Latamoxef for Neonates With Early-Onset Neonatal Sepsis: A Study Protocol for a Randomized Controlled Trial

Early-onset neonatal sepsis (EONS), a bacterial infection that occurs within 72 h after birth, is associated with high likelihood of neonatal mortality. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has been brought back into empirical EONS treatment in recent years. In the preliminary work, we established a population pharmacokinetics (PPK) model for latamoxef in Chinese neonates. Moreover, in order to better guide clinical treatment, we conducted dose simulation and found that ascending administration frequency could improve the target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval (70% fT > MIC). Accordingly, this study is aimed to compare the 70% fT > MIC, efficacy and safety between conventional regimen and PPK model regimen for rational use of latamoxef in EONS treatment. A single-blind, multicenter randomized controlled trial (RCT) for latamoxef will be conducted in Chinese EONS patients. Neonates (≤3 days of age, expected number = 114) admitted to the hospital with the diagnosis of EONS and fulfilling inclusion and exclusion criteria will be randomized (ratio of 1:1) to either a conventional regimen (30 mg/kg q12h) or model regimen (20 mg/kg q8h) latamoxef treatment group for at least 3 days. Primary outcome measure will be 70% fT > MIC and secondary outcome indicators will be the latamoxef treatment failure, duration of antibiotic therapy, changes of white blood cell count (WBC), C-reactive protein (CRP) and procalcitonin (PCT), blood culture results during administration and incidence of adverse event (AE)s. Assessments will be made at baseline, initial stage of latamoxef treatment (18–72 h) and before the end of latamoxef treatment. Ethical approval of our clinical trial has been granted by the ethics committee of the Beijing Children’s Hospital (ID: 2020-13-1). Written informed consent will be obtained from the parents of the participants. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR 2000040064).It is hoped that our study will provide a clinical basis for the rational clinical use of latamoxef in EONS treatment.

P461 Vedolizumab Dose Escalation in a Real-World Cohort of IBD Patients

Background Vedolizumab (VDZ) effectively induces and maintains remission in inflammatory bowel disease (IBD). The loss of response to VDZ has been shown to be recaptured with dose escalation but the data in this field are still scarce. In addition, data on pharmacokinetics (PK) of dose escalation are limited and it is unclear whether PK should used in decision-making algorithm in adjusting VDZ dose regimen. Therefore, the aim of our study was to assess clinical efficacy and pharmacokinetic profile of VDZ dose escalation. Methods All IBD patients treated with VDZ in one tertiary IBD centre were retrospectively retrieved from the database. According to local protocol, non-responders to standard dosing of 300 mg i.v. of VDZ every 8 weeks, received escalated dose of 300mg i.v. every 6 or 4 weeks. Disease activity was assessed by Harvey-Bradshaw index (HBI) and partial Mayo score in Crohn’s disease (CD) and ulcerative colitis (UC) pts; respectively. VDZ dose was escalated in case of clinically assessed primary non response by week 22 of the treatment or in case of secondary loss of response. Response to dose escalation was defined as a decrease of HBI of ≥2 points, partial Mayo score ≥3 points or endoscopic improvement. VDZ through levels were assessed at the completion of induction and in dose escalated patients after at least two VDZ administrations in shortened interval. Results In total, 75 IBD patients were included (mean age 47 years, range 20–90; 36 men; 35 CD/39UC/1 IBD-U). Fifty two pts (69%) were primary responders, out of these 23 pts (44%) required dose escalation at some point of the treatment due to secondary loss of response. Out of 23 primary non-responders, 10 stopped the treatment, the remaining 13 received escalated dose of VDZ. Altogether, dose escalation was used in 36 pts (48%). There were no differences in the proportion of CD and UC between conventional and escalated dose regimen groups. Among secondary loss of response, the response was recaptured in 15 out of 23 pts (65%} while only two out of thirteen primary non-responders responded to dose escalation. There were no significant differences in VDZ levels between pts requiring dose escalation and pts with stable response to conventional regimen (mean levels 9,97±1,276 vs. 12,79±1,771 µg/mL; p=n.s.). VDZ levels increased significantly in patients who responded to dose escalation (from 10,12±3,460 to 20,81±3,326 µg/mL; p=0.0497). Conclusion Response to vedolizumab can be successfully recaptured in two thirds of secondary non responders by dose escalation. Patients requiring dose escalation do not seem to differ from stable responders with regards to vedolizumab pharmacokinetics.

Preclinical models of pancreatic ductal adenocarcinoma: challenges and opportunities in the era of precision medicine

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal malignancy, with an average 5-year survival rate of 9% (Siegel RL, Miller KD, Jemal A. Ca Cancer J Clin. 2019;69(1):7-34). The steady increase in mortality rate indicates limited efficacy of the conventional regimen. The heterogeneity of PDAC calls for personalized treatment in clinical practice, which requires the construction of a preclinical system for generating patient-derived models. Currently, the lack of high-quality preclinical models results in ineffective translation of novel targeted therapeutics. This review summarizes applications of commonly used models, discusses major difficulties in PDAC model construction and provides recommendations for integrating workflows for precision medicine.

Clinical efficacy and safety in patients treated with teicoplanin with a target trough concentration of 20 μg/mL using a regimen of 12 mg/kg for five doses within the initial 3 days

Background: A trough concentration (Cmin) ≥20 μg/mL of teicoplanin is recommended for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. However, sufficient clinical evidence to support the efficacy of this target Cmin has not been obtained. Even though the recommended high Cmin of teicoplanin was associated with better clinical outcome, reaching the target concentration is challenging.Methods: Pharmacokinetics and adverse events were evaluated in all eligible patients. For clinical efficacy, patients who had bacteremia/complicated MRSA infections were analyzed. The primary endpoint for clinical efficacy was an early clinical response at 72–96 h after the start of therapy. Five dosed of 12 mg/kg or 10 mg/kg was administered as an enhanced or conventional high loading dose regimen, respectively. The Cmin was obtained at 72 h after the first dose.Results: Overall, 512 patients were eligible, and 76 patients were analyzed for treatment efficacy. The proportion of patients achieving the target Cmin range (20–40 μg/mL) by the enhanced regimen was significantly higher than for the conventional regimen (75.2% versus 41.0%, p < 0.001). In multivariate analysis, Cmin ≥20 μg/mL was an independent factor for an early clinical response (odds ratio 3.95, 95% confidence interval 1.25–12.53). There was no significant difference in the occurrence of adverse events between patients who did or did not achieve a Cmin ≥20 μg/mL.Conclusion: A target Cmin ≥20 μg/mL might improve early clinical responses during the treatment of difficult MRSA infections using 12 mg/kg teicoplanin for five doses within the initial 3 days.

Clinical efficacy and safety in patients treated with teicoplanin with a target trough concentration of 20 μg/mL using a regimen of 12 mg/kg for five doses within the initial 3 days

Background: A trough concentration (Cmin) ≥20 μg/mL of teicoplanin is recommended for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. However available data are limited because it is difficult to attain this target Cmin.Methods: Pharmacokinetics and adverse events were evaluated in all eligible patients. For clinical efficacy, patients who had bacteremia/complicated MRSA infections were analyzed. The primary endpoint for clinical efficacy was an early clinical response at 72–96 h after the start of therapy. Five dosed of 12 mg/kg or 10 mg/kg was administered as an enhanced or conventional high loading dose regimen, respectively. The Cmin was obtained at 72 h after the first dose.Results: Overall, 512 patients were eligible, and 76 patients were analyzed for treatment efficacy. The proportion of patients achieving the target Cmin range (20–40 μg/mL) by the enhanced regimen was significantly higher than for the conventional regimen (75.2% versus 41.0%, p < 0.001). In multivariate analysis, Cmin ≥20 μg/mL was an independent factor for an early clinical response (odds ratio 3.95, 95% confidence interval 1.25–12.53). There was no significant difference in the occurrence of adverse events between patients who did or did not achieve a Cmin ≥20 μg/mL.Conclusion: A target Cmin ≥20 μg/mL might improve early clinical responses during the treatment of difficult MRSA infections using 12 mg/kg teicoplanin for five doses within the initial 3 days.

An Intensified Regimen Containing Linezolid Could Improve Treatment Response in Mycobacterium abscessus Lung Disease

Background. Treatment response for the Mycobacterium abscessus (M. abscessus) lung disease remains far from satisfying. An effective regimen is needed to solve the problem. Methods. We retrospectively reviewed the medical records of all patients with M. abscessus lung disease who received antibiotics regimen at Beijing Chest Hospital Affiliated to Capital Medical University between July 1, 2010, and February 1, 2018. Patients were administered a conventional antibiotics regimen (including macrolide and moxifloxacin, along with an initial 12-week course of low-dose cefoxitin and amikacin) or intensified regimen (including a higher dosage of cefoxitin and linezolid besides conventional drugs), respectively. The time to sputum-culture conversion and proportion of sputum-culture conversion in liquid broth were investigated to evaluate the efficacy and evaluation of safety by performing the classification of adverse events according to the Division of AIDS, National Institute of Allergy and Infectious Disease. Patients were followed for 18 months from baseline. Results. In the conventional regimen group, the sputum conversion rate at 18 months was 29.4% (10/34), and the median time until sputum conversion was 2 months (IQR, 1-2 mo). Furthermore, in the intensified regimen group, the sputum conversion rate was 81.3% (13/16), and the median time until sputum conversion was 1 month (IQR, 1-1 mo). Leukopenia and drug-induced hepatotoxicity occurred more frequently in the intensified regimen group in contrast with the conventional regimen group patients. However, only 1 adverse event in the intensified regimen group was classified as severe adverse event. Conclusions. The intensified regimen could improve sputum conversion of M. abscessus lung disease compared with conventional regimen, but close safety surveillance is necessary to monitor adverse events.

Hypofractionation in Breast Cancer - A Retrospective Study in a Tribal Population Based Medical College in West Bengal, India

Introduction: In a tribal population based area in West Bengal, India though carcinoma cervix is the commonest malignancy in female patients, yet apart from that carcinoma breast is also increasing in number in the recent years. Breast cancer accounts for approximately 26.6% of female malignancy in the radiation oncology out-patient-department of our teaching hospital. Aims and Objectives: To compare conventional RT regimen (50 Gy in 25 fractions over 5 weeks) with one hypofractionated regimen (40Gy in 15 fractions over 3 weeks) in stage II & stage III breast cancer patients as adjuvant radiation therapy in terms of local control, survival and adverse reactions. Materials and Methods: It is a retrospective study which has been conducted in the department of Radiotherapy in BSMC (Bankura Sammilani Medical College) spanning from May 2012 to April 2017. A total number of patients included in this study was 302, out of which thirty six patients failed to follow up. So total of 266 patients included in the study were all histologically proved carcinoma breast treated surgically (97.74% by MRM & rest by BCS) with curative intent following which RT was used as adjuvant therapy. In one group (consisting of 133 patients) conventional regimen (50Gy in 25 fractions) was used. In another group (consisting the other 133 patients) dose-schedule used was a hypofractionated one i.e. 40Gy in 15 fractions. Dose per fraction in the 1st group was 2 Gy whereas in 2nd group it was 2.66 Gy. In all patients, RT was given in 5 days a week. Systemic therapy was administered as and when indicated. Results: 4-year disease-free-survival (DFS) in conventional group was 78.94% and in hypofractionated group was 82.70%, (p value >0.05). 4-year overall survival (OS) in conventional group was 81.20% & in hypofractionated group was 85.70%, (p value >0.05). While adverse reactions in terms of both acute & chronic radiation toxicities were considered, there was no significant difference in between the two groups. Conclusion: There is no significant difference between the conventional regimen and this hypofractionated regimen in terms of OS DFS & adverse reactions in this tribal-based Indian population. Hence, in our institution, we usually prefer Hypofractionated radiotherapy (40Gy/15 fractions) in adjuvant settings for breast cancer patients.