Antimicrobial resistance in pathogenic gram-negative bacteria is one of the most pressing challenges in the field of infectious diseases and is one of 4 key areas of unmet medical need identified by the Antibacterial Resistance Leadership Group (ARLG). The mission of the Gram-Negative Committee is to advance our knowledge of these challenging infections and implement studies to improve patient outcomes. Studies have fallen primarily into 2 broad categories: prospective cohort studies and interventional trials. Among the observational studies, CRACKLE (Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae and Other Enterobacteriaceae) has contributed seminal multicenter data describing risk factors and clinical outcomes of carbapenem-resistant Enterobacteriaceae (CRE) in sentinel US hospitals. Building on this success, CRACKLE II will expand the network to hospitals across the United States and Colombia. Similar protocols have been proposed to include Acinetobacter baumannii and Pseudomonas aeruginosa (SNAP and POP studies). In addition, the CREST study (Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplant Patients) has provided pivotal data on extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and CRE carriage among solid organ transplant recipients to inform management of this vulnerable patient population. Two clinical trials to define novel ways of using an existing antibiotic, fosfomycin, to treat ESBL-producing Enterobacteriaceae (one that has completed enrollment and the other in late protocol development) will determine the clinical efficacy of fosfomycin as step-down oral therapy to treat complicated urinary tract infections. Additional clinical studies and trials using immunotherapeutic or newly approved agents are also in the planning stage, with the main goals of generating actionable data that will inform clinical decision making and facilitate development of new treatment options for highly resistant gram-negative bacterial infections.
Bibliographical noteFunding Information:
Financial support. This article was supported by the National Institute of Allergy and Infectious Diseases of the NIH (award number UM1AI104681).
Potential conflicts of interest. Y. D. has served on advisory boards for Shionogi, Meiji, Tetraphase, Achaogen, and Allergan; has received speaking fees from Merck; and has received research funding from The Medicines Company. R. A. B. has received research funding from the NIH and VA Merit Review Board and research grants from Merck, Wockhardt, Allergan, and Roche for preclinical work on β-lactamase inhibitors. K. S. K. has served as a consultant for Achaogen, Merck, and The Medicines Company and has received research grants from NIH, Merck, and The Medicines Company. J. R. J. has received research grants from Merck, Tetraphase, and Actavis/Forest; has done consulting for Janssen/Crucell; and has patent applications for tests to detect specific E. coli strains. C. J. C. has received grants from Merck, Pfizer, Astellas, and Cidaris and personal fees from Merck. M. E. S. has been a consultant for Achaogen, Cempra, Cerexa, The Medicines Company, and Theravance and has received funding from the Duke Clinical Research Institute, JMI Laboratories, and ARLG. D. v. D. has received research funding from Actavis, Tetraphase, Sanofi-Pasteur, MedImmune, and Astellas and has served on advisory boards for Steris Inc and Scynexis. All other authors report no potential conflicts. The authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
- Antimicrobial resistance
- Clinical trials
- Interventional studies
- Observational studies