White Paper: Recommendations on the Conduct of Superiority and Organism-Specific Clinical Trials of Antibacterial Agents for the Treatment of Infections Caused by Drug-Resistant Bacterial Pathogens

Abstract

There is a critical need for new pathways to develop antibacterial agents to treat life-threatening infections caused by highly resistant bacteria. Traditionally, antibacterial agents have been studied in noninferiority clinical trials that focus on one site of infection (eg, pneumonia, intra-abdominal infection). Conduct of superiority trials for infections caused by highly antibiotic-resistant bacteria represents a new, and as yet, untested paradigm for antibacterial drug development. We sought to define feasible trial designs of antibacterial agents that could enable conduct of superiority and organism-specific clinical trials. These recommendations are the results of several years of active dialogue among the white paper's drafters as well as external collaborators and regulatory officials. Our goal is to facilitate conduct of new types of antibacterial clinical trials to enable development and ultimately approval of critically needed new antibacterial agents.

Exploiting Interkingdom Interactions for Development of Small-Molecule Inhibitors of Candida albicans Biofilm Formation

“…Consequently, there is an urgent need to create innovative new options for the targeted prevention of microbial infection while avoiding the inevitable emergence of resistance that is the hallmark of broad-spectrum antibiotic therapies (59,60). Increasingly, industry, academia, and regulatory bodies have become interested in single-pathogen therapies to treat highly resistant or totally resistant bacterial pathogens, rightly viewed as an area of high unmet need (61)(62)(63). Exploiting interkingdom com- The data represent four independent biological replicates, and all the data points are normalized to Triton X-100 as described for panel a.…”

Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges

“…One of the hypervirulent strains was also tested; A. baumannii HUMC1 is a lung and blood clinical isolate (simultaneously isolated from a patient with bacteremic ventilatorassociated pneumonia) that is extremely drug resistant (XDR)-clinically resistant to all antibiotics except colistin (127). In contrast to ATCC 17978, HUMC1 was already relatively resistant to innate effector clearance at baseline, so disruption of individual effectors only marginally impacted its bacterial density (70).…”

“…Acinetobacter is one of several Gram-negative species that routinely demonstrates an XDR phenotype, defined as resistance to all available systemic antibiotics except for those that are known to be less effective or more toxic compared to first-line agents used to treat susceptible pathogens (127). The hallmark of the XDR phenotype is carbapenem resistance.…”

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

“…In much the same way that we need novel inhibition mechanisms, researchers, clinicians, and policy makers alike need to embrace a diverse and multifaceted approach to this problem. The Infectious Disease Society of America outlined in their 2012 white paper a new approach to streamline and expedite trials for treatment of highly resistant bacteria (120). Additionally, authorities have advocated focusing not just on incentivizing new drug development but also on interventions such as requiring transparency through public reporting of antibiotic use tied to reimbursement, harnessing molecular techniques for diagnostic confirmation of antibiotic indications, and exploring agents that modify host immune responses to pathogens to circumvent resistance selection (121).…”