Antibacterial agents active against Gram Negative Bacilli in phase I, II, or III clinical trials

ABSTRACT

Introduction

Antimicrobial resistance is a major threat to modern healthcare, and it is often regarded that the antibiotic pipeline is ‘dry.’

Areas covered

Antimicrobial agents active against Gram negative bacilli in Phase I, II, or III clinical trials were reviewed.

Expert Opinion

Nearly 50 antimicrobial agents (28 small molecules and 21 non-traditional antimicrobial agents) active against Gram-negative bacilli are currently in clinical trials. These have the potential to provide substantial improvements to the antimicrobial armamentarium, although it is known that ‘leakage’ from the pipeline occurs due to findings of toxicity during clinical trials. Significantly, a lack of funding for large phase III clinical trials is likely to prevent trials occurring for the indications most relevant to loss of life attributed to antimicrobial resistance such as ventilator-associated pneumonia. Non-traditional antimicrobial agents face issues in clinical development such as a lack of readily available and reliable susceptibility tests, and the potential need for superiority trials rather than non-inferiority trials. Most importantly, concrete plans must be made during clinical development for access of new antimicrobial agents to areas of the world where resistance to Gram negative bacilli is most frequent.

KEYWORDS:

• Acinetobacter
• antimicrobial agents
• antimicrobial resistance
• CRE
• ESBL
• phage
• pseudomonas

Article highlights

• Carbapenem-resistant Gram negative organisms such as Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa are responsible for substantial mortality.

• 28 small molecules active against Gram negative bacilli are currently in clinical trials. Nearly half of these are new beta-lactamase inhibitors combined with existing beta-lactam antibiotics.

• 21 non-traditional antimicrobial agents active against Gram negative bacilli are currently in clinical trials. These include phages, peptides, anti-virulence strategies, and antibody-based therapies.

• These non-traditional antimicrobial agents face difficulty in clinical development due to a lack of standardized susceptibility tests and the need for demonstration of superiority if they are an adjunct to standard of care antibiotics.

• Leakage from the clinical development pipeline is always to be expected due to toxicity and lack of investment returns.

Declaration of interests

D Paterson is a Consultant to CARB-X and is on the Scientific Advisory Board of the AMR Action Fund. He has received funding from the Wellcome Trust to facilitate Phase II clinical trials of new antimicrobial agents. He directs ADVANCE-ID, which conducts Phase II-IV clinical trials of new antimicrobial agents in Asia and the Middle East. He is on the Steering Committee of ARLG and the Scientific Advisory Board of ECRAID, both of which conduct clinical trials of new antimicrobial agents.

D Paterson’s institution has received research grants or been provided equipment for research from Shionogi, Merck, Pfizer, Gilead, BioVersys, Accelerate, T2 Diagnostics, and BioMerieux. He has been paid by Shionogi and Entasis for giving presentations at FDA Advisory Committee Meetings (related to approval considerations for cefiderocol and sulbactam-durlobactam, respectively). He has provided consultancy or received honoraria from Pfizer, Merck, GSK, Roche, QPex, Spero, Entasis, Venatorx, Arrepath, Aurobac, Mutabilis, BioMerieux and Cepheid and has received travel assistance from Wockhardt.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The critical review of a draft version of the manuscript by Neha Prasad, ORISE Fellow, BARDA, US Department of Health and Human Services and Henni-Karoliina Ropponen and Isabella Santi, Venture Analysts, AMR Action Fund is gratefully acknowledged.

Additional information

Funding

This paper was not funded.