Preclinical Services News

Image0 225x300March 2, 2020

More than 40 individuals from across the country came to Washington Feb. 25-27, as part of The Pew Charitable Trusts’ Stand Up To Superbugs initiative. This year’s ambassadors include health care professionals, public health officials, scientists, farmers and ranchers, veterinarians, superbug survivors, and people who have lost loved ones to an antibiotic-resistant infection. They met with their representatives on Capitol Hill to share their superbug stories and expertise, and urge increased action to preserve the effectiveness of existing antibiotics and develop urgently needed new ones.

Bill Weiss had the opportunity to participate for the 2nd year in the Pew Charitable Trusts #StandUptoSuperbugs fly in. He spent two days meeting with senators, congressman including Rep Bill Flores (TX 17th district), Rep Kay Granger (TX 12th district), Rep Marc Veasey (TX 33rd district), Rep John Carter (TX 31st district), Rep Pete Olson (TX 22nd district), Rep Henry Cueller (TX 28th district), Rep Kenny Marchant (TX 24th district), Rep Michael Burgess (TX 26th district), Rep Cheri Bustos (IL 17th district), Rep Darin Lahood (IL 18th district), Sen Dick Durbin (IL) and Rep Bobby Rush (IL 1st district) as well as the House Ways and Means Committee.


February 25, 2020

Antimicrobial Resistance (AMR) is a public health crisis, but developing new classes of antibiotics to combat drug resistant bacteria is challenging on many levels.

In November, the Centers for Disease Control and Prevention (CDC) released a report, Antibiotic Resistance Threats in the United States 2019 . The report found that antibiotic-resistant “superbugs” cause almost 3 million infections and 35,000 deaths per year—more than previously projected. The World Health Organization predicts drug-resistant infections could cause 10 million deaths a year — more than cancer — by 2050.

“Estimates show that it takes more than a decade to develop a new antibiotic or vaccine and can cost more than $1 billion. But even when a product does make it to the market, it might take 23 years to break even on its R&D investment. Bipartisan legislation, the DISARM Act was introduced in Congress last July that would help spur investment in new antibiotics. The bill would create a separate reimbursement payment for antibiotics under Medicare, allowing hospitals to fully recoup the cost of newer treatments.


February 18, 2020

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European Congress of Clinical Microbiology and Infectious Disease (ECCMID) meeting (April 18-21, Paris, France) – PreClinical Services will be presenting one poster (Mark Pulse) and have one oral presentation (Bill Weiss) at this years meeting. In addition Bioversys, a European biotechnology company, will presenting a poster and oral talk in conjunction:

  1. Oral Immunotherapy with Secretory IgA Improves Survival in the Hamster Model of C. difficile Infection. W. J. Weiss4, M. R. Simon1,5, S. Kiessig3, E. F. Chiari1, M. E. Pulse4, S. C. Brown1, Ch. von Eichel-Streiber2, H. Gerding3, M. Mandago3 1Secretory IgA, Inc. Ann Arbor, MI, ²tgcBIOMICS GmbH, Bingen, Germany ³PreviPharma Consulting GmbH, Mannheim, Germany 4UNT System College of Pharmacy – PreClinical Services, Fort Worth, TX, 5Wayne State University School of Medicine, Detroit, MI, USA and Oakland University William Beaumont School of Medicine, Rochester, MI, USA
  2. In vivo efficacy of BV100 in mouse models of infection. G.E. Dale1, C. Kemmer1, V. Trebosc1, B. Schellhorn1, M. Gitzinger1, S. lociuro1, M. E. Pulse2, W. J. Weiss2,1BioVersys AG, 4057 Basel, Switzerland, 2University of North Texas Health Science Center, Fort Worth, TX 76107-2699, USA;
  3. Pharmacokinetics and Pharmacodynamics of BV100 in neutropenic lung infection models. G.E. Dale1, C. Kemmer1, V. Trebosc1, B. Schellhorn1, M. Gitzinger1, S. lociuro1, M. E. Pulse2, W. J. Weiss2. 1BioVersys AG, 4057 Basel, Switzerland, 2University of North Texas Health Science Center, Fort Worth, TX 76107-2699, USA;
  4. Epidemic Clostridioides difficile isolates are signifcantly more lethal and persist at higher rates than non-epidemic isolates in hamsters following vancomycin treatment. M. E. Pulse, J. C. Vitucci, W. J. Weiss, J. W. Simecka. UNT System College of Pharmacy – PreClinical Services, Fort Worth, TX

May 7, 2019

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Models for antimicrobial R&D: Development and use of in vivo models for infectious disease research


Speaker: William J. Weiss, Director, PreClinical Services, University of North Texas System College of Pharmacy

Moderator: Peter Warn, Senior Vice President, Anti-infective Discovery, Evotec


In this webinar, William J. Weiss will introduce experimental design of animal models for antimicrobial research. He will discuss questions such as

  1. Where to start and what model to use?
  2. Are animal models of bacterial infection reflective of the clinical condition?
  3. Are in vivo animal model results predictive of clinical efficacy?

https://revive.gardp.org/development-and-use-of-in-vivo-models-for-infectious-disease-research/

April 4, 2019

The results of research studies performed by PreClinical Services under the direction of Mark Pulse appeared in Nature Scientific Report volume 9, Article number: 2904 (2019)

Novel Chitohexaose Analog Protects Young and Aged mice from CLP Induced Polymicrobial Sepsis

Pragnya Das, Santosh K. Panda, Beamon Agarwal, Sumita Behera, Syed M. Ali, Mark E. Pulse, Joseph S. Solomkin, Steven M. Opal, Vineet Bhandari & Suchismita Acharya

In Gram-negative bacterial sepsis, production of excess pro-inflammatory cytokines results in hyperinflammation and tissue injury. Anti-inflammatory cytokines such as IL-10 inhibit inflammation and enhance tissue healing. Here, we report a novel approach to treat septicemia associated with intra- abdominal infection in a murine model by delicately balancing pro- and anti-inflammatory cytokines. A novel oligosaccharide compound AVR-25 selectively binds to the TLR4 protein (IC50 = 0.15 μM) in human peripheral blood monocytes and stimulates IL-10 production. Following the cecal ligation and puncture (CLP) procedure, intravenous dosing of AVR-25 (10 mg/kg, 6–12 h post-CLP) alone and in combination with antibiotic imipenem protected both young adult (10–12 week old) and aged (16–18 month old) mice against polymicrobial infection, organ dysfunction, and death. Proinflammatory cytokines (TNF- α, MIP-1, i-NOS) were decreased significantly and restoration of tissue damage was observed in all organs. A decrease in serum C-reactive protein (CRP) and bacterial colony forming unit (CFU) confirmed improved bacterial clearance. Together, these findings demonstrate the therapeutic ability of AVR-25 to mitigate the storm of inflammation and minimize tissue injury with high potential for adjunctive therapy in intra-abdominal sepsis.


March 11, 2019

HSC PreClinical Services to present research at ASM Microbe 2019, San Francisco, CA, June 20-24, 2019.

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Track Hub

June 21, 2019, 1:15 PM – 2:00 PM

AAR Track Hub (Booth 5053), Learn, Exhibit and Poster Hall

Use of Animal Infection Models in the Evaluation of Novel Antimicrobial Therapies
Slide Session S339 – Pipeline Drugs to Treat Gram-negative Infections
June 23, 2019, 3:30 PM – 3:45 PM

Pharmacokinetics and Efficacy of TP-6076 in the Murine Lung Infection Model with Acinetobacter baumannii

Poster Sessions

  • Abstract control number 4043, titled Efficacy of a Novel Antimicrobial Compound in the Murine Thigh Infection Model with A. baumannii
  • Abstract control number 4023, titled In Vitro and In Vivo Effects of Fosfomycin Resistant Mutants on Bacterial Growth and Efficacy in the Murine UTI Model
  • Abstract control number 4056, titled Pharmacokinetics and Efficacy of Ceftazidime-Avibactam and Aztreonam in the Murine Thigh Infection Model
  • Abstract control number 4076, titled Pharmacokinetics and Efficacy of TP-6076 in the Murine Lung Infection Model with Acinetobacter baumannii
  • Abstract control number 4653, titled Pathogenicity of Pseudomonas Mutant Strains and Efficacy of Aerosolized OTG005 in a Murine Lung Infection Model
  • Abstract control number 4057, titled Efficacy of TP-6076 in the Murine Thigh Infection Model with Acinetobacter baumannii
  • Abstract control number 4019, titled Efficacy of Ceftibuten + VNRX-7145 a Novel Beta-Lactamase Inhibitor against ESBL E. coli Strains in a Murine UTI Model

March 2, 2019

2019 Stand Up To Superbugs

A team of people from around the country will travel to Washington from March 5 to 7 as part of the Stand Up to Superbugs movement to meet with members of Congress and policymakers. These individuals are part of The Pew Charitable Trusts’ network of survivors, farmers, doctors, researchers, and others with a personal connection to the issue of antibiotic resistance. They are sharing their unique experiences and perspectives to help raise awareness about the growing public health and national security threat posed by drug-resistant bacteria. Together, our ambassadors are working to ensure the responsible use of antibiotics in veterinary and human medicine, spur a robust pipeline of new drugs, and increase funding across the federal government to combat antibiotic-resistant bacteria.

https://www.pewtrusts.org/en/research-and-analysis/articles/2019/03/05/meet-our-2019-stand-up-to-superbugs-ambassadors


March 1, 2019

HSC PreClinical Services to present research at the 29th ECCMID meeting, April 13-16, 2019.

 

Eccmid 2019

  • Weiss, W., K. Carter, M. Pulse, P. Nguyen, D. Valtierra, K. Peterson, R. Tommasi, J. Mueller, J. O’Donnell. 2019. Efficacy of cefpodoxime proxetil and ETX0282 in a murine UTI model with Escherichia coli and Klebsiella pneumoniae. 29th ECCMID, Amsterdam, NE.
  • Hans-Jürgen, H., M. Pulse, W. Weiss, A. Lange, K. Gisch, Heike Kliem, M. Pfaffl, U. Kulozik, C. Von Eichel-Streiber. 2019. Concurrent treatment and prevention of recurrent Clostridium difficile infection with specific antibodies obtained from bovine milk in a hamster primary infection model. 29th ECCMID, Amsterdam, NE.
  • Olesky, M., J. Newman, J. Zhou, C. Fyfe, W. Weiss, M. Pulse. 2019. In vivo efficacy of TP-6076 in murine thigh and lung infection models challenged with Acinetobacter baumannii. 29th ECCMID, Amsterdam, NE.

 


February 2019

Recent publications from the PreClinical Services group

Antimicrob Agents Chemother. 2019: Accepted for publication.

Pharmacological, Toxicological, and Dose Range Assessment of OG716, a Novel Lantibiotic for the Treatment of Clostridium difficile-Associated Infection

Mark E. Pulse,a William J. Weiss,a Johan A. Kers,b* Anthony W. DeFusco,c* Jae H. Park,c Martin Handfieldc

aPreClinical Services, UNT System College of Pharmacy, Fort Worth, Texas, USA bIntrexon Corp., Industrial Products Division, South San Francisco, California, USA cOragenics, Inc., Alachua, Florida, USA

Abstract

Lantibiotics present an attractive scaffold for the development of novel antibiotics. We report here a novel lantibiotic for the treatment of Clostridium difficile infection. The lead compounds were selected from a library of over 700 single- and multiple-substitution variants of the lantibiotic mutacin 1140 (MU1140). The best performers in vitro and in vivo were further used to challenge Golden Syrian hamsters orally in a Golden Syrian hamster model of Clostridium difficile-associated disease (CDAD) in a dose-response format, resulting in the selection of OG716 as the lead compound. This lantibiotic was characterized by a 50% effective dose of 23.85 mg/kg of body weight/day (10.97 mol/kg/day) in this model. Upon oral administration of the maximum feasible dose (1,918 mg/kg/day), no observable toxicities or side effects were noted, and no effect on intestinal motility was observed. Compartmentalization to the gastrointestinal tract was confirmed. MU1140-derived variants offer a large pipeline for the development of novel antibiotics for the treatment of several indications and are particularly attractive considering their novel mechanism of action. Based on the currently available data, OG716 has an acceptable profile for further development for the treatment of CDAD.


Antimicrob Agents Chemother. 2019 Jan 14. pii: AAC.02214-18. doi: 10.1128/AAC.02214-18.

In vivo efficacy of novel monobactam LYS228 in murine models of carbapenemase-producing Klebsiella pneumoniae infection.

Weiss WJ1, Pulse ME1, Nguyen P1, Growcott EJ2.

1Pre-Clinical Services at University of North Texas Health Science Center, Fort Worth, Texas, USA.
2Novartis Institute of BioMedical Research, Emeryville, CA, USA ellie.growcott@novartis.com.

Abstract
LYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae. LYS228 was efficacious in neutropenic thigh models established with K. pneumoniae producing either KPC-2 or NDM-1; pre-treatment with uranyl nitrate considerably shifted calculated static doses of LYS228. In murine ascending pyelonephritis, LYS228 reduced bacterial burden in the kidney, urine and bladder. The successful treatment of murine infection models established with carbapenem resistant K. pneumoniaefurther supports the clinical development of LYS228.

Copyright © 2019 American Society for Microbiology.PMID: 30642927 DOI: 10.1128/AAC.02214-18


Antimicrob Agents Chemother. 2019 Jan 22. pii: AAC.01904-18. doi: 10.1128/AAC.01904-18.

Pharmacological, Toxicological and Dose-Range Assessment of OG716, a Novel Lantibiotic for the Treatment of Clostridium difficile Associated Infection (CDI).

Pulse ME1, Weiss WJ1, Kers JA2, DeFusco AW3, Park JH3, Handfield M4.
Author information

Abstract
Lantibiotics present an attractive scaffold for the development of novel antibiotics. We report here a novel lantibiotic for the treatment of C. difficile infection. The lead compounds were selected from a library of over 700 single and multiple substitution variants of the lantibiotic Mutacin 1140 (MU1140). The best performers in vitro and in vivo, were further challenged orally in the Golden Syrian hamster model of Clostridium difficile associated disease CDAD in a dose-response format, resulting in selection of OG716 as the lead compound. This lantibiotic was characterized by an ED50 of 23.85 mg/Kg/day (10.97 μmole/Kg/day) in this model. Upon oral administration of the maximum feasible dose (≥1,918 mg/Kg/day), no observable toxicities and side effects were noted and no effect on intestinal motility was observed. Compartmentalization to the GI tract was confirmed. MU1140-derived variants offer a large pipeline for the development of novel antibiotics in several indications and are particularly attractive considering their novel mechanism of action. Based on the currently available data, OG716 has an acceptable profile for further development for the treatment of CDAD.

Copyright © 2019 American Society for Microbiology.PMID: 30670434 DOI: 10.1128/AAC.01904-18


Antimicrobial Agents and Chemotherapy: October 2018 Volume 62 Issue 10 e00925-18

Antibiotic-Induced Dysbiosis Predicts Mortality in an Animal Model of Clostridium difficile Infection

Charles Burdet,a,b Sakina Sayah-Jeanne,c Thu Thuy Nguyen,a Perrine Hugon,c Frédérique Sablier-Gallis,c Nathalie Saint-Lu,c Tanguy Corbel,c Stéphanie Ferreira,d Mark Pulse,e William Weiss,e Antoine Andremont,a France Mentré,a,b Jean de Gunzburgc aINSERM and Paris Diderot University, IAME, UMR 1137, Paris, France bDepartment of Epidemiology, Biostatistic and Clinical Research, Bichat Hospital, Assistance Publique- Hopitaux de Paris, Paris, France cDa Volterra, Paris, France dGenoScreen, Lille, France eUniversity of North Texas Health Science Center, Fort Worth, Texas, USA

Abstract

Antibiotic disruption of the intestinal microbiota favors colonization by Clostridium difficile. Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis and quantified the link between this intensity and mortality. We administered either moxifloxacin (n 70) or clindamycin (n 60) to hamsters by subcutaneous injection from day 1 (D1) to D5 and challenged them with a C. difficile toxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0 and D3 using diversity indices determined from 16S rRNA gene profiling. Survival was monitored until D16. We analyzed the relationship between fecal antibiotic concentrations and dysbiosis at the time of C. difficile challenge and studied their capacity to predict subsequent death of the animals. Increasing doses of DAV131A reduced fecal concentrations of both antibiotics, lowered dysbiosis, and increased survival from 0% to 100%. Mortality was related to the level of dysbiosis (P 105 for the change of Shannon index in moxifloxacin-treated animals and P 109 in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the receiver operating curve (ROC) of 0.89 (95% confidence interval [CI], 0.82, 0.95) and 0.95 (0.90, 0.98), respectively. Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency on the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in similar manners with the two antibiotics. KEYWORDS antibiotics, dysbiosis, C. difficile infection, hamster animal model,


Toxins (Basel). 2019 Feb 6;11(2).

Treatment and Prevention of Recurrent Clostridium difficile Infection with Functionalized Bovine Antibody-Enriched Whey in a Hamster Primary Infection Model.

Heidebrecht HJ1,2, Weiss WJ3, Pulse M4, Lange A5, Gisch K6, Kliem H7, Mann S8, Pfaffl MW9,10, Kulozik U11,12, von Eichel-Streiber C13. 1 Chair of Food and Bioprocess Engineering, Technical University of Munich, 85354 Freising, Germany. Hans-Juergen.Heidebrecht@tum.de. 2 ZIEL Institute for Food & Health, Technical University of Munich, 85354 Freising, Germany. Hans-Juergen.Heidebrecht@tum.de. 3 University of North Texas Health Science Center, Fort Worth, TX 76107-2699, USA. William.Weiss@unthsc.edu. 4 University of North Texas Health Science Center, Fort Worth, TX 76107-2699, USA. Mark.Pulse@unthsc.edu. 5 tgcBIOMICS GmbH, 55411 Bingen, Germany. a.lange@tgcbiomics.de. 6 tgcBIOMICS GmbH, 55411 Bingen, Germany. k.gisch@tgcbiomics.de. 7 Chair of Animal Physiology and Immunology, Technical University of Munich, 85354 Freising, Germany. kliem@wzw.tum.de. 8 Biosys UK Limited, London, SW1H, 9BP, UK. sacha.mann@gmail.com. 9 Chair of Animal Physiology and Immunology, Technical University of Munich, 85354 Freising, Germany. michael.pfaffl@wzw.tum.de. 10 School of Life Science, Technical University of Munich, 85354 Freising, Germany. michael.pfaffl@wzw.tum.de. 11 Chair of Food and Bioprocess Engineering, Technical University of Munich, 85354 Freising, Germany. ulrich.kulozik@tum.de. 12 ZIEL Institute for Food & Health, Technical University of Munich, 85354 Freising, Germany. ulrich.kulozik@tum.de. 13 tgcBIOMICS GmbH, 55411 Bingen, Germany. chv.eichel@tgcbiomics.de

Abstract

Toxin-induced Clostridium difficile infection (CDI) is a major disease characterized by severe diarrhea and high morbidity rates. The aim with this study was to develop an alternative drug for the treatment of CDI. Cows were repeatedly immunized to establish specific immunoglobulin G and A titers against toxins A (TcdA) and B (TcdB) and against C. difficile cells in mature milk or colostrum. The effect of three different concentrations of anti-C. difficile whey protein isolates (anti-CD-WPI) and the standard of care antibiotic vancomycin were investigated in an animal model of CD infected hamsters (6 groups, with 10 hamsters each). WPI obtained from the milk of exactly the same cows pre-immunization and a vehicle group served as negative controls. The survival of hamsters receiving anti-CD-WPI was 50, 80 and 100% compared to 10 and 0% for the control groups, respectively. Vancomycin suppressed the growth of C. difficile and thus protected the hamsters at the time of administration, but 90% of these hamsters nevertheless died shortly after discontinuation of treatment. In contrast, the surviving hamsters of the anti-CD-WPI groups survived the entire study period, although they were treated for only 75 h. The specific antibodies not only inactivated the toxins for initial suppression of CDI, but also provoked the inhibition of C. difficile growth after discontinuation, thus preventing recurrence. Oral administration of anti-CD-WPI is a functional therapy of CDI in infected hamsters for both primary treatment and prevention of recurrence. Thus, anti-CD-WPI could address the urgent unmet medical need for treating and preventing recurrent CDI in humans.


May 7, 2018

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ASM Microbe 2018 (June 7–11, 2018, Atlanta, GA) showcases the best microbial sciences in the world, and provides a one-of-a-kind forum to explore the complete spectrum of microbiology from basic science to translation and application.

The UNTHSC Pre-Clinical Services group will be in attendance at the ASM Microbe meeting and welcomes the opportunity to meet with current as well as prospective collaborators to discuss ongoing and future projects. If interested, please contact William Weiss (817-735-2111 or william.weiss@unthsc.edu) to arrange for a convenient day and time to meet.

In addition, please plan to view the following posters / presentations:

Efficacy of Cefepime + VNRX-5133, a novel β-lactamase inhibitor Against an ESBL E. coli in a Murine UTI Model

W. J. WEISS1, M. E. PULSE1, P. NGUYEN1, D. VALTIERRA1, K. PETERSON1, K. CARTER1, D. C. PEVEAR2, C. J. BURNS2, L. XERRI2

1UNT Health Science Center, Ft. Worth, TX, 2Venatorx Pharmaceuticals, Malvern, PA

Background: The increase in ESBL-producing uropathogenic E coli among community-onset urinary tract infections (UTI) is an important public health concern. This study was conducted to evaluate the efficacy of Cefepime w/wo co-administration of -lactamase inhibitor (VNRX-5133) in the murine ascending UTI model against a CTX-M-15-expressing strain of E. coli

Methods: The in vitro MIC values of selected compounds were determined by broth microdilution methods in accordance with CLSI guidelines Female C3H/HeJ mice were placed on 5% glucose water for 6 days and then transurethrally infected with 9.23 log10 CFU of an ESBL E. coli isolate. Treatments of Cefepime (Cef) alone, Cef:VNRX-5133 (2:1), Cef:tazobactam (2:1) or ceftazidime:avibactam (4:1) were initiated 4 days post-infection and administered subcutaneously (SC), every 12 hours for 3 days. Kidneys, bladders, and urine were collected and processed for CFU counts 18 hours after the final dose. Efficacy was determined by comparing the mean CFU of treated groups to untreated controls.

Results: Bacterial titers of 6.85 and 5.89 log10 CFU in kidneys and bladders and 6.32 log10 CFU/mL in urine on Day 4 after infection. At Day 7 after infection, titers were 6.79, 7.71 and 7.70 log10 CFU in kidney, bladder and urine in the untreated controls, respectively. Administration of cefepime alone from 16 – 128 mg/kg resulted in bacterial kidney titers of 4.90 – 7.25 log10 CFU, bladder counts of 3.44 – 6.87 log10 CFU and urine counts of 4.35 – 6.56 log10 CFU/mL. The addition of VNRX-5133 to cefepime resulted in increased efficacy with kidney, bladder and urine counts that were 1 – 2 log10 CFU lower than with cefepime alone. Both cefepime:tazobactam (2:1) and ceftazidime:avibactam showed similar overall counts and reductions in bacterial titers relative to those exhibited by cefepime:VNRX-5133

Conclusion: In this UTI study with an ESBL E. coli isolate, cefepime alone exhibited a dose dependent reduction in bacterial titers. Co-administration of VNRX-5133 (2:1) further reduced the bacterial titers in all three tissues as compared with cefepime alone. The results demonstrate that VNRX-5133 rescues cefepime activity in a urinary tract infection model against a uropathogenic strain of E. coli expressing CTX-M-15.


February 1, 2018

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Research performed in the PreClinical Services group has been selected for presentation at 28th ECCMID meeting in Madrid, Spain, April 21-24, 2018. Selected presentations are detailed in the abstracts below.

Efficacy of Cefepime/VNRX-5133, a Novel broad-spectrum b-Lactamase Inhibitor, in a Murine Bacteremia Infection Model with Carbapenem Resistant Enterobacteriaceae (CREs)
E. Pulse1, W. J. Weiss1, P. Nguyen1, D. Valtierra1, D. C. PEVEAR2, C. J. BURNS2, L. Xerri2

1UNT College of Pharmacy, Ft. Worth, TX, 2VenatoRx Pharmaceuticals, Malvern, PA

Background: Existing β-lactamase inhibitors are not effective against all the emergent extended spectrum β-lactamases (ESBLs) and carbapenem-hydrolyzing β-lactamases, including the metallo enzymes. The current study was performed to determine the in vivo efficacy of cefepime (FEP) alone and in combination with VNRX-5133, a novel broad-spectrum, potent and selective direct β-lactamase inhibitor in a murine bacteremia model against carbapenem resistant E. coli and K. pneumoniae clinical isolates.

Methods: The in vitro MIC values of selected compounds were determined by broth microdilution methods against a panel of Gram-negative bacteria in accordance with CLSI guidelines. In vivo studies utilized mice that were challenged by intraperitoneal injection of a defined inoculum of E. coli (NDM-1) or K. pneumoniae (KPC-2, VIM-4, CMY-4), resulting in a lethal systemic infection within 24-36 hours. Doses of FEP alone or in a 2:1 ratio with VNRX-5133 or tazobactam (Tzb) were administered subcutaneously at 1 hr post-infection. A census of survivors was recorded over 6 days and the median effective dose (ED50) for each treatment was calculated using Probit analysis.

Results: The ED50 for FEP alone against the E. coli (NDM-1 producer) infection was 15.4 mg/kg and was was reduced to 3.3 mg/kg when combined at 2:1 with VNRX-5133 and 17.9 mg/kg when combined with Tzb. Against the K. pneumoniae (KPC-2, VIM-4, CMY-4 producer) infection, the ED50 of 4.6 mg/kg for FEP alone was reduced to 0.99 mg/kg for FEP/VNRX-5133 while remaining at 5.8 mg/kg for FEP/Tzb. In each of these infection models, the addition of VNRX-5133 reduced the FEP ED50 by approximately 5-fold, while the FEP ED50 remained relatively unchanged when combined with Tzb.

Conclusion: Administration of VNRX-5133 was shown to enhance the efficacy of cefepime for the treatment of systemic infections with CRE strains producing multiple enzymes including NDM-1, KPC-2, CMY-4 and VIM-4. VNRX-5133 was more effective than tazobactam in restoring cefepime efficacy and warrants further studies to explore the clinical therapeutic utility of this novel broad-spectrum selective and direct b-lactamase inhibitor.


Efficacy of Cefepime/ VNRX-5133, a Novel b-lactamase Inhibitor, against a Cephalosporin-Resistant, ESBL-producing K. pneumoniae in a Murine Lung infection Model

W. J. Weiss1, M. E. Pulse1, P. Nguyen1, D. Valtierra1, K. PETERSON1, K. CARTER1, D. C. PEVEAR2, C. J. BURNS2, L. Xerri2

1UNT College of Pharmacy, Ft. Worth, TX, 2Venatorx Pharmaceuticals, Malvern, PA

Background: Extended-spectrum β-lactamases (ESBLs) are a problematic resistance mechanism associated with cephalosporin-resistant K. pneumoniae, a pathogen prevalent in both community- and hospital-acquired pneumonia. VNRX-5133 is a new β-lactamase inhibitor with potent and selective direct inhibitory coverage for Class A, C, D Serine- and VIM/NDM class B metallo-β-lactamases. VNRX-5133 in combination with cefepime (FEP) achieves potent antibacterial activity against a significant proportion of Carbapenem-Resistant Enterobacteriaceae (CRE). The current study was performed to evaluate the efficacy FEP in combination with VNRX-5133 in a murine lung infection model with a cephalosporinase-producing K. pneumoniae strain.

Methods: In vitro MICs of selected compounds were determined by broth microdilution in accordance with CLSI guidelines. Neutropenia was generated in mice with two doses of cyclophosphamide administered 1 (100 m/kg) and 4 (150 mg/kg) days pre-infection. Anesthetized mice were intranasally inoculated with 6.5 log10 CFU of K. pneumoniae (CTX-M-14). Treatment was initiated 2 hours post-inoculation by subcutaneous administration of FEP alone, FEP/VNRX-5133 (2:1), FEP/tazobactam (2:1) or ceftazidime/avibactam (4:1). Mice were euthanized by CO2 asphyxiation 24 hrs post-inoculation, and lungs were aseptically removed, processed and plated to determine bacterial burden.

Results: Mean bacterial lung titers for untreated controls were 6.21 and 9.84 log10 CFU at 2 and 24 hrs post-inoculation, respectively. FEP alone was minimally efficacious at doses ranging from 16 – 128 mg/kg with a mean bacterial lung titer range of 9.32 – 9.53 log10 CFU. FEP/VNRX-5133 exhibited excellent efficacy with mean bacterial lung titers of 4.59, 4.59, 5.69 and 6.82 log10 CFU at doses of 64:32, 32:16, 16:8 and 8:4 mg/kg, respectively, while FEP/tazobactam was less efficacious with mean bacterial titers of 6.03, 6.49, 8.43 and 8.49 log10 CFU at the 64:32, 32:16, 16:8 and 8:4 mg/kg doses, respectively. Ceftazidime:avibactam administration resulted in mean bacterial lung titers of 4.42, 5.51, 7.39 and 8.77 log10 CFU at 64:16, 32:8, 16:4 and 8:2 mg/kg, respectively

Conclusion: VNRX-5133 provided excellent protection of FEP against this cephalosporin-resistant K. pneumoniae. FEP/VNRX-5133 administration resulted in mean bacterial lung titers that were >4 log10 CFU lower than in animals administered FEP alone, demonstrating consistent rescue of FEP in the neutropenic murine lung infection model.


January 5, 2018

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SMi Group is thrilled to announce the 20th Annual Superbugs & Superdrugs Conference in London on 19th – 20th March 2018. As the global threat of antimicrobial resistance continues to develop, it is clear that a global commitment is required in order to tackle the ever-increasing problem of multidrug-resistant bacteria.

This year’s event will gather leaders from pharmaceutical companies, academia and the wider scientific community together with regulatory agencies and public-private partnerships, to discuss the growing threat of antibiotic resistance.

Join us to learn about various strategies in place to support antimicrobial resistance research & development, evaluate the latest scientific advancements for tackling antimicrobial resistance and consider potential novel candidates and alternatives to anti-microbials.

The event will also focus on the strategies pharmaceutical companies use to assist the development of new therapeutics & drugs, how to obtain funding for new projects and address why there is a current lack of incentives for researchers working in antimicrobial resistance research and development.

Presentations include:

CHALLENGES IN ANTIMICROBIAL EVALUATION OF NOVEL THERAPIES USING ANIMAL MODELS

William Weiss, Director of Pre-Clinical Services, University of North Texas Health Science Center

Where to start / What model to use
Dose / Regimen – How to choose
Test articles with no intrinsic activity
How to evaluate combination therapy
What does the data tell us?


November 30, 2017

Antimicrobial resistance: A threat to modern medicine
Iselin, NJ, November 14, 2017—William Weiss, Director, UNT Health Science Center, Fort Worth, TX, gives a brief overview of the current state of antimicrobial resistance.

https://www.mdlinx.com/infectious-disease/conference-interview/article/981


October 19, 2017

Research performed by the PreClinical Services group on behalf of industry sponsors The Medicines Co. and DaVolterra has recently been accepted for publication in Antimicrobial Agents and Chemotherapy:

Activity of Meropenem-Vaborbactam Against Carbapenem-resistant Enterobacteriaceae in a Murine Model of Pyelonephritis
William J. Weiss, Mark E. Pulse, Phung Nguyen, Kelly Peterson, Jessica Silva, Jerry W. Simecka, David Valtierra, Morgan Sabet and David C. Griffith

Antimicrob. Agents Chemother. Accepted manuscript posted online 16 October 2017 doi:10.1128/AAC.01439-17

Protection of Hamsters from Mortality by Reducing Fecal Moxifloxacin Concentration with DAV131A in a Model of Moxifloxacin-Induced Clostridium difficileColitis
Charles Burdet, Sakina Sayah-Jeanne, Thu Thuy Nguyen, Christine Miossec, Nathalie Saint-Lu, Mark Pulse, William Weiss, Antoine Andremont, France Mentré, and Jean de Gunzburg

Antimicrob. Agents Chemother. October 2017; 61:10 9 Accepted manuscript posted online 24 July 2017 doi:10.1128/AAC.00543-17


September 21, 2017

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BioEurope 2017, November 6-8, 2017, Berlin, Germany: BIO-Europe’s world-class workshops, panels and active exhibition along with thousands of prescheduled one-to-one meetings make this event an unrivaled forum for companies across the biotech value chain to meet and do business.

The UNTHSC Pre-Clinical Services group will be in attendance at the BioEurope meeting and welcomes the opportunity to meet with current as well as prospective collaborators to discuss ongoing and future projects. If interested, please contact William Weiss (817-735-2111 or william.weiss@unthsc.edu) to arrange for a convenient day and time to meet

 


September 13, 2017

William Weiss

Superbugs & Superdrugs USA – November 13-14, 2017, Woodbridge, NJ

Strengthening the pipeline; new incentives and approaches to combating bacterial resistance

William Weiss


September 6, 2017

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The UNTHSC Pre-Clinical Services group will be in attendance at ID Week meeting in San Diego, CA (Oct. 4-8, 2017) and welcomes the opportunity to meet with current as well as prospective collaborators to discuss ongoing and future projects. If interested, please contact William Weiss (817-735-2111 or william.weiss@unthsc.edu) to arrange for a convenient day and time to meet.


March 6, 2017

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ASM Microbe 2017 (June 1–5, 2017, New Orleans, LA) showcases the best microbial sciences in the world, and provides a one-of-a-kind forum to explore the complete spectrum of microbiology from basic science to translation and application.

The UNTHSC Pre-Clinical Services group will be in attendance at the first ASM Microbe meeting in New Orleans, LA (June 1-5, 2017) and welcomes the opportunity to meet with current as well as prospective collaborators to discuss ongoing and future projects. If interested, please contact William Weiss (817-735-2111 or william.weiss@unthsc.edu) to arrange for a convenient day and time to meet.

In addition, please plan to view the following posters / presentations:

Efficacy of Novel Cationic Peptide SPR741 and Gyrase Inhibitor SPR720 Combinations Against Carbapenem-resistant K. pneumoniae in a Murine UTI Model

W. J. Weiss*1, M. Pulse1, P. Nguyen1, T. R. Parr Jr2, T. Listerand A. Rubio2

1UNT Health Science Center, Ft. Worth, TX, USA; Spero Therapeutics, Cambridge, MA, USA

In vivo Efficacy of Combinations of Novel Antimicrobial Peptide SPR741 and Rifampin in a K. pneumoniae Murine Model of Urinary Tract Infection.

A Rubio*1, W Weiss2, M Pulse2, T Lister1 T R Parr Jr1

Spero Therapeutics, Cambridge, USA; 2. UNT Health Science Center, Fort Worth, TX, USA

The Novel Fluorocycline TP-271 is Efficacious in a Murine A. baumannii Pneumonia Model.

J. Newman1, T. H. Grossman2, M. E. Pulse3, W. J. Weiss3

Tetraphase Pharmaceuticals, Watertown, MA1; Consultant to Tetraphase Pharmaceuticals2, UNT Health Science Center, Fort Worth, TX3

PK/PD of the Novel Fluorocycline Eravacycline is Efficacious in a Murine E. coli Thigh Model.

J. Newman1, M. E. Pulse2, W. J. Weiss2

Tetraphase Pharmaceuticals, Watertown, MA1; UNT Health Science Center, Fort Worth, TX2

DAV131A prevents alterations of the intestinal microbiota and Clostridium difficile infection in hamsters treated with moxifloxacin and clindamycin

N. Saint-Lu1, T. Corbel1, F. Sablier-Gallis1, M. Pulse2, C. Burdet3, Céline Wahl4, T.T. Nguyen3, W. Weiss2, F. Mentré3, S. Ferreira4, A. Andremont3 and J. de Gunzburg1

1Da Volterra, Paris, France; 2UNT Health Science Center, Fort Worth, TX, USA; 3University Paris-Diderot Medical School and INSERM UMR 1137, IAME, Paris, France; 4GenoScreen, Lille, France

Development of OG716, a Novel Lantibiotic Against Clostridium difficile

A. DeFusco1, J. Ngoje1, G. Phillips1, M. Sivaram1, J. Park1, B. Tilley1, E. Richeson1, V. Sylva1, Z. Lamon1, F. Anazco1, M. Pulse2, W. J. Weiss2, M. Handfield1 1Oragenics, Inc., Alachua, FL, 2Univ. of North Texas Health. Sci. Ctr., Fort Worth, TX


March 1, 2017

Antimicrob Agents Chemother. 2017 Feb 6. pii: AAC.02243-16. doi: 10.1128/AAC.02243-16. [Epub ahead of print]

Can ceftazidime/avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?

Marshall S1, Hujer AM1,2, Rojas LJ1,2,3, Papp-Wallace KM1, Humphries RM4, Spellberg B5, Hujer KM1,2, Marshall EK1, Rudin SD1,2, Perez F1,2, Wilson BM1, Wasserman RB6, Chikowski L7, Paterson DL8, Vila AJ9, van Duin D10, Kreiswirth BN11, Chambers HF12, Fowler VG Jr13, Jacobs MR14, Pulse ME15, Weiss WJ15, Bonomo RA16,2,3,17.

1Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH. 2Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH. 3Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio. 4Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA. 5Division of Infectious Diseases, Keck School of Medicine at USC and the Los Angeles County-USC Medical Center, Los Angeles, CA. 6Infectious Disease Doctors Medical Group, Walnut Creek, CA. 7John Muir Health, Walnut Creek, CA. 8The University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia. 9Instituto de Biología Molecular y Celular de Rosario Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Universidad Nacional de Rosario, Argentina. 10Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC. 11Public Health Research Institute Center, New Jersey Medical School-Rutgers University, Newark, NJ. 12University of California, San Francisco General Hospital, San Francisco, CA. 13Division of Infectious Diseases, Department of Medicine, and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC. 14Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH. 15University of North Texas Health Science Center, Fort Worth, TX. 16Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 17Departments of Pharmacology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH.

Abstract Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram negative bacteria, we tested the effectiveness of the combination of ceftazidime/avibactam (CAZ/AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk-diffusion and agar based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ/AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ/AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ/AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥ 21 mm. All isolates demonstrated a reduction in CAZ/AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥ 4 log10 CFU decrease for all groups that had CAZ/AVI plus ATM (8 μg/ml) added, compared to the CAZ/AVI alone group. In the murine neutropenic thigh infection model, an almost 4 log10 reduction in CFUs was noted at 24 h for CAZ/AVI (32 mg/kg q8h) plus ATM (32 mg/kg q8h) vs. CAZ/AVI (32 mg/kg q8h) alone. The data presented herein, requires us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

Copyright © 2017 American Society for Microbiology.


February 21, 2017

FDA Workshop – March 1, 2017: Silver Springs, MA

Current State and Further Development of Animal Models of Serious Infections Caused by Acinetobacter baumannii and Pseudomonas aeruginosa

Meeting Summary: The Food and Drug Administration (FDA) is announcing this public workshop regarding the current state and further development of animal models for serious infections caused by Acinetobacter baumanii and Pseudomonas aeruginosa. FDA is conducting this workshop in order to facilitate the development of narrow-spectrum antibacterial drugs, such as those that are active against only a single species of bacteria that may not occur frequently. When the species occurs infrequently, performing clinical trials can be extremely challenging. Therefore, animal models of infection may be useful to explore the activity of a candidate antibacterial drug and may help to predict whether the drug will be efficacious in humans. A discussion of the additional scientific work needed to evaluate current animal models of infection and evaluate potential animal models that may predict response in humans could advance the development of antibacterial drugs targeting a single species. The input from this public workshop will also help in developing topics for future discussion. The Agency encourages health care providers, other U.S. Government Agencies, academic experts, contract research organizations, industry and other interested persons to attend this public workshop.


February 2, 2017

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Translatable Therapeutic Effects of Extracellular Superoxide Dismutase (ecSOD) in the Treatment of Staphylococcus aureus Infections

M. E. Pulse, W. J. Weiss, L. Dory, J. W. Simecka

HSC, Fort Worth, TX,

Objectives: Alternatives to antibiotics is an expanding area of research that focuses on non-traditional approaches to treating bacterial infections, which includes approaches that target various host responses during an infection. Extracellular superoxide dismutase (ecSOD) has previously been proposed as possible target since it regulates the amount of reactive oxygen and nitrogen species generated during an immune response. In an effort to further validate ecSOD as a potential therapeutic target, mice expressing varying amounts of ecSOD were used in experimental models of bacterial sepsis, pneumonia, and skin-associated abscess infections caused by Staphylococcus aureus. Additionally, a non-specific SOD inhibitor was used to therapeutically treat wild-type mice that had skin-associated abscess infections.

Methods: C57BL/6 mice that either did not express ecSOD (ecSOD-KO) or expressed wild-type levels of ecSOD (ecSOD-WT) were used in the experimental infection models. The sepsis model involved intraperitoneal (IP) injection with 7 log10 CFU of S. aureus and monitoring survival for 5 days post-infection. The pneumonia model involved intranasal infection of anesthetized mice with 8 log10 CFU of S. aureus and harvesting lungs for CFU counts 26 hours post-infection, or monitoring survival for 5 days post-infection. The skin-associated abscess model involved subcutaneous infection of anesthetized mice with 8 log10 CFU of S. aureus, diluted in sterile dextran beads, recording abscess severity and harvesting abscesses 4 days post-infection for CFU enumeration. Additional skin abscess studies involved treating infected ecSOD-WT mice with vancomycin and/or diehtyldithiocarbamate (DDTC), an SOD inhibitor, (600-1200 mg/kg, IP or topically) for 4 days post-infection, with abscess severity and CFU recovery being accessed.

Results: All of the ecSOD-KO mice survived lethal sepsis infections with S. aureus, while only 40% of the ecSOD-WT mice survived in the same studies. Between 40-80% of the ecSOD-KO mice survived lethal pneumonia infections with S. aureus and had about 7.5 log10 CFU in their lungs 26 hours after infection. In contrast, only 20% of the ecSOD-WT mice with S. aureus pneumonia infections survived, and they had approximately 9 log10 CFU in their lungs 26 hours after infection. The amount of S. aureus recovered from skin-associated abscesses 4 days after infection was approximately equal for both infected ecSOD-WT and ecSOD-KO mice. However, between 80% of the abscesses formed in ecSOD-WT mice were severely cavitated, while only 22% of abscesses formed in ecSOD-KO mice were cavitated. Abscess studies with DDTC generated similar results to the ecSOD-KO mice, in that S. aureus CFU abscess counts remained relatively unchanged but abscess severity was noticeably better with DDTC treatment.

Conclusion: The described results clearly suggest that inhibition of ecSOD is a potential path for treating various infectious diseases; additional investigations are needed to fully determine if this is an attainable target for drug development.


January 7, 2017

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SMi is proud to present the 2017 19th annual Superbugs & Superdrugs conference, taking place on 20th and 21st March in Central London.
Expanding horizons on the growing threat of anti-microbial resistance for almost two decades, the flagship show in the global Superbugs portfolio of events will once again play host to an international audience of scientific leaders, funding bodies and drug discovery specialists, providing a focal point to push industry collaboration through updates on clinical advancements and investment opportunities.

Each year, around 2 million people are taken ill in the US from antibiotic-resistant bacteria and kills at least 23,000, according to estimates by the Centers for Disease Control and Prevention. The threat is so high that in September 2014 President Barack Obama issued an executive order Combating Antibiotic-Resistant Bacteria. *

The threat is the same in Europe, big pharmaceutical companies are re-entering the space into development of new antibiotics after decades. In January 2016, more than 80 pharmaceutical, biotechnology and diagnostics companies including Roche, Pfizer, Novartis AG and GlaxoSmithKline pledged at the World Economic Forum to fight the threat of antimicrobial resistance.*

The industry’s premier event on antibiotic resistance will provide a perfect platform for its growing “superbugs” community to network, exchange novel solutions and consolidate current strategies. A must attend for both new and seasoned stakeholders involved in AMR and infectious disease.

THE USE OF IN VIVO MODELS FOR INFECTIOUS DISEASE RESEARCH

William Weiss, Director of Pre-Clinical Services, University of North Texas Health Science Center

Experimental Design of Animal Models
Bridging the gap – in vitro activity to in vivo effi cacy
Where to start / What model to use
What does the data tell us

WORKSHOP PROGRAMME
William Weiss, Director of Pre-Clinical Services, University of North Texas Health Science Center

Mark Pulse, Assistant Director , University of North Texas Health Science Center

PRECLINICAL DRUG DEVELOPMENT

Overview of preclinical testing
Discovery to lead selection
The development model: then and now
Antibacterial research efforts

EXPERIMENTAL DESIGN AND METHODOLOGY

Experimental design profoundly influences the outcome of a research study
Clearly define the question or problem being studied
Realistic objectives (achievable)
Choose the best research model

ANIMAL MODELS – EXAMPLES

Acute infection models – Bacteremia, Sepsis
Chronic infection models – Pneumonia, skin, abscesses
GI related – C. difficile, H. pylori
Device related – Biofilm, endocarditis, prosthetic joint

ANIMALS IN RESEARCH

Institutional Animal Care and Use Committee (IACUC)
Justify why animals are necessary, minimize pain and distress, husbandry and care
Use of appropriate euthanasia methods
The 3 R’s


November 17, 2016

Dr. William Weiss is the Director of Pre-Clinical Services at University of North Texas in Fort Worth, working to develop animal models in infectious disease for the evaluation of new and novel therapies in antibacterial, antifungal and antiviral research. He has been using a Don Whitley Scientific DG250 and an A35 anaerobic workstation for about 2 decades.

Read more about his research on novel antibiotics for the treatment of Clostridium difficile infectionhere.
http://800ezmicro.com/Univ-North-Texas-Interview.html


September 7, 2016

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SMI-USA

Broadening horizons on the growing global threat of Antimicrobial resistance (AMR) for almost two decades at the sell-out Superbugs & Superdrugs conference in Europe, SMi is thrilled to announce the expansion of its antimicrobial portfolio of events across the Atlantic with the release of Superbugs & Superdrugs USA. This year’s show in Iselin, New Jersey, will play host to an audience of scientific leaders, funding bodies and drug discovery specialists, providing a focal point to discuss the latest clinical advancements and funding opportunities.

With huge interest from leaders in the field including PAHO/WHO, BARDA, NIH, Pfizer, AstraZeneca, Janssen and other senior industry representatives, we have worked closely with an expert panel of speakers to present an agenda that is shaping up to be the best Superbugs & Superdrugs event to date.

The program will hone in on key topics such as public private partnerships, collaboration, R&D, scientific priorities for antibiotic discovery, novel antibacterial therapeutic approaches, antibiotic stewardship, rapid diagnostic tools, combination therapies, resistance prevention, plus much more!

ANTIMICROBIAL COMBINATION THERAPY: USE AND DISUSE
William Weiss, Director of Pre-Clinical Services, University of North Texas Health Science Center

Rationale for the use of antibiotic combinations
Advantages / disadvantages of combining antimicrobial agents
Currently used antibiotic combinations
Novel and non-traditional antimicrobial combinations

WORKSHOP PROGRAMME
William Weiss, Director of Pre-Clinical Services, University of North Texas Health Science Center

Mark Pulse, Assistant Director , University of North Texas Health Science Center

PRECLINICAL DRUG DEVELOPMENT

Overview of preclinical testing
Discovery to lead selection
The development model: then and now
Antibacterial research efforts

EXPERIMENTAL DESIGN AND METHODOLOGY

Experimental design profoundly influences the outcome of a research study
Clearly define the question or problem being studied
Realistic objectives (achievable)
Choose the best research model

ANIMAL MODELS – EXAMPLES

Acute infection models – Bacteremia, Sepsis
Chronic infection models – Pneumonia, skin, abscesses
GI related – C. difficile, H. pylori
Device related – Biofilm, endocarditis, prosthetic joint

ANIMALS IN RESEARCH

Institutional Animal Care and Use Committee (IACUC)
Justify why animals are necessary, minimize pain and distress, husbandry and care
Use of appropriate euthanasia methods
The 3 R’s


April 15, 2016

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The UNTHSC Pre-Clinical Services group will be in attendance at the first ASM Microbe meeting in Boston, MA (June 16-20, 2016) and welcomes the opportunity to meet with current as well as prospective collaborators to discuss ongoing and future projects. If interested, please contact William Weiss (817-735-2111 or william.weiss@unthsc.edu) to arrange for a convenient day and time to meet.

In addition, please plan to view the following posters:

Monday June 20 at 12:30 – 2:30pm

In Vivo Efficacy of Dual-Action Molecule TNP-2092 in Mouse H. pylori Infection Model as Compared to Triple Therapies and Distribution within the Gastric Mucosal Layer

W. J. Weiss,1 M. Pulse,1 P. Nguyen,1 Z. Ma;2

1UNT Health Science Center, Fort Worth, TX; 2TenNor Therapeutics Ltd, Suzhou, China

In Vivo Efficacy of Dual-Action Molecule TNP-2092 in Mouse H. pylori Infection Model: Dose Relationship and Impact of Proton Pump Inhibitor

M. Pulse,1 W. J. Weiss,1 P. Nguyen,1 Z. Ma;2

1UNT Health Science Center, Fort Worth, TX; 2TenNor Therapeutics Ltd, Suzhou, China

In Vivo Efficacy of Dual-Action Molecule Tnp-2092 in Hamster and Mouse Clostridium difficile Infection Models

X. Xu1, W. J. Weiss2, G. T. Robertson3, F. Guo4, C. Li4, J. Zhang4, L. Jiang4, M. Yang4, D. Xu4, X. Wang1, Z. Ma1;

1TenNor Therapeutics Ltd, Suzhou, China, 2UNT Health Science Center, Fort Worth, TX, 3Colorado State Univ., Fort Collins, CO, 4WuXi AppTec (Shanghai) Co., Ltd, Shanghai, China

Late breaker:

Extended protection by DAV131 against antibiotic-induced Clostridium difficile infection in hamsters

Saint-Lu1, S. Sayah-Jeanne1, F. Sablier-Gallis1, M. Pulse2, C. Burdet3, T.T. Nguyen3, W. Weiss2, F. Mentré3, E. Chachaty4A. Andremont3 and J. de Gunzburg1

1Da Volterra, Paris, France; 2UNT Health Science Center, Fort Worth, TX, USA; 3University Paris-Diderot Medical School and INSERM UMR 1137, IAME, Paris, France; 4Institut Gustave-Roussy, Villejuif, France


April 5, 2016

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TP-6076 is efficacious in a mouse pneumonia model with carbapenem-resistant Acinetobacter baumannii (CRAB) and retains potency against common tetracycline-resistance mechanisms

T. Grossman, C. Fyfe, K. Kerstein, X. Xiao, C. Sun, J. Newman, P. Nguyen, M. Pulse, W. Weiss, J. Dumas, J. Sutcliffe

Tetraphase Pharmaceuticals, Watertown, MA, UNT Health Science Center, Fort Worth, TX

 


November 5, 2015

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Combination Antibiotic Therapy
The Use of Combination Antibiotic Therapy
History of antibiotic combinations
Rationale for combination therapy
Advantages / disadvantage of combining antibiotics
Testing regimens for combination therapy
William Weiss, Director, Pre-Clinical Services,

UNT Health Science Center


September 1, 2015

The University of North Texas Health Science Center Pre-Clinical Services group has recently become a part of the UNT System College of Pharmacy.

Myron Jacobson, PhD., Dean of the College of Pharmacy, said “I am delighted to announce that Jerry Simecka and William Weiss will be joining the faculty of the College of Pharmacy effective September 1, 2015. Additionally, the outstanding staff of the Pre-Clinical Services Program that they lead will also be joining the College. The staff members of the team include Mark Pulse, Assistant Director, David Valtierra, Kelly Peterson, Kiahrae, Carter, Phung Nyugen, Jessica Silva and Monica Castillo. Both Jerry and Bill have already been making high quality teaching contributions to our doctor of pharmacy program and we look forward to their continued involvement. Additionally, the outstanding Pre-Clinical Sciences Program integrates perfectly with the translational research efforts of the College of Pharmacy.”

The PreClinical Services group will continue to function as before, providing guidance and support for the research and development of new and novel therapies with an emphasis on infectious disease.


July 17, 2015

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Dav132, an Adsorbent-Based Product, Protects the Gut Microbiome and Prevents Clostridium difficile Infections during Moxifloxacin Treatments

Jean De Gunzburg, PhD1, Amine Ghozlane, PhD2, Annie Ducher, MD1, Xavier Duval, MD, PhD3, Etienne Ruppé, PharmD, PhD2, Mark Pulse, MS4, Caroline Chilton, PhD5, Laurence Armand-Lefevre, PharmD, PhD6, Elisabeth Chachaty, PharmD, PhD7, Sakina Sayah-Jeanne, PhD1, Joël Doré, PhD2, Emmanuelle Le Chatelier, PhD2, Florence Levenez, BS2, Sean Kennedy, PhD2, Nicolas Pons, PhD2, William Weiss, MS4, Mark Wilcox, MD5,8, France Mentré, MD, PhD6, Antoine Andremont, MD, PhD6 and Stanislav Dusko Ehrlich, PhD2

(1)Da Volterra, Paris, France, (2)Metagenopolis, INRA, Jouy-en-Josas, France, (3)Bichat Claude Bernard Hospital; Paris 7 University, Paris, France, (4)UNT Health Science Center, Fort Worth, TX, (5)University of Leeds, Leeds, United Kingdom, (6)University Paris-Diderot Medical School and INSERM, UMR 1137, IAME, Paris, France, (7)Institut Gustave-Roussy, Villejuif Cedex, France, (8)Leeds Teaching Hospitals, Leeds, United Kingdom


June 24, 2015
The UNTHSC Pre-Clinical Services group will be in attendance at the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in San Diego, CA (September 17 – 21, 2015) and welcomes the opportunity to meet with current as well as prospective collaborators to discuss ongoing and future projects. If interested, please contact William Weiss (817-735-2111 or william.weiss@unthsc.edu) to arrange for a convenient dayand time to meet.
Efficacy of Carbavance (Meropenem-RPX7009) against Carbapenem-resistant E. coli in a murine UTI infection model

W. J. Weiss1, M. Pulse1, P. Nguyen1, K. Peterson1, J. Silva1, J. W. Simecka1, D. Valtierra1, M. Sabet2, D. C. Griffith2

1UNT Health Science Center, Ft. Worth, TX, 2 The Medicines Company, San Diego, CA

 

Efficacy of a Bacteriophage Cocktail in a Staphylococcus aureus Mouse Pneumonia Model is Comparable to Vancomycin

J. Shaw1,3*, W. J. Weiss2, M. E. Pulse2, S. M. Lehman1, F. Smrekar1, S. P. Morales1

1AmpliPhi Biosciences Corporation, Richmond, VA; 2 UNT Health Science Center, Fort Worth, TX; 3Hearts Consulting Group, Poway, CA.


January 30, 2015

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President’s 2016 budget proposes historic investment to combat antibiotic-resistant bacteria to protect public health.
“We now have a national strategy to combat antibiotic-resistant bacteria, to better protect our children and grandchildren from the reemergence of diseases and infections that the world conquered decade ago”
– President Barack Obama’s remarks at the Global Health Security Agenda Summit, regarding the Executive Order to Combat Antibiotic Resistance, September 26, 2014.

http://www.whitehouse.gov/the-press-office/2015/01/27/fact-sheet-president-s-2016-budget-proposes-historic-investment-combat-a


January 27, 2015

Eccmid 2015

The 25th European Congress of Clinical Microbiology and Infectious Disease (ECCMID) meeting will be held from April 25-28, 2015 in Copenhagen, Denmark. The meeting will feature a series of keynote lectures, symposia, educational workshops and meet-the-experts sessions on parallel tracks, covering the entire field of infectious diseases and clinical microbiology. Among the presentations will be:
Evaluating the induction potential of three antibiotics in the hamster Clostridium difficile infection model.
M. Pulse, T. Murphy, P. Nguyen, K. Peterson, J. Silva, J. Simecka, D. Valtierra, W. Weiss, S. Sayah-Jeanne, J. de Gunzburg
UNT Health Science Center, Fort Worth, TX & Dalvolterra, Paris, France
Efficacy evaluation of TP-271, a novel fluorocycline, in a neutropenic murine pneumonia model against susceptible and resistant gram-positive pathogens

W. Weiss, T. Murphy, M. Pulse, P. Nguyen, D. Valtierra, K. Peterson, J. Silva, J. Simecka, J. Sutcliffe, T. Grossman

UNT Health Science Center, Fort Worth, TX & Tetraphase Pharmaceuticals, Watertown, MA

Synthetic novel host defense protein mime tics for the treatment of gram-negative bacterial infections

S. Ram, K. Menon, R. Scott, D. Weaver, K. Freeman, G. Tew, W. Weiss, W. DeGrado, K. Fadela, A. Kumar, D. Brennan, S. Holden

Fox Chase Chemical Diversity Center, Doylestown, PA & UNT Health Science Center, Fort Worth, TX

www.eccmid.org


January 15, 2015

Superbugs

UNTHSC PreClinical Services to present at the SMI 17th Annual conference on SuperBugs & SuperDrugs, March 25-26, 2015 in London, UK.

The Changing Role of Academia in Drug Discovery
Historical perspective of academic involvement in drug development
Growth of the modern pharmaceutical industry and detachment from academia
Downturn in antibacterial discovery and development and current needs
Collaboration of industry and academia in drug discovery
Novel partnering models to increase innovation
William Weiss, Director of PreClinical Services, UNT Health Science Center

www.smi-online.co.uk/pharmaceuticals/uk/superbugs-superdrugs


July 3, 2014

Icaac 2014

The UNTHSC Pre-Clinical Services group will be in attendance at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in Washington DC (September 5 – 9, 2014) and welcomes the opportunity to meet with current as well as prospective collaborators to discuss ongoing and future projects. If interested, please contact William Weiss (817-735-2111 or william.weiss@unthsc.edu) to arrange for a convenient dayand time to meet.
In addition, please plan on attending the following presentations:

Poster Session 172 – New Spins on Protein Synthesis Inhibitors

Monday, Sept. 08, 2014; 11:00am – 1:00pm

Pharmacodynamic evaluation of TP-271, a novel fluorocycline, in a neutropenic murine lung model infected with Streptococcus pneumoniae – presentedby Tim Murphy

Pharmacodynamics of the fluorocycline TP-271 in a neutropenic murine lung infection model with methicillin-resistant Staphylococcus aureus – presentedby Bill Weiss

Slide Session 200 – Clostridium difficile : Pathogenesis, Immune Response and Therapy

Monday, Sept. 08, 2014; 4:00pm – 4:15pm

Epidemic Clostridium difficile ribotype 027 strains are more virulent than other non-epidemic strains in the hamster CDAD model – presented by MarkPulse


April 24, 2014

Top

The UNTHSC Pre-Clinical Services group will be attending the 24th ECCMID meeting in Barcelona, Spain from May 9-14 and welcomes the opportunity to meet with interested parties. Please contact William Weiss (817-735-2111 or william.weiss@unthsc.edu) to arrange for a convenient day and time tomeet.
In addition, please stop by the following poster presentations:
Saturday – May 10th – 3:30pm: Poster P0112 – Ileal Dosing of Nisin and Miconazole Combination is Efficacious in the Hamster Clostridium difficile Associated Disease Model (Presented by Mark Pulse, Assistant Director UNTHSC Pre-Clinical Services).
Sunday – May 11th – 1:30pm: Poster 0804 – DAV131, an oral absorbent-based product, exerts dose-dependent protection of hamsters againstmoxifloxacin-induced Clostridium difficile lethal infection (Presented by DaVolterra in conjunction with UNTHSC).


March 1, 2014

SMI presents Superbugs & Superdrugs – A Focus on Antibacterials
May 5 – 6, 2014, London, UK
“Research and Development in Neglected Diseases” (presented by William Weiss, Director of UNTHSC Pre-Clinical Services)
– Overview and Clinical Relevance
– Current therapies and issues
– Why pursue research of neglected diseases?
– New efforts and treatment options


June 7, 2013

The UNTHSC Pre-Clinical Services group will be in attendance at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in Denver, Colorado (September 10-13, 2013) and welcomes the opportunity to meet with current Sponsors as well as prospective collaborators to discuss ongoing and future projects. If interested, please contact William Weiss (817-735-2111 or william.weiss@unthsc.edu) to arrange for a convenient day and time to meet.
In addition, please plan on attending the following presentations by Mark Pulse, Assistant Director of the Pre-Clinical Services group:
Wednesday, Sept 11. – Slide Session 066 – Clostridium difficile: Pathogenesis
10:00 – 10:15 am : Dosing clindamycin before and after infection dramatically impacts disease outcome in the hamster Clostridium difficile -associated disease model
Thursday, Sept. 12 – Poster Session 143 – Antimicrobial Resistance and Immune Therapy
11:00am – 1:00 pm : Characterization of the programmed death 1 (PD1) and its ligand, PD-L1, in a murine cecal ligation model of sepsis


April 27, 2013

23rd ECCMID Meeting, Berlin, Germany

Oral Session – New Antibacterial agents
In vivo Efficacy of the novel monosulfactam BAL300072 alone and in combination with meropenem against clinically important gram-negative pathogens
William Weiss, Director of Pre-Clinical Services, University of North Texas Health Science Center


March 1, 2013

SMI Presents: Superbugs & Superdrugs – A Focus on Antibacterials
4th March to 5th March 2013, London, UK
AN UPDATE ON CURRENT ISSUES AND PROGRESS IN C. DIFFICILE DISEASE (CDAD)
William Weiss, Director of Pre-Clinical Services, University of North Texas Health Science Center

A brief history and review
The changing epidemiology and resistance development in CDAD
Transmission, Virulence factors and clinical manifestations
Surveillance, diagnosis and clinical testing
Prevention, emerging therapies and potential for efficacy


November 12, 2012

UNTHSC Pre-Clinical Services (PCS) is pleased to announce the recent hire of Timothy Murphy who joins the group as Project Manager.
Tim comes to the group with 16 years experience in the drug discovery and pharmacology industry. He has previously held positions of increasing responsibility in ViviSource Laboratories, Arpida Inc., Enanta Pharmaceuticals and Wyeth Research. Tim brings with him extensive experience and expertise in the design and performance of anti-infective efficacy models: antibacterial and antiviral, pharmacology and oncology studies as well asPK/PD evaluations and vaccine discovery research. He has earned both B.S. and M.S. degrees in biology and has co-authored or presented numerousmanuscripts and presentations.
UNTHSC PCS welcomes Tim and looks forward to the contributions that he will make along with expanding the expertise and scope of testing that thegroup has to offer to our Sponsors.


July 30, 2012

The UNTHSC Pre-Clinical Services group will be in attendance at the 52nd Interscience Conference of Antimicrobial Agents and Chemotherapy (ICCAC) inSan Francisco, CA (September 9 – 12, 2012) and welcomes the opportunity to meet with current collaborators as well as prospective Sponsors to discussongoing and future research projects, utilizing our expertise to meet your R & D requirements. If interested, please contact William Weiss (817-725-2111or william.weiss@unthsc.edu) to arrange for a convenient day and time to meet.


April 2, 2012

UNTHSC Pre-Clinical services, in conjunction with Affinium Pharmaceuticals, presented their findings on the effects of AFN-1252, a novel fatty acidbiosynthesis inhibitor antibacterial agent, on the in vitro and in vivo expression of S. aureus virulence genes at the 22nd European Congress of ClinicalMicrobiology and Infectious Disease (ECCMID) in London, UK.
Presentation Summary: (full details and time can be found on the ECCMID Congress website)
Poster P2058 – AFN-1252 Alters In Vitro and In Vivo Staphylococcus aureus Gene Expression and Reduces Bacterial Counts in a Mouse GranulomaInfection Model
M. E. Pulse1, N. Kaplan2, J. Parsons3, C. O. Rock3, M. Kukula1, P. Nguyen1, J. Pierce1, D. Valtierra1, W. J. Weiss1, J. W. Simecka1
1UNTHSC, Fort Worth, TX, 2Affinium Pharmaceuticals, Toronto, Canada, 3St. Jude Children’s Res. Hosp., Memphis, TN
Exposure of S. aureus cultures to AFN-1252 resulted in the anticipated up-regulation of genes involved in the FAS II pathway associated with the FapRregulon and the unpredicted down-regulation of several virulence genes that are controlled by the SaeRS two-component regulator. In the MG infectionmodel, a single oral dose of AFN-1252 at 2 hours post-infection resulted in mean log10 CFU reductions of 2.9 – 3.1 in 24 – 48 hours after dosing. PKanalysis of this fluid revealed that the relative exposure (AUC) of AFN-1252 in the granuloma fluid was 85% of the corresponding plasma levels, andqRT-PCR of S. aureus RNA extracted from granuloma fluid indicated that fabH expression was up-regulated and virulence factor expression was down-regulated following the single dose of AFN-1252. AFN-1252 was also dosed consecutively (2, 26, 50 hours) in the MG model, which maximally reducedgranuloma-associated S. aureus counts by 5.3 log10 CFU within 72 hours of the first dose. AFN-1252 triggered the up-regulation of genes associated with the FASII pathway in S. aureus, and it simultaneously down-regulated virulence genes controlled by the SaeRS regulator. AFN-1252 not only alteredS. aureus gene expression in the granuloma fluid, but it also therapeutically reduced the CFU counts in the fluid as well.