Continuous Infusion of Aztreonam-Avibactam After High Loading Dose for an Infection Caused by an OXA-48- and NDM-1-Co-producing ST147 Klebsiella pneumoniae.

It was an important and indeed remarkable observation when several trials reported the consistent finding that dual antiplatelet therapy with aspirin and a thienopyridine was superior to aspirin and oral anticoagulation for prevention of major adverse cardiac events after deployment of a stent in a coronary artery.1 A major benefit of dual antiplatelet therapy was a lower rate of stent thrombosis. The incidence of coronary stent thrombosis in the modern era is reported to be approximately 1%, with an increased likelihood of occurrence in high-risk patient or lesion subsets. Although this rate may seem relatively low, stent thrombosis is associated with major myocardial infarction (MI) in 60% to 70% of cases, resulting in an early mortality rate of 20% to 25%. With increased use of percutaneous coronary intervention (PCI) as a revascularization strategy and implantation of stents in coronary arteries with a small diameter, it is anticipated that the number of patients at risk for stent thrombosis may increase. It therefore continues to be important to construct pharmacological regimens that minimize its occurrence. Several risk factors for stent thrombosis have been identified, including patient- and/or lesion-specific characteristics, procedure-related factors, and inherent stent thrombogenicity.2 These risk factors, in turn, contribute to a state of enhanced platelet reactivity and thrombus formation, which promotes abrupt vessel closure. See p 1153 Although initial studies highlighting the benefits of dual antiplatelet therapy used aspirin and ticlopidine, clopidogrel is the thienopyridine of choice today because it is associated with a lower rate of intolerable side effects. It is noteworthy that clopidogrel as part of the dual antiplatelet regimen to support PCI has not undergone the type of extensive evaluation demanded of ACE inhibitors, angiotensin receptor blockers, or such devices as implantable cardioverter-defibrillators before they were recommended in practice guidelines for management of patients with …

Therapeutic drug monitoring (TDM) of teicoplanin is aimed at minimizing the clinical impact of pharmacokinetic variability; however, its benefits are still being defined. We performed a retrospective study of teicoplanin TDM focusing on the dose-serum concentration relationship and clinical outcomes in a clinical setting. From January 2017 to December 2018, patients receiving teicoplanin ≥ 72h with TDM were enrolled. Patients were divided into three groups: non-loading (NL) group, low-dose loading (LD) group (loading dose < 9mg/kg), and high-dose loading (HD) group (≥ 9mg/kg). Serum teicoplanin trough concentration (Cmin) and adverse events (AEs) were evaluated in each regimen. A subgroup of patients with bacteremia was analyzed to evaluate clinical efficacy. Among 65 patients, 12, 18, and 35 were grouped in NL, LD, and HD, respectively. Achievement rates of Cmin > 20mg/L within 10days were significantly different among the groups (25.0%, 38.9%, and 68.6% in the NL, LD, and HD groups, respectively; P = 0.014). Fourteen patients (21.5%) had AEs, and higher Cmin over 10days (adjusted odds ratio 2.08 per every 20mg/L increases, 95% CI 1.13-3.84, P = 0.019) and age ≥ 65years (P = 0.009) were identified as independent risk factors. In the subgroup analysis, HD regimen (P = 0.050) and high mean Cmin over 10days (P = 0.025) were significantly associated with treatment success. Although HL regimen could achieve Cmin targets and improve clinical outcome during teicoplanin treatment, high Cmin was associated with AEs during treatment. Routine TDM can be helpful to optimize teicoplanin administration.

ObjectiveTo observe the effects of high loading doses and high maintenance dose of atorvastatin on platelet activity, function of vascular endothelium and inflammation as well as prognosis in patients with...

To assess the appropriateness of teicoplanin loading dose and therapeutic drug monitoring (TDM) in single-daily regimen (SDR) versus thrice-weekly regimen (TWR), and to compare safety and effectiveness. This single-centre observational retrospective cohort study included adult patients treated with TDM-based teicoplanin for infections between April 2015 and December 2021. Appropriateness of loading dose and TDM, adverse events (AEs) and clinical outcomes were evaluated. A post hoc analysis assessed achievement of target TDM concentrations following appropriate loading dose. Among 183 patients (103 SDR, 80 TWR), appropriate loading doses were less frequent in the SDR group [33/103 (35.9%, missing = 11) versus 56/80 (72.7%, missing = 3); P < 0.001]. First TDM was less commonly performed as recommended in the SDR group on Day 4 [89/103 (86.4%) versus 79/80 (98.8%); P = 0.002] and on Day 7 [31/103 (30.1%) versus 47/80 (58.8%); P < 0.001]. No significant differences were observed in AEs [15/103 (14.6%) versus 8/80 (10%); P = 0.38] or clinical success [60/103 (58.3%) versus 49/80 (61.3%); P = 0.681] between groups. Post hoc analysis showed that 2/16 (13%) patients with deep infections and 9/11 (82%) with non-deep infections on a TWR achieved target concentrations after loading dose. Higher adherence to loading dose and TDM recommendations was observed for TWR compared with SDR. However, the TWR often failed to achieve adequate TDM levels for higher targets, highlighting the need for optimized TWR loading dose strategies.

Platelet aggregation response to 150-mg maintenance dose of clopidogrel compared to the conventional dose of 75 mg for patients scheduled for elective PCI. Six-month follow-up study

The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response: An Analysis From the PRINC (Plavix Response in Coronary Intervention) Trial

In neonates, β-Lactam antibiotics are almost exclusively administered by intermittent infusion. However, continuous or prolonged infusion may be more beneficial because of the time-dependent antibacterial activity. In this pharmacokinetic/pharmacodynamic simulation study, we aimed to compare treatment with continuous, extended and intermittent infusion of β-lactam antibiotics for neonates with infectious diseases. We selected population pharmacokinetic models of penicillin G, amoxicillin, flucloxacillin, cefotaxime, ceftazidime and meropenem, and performed a Monte Carlo simulation with 30,000 neonates. Four different dosing regimens were simulated: intermittent infusion in 30min, prolonged infusion in 4h, continuous infusion, and continuous infusion with a loading dose. The primary endpoint was 90% probability of target attainment (PTA) for 100% ƒT>MIC during the first 48h of treatment. For all antibiotics except cefotaxime, continuous infusion with a loading dose resulted in a higher PTA compared with other dosing regimens. Sufficient exposure (PTA>90%) using continuous infusion with a loading dose was reached for amoxicillin (90.3%), penicillin G (PTA 98.4%), flucloxacillin (PTA 94.3%), cefotaxime (PTA 100%), and ceftazidime (PTA 100%). Independent of dosing regimen, higher meropenem (PTA for continuous infusion with a loading dose of 85.5%) doses might be needed to treat severe infections in neonates. Ceftazidime and cefotaxime dose might be unnecessarily high, as even with dose reductions, a PTA >90% was retained. Continuous infusion after a loading dose leads to a higher PTA compared with continuous, intermittent or prolonged infusion, and therefore has the potential to improve treatment with β-lactam antibiotics in neonates.

The effect of CYP2C19 gene polymorphism on clinical outcomes of patients with coronary artery disease (CAD) treated with clopidogrel remains controversial. Ethnicity has been proposed to influence clopidogrel response following stent implantation in CAD patients with different CYP2C19 genotypes. Furthermore, Asian populations are reported to have a relatively greater prevalence of CYP2C19 loss-of-function (LOF) alleles. We aimed to evaluate the impact of CYP2C19 gene polymorphism on clinical outcomes in Asian populations who underwent percutaneous coronary interventions (PCI) and received clopidogrel therapy. We conducted a comprehensive search in PubMed, EMBASE, and Cochrane Library from their inceptions to January 20, 2017. Studies that reported clopidogrel therapy information, clinically relevant outcomes (adverse cardiovascular events, stent thrombosis and bleeding), and CYP2C19 genotypes among Asian populations were included. The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death and myocardial infarction. The safety endpoint was any kind of bleeding. We retrieved 20 studies of 15056 patients reporting 1301 cardiovascular events. The primary analysis showed at least one CYP2C19 LOF allele (*2 and/or *3) carriers were at an increased risk of MACE compared with non-carriers (10.58% vs. 6.07%, OR: 1.99, 95% CI: 1.64 to 2.42, p < .001). Stent thrombosis (ST) was also more frequent in LOF allele carriers (2.22% vs. 0.44%, OR: 4.77, 95% CI: 2.84 to 8.01, p < .001). Inversely, the risk of bleeding was lower in LOF allele carriers (OR: 0.66, 95% CI: 0.46 to 0.96, p < .001). Subgroup analysis was performed to assess differences by high (600 mg) or routine (300 mg) loading dose of clopidogrel and by different nationalities. The risk of MACE in LOF allele carriers remained significantly higher even in high loading dose group (high loading dose: OR 1.72, 95% CI: 1.37 to 2.16, and routine loading dose: OR 2.22, 95% CI: 1.68 to 2.94, p for subgroup heterogeneity = 0.16). Subgroup analysis between three nationalities of China, Korea, and Japan demonstrated that the risk of MACE among Chinese LOF allele carriers was the greatest (OR: 2.28; 95% CI:1.91 to 2.73). In conclusion, among Asian populations with CAD undergoing stent implantation, CYP2C19 LOF allele carriers are at greater risk of adverse cardiovascular events and lower risk of bleeding compared with non-carriers. Genetic testing may be helpful for clinicians to personalize antiplatelet therapy especially in Asian population.

The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5–6 g/24 h with preceding loading doses (administered as 30 min infusion) of 0.15–2 g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration–time profile did not drop at any time below four times the S/I breakpoint (= 2 mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33 g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5 g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5 g meropenem over 30 min immediately followed by continuous infusion.

Antithrombin Alfa in Hereditary Antithrombin Deficient Patients at High Risk for Thromboembolic Complications

Meta-Analysis Appraising High Clopidogrel Loading in Patients Undergoing Percutaneous Coronary Intervention

Effect of 300- and 450-mg clopidogrel loading doses on membrane and soluble P-selectin in patients undergoing coronary stent implantation

Real-World Ravulizumab Dosing Patterns Among Patients with Paroxysmal Nocturnal Hemoglobinuria in a US Population

Antiplatelet Effect of Different Loading Doses of Ticagrelor in Patients With Non–ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: The APELOT Trial

Background Reviewing compliance to our Trust guidelines on AICU led us to investigate whether the loading dose prior to continuous infusion was sufficient to achieve therapeutic levels at first measurement. Methods Retrospective data was pulled (January 2011 - June 2017) from a data interrogation system (SAS Enterprise Guide) which linked patients receiving continuous infusion vancomycin at a concentration of 500mg/50ml. This was presented into Excel spreadsheets, additional headings added for data interpretation, then manipulated into pivot tables to determine objectives. Results In 82 courses of vancomycin continuous infusions in 70 patients, 53 received correct loading doses. 31 courses had continuous infusion started within 2 hours of loading dose finishing. 13 courses started at the correct rate. 12/13 courses had vancomycin levels taken. Only one course reached therapeutic range at the first level taken (19.5mg/kg). Of the remaining 11 courses which were out of range, 7 were titrated appropriately – 6 became therapeutic, one remained out of range and was stopped. 3 were not titrated correctly and remained out of range or not titrated at all. Conclusion 16% (13/82) of all continuous vancomycin infusions on AICU complied with guidelines. Only one patient who received the highest weight-based loading dose of 19.5mg/kg reached therapeutic range at the first level monitored, suggesting that doses of ≥20mg/kg at loading are required.