Ursula Theuretzbacher1, Lindley Barbee2, Kristie Connolly3, George Drusano4, Prabha Fernandes5, Edward Hook6, Ann Jerse3, John O'Donnell7, Magnus Unemo8, Françoise Van Bambeke9, Brian VanScoy10, Peter Warn11, Brian J Werth12, François Franceschi13, Emilie Alirol13. 1. Centre for Anti-Infective Agents, Vienna, Austria. Electronic address: utheuretzbacher@cefaia.com. 2. University of Washington, Division of Allergy and Infectious Diseases, Department of Medicine, Seattle, WA, USA. 3. Uniformed Services University, Bethesda, MD, USA. 4. Institute for Therapeutic Innovation, University of Florida, Lake Nona, FL, USA. 5. Chair, Scientific Advisory Committee, GARDP, Geneva, Switzerland. 6. University of Alabama at Birmingham, Birmingham, AL, USA. 7. Entasis Therapeutics, Waltham, MA, USA. 8. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Örebro University, Örebro, Sweden. 9. Université Catholique de Louvain, Brussels, Belgium. 10. Institute for Clinical Pharmacodynamics, Latham, New York, USA. 11. Magic Bullet Consulting, London, UK. 12. University of Washington, School of Pharmacy, Seattle, WA, USA. 13. Global Antibiotic R&D Partnership (GARDP), Geneva, Switzerland.
Abstract
BACKGROUND: Increasing multidrug resistance rates in Neisseria gonorrhoeae have raised concerns and an urgent call for new antibiotics for treatment of gonorrhoea. Several decades of subdued drug development in this field and the recent failures of two new antibiotics to show non-inferiority compared with the current first-line antibiotics ceftriaxone plus azithromycin highlight the need for improved preclinical tools to predict clinical outcome of new drugs in the development process. OBJECTIVES: To summarize current pharmacokinetic/pharmacodynamic (PK/PD) knowledge and dose-finding strategies for antibiotics against gonorrhoea. SOURCES: Literature review of published papers and discussions by global experts at a special workshop on this topic. CONTENT: We review current knowledge of gonococcal specific PK/PD principles and provide an update on new in vitro and in vivo models to correlate drug exposure with clinical outcome, and identify challenges and gaps in gonococcal therapeutic research. IMPLICATIONS: Identifying the ideal antimicrobial agent and dose for treating uncomplicated urogenital and pharyngeal gonococcal disease requires appropriate validated non-clinical PK/PD models. Recent advances in adapting in vitro and in vivo models for use in gonorrhoea are an important step for enabling the development of new drugs with reduced risk of failure in Phase 3 clinical development and diminish the risk of emergence of resistance.
BACKGROUND: Increasing multidrug resistance rates in Neisseria gonorrhoeae have raised concerns and an urgent call for new antibiotics for treatment of gonorrhoea. Several decades of subdued drug development in this field and the recent failures of two new antibiotics to show non-inferiority compared with the current first-line antibiotics ceftriaxone plus azithromycin highlight the need for improved preclinical tools to predict clinical outcome of new drugs in the development process. OBJECTIVES: To summarize current pharmacokinetic/pharmacodynamic (PK/PD) knowledge and dose-finding strategies for antibiotics against gonorrhoea. SOURCES: Literature review of published papers and discussions by global experts at a special workshop on this topic. CONTENT: We review current knowledge of gonococcal specific PK/PD principles and provide an update on new in vitro and in vivo models to correlate drug exposure with clinical outcome, and identify challenges and gaps in gonococcal therapeutic research. IMPLICATIONS: Identifying the ideal antimicrobial agent and dose for treating uncomplicated urogenital and pharyngeal gonococcal disease requires appropriate validated non-clinical PK/PD models. Recent advances in adapting in vitro and in vivo models for use in gonorrhoea are an important step for enabling the development of new drugs with reduced risk of failure in Phase 3 clinical development and diminish the risk of emergence of resistance.
Authors: Kristie L Connolly; Michelle Pilligua-Lucas; Carolina Gomez; Allison C Costenoble-Caherty; Anthony Soc; Knashka Underwood; Andrew N Macintyre; Gregory D Sempowski; Ann E Jerse Journal: J Infect Dis Date: 2021-08-16 Impact factor: 7.759
Authors: Amir Hossein Miri; Mojtaba Kamankesh; Antoni Llopis-Lorente; Chenguang Liu; Matthias G Wacker; Ismaeil Haririan; Hamid Asadzadeh Aghdaei; Michael R Hamblin; Abbas Yadegar; Mazda Rad-Malekshahi; Mohammad Reza Zali Journal: Front Pharmacol Date: 2022-06-27 Impact factor: 5.988