Continuing the Fight Against Gram-Negative Infections: What's in the Pipeline—Part 3

Agents in the Pipeline

ASM Microbe 2017 also featured presentations of several agents at various stages of development. Lynn Connolly, MD, presented results from the CARE study, an open-label, phase 3 study assessing the aminoglycoside plazomicin (ACHN-490) against hospital- or ventilator-acquired pneumonia or bloodstream infections arising from CRE.²⁹ Compared with colistin, plazomicin was associated with a 26% reduction and 53.0% relative reduction in all-cause mortality or significant disease-related complications at 28 days of follow-up, and this difference was sustained through 60 days of follow-up. Dr. Castanheira reported that a study of UTI isolates collected from hospitals in the United States and Europe found an MIC₉₀ of 2 μg/mL against Enterobacteriaceae isolates, with a susceptibility rates of 95.8% among all isolates and 99% among ESBL producing isolates at MIC ≤ 2 μg/mL.³⁰ Plazomicin also showed activity against Pseudomonas aeruginosa isolates, but its activity was twofold lower than that of amikacin. George Zhanel, PharmD, PhD, reported that plazomicin exhibited activity against Enterobacteriaceae isolates collected from patients at Canadian hospitals, with an MIC₉₀ ranging from 0.5 to 16 μg/mL, and showed similar activity to gentamicin against Pseudomonas aeruginosa (MIC₉₀ 16 μg/mL) and Acinetobacter baumannii (MIC₉₀ 2 μg/mL).³¹

Masakatsu Tsuji, PhD, reported results from surveillance studies of the siderophore cephalosporin cefiderocol (S-649266) in North America and Europe. In the SIDERO-WT-2014 study in the United States and Canada, cefiderocol showed an MIC₉₀ of .5 μg/mL against all Gram-negative bacteria and 4 μg/mL or less against carbapenem-resistant isolates.³² In the SIDERO-WT-2015 study in North America and Europe, the MIC₉₀ for cefiderocol ranged from .5 μg/mL to 2 μg/mL for all Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia isolates and from 1 μg/mL to 4 μg/mL for those isolates non-susceptible to meropenem.³³ In a study of globally isolated meropenem-non-susceptible isolates, the MIC₉₀ for cefiderocol was 2 μg/mL against KPC-producing Enterobacteriaceae and 4 μg/mL against strains producing metallo-type carbapenemases.³⁴ Cefiderocol also showed activity against OXA-producing isolates (MIC₉₀ 1 μg/mL to 4 μg/mL), although the range of MICs for these isolates was fairly wide (.002 μg/mL to 64 μg/mL). Marguerite Monogue, PharmD, reported that in vivo, cefiderocol induced stasis or a reduction of 1-log or more in 75% to 85% of isolates with MICs of 4 μg/mL or less.³⁵

Cefiderocol is in clinical trials for the treatment of nosocomial pneumonia caused by Gram-negative pathogens and for severe infections caused by carbapenem-resistant Gram-negative pathogens.^36,37

In a session on New Agents Discovery, Folkert Reck, PhD, summarized posters describing LYS228, a novel monobactam with activity against all MDR bacteria, particularly CRE (MIC₉₀ = 4 μg/mL), and improved stability against serine- and metallo-type beta-lactamases.³⁸ LYS228 has been granted Fast Track and Qualified Infectious Disease Product designations by the FDA. Georg Rueedi, PhD, summarized posters on ACT-051, a new bacterial topoisomerase II inhibitor with that has demonstrated MIC₉₀s ranging from 0.5 μg/mL to 4 μg/mL against Gram-negative pathogens and has been associated in vivo with a 3-log reduction in bacterial burden.³⁹ Nobuhisa Masuda, PhD, summarized posters on DS86760016, a novel tRNA synthase inhibitor that shows potent in vitro activity against most Gram-negative bacteria (MICs ranging from .25 μg/mL to 2 μg/mL) and induces a 4-log reduction in bacterial load among susceptible and MDR strains in vivo.⁴⁰ In a separate poster session, Rodrigo Mendes, PhD, reported that SPR741, a polymyxin derivative, demonstrates synergistic activity with either of the new gyrase inhibitors SPR750 and SPR751 against Acinetobacter baumannii, Enterobacteriaceae, and ESBL-producing Enterobacteriaceae.⁴¹ Susceptibility rates for each of these combinations were around 96%.

Summary and Conclusion

MDR Gram-negative bacterial infections are widespread and increasing worldwide. Clinicians, faced with critically ill patients and very little time, must make difficult decisions about empiric antimicrobial therapy considering increasing AMR to first-line agents. The newest approved antimicrobials