BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious threat to public health. Vancomycin (VAN) remains the primary treatment for these infections, and achieving the recommended area under the curve (AUC) target has been linked to improved clinical outcomes. The current VAN therapeutic monitoring guidelines recommend a loading dose (LD) of 20-35 mg/kg to rapidly attain targeted VAN exposures within 24 h of therapy. However, there is a paucity of data describing the impact of VAN LD on day 1 area under the curve (AUC0-24). This study aims to employ pharmacokinetic (PK) equations to calculate and describe the AUC0-24 following a VAN LD of 20 mg/kg.
METHODS: This was a retrospective study of adult patients who were loaded with VAN 20 mg/kg, received ≥ 48 h of treatment, and had two consecutive serum VAN levels collected within 24 h. Linear, non-trapezoidal PK equations and two post-infusion VAN levels were used to calculate AUC0-24. Therapeutic AUC0-24 was defined as 400-600 mg/l*h.
RESULTS: Among 123 included patients, the median age was 46 years (IQR 36, 62), 54% (67/123) of the patients had a body mass index (BMI) ≥ 30 kg/m2 and 27% (33/123) were admitted to the intensive care unit (ICU). Following a LD of 20 mg/kg, 50% (61/123) of the patients met the therapeutic AUC0-24, while 22% (27/123) of the patients were subtherapeutic, and 28% (35/123) were supratherapeutic. Compared with patients who achieved therapeutic AUC0-24, patients with subtherapeutic AUC0-24 were more likely to be younger (44 vs. 37 years old) and have a BMI ≥ 30 kg/m2 (67 vs. 52%). In contrast, patients with supratherapeutic AUC0-24 were more likely to be older (64 vs. 44 years old) and to have chronic kidney disease diagnosis (23 vs. 7%) when compared to patients who achieved a therapeutic AUC0-24. CONCLUSIONS: Only 50% of patients achieve the target AUC0-24 following a VAN 20 mg/kg LD, with younger, heavier patients underexposed and older patients with renal impairment overexposed, suggesting that different dosing strategies are needed for these populations.

This retrospective chart review evaluated whether 20 mg/kg vancomycin loading doses increase early area under the curve (AUC) target attainment within 48 hours in comparison to non-loading dose regimens. There were no differences between groups for the primary outcome (46 % vs. 50 %; P = 0.58).

BACKGROUND: Makena (17-hydroxyprogesterone caproate) was approved by the United States Food and Drug Administration for the prevention of recurrent spontaneous preterm birth in 2011 under the accelerated approval pathway, but fundamental pharmacokinetic or pharmacodynamic (Phase 1 and Phase 2) studies were not performed. At the time, there were no dose-response or concentration-response data. The therapeutic concentration was not known. The lack of such data brings into question the dosing regimen for 17-hydroxyprogesterone caproate and if it was optimized.
OBJECTIVE: The purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing 3 data sets in which the 17-hydroxyprogesterone caproate pharmacology was evaluated, namely the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study, and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy.
METHODS: Data from the Omega 3 study were used to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes.
RESULTS: Analysis of the Omega 3 data set indicated that the risk for spontaneous preterm birth decreased as the log concentration of 17-hydroxyprogesterone caproate increased (odds ratio, 0.04; 95% confidence interval, 0.00-0.90). A steady state concentration of >9 ng/mL (equivalent to >8 ng/mL at 25-28 weeks) was associated with the lowest risk for spontaneous preterm birth (hazard ratio, 0.52; 95% confidence interval, 0.27-0.98; P=.04); this concentration was not achieved in 25% of subjects who received the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and interquartile range) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, >5 weekly injections were required to reach the 9 ng/mL target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/mL concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/mL concentration within 2 weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/mL target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects who received a weekly dose of 500 mg exceeded the 9 ng/mL steady state.
CONCLUSIONS: The dosing regimen for 17-hydroxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. The risk was lowest when the concentration exceeded 9 ng/mL, but 25% of women who received the 250 mg weekly dose never reached or maintained this concentration. The drug\'s long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections pose a serious threat, with high morbidity and mortality rates. This retrospective cohort study, conducted at Nakornping Hospital between January 2015 and October 2022, aimed to evaluate the efficacy and safety of a high loading dose (LD) of colistin combined with nebulized colistin in critically ill patients with CRAB pneumonia. Of the 261 patients included, 95 received LD colistin, and 166 received LD colistin with nebulized colistin. Multivariate Cox regression analysis, adjusted for baseline covariates using inverse probability weighting, showed no significant difference in 30-day survival between patients who received LD colistin and those who received LD colistin with nebulized colistin (adjusted hazard ratio [aHR]: 1.17, 95% confidence interval [CI]: 0.80-1.72, p = 0.418). Likewise, there were no significant differences in clinical response (aHR: 0.93, 95% CI: 0.66-1.31, p = 0.688), microbiological response (aHR: 1.21, 95% CI: 0.85-1.73, p = 0.279), or nephrotoxicity (aHR: 1.14, 95% CI: 0.79-1.64, p = 0.492) between the two treatment groups. No significant adverse events related to nebulized colistin were reported. These findings suggest that the addition of nebulized colistin may not offer additional benefits in terms of 30-day survival, clinical or microbiological response, or nephrotoxicity in these patients.

A loading dose of voriconazole (VRCZ) is recommended to increase its blood concentration at an early stage. However, the trends in the implementation of the loading dose in VRCZ in Japan has not yet been clarified. In addition, although pharmacists play many important roles in antimicrobial stewardship, the effect of pharmacist intervention on the implementation of a loading dose of VRCZ has not yet been reported. Therefore, this study aimed to clarify the implementation of loading dose of VRCZ and the influencing factors of loading dose. This study used an administrative claims database that included patients who received injectable VRCZ between 2010 and 2019. The implementation of loading doses in the VRCZ was evaluated annually. Multivariate logistic regression analysis was performed to identify the factors influencing loading dose. Overall, 2197 patients were included. The implementation rate of the loading dose remained below 65% throughout the study period. Among medical fees that can be calculated through pharmacist intervention, only the infection prevention and control premium significantly increased the implementation of loading dose of VRCZ (odds ratio: 1.587, 95% confidence interval: 1.053-2.392). In conclusion, antifungal stewardship may have been promoted at medical institutions that established infection prevention and control. In the future, pharmacists will need to intervene more actively from the beginning of VRCZ administration.

BACKGROUND: The loading dose of teicoplanin (TEIC) is recommended for implementation. However, there is significant discrepancy between the dose settings in the package insert and, in the guidelines, and the actual status of loading doses in Japan is unclear. Furthermore, TEIC causes liver injury as side effect. Although the risk of developing liver injury has not been reported to be increased following a loading dose based on the guidelines, there is a lack of reports in large populations. Therefore, we evaluated the trend in the loading dose and factors affecting the efficacy and safety of TEIC administration.
METHODS: A Japanese administrative claims database was used in this study. Trends in loading doses were evaluated in target populations administered TEIC between 2010 and 2019. Patient characteristics were adjusted by propensity score matching based on the guideline group (total dose of 3 days > 1,600 mg) and non-guideline group (≤ 1,600 mg) of the loading dose. Finally, univariable and multivariable conditional logistic regression analysis was performed to evaluate factors affecting 30-day mortality and liver injury.
RESULTS: A total of 10,030 patients were selected based on these criteria. The proportion of loading doses based on the recommended guidelines showed an increase over time, regardless of the implementation of therapeutic drug monitoring (TDM), but especially so in cases where TDM was implemented, the loading doses were administered in accordance with the recommendations of the guidelines. Conditional logistic regression analysis showed a relationship between drug management and guidance fees (odds ratio [OR]: 0.45, 95% confidence interval [CI]: 0.36‒0.55), a reimbursement indicating pharmacist intervention, and a reduction in 30-day mortality. In addition, loading doses based on the recommended guidelines had no influence on liver injury, and other factors were not significantly associated with increased incidence of liver injury.
CONCLUSIONS: Thus, this study implies the benefits of pharmacological management as indicated by drug management and guidance fee and supports the implementation of loading doses based on the guideline on TEIC administration.

This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it.
Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function.
A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient\'s renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week.
Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient\'s renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

BACKGROUND: Although the loading dose (LD) of vancomycin (VCM) contributes to its efficacy, it may not be conducted adequately. Herein, the objective was to evaluate the effect of LD on patient prognosis using therapeutic drug monitoring by pharmacists and elucidate the impact of an antimicrobial stewardship program (ASP)-driven educational intervention on the LD implementation rate and patient prognosis.
METHODS: First, a retrospective cohort study was conducted involving 121 adult patients administered with VCM and compared with 28-day mortality in LD and non-LD groups. To avoid confounding, the propensity score method was employed. Second, post-training with ASP-driven lectures, a questionnaire survey was conducted for healthcare workers, including physicians, nurses, and pharmacists. The rates of VCM LD implementation and 28-day mortality were compared during a period of one year and 9 months between the pre-ASP (n = 38) and post-ASP (n = 33) groups.
RESULTS: After propensity score matching, the 28-day mortality in the LD group was significantly improved, suggesting that the early increase in blood levels of VCM due to an LD is an important factor influencing patient prognosis. After the lecture, a questionnaire survey revealed that the understanding rates of \"well\" and \"slightly well\" for educational lectures exceeded 80% of all healthcare workers. The rate of LD implementation significantly increased to 63.6% (21/33) in the post-ASP group compared with 31.6% (12/38) in the pre-ASP group (p = 0.007), and the 28-day mortality declined from 23.7% (9/38) to 6.1% (2/33) (p = 0.041).
CONCLUSIONS: This method of ASP-driven educational intervention would facilitate LD implementation, improving patient prognosis.

Despite their limitations, the pharmacokinetics (PK) and pharmacodynamics (PD) indices form the basis for our current understanding regarding antibiotic development, selection, and dose optimization. Application of PK-PD in medicine has been associated with better clinical outcome, suppression of resistance, and optimization of antibiotic consumption. Beta-lactam antibiotics remain the cornerstone for empirical and directed therapy in many patients. The percentage of time of the dosing interval that the free (unbound) drug concentration remains above the minimal inhibitory concentration (MIC) (%fT > MIC) has been considered the PK-PD index that best predicts the relationship between antibiotic exposure and killing for the beta-lactam antibiotics. Time dependence of beta-lactam antibiotics has its origin in the acylation process of the serine active site of penicillin-binding proteins, which subsequently results in bacteriostatic and bactericidal effects during the dosing interval. To enhance the likelihood of target attainment, higher doses, and prolonged infusion strategies, with/or without loading doses, have been applied to compensate for subtherapeutic levels of antibiotics related to PK-PD changes, especially in the early phase of severe sepsis. To minimize resistance and maximize clinical outcome, empirical therapy with a meropenem loading dose followed by high-dose-prolonged infusion should be considered in patients with high inoculum infections presenting as severe (Gram negative) sepsis. Subsequent de-escalation and dosing of beta-lactam antibiotics should be considered as an individualized dynamic process that requires dose adjustments throughout the time course of the disease process mediated by clinical parameters that indirectly assess PK-PD alterations.

UNASSIGNED: Dual antiplatelet therapy is standard for patients undergoing percutaneous coronary intervention (PCI) with stents. Traditionally, patients swallow the loading dose of a P2Y12 inhibitor before or during PCI. Time to achieve adequate platelet inhibition after swallowing the loading dose varies significantly. Chewed tablets may allow more rapid inhibition of platelet aggregation. However, data for this strategy in patients with stable ischemic heart disease or non-ST-elevation acute coronary syndrome (NSTE-ACS) are less robust.
UNASSIGNED: In this single-center prospective trial, 112 P2Y12-naïve patients with stable ischemic heart disease or NSTE-ACS on aspirin therapy and who received ticagrelor after coronary angiography but before PCI were randomized to chewing (n=55) or swallowing (n=57) the ticagrelor loading dose (180 mg). Baseline variables were compared using 2-sample t-test and chi-squared/Fisher\'s exact tests as appropriate, with alpha set at 0.05. P2Y12 reaction units (PRU) were compared at baseline, 1 hour, and 4 hours using Wilcoxon rank-sum test. Patients then received standard ticagrelor dosing.
UNASSIGNED: After exclusions, P2Y12 PRU in the chewed and swallowed groups at baseline, 1 hour, and 4 hours after ticagrelor loading dose were 243 vs 256 (P=0.75), 143 vs 210 (P=0.09), and 28 vs 25 (P=0.89), respectively. No differences were found in major adverse cardiac events (MACE) or major bleeding at 30 days and 1 year.
UNASSIGNED: In patients with stable ischemic heart disease or NSTE-ACS, chewing rather than swallowing ticagrelor may lead to slightly faster inhibition of platelet aggregation at 1 hour with no increase in MACE or major bleeding.