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Hongfei Liu,1 Jiaao Mei,1 Ying Xu,1 Lei Tang,1 Daquan Chen,2 Yating Zhu,1 Shuguang Huang,1 Thomas J Webster,3 Hui Ding4 1College of Pharmacy, Jiangsu University, Zhenjiang 212013, People’s Republic of China; 2School of Pharmacy, Yantai University, Yantai 264005, People’s Republic of China; 3Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA; 4Department of Respiratory and Critical Care Medicine, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, People’s Republic of ChinaCorrespondence: Hui DingDepartment of Respiratory and Critical Care Medicine, The Affiliated Yixing Hospital Of Jiangsu University, Yixing, Jiangsu 214200, People’s Republic of ChinaTel +8601370656506Email dh1350519@163.comThomas J WebsterDepartment Of Chemical Engineering, Northeastern University, Boston, MA 02115, USA, Tel +1 617 373 6585Email th.webster@neu.eduObjective: Nintedanib (NDNB) is a triple receptor tyrosine kinase inhibitor with poor solubility in neutral conditions and low bioavailability. A self-microemulsifying drug delivery system (SMEDDS) of NDNB was developed to improve drug solubility in physical conditions and absorption in vivo.Methods: The NDNB-SMEDDS formulation was optimized via pseudo-ternary phase diagrams. The physicochemical properties of NDNB-SMEDDS, viz., morphological observation, droplet size, stability, compatibility and in vitro release were investigated. The permeability of NDNB-SMEDDS was detected using both a Caco-2 cell monolayer in vitro and an intestinal perfusion study in vivo. Furthermore, the pharmacokinetic characteristics of NDNB-SMEDDS were evaluated.Results: The optimal formulation was composed of MCT as an oil phase, RH 40 as a surfactant and ethylene glycol as a co-surfactant. The average droplet size of the microemulsion was about 23 nm with good stability within 30 days. The formulation did not exhibit any obvious cytotoxic effect on Caco-2 cells. Permeability of nintedanib in a Caco-2 cell monolayer was enhanced by 2.8-fold upon incorporation in SMEDDS compared with the drug solution. The intestinal perfusion study demonstrated that the Papp of NDNB-SMEDDS increased by 3.0-fold in the entire intestine and 3.2-fold in the colon in comparison with the drug solution. The pharmacokinetics study showed that the AUC of the NDNB-SMEDDS increased significantly.Conclusion: This study showed that the self-microemulsion formulations could improve the absorption of nintedanib, and can thus serve as a promising carrier for the oral delivery of nintedanib.Keywords: nintedanib, self-microemulsion drug delivery system, solubility, permeability, Caco-2 cell, intestinal perfusion, pharmacokinetics, bioavailability

David Baunoch,1,2 Natalie Luke,2 Dakun Wang,3 Annah Vollstedt,4 Xinhua Zhao,5 Dicken SC Ko,6 Shuguang Huang,5 Patrick Cacdac,2 Larry T Sirls4 1Research/Development, Pathnostics, Irvine, CA, USA; 2Clinical Affairs, Pathnostics, Irvine, CA, USA; 3Medical Writing, Stat4ward, Pittsburgh, PA, USA; 4Women’s Urology and Pelvic Health Center, Beaumont Hospital, Royal Oak, MI, USA; 5Statistics, Stat4ward, Pittsburgh, PA, USA; 6Department of Bio Med Surgery, Warren Alpert Medical School of Brown University, Providence, RI, USACorrespondence: David Baunoch Email dbaunoch@pathnostics.comPurpose: Studies have shown that multiple genes influence antibiotic susceptibility, but the relationship between genotypic and phenotypic antibiotic susceptibility is unclear. We sought to analyze the concordance between the presence of antibiotic resistance (ABR) genes and antibiotic susceptibility results in urine samples collected from patients with symptomatic urinary tract infection (UTI).Patients and Methods: Urine samples were collected from patients presenting to 37 geographically disparate urology clinics across the United States from July 2018 to February 2019. Multiplex polymerase chain reaction was used to detect 27 ABR genes. In samples containing at least one culturable organism at a concentration of ≥ 104 cells per mL, pooled antibiotic susceptibility testing (P-AST), which involves simultaneous growing all detected bacteria together in the presence of antibiotic and then measure susceptibility, was performed against 14 antibiotics. The concordance rate between the ABR genes and the P-AST results was generated for the overall group. The concordance rates for each antibiotic between monomicrobial and polymicrobial infection were compared using chi-square test.Results: Results from ABR gene detection and P-AST of urine samples from 1155 patients were included in the concordance analysis. Overall, there was a 60% concordance between the presence or absence of ABR genes and corresponding antimicrobial susceptibility with a range of 49– 78% across antibiotic classes. Vancomycin, meropenem, and piperacillin/tazobactam showed significantly lower concordance rates in polymicrobial infections than in monomicrobial infections.Conclusion: Given the 40% discordance rate, the detection of ABR genes alone may not provide reliable data to make informed clinical decisions in UTI management. However, when used in conjunction with susceptibility testing, ABR gene data can offer valuable clinical information for antibiotic stewardship.Keywords: urinary tract infection, antibiotic resistance, antibiotic resistance genes, bacteria, culture, antibiotic susceptibility test, polymerase chain reaction