New therapies with reliable activity against CRE are urgently needed, as clinicians have increasingly been forced to use such agents as polymyxins and tigecycline, which have efficacy and safety concerns. Increased use of both has, in turn, led to the emergence of resistance to these last-line agents. Colistin-resistant KPC-producing K. pneumoniae
strains are now widely disseminated in some endemic countries.18,19,20,21
In a surveillance study of K. pneumoniae
isolates collected in 18 US hospitals between 2011 and 2013, 46% of carbapenemresistant strains were not susceptible to tigecycline and receipt of tigecycline was an independent risk factor for nonsusceptibility to tigecycline.22
More recently, resistance to ceftazidime-avibactam, a newly approved agent with in vitro activity against CRE, was reported to emerge following ceftazidime-avibactam treatment in 30% (3/10) patients with CRE experiencing recurrent infections.23
The emergence of resistance to these antibiotics reinforces the need for additional agents and treatment strategies for CRE infection.
Although agents for CRE infection are urgently needed, the study of such patients under traditional antibacterial-development programs is challenging due to limited patient numbers, evolving epidemiology, competition for clinical trials, and the complex medical nature of patients with CRE. Many companies have shifted away from developing antimicrobials due to hurdles that render antibiotic development less attractive compared with more lucrative therapeutic areas. However, recently, certain incentives, like the Generating Antibiotic Incentives Now act have been put into place to attempt to reinvigorate the pipeline.
CARB-X (Xccelerating global antibacterial innovation), the world’s largest global antibacterial public–private partnership to combat antibioticresistant bacteria, was formed in July 2016 in response to the 2015 US National Action Plan on Combating Antibiotic-Resistant Bacteria (CARB). In its first year, the CARB-X portfolio will largely focus on therapeutics to treat gram-negative bacteria, including CRE.24 The Figure25,26
lists antibiotics currently in phase 2 or 3 development that have activity against CRE.
Antibiotics Currently in Clinical Development 25,26
|PIPELINE AGENT (COMPANY)
|Aztreonam + avibactam (AstraZeneca PLC/Allergan PLC [formerly Actavis])
||Monobactam + novel beta-lactamase inhibitor
||Complicated intra-abdominal infections
|Fosfomycin (IV) (Zavante Therapeutics)
||Complicated urinary tract infections, including acute pyelonephritis
||Health care-associated pneumonia, bloodstream infections, hospital- acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, complicated urinary tract infections
|Imipenem/cilastatin + relebactam
(Merck & Co, Inc)
|Carbapenem + novel beta-lactamase inhibitor
||Complicated urinary tract infections, including acute pyelonephritis; complicated intra-abdominal infections; hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia
||Carbapenem + novel
||Complicated urinary tract infections, complicated intra-abdominal
|Vaborbactam (Rempex Pharmaceuticals,
Inc, a wholly owned subsidiary of The Medicines Company)
|boronic beta-lactamase inhibitor
||infections, hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, febrile neutropenia, bacteremia, acute carbapenem-resistant Enterobacteriaceae)
pyelonephritis (some indications specifically target infections caused by
|Eravacycline (Tetraphase Pharmaceuticals, Inc)
||Complicated intra-abdominal infections, complicated urinary tract infections
|Plazomicin (Achaogen, Inc)
||Complicated urinary tract infections, including acute pyelonephritis; bloodstream infections; hospital-acquired bacterial pneumonia/ventilator- associated bacterial pneumonia, in patients with limited treatment options (some indications specifically target infections caused by carbapenem- resistant Enterobacteriaceae)
The authors acknowledge John Mohr, PharmD, and Katie Luepke, PharmD, BCPS, for their contributions in developing this manuscript.
Keith Kaye, MD, MPH, is an infectious diseases physician and professor of internal medicine at the University of Michigan Medical School, where he is the director of clinical research in the Division of Infectious Diseases. He is the current vice president for the Society for Healthcare Epidemiology of America.
Lynn Connolly, MD, PhD, is an infectious diseases physician and assistant clinical professor of Medicine at the University of California in San Francisco. She is the senior medical director and head of late development at Achaogen.