only moderate log-linear relationships between estimated renal function (CLCR) on one hand and either Cmin (r2=0.08, 0.28) or estimated AUC24 (r2=0.10, 0.34) on the other hand were found. Median PD BP, respectively, in the 200 mg twice daily group and the 400 mg twice daily group, were 0.16 and 0.28 mg/L for Cmax, and 0.19 and 0.29 mg/L for AUC24. CONCLUSIONS: Lowering ciprofloxacin dosage in the presence of renal failure seems in most cases unnecessary, since drug accumulation occurred only in a few cases. Optimal pharmacodynamic exposure with fixed 200 or 400 mg twice daily regimens of ciprofloxacin may be ensured only against fully susceptible microorganisms with an MIC<0.3 mg/L. This supports the use of higher dosages in critically ill hospitalized patients, whereas the wide unpredictable interindividual pharmacokinetic variability suggests the usefulness of TDM with the intent of optimizing efficacy with ciprofloxacin therapy

Oral and intravenous disposition of cyclosporine in psoriatic patients.

After informed consent was obtained and with the approval of the Local Ethical Committee, cyclosporine A (CsA) kinetics was studied in 63 psoriatic patients by giving them 2.5 mg/kg CsA orally. In order to calculate oral bioavailability, F, 22 patients were given the same dose i.v. Values of the calculated kinetic parameters were oral F = 22\u201363%; half-life, t 1/2\u3b2, = 11.05\u201313.70 h; volume of distribution, V d, = 4.00\u20135.02/L/kg; total body clearance, Cl, = 4.25\u20134.14 ml/min/kg. The area under the blood concentration time curve was more closely related to the dose (r = 0.66) than were trough levels (r = 0.52). No significant relationship was observed between the kinetic parameters studied and the age of the patien

TDM coupled with Bayesian forecasting should be considered an invaluable tool for optimizing vancomycin daily exposure in unstable critically ill patients

A randomized two-arm prospective study was planned to assess the role of therapeutic drug monitoring (TDM) coupled with a Bayesian approach in tailoring vancomycin dosages in unstable critically ill patients. Group A (n=16) had their regimen adjusted day-by-day according to TDM and Bayesian forecasting (D(a)); group B (n=16) had their regimen adjusted day-by-day according to Moellering's nomogram (D(M)). Blood samples were collected every 1-2 days to assess the trough and peak plasma concentrations. In group A, the tailored D(a) required for optimizing vancomycin exposure were considerably higher than the D(M) in 7/16 cases, and lower than the D(M) in 1/16 cases. In group B, standard D(M) caused under-treatment in 3/16 cases and over-treatment in 4/16 cases. Most of these patients concomitantly had some conditions that might have altered vancomycin disposition. The TDM-guided Bayesian-based approach should be considered an invaluable tool for clinicians to handle appropriately on real-time vancomycin therapy in critically ill patients

Monocyte distribution width (MDW): a useful biomarker to improve sepsis management in Emergency Department

Objectives Sepsis is a time-dependent and life-threating condition. Despite several biomarkers are available, none of them is completely reliable for the diagnosis. This study aimed to evaluate the diagnostic utility of monocyte distribution width (MDW) to early detect sepsis in adult patients admitted in the Emergency Department (ED) with a five part differential analysis as part of the standard clinical practice. Methods A prospective cohort study was conducted on 985 patients aged from 18 to 96 and included in the study between November 2019 and December 2019. Enrolled subjects were classified into four groups based on sepsis-2 diagnostic criteria: control, Systemic Inflammatory Response Syndrome (SIRS), infection and sepsis. The hematology analyzer DxH 900 (Beckman Coulter Inc.) provides the new reportable parameter MDW, included in the leukocyte 5 part differential analysis, cleared by Food and Drug administration (FDA) and European Community In-Vitro-Diagnostic Medical Device (CE IVD) marked as early sepsis indicator (ESId). Results MDW was able to differentiate the sepsis group from all other groups with Area Under the Curve (AUC) of 0.849, sensitivity of 87.3% and specificity of 71.7% at cut-off of 20.1. MDW in combination with white blood cell (WBC) improves the performance for sepsis detection with a sensitivity increased up to 96.8% when at least one of the two biomarkers are abnormal, and a specificity increased up to 94.6% when both biomarkers are abnormal. Conclusions MDW can predict sepsis increasing the clinical value of Leukocyte 5 Part Differential analysis and supporting the clinical decision making in sepsis management at the admission to the ED

Risk of recurrence after discontinuing anticoagulation in patients with COVID-19- associated venous thromboembolism: a prospective multicentre cohort studyResearch in context

Summary: Background: The clinical relevance of recurrent venous thromboembolism (VTE) after discontinuing anticoagulation in patients with COVID-19-associated VTE remains uncertain. We estimated the incidence rates and mortality of VTE recurrences developing after discontinuing anticoagulation in patients with COVID-19-associated VTE. Methods: A prospective, multicenter, non-interventional study was conducted between March 25, 2020, and July 26, 2023, including patients who had discontinued anticoagulation after at least 3 months of therapy. All patients from the registry were analyzed during the study period to verify inclusion criteria. Patients with superficial vein thrombosis, those who did not receive at least 3 months of anticoagulant therapy, and those who were followed for less than 15 days after discontinuing anticoagulation were excluded. Outcomes were: 1) Incidence rates of symptomatic VTE recurrences, and 2) fatal PE. The rate of VTE recurrences was defined as the number of patients with recurrent VTE divided by the patient-years at risk of recurrent VTE during the period when anticoagulation was discontinued. Findings: Among 1106 patients with COVID-19-associated VTE (age 62.3 ± 14.4 years; 62.9% male) followed-up for 12.5 months (p25-75, 6.3–20.1) after discontinuing anticoagulation, there were 38 VTE recurrences (3.5%, 95% confidence interval [CI]: 2.5–4.7%), with a rate of 3.1 per 100 patient-years (95% CI: 2.2–4.2). No patient died of recurrent PE (0%, 95% CI: 0–7.6%). Subgroup analyses showed that patients with diagnosis in 2021–2022 (vs. 2020) (Hazard ratio [HR] 2.86; 95% CI 1.45–5.68) or those with isolated deep vein thrombosis (vs. pulmonary embolism) (HR 2.31; 95% CI 1.19–4.49) had significantly higher rates of VTE recurrences. Interpretation: In patients with COVID-19-associated VTE who discontinued anticoagulation after at least 3 months of treatment, the incidence rate of recurrent VTE and the case-fatality rate was low. Therefore, it conceivable that long-term anticoagulation may not be required for many patients with COVID-19-associated VTE, although further research is needed to confirm these findings. Funding: Sanofi and Rovi, Sanofi Spain