1106. Evaluation of Penetration of Cefiderocol into Cerebrospinal Fluid Using a Rat Meningitis Model

Background Central nervous system (CNS) infections caused by Gram-negative bacteria (GNB) are sometimes hard to treat due to antibiotic resistance and difficulty with penetration into cerebrospinal fluid (CSF). Cefiderocol (CFDC) which was approved by the FDA and the EMA in 2019 to 2020 is a siderophore cephalosporin with potent activity against various GNB including carbapenem-resistant strains. In this study, we evaluated the penetration of CFDC into CSF using a rat meningitis model. Methods To induce meningitis, the anesthetized immunocompetent rats were infected by intracisternal inoculation of a bacterial suspension of 8.7×101 CFU of E. coli SR200138. 200 mg/kg or 50 mg/kg of CFDC was administered via tail vein bolus injection to uninfected rats (n=4/sampling point) and rats with meningitis (n=4/sampling point) 24 hours after infection. CSF was collected by cisternal puncture and blood was collected from heart. The samplings were performed 0.25, 0.5, 1, 3, and 5 hours after dosing. The concentrations of CFDC in plasma and CSF for individuals were determined by LC/MS/MS. PK parameters for the average values in plasma and CSF were calculated. Results CFDC concentration and the PK parameters are shown in Figure and Table, respectively. The penetration of CFDC from plasma to CSF was observed in both uninfected and meningitis groups, and the penetration rates increased in the rats withs meningitis (AUCCSF/AUCplasma: 0.149-0.183) compared with the uninfected rats (AUCCSF/AUCplasma: 0.0508-0.0588). The penetration rates of CFDC in the meningitis were comparable to those of piperacillin, cefepime, and meropenem in human (0.32, 0.103, and 0.39 in strongly inflamed meninges, respectively) [1]. In both groups, elimination of CFDC from CSF was slower compared with that from plasma as seen with other β-lactam antibiotics such as meropenem, suggesting that T> MIC, an indicator that correlates with the efficacy of β-lactams, may be higher in CSF [2]. Table. PK Parameters of Cefiderocol after Intravenous Bolus Administration in Uninfected Rats and Rats with Meningitis Figure. Concentrations of Cefiderocol after Intravenous Bolus Administration in Uninfected Rats and Rats with Meningitis Conclusion It was confirmed that CFDC penetrates into CSF from plasma in a rat model and the penetration rate was increased 3-fold in meningitis. References 1. Nau, R. et al. Clin Microbiol Rev. 2010 Oct;23(4):858–883. 2. Nau, R. et al. Antimicrob Agents Chemother. 1998 Aug;42(8):2012–2016. Disclosures Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Sachi Kanazawa, PhD, Shionogi & Co., Ltd. (Employee) Naoki Kohira, PhD, Shionogi & Co., Ltd. (Employee) Yuki Aoe, BS, Shionogi TechnoAdvance Research Co., Ltd. (Employee) Atsushi Morimoto, n/a, Shionogi TechnoAdvance Research Co., Ltd. (Employee) Kana Horiuchi, MPharm, Shionogi & Co., Ltd. (Employee) Yuji Inoue, MPharm, Shionogi & Co., Ltd. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee)

Pulmonary edema in a pediatric patient undergoing ureteroscopy: a case report

Background This report demonstrates a case of pediatric pulmonary edema, detected due to the overuse of irrigation fluids during ureteroscopy. Case presentation A 7-year-old girl was hospitalized due to the large number of opaque stones in the right kidney. After extubation, the patient’s oxygen saturation dropped down to 85%, and respiratory distress was observed. It was determined that the surgical team used 5 Lt 0.9% NaCl solution as irrigation fluid. Positive pressure ventilation with mask continued, and intravenous bolus injection of furosemide was administered to the patient with a preliminary diagnosis of pulmonary edema. Conclusions In prolonged operations, patients should be checked for the presence of pulmonary edema with lung auscultation, and noninvasive mechanical ventilation and diuretic treatment should be instituted if necessary.

Population Pharmacokinetics Modeling of Levofloxacin In Rabbit By Intravenous Bolus Injection and Peroral Administration

The population-based approach has been widely applied to describe the pharmacokinetic profile of many drugs. The aim of this current research was to study the implementation of the population-based pharmacokinetics of levofloxacin in rabbits administered by intravenous bolus injection and peroral delivery. Modeling analyses were performed using Monolix, one of the alternative tools for the population-based approach. Monolix works based on the Stochastic Approximation Expectation-Maximization (SAEM) method. The analysis was performed based on the population model using one-compartmental and two-compartmental disposition models. The combination error model was used during the analyses. Modeling appropriateness was determined based on the goodness of fit analyses, i.e., 1) the individual fit, 2) the observed versus population prediction values; and 3) the observed versus individual prediction values Plasma concentration profiles of levofloxacin by intravenous bolus injection and oral administration are better described by an appropriate model using a two-compartmental disposition model. All goodness of fit analyses demonstrates the power of the chosen model. However, the estimated disposition parameter values obtained based on the intravenous bolus injection and peroral administration are different for each subject. To confirm this phenomenon, we performed a simultaneous fitting of all intravenous bolus as well as peroral administration data. The goodness of fit analyses indicates an adequate fitting of all data.

Enhanced Drug Permeation into Human Keloid Tissues by Sonophoresis-Assisted Microneedling

Keloids are disfiguring pathological scars that could cause pain and pruritus. The conventional treatments, such as bolus injection of drugs or surgery, are invasive and require a personal visit to clinic. Microneedle (MN) technology has great potential to offer a self-administered and minimally invasive treatment of keloids. However, drugs delivered using MNs suffer from limited penetration in keloid tissue. This study demonstrates enhanced drug penetration in human keloid scar tissue by combining MN and sonophoresis.

Insect flight metabolic rate revealed by bolus injection of the stable isotope 13 C

Measuring metabolic rate (MR) poses a formidable challenge in free-flying insects who cannot breathe into masks or be trained to fly in controlled settings. Consequently, flight MR has been predominantly measured on hovering or tethered insects flying in closed systems. Stable isotopes such as labelled water allow measurement of MR in free-flying animals but integrates the measurement over long periods exceeding the average flight duration of insects. Here, we applied the ‘bolus injection of isotopic 13 C Na-bicarbonate’ method to insects to measure their flight MR and report a 90% accuracy compared to respirometry. We applied the method on two beetle species, measuring MR during free flight and tethered flight in a wind tunnel. We also demonstrate the ability to repeatedly use the technique on the same individual. Therefore, the method provides a simple, reliable and accurate tool that solves a long-lasting limitation on insect flight research by enabling the measurement of MR during free flight.

Hyperpolarized Metabolic MRI—Acquisition, Reconstruction, and Analysis Methods

Hyperpolarized metabolic MRI with 13C-labeled agents has emerged as a powerful technique for in vivo assessments of real-time metabolism that can be used across scales of cells, tissue slices, animal models, and human subjects. Hyperpolarized contrast agents have unique properties compared to conventional MRI scanning and MRI contrast agents that require specialized imaging methods. Hyperpolarized contrast agents have a limited amount of available signal, irreversible decay back to thermal equilibrium, bolus injection and perfusion kinetics, cellular uptake and metabolic conversion kinetics, and frequency shifts between metabolites. This article describes state-of-the-art methods for hyperpolarized metabolic MRI, summarizing data acquisition, reconstruction, and analysis methods in order to guide the design and execution of studies.

Technical Note: In vivo estimation of lipogenesis using a bolus injection of [U- 13C]glucose in pigs

The use of radioactive isotopes to measure de novo lipogenesis in pigs has been well established. Different from radioactive isotopes, stable isotopes present little or no risk to human and animal subjects. Therefore, the objective of this study was to adapt the method of bolus injection of radioactive glucose ( 14C) to use 13C-labelled glucose to estimate de novo lipogenesis in finishing pigs. Five vein-catheterized gilts received 3.0 kg/day of a commercial diet for 2 wk. The last day, the pigs received a bolus injection of [U- 13C]glucose (12 mg/kg BW). A serial of blood samples was taken for 4 h to determine glucose rate of disappearance (Rd) from plasma glucose isotopic enrichment (IE). The 13C IE of lipids was determined from adipose tissue biopsies collected at 1, 2 and 3 h after the bolus injection, and from adipose tissue collected after pig euthanasia 4 h after the bolus. Lipogenesis was estimated from the incorporation of 13C from glucose into adipose tissue lipids. Glucose Rd, estimated using a double exponential function, averaged 5.4 ± 1.4 mmol/min. The IE of lipids increased linearly during the 4 h following the bolus injection (P < 0.05). The rate of incorporation of glucose into lipids, estimating lipogenesis, averaged 9.0 µg glucose/(min × g of lipids) 4 h after the bolus injection. In conclusion, the in vivo method using a bolus injection of [U- 13C]glucose allows a successful estimation of de novo lipogenesis in finishing pigs.

Audit on Steroid Replacement in Confirmed or Suspected COVID-19 Patients With Adrenal Insufficiency or Adrenal Suppression in a District General Hospital

Aim: In response to new updated guidance from Society For Endocrinology April 2020, this Audit was conduct to assess the adequacy of steroid replacement in confirmed or suspected COVID-19 patients with adrenal insufficiency or adrenal suppression admitted to Bedford District General Hospital. In steroid dependent patients (Addison’s disease, adrenal insufficiency, pituitary steroid insufficiency, use of long term steroids for other conditions - 5mg or more of prednisolone (or equivalent doses) daily for longer than 4 weeks) admitted to hospital very unwell with confirmed or suspected COVID recommendations is to start on Hydrocortisone 100 mg per IV injection followed by continuous IV infusion of 200 mg hydrocortisone/24h (alternatively 50 mg every 6 h per intravenous or IM bolus injection). Method: Retrospect data collection on Patients admitted in May 2020 to Bedford Hospital with suspected or confirmed COVID 19 disease with adrenal insufficiency or on long term steroid use. Those patients should be started on Hydrocortisone 100 mg per IV injection followed by continuous IV infusion of 200 mg hydrocortisone/24h (alternatively 50 mg every 6 h per intravenous or IM bolus injection). Results: In May 2020, 295 patients admitted under the medical team in Bedford Hospital with confirmed or suspected COVID-19. Only 12 patients met the inclusion criteria, one patient with a diagnosis of Addison disease and the remaining 11 patients on long term steroids. None of these patients were managed as per updated guidelines. 6 patients had less than the adequate dose, they were started on prednisolone 30-40mg. 4 patients dose of oral steroids was only doubled, 1 patient received the same dose of oral steroid and the only confirmed Addison had higher dose of hydrocortisone. Moreover, In June 2020, The RECOVERY Outcome trial results showed that Dexamethasone 6mg for 10 days reduces the death by one third in hospitalised patient with severe respiratory complications of COVID-19. Dexamethasone 6mg is 12 times the physiological required steroid dose, this is equivalent to 240mg hydrocortisone, which is adequate for steroid replacement in patients with adrenal insufficiency or suppression. Conclusion: In view of these results and the outcome of the RECOVERY Trial, Local trust guidelines updated, indicated that any patient with Adrenal insufficiency or suppression including those on long term steroids very unwell admitted to the hospital should receive Dexamethasone if requiring oxygen or Hydrocortisone if not requiring oxygen. Recommendation of changes included teaching sessions delivered to doctors, posters on updated guidelines distributed in major areas in hospital and trust guidelines updated on the intranet.

Evaluation of different contrast medium injection techniques in the Angio-CT study of the lower limbs in patients with obliterating arteriopathy

The need to write this article was born with the aim of optimizing the Angio-CT study protocol of the lower limbs, comparing two Mdc injection techniques: standard and split bolus, performing a parameter check vital collected before and during injection of the Mdc in order to establish the plateau between reaching the peak of enhancement during the smartprep and the start of the scan. Then well defined parameters are assigned for the evaluation of the images obtained with the different techniques. In the study the inclusion or exclusion parameters of the patient are defined, recruiting 133 cases. The Split Bolus injection technique is optimal together with an accurate evaluation of the patient's vital parameters. Although appreciating the excellent results, the limits of this study are also described.