Validation and Clinical Application of a New Liquid Chromatography Coupled to Mass Spectrometry (HPLC-MS) Method for Dalbavancin Quantification in Human Plasma

Dalbavancin (DBV) is an intravenous long-acting second-generation glycolipopeptide antibiotic with high efficacy and excellent tolerability, approved for use in the treatment of Gram-positive skin and skin structure infections (ABSSSI). Nevertheless, little is known about its pharmacokinetic/pharmacodynamic (PK/PD) properties in real life, which is also due to technical challenges in its quantification in human plasma, preventing an effective application of therapeutic drug monitoring (TDM). In fact, DBV has a high affinity to plasma proteins, possibly resulting in poor recovery after extraction procedure. The aim of this study was to validate a simple, cheap and reliable HPLC-MS method for use in TDM, in accordance with FDA and EMA guidelines. The optimized protein precipitation protocol required 50 μL of plasma, while chromatographic analysis could be performed in 12 min/sample. This method fulfilled the guidelines requirements and then, it was applied for routine DBV TDM in patients receiving off-label high doses (two 1500 + 1500 mg weekly infusions instead of 1000 + 500 mg), with normal renal function or undergoing hemodialysis: continuous hemodiafiltration caused a relevant reduction in DBV exposure, while intermittent dialysis showed comparable DBV concentrations with those of patients with normal renal function. This confirmed the eligibility of the presented method for use in TDM and its usefulness in clinical practice.

Effectiveness of polymyxin B hemoperfusion for sepsis depends on the baseline SOFA score: a nationwide observational study

Background Polymyxin B hemoperfusion (PMX) aims to treat septic shock by removing endotoxin from the patient’s blood. However, the relationship between the severity of the patient's organ damage and the survival benefit of PMX treatment is not clear. Methods We analyzed the efficacy of PMX on adult sepsis patients using the propensity score matching method and the Japanese Diagnosis Procedure Combination (DPC) national inpatient database from April 2018 to March 2020. We stratified the patients into five categories based on their baseline Sequential Organ Failure Assessment (SOFA) score and compared the mortality between PMX-treated and non-treated groups in each category. We also compared continuous hemodiafiltration (CHDF)-, ventilator- and noradrenaline-free days between the groups. Results Of 44,177 patients included in the study, 2191 received PMX. After 1:1 propensity score matching, we created matched cohorts of 2033 pairs. PMX significantly improved the survival of the patients in the SOFA score categories of 7–9 and 10–12. On the other hand, there was no significant difference in the survival rate in SOFA score categories of 0–6, 13–15, and 16–24. In analyzing organ support-free days, PMX was also beneficial in the 7–9 and 10–12 SOFA categories compared to other categories. Conclusion Analysis of a large-scale Japanese inpatient database found a significant association between PMX efficacy and baseline SOFA score. This result indicates higher efficacy in patients with medium SOFA scores in the range of 7–12. The result provides a promising hypothesis for selecting appropriate patients for PMX and should be validated in future RCTs.

Evaluation of plasma levels of meropenem in septic patients during extracorporeal blood purification

The relevance. Meropenem is a broad-spectrum carbapenem antibiotic widely used to treat patients with sepsis / septic shock. Critically ill patients are usually supported with one of the forms extracorporeal blood purification. However, data on the effect of various extracorporeal support techniques on the pharmacokinetics and pharmacodynamics of meropenem are insufficient or contradictory. Aim: To evaluate the effectiveness of meropenem dosage regimens in the treatment of septic patients during extracorporeal blood purification. Materials and methods. Plasma concentrations of meropenem were monitored in three critically ill patients with sepsis or septic shock. Patients were treated using various extracorporeal support techniques. Meropenem was used as empirical antibacterial mono- or complex therapy (1 g every 8 or 12 hours). Meropenem concentrations in plasma were determined by validated assay methods on Acquity ultraefficient liquid chromatography (UPLC) H-Class system. Results. It is shown that the meropenem plasma concentration in critically ill patients changes significantly. It was found that the standard meropenem dosing regimens in patients with sepsis / septic shock during continuous hemodiafiltration do not ensure the achievement of the PK/PD target of 100% TMIC for sensitive strains (MIC2 mg/L) and for intermediate resistance pathogens (2MIC8 mg/L). Continuous hemofiltration and selective adsorption of lipopolysaccharide have a less pronounced effect on the clearance of meropenem. Conclusion. To increase the effectiveness of antibacterial therapy, it is necessary to conduct research aimed at developing protocols for dosing antibacterial drugs for the treatment of sepsis during extracorporeal blood purification.

Effects of Polymyxin B Hemoperfusion on Septic Shock Patients Requiring Noradrenaline: Analysis of a Nationwide Administrative Database in Japan

<b><i>Introduction:</i></b> Polymyxin B hemoperfusion (PMX) reduces endotoxin in septic shock patients’ blood and can improve hemodynamics and organ functions. However, its effects on the reduction of septic shock mortality are controversial. <b><i>Methods:</i></b> Using the Japanese diagnosis procedure combination database from April 2016 to March 2019, we identified adult septic shock patients treated with noradrenaline. This study used propensity score matching to compare the outcome between PMX-treated and non-treated patients. The primary endpoint was 28-day mortality, counting from the day of noradrenaline initiation. The secondary endpoints were noradrenaline-, ventilator-, and continuous hemodiafiltration (CHDF)-free days at day 28. <b><i>Results:</i></b> Of 30,731 eligible patients, 4,766 received PMX. Propensity score matching produced a matched cohort of 4,141 pairs with well-balanced patient backgrounds. The 28-day survival rate was 77.9% in the PMX group and 71.1% in the control group (<i>p</i> &#x3c; 0.0001). Median days of noradrenalin-, CHDF-, and ventilator-free days were 2 days (<i>p</i> &#x3c; 0.0001), 2 days (<i>p</i> &#x3c; 0.0001), and 6 days (<i>p</i> &#x3c; 0.0001) longer in the PMX group than in the control group, respectively. When stratified with the maximum daily dose of noradrenaline, the PMX group showed a statistically significant survival benefit in the groups with noradrenaline dose &#x3c;20 mg/day but not in the noradrenaline group dose ≥20 mg/day. <b><i>Conclusion:</i></b> Analysis of large Japanese databases showed that septic shock patients who received noradrenaline might benefit from PMX treatment.

Tocilizumab and PMX-DHP have efficacy for severe COVID-19 pneumonia

In coronavirus disease 2019 pneumonia, a cytokine storm resulting from an excessive inflammatory response to the viral infection is thought to play a role in the exacerbation of the pneumonia and its prognosis. Favipiravir and ciclesonide are not effective in the inhibition of the cytokine storm. In this case report, we describe the experience of tocilizumab administration and polymyxin B immobilized fiber direct hemoperfusion in severe coronavirus disease 2019 pneumonia patient. A 52-year-old man presented with fever and dyspnea and was diagnosed with coronavirus disease 2019 pneumonia based on a polymerase chain reaction test. Mechanical ventilation and favipiravir administration were started for respiratory failure. However, favipiravir could not be continued due to hepatic dysfunction. Consequently, tocilizumab was administered, and continuous hemodiafiltration and endotoxin adsorption therapy (polymyxin B immobilized fiber direct hemoperfusion) were performed for acute renal failure. C-reactive protein decreased from 44 to 3.52 mg/dL, and the patient’s respiratory status improved over time, enabling mechanical ventilation to be withdrawn. This case indicates that adding polymyxin B immobilized fiber direct hemoperfusion to tocilizumab administration may further increase efficacy in coronavirus disease 2019 treatment; however, more case–control studies are needed.