General Infectious Disease

Reason for Hope: Promising Gram-Negative Infection Treatments in the Pipeline

James A. McKinnell, MD
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Oral Omadacycline for Community-Acquired Bacterial Pneumonia

The results of the OPTIC (Omadacycline for Pneumonia Treatment In the Community; ClinicalTrials.gov identifier: NCT02531438) trial18 confirmed the value of IV and once-daily oral omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, compared with once-daily oral moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP).

In the OPTIC trial, 774 adult patients with CABP were randomly assigned to a 3-day course of IV omadacycline or moxifloxacin. Early clinical response was evaluated as the primary endpoint. Patients were continued on the IV treatment or were switched to a once-daily oral drug regimen for up to 12 days. Posttreatment evaluation was performed 5 to 10 days after the last dose. Omadacycline was noninferior to moxifloxacin with respect to the primary endpoint. Clinical success at the conclusion of the study was comparable. Clinical failure was low and comparable at 3 days and at study conclusion. The eradication of all assessed bacterial pathogens was high. Omadacycline had a safety profile that was comparable to moxifloxacin. The OPTIC results will support pending FDA and European Medicines Agency regulatory applications.

Eravacycline

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In the IGNITE 1 (Investigating Gram-Negative Infections Treated with Eravacycline; ClinicalTrials.gov identifier: NCT01844856)19,20,22 phase 3 trial, twice-daily IV infusions of the broad-spectrum fluorocycline antibiotic, eravacycline, met the primary endpoint of noninferiority compared with ertapenem for cIAI. In the IGNITE 2 phase 3 trial involving 600 patients, the IV-to-oral regimen of eravacycline proved inferior to IV-to-oral levofloxacin for the treatment of cUTI.20 However, more prolonged time of IV eravacycline improved the drug’s comparative performance. These results prompted the IGNITE 3 trial, which will evaluate just the IV formulation of eravacycline for the treatment of cUTIs. A phase 1 study presented at IDWeek21 is the first step in refining an oral formulation for cUTI. Volunteers received an IV dose followed by different oral doses taken at various times after a meal. A longer time between a meal and the once-daily 250-mg oral dose produced drug levels that are anticipated to be effective against cUTI. Top-line results of the 500-patient IGNITE 4 phase 3 trial22 indicate the noninferiority of IV eravacycline compared with meropenem in the treatment of cIAI.

The results to date will be the basis of an NDA submission to the FDA early in 2018 for IV eravacycline in the treatment of cIAI. More data will be required before approval is sought for oral eravacycline. 

Fosfomycin for cUTI

The phase 2/3 ZEUS trial (ClinicalTrials.gov identifier: NCT02753946) evaluated the efficacy and safety of ZTI-01 (ZOLYD, fosfomycin for injection, Zavante Therapeutics, Inc.), a first-in-class IV-administered fosfomycin in patients hospitalized with cUTI or AP. In this study, 465 patients were randomly assigned to IV ZTI-01 or piperacillin/tazobactam.23 The clinical response and eradication of the target bacteria was evaluated about 2 and 4 weeks after completion of treatment. The primary endpoint was met, with ZTI-01 being noninferior to piperacillin/tazobactam in overall success. The clinical rates were comparable and high, and ZTI-01 was generally well-tolerated. The majority of AEs were mild or moderate. Drug-related AEs and serious AEs were uncommon, and there were no deaths.

IV fosfomycin is currently approved outside the United States for difficult-to-treat infections, including cUTI. The latest results from the ZEUS study will be the basis for an NDA submission to the FDA within the next 12 months.

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Other Notables

Lefamulin is a pleuromutilin antibiotic that targets a ribosomal subunit protein. The phase 3 LEAP 1 (ClinicalTrials.gov identifier: NCT02559310) trial demonstrated the efficacy and safety of IV and oral lefamulin in the treatment of CABP.24 The phase 3 LEAP 2 (ClinicalTrials.gov identifier: NCT02813694) trial will assess oral lefamulin compared with oral moxifloxacin for CABP.

Finally, the combination of the β-lactamase inhibitor relebactam and imipenem restores the in vitro activity of imipenem against Enterobacteriaceae. An examination of clinical isolates from 45 hospitals in 17 countries revealed the efficacy of the combination.25 The majority of P aeruginosa and Enterobacteriaceae isolates that were resistant to imipenem proved susceptible to imipenem-relebactam. Further studies will seek to develop a fixed-dose combination as a treatment for lower respiratory tract infections.

Gram-negative bacteria often lurk behind cUTIs, cIAIs, and CABP. These infections are prevalent, costly (particularly among high-risk patients), and deadly. Continued efforts toward researching and developing innovative new therapies give us reason for hope.

Disclosure

Dr McKinnell has served as a research consultant for Achaogen, Allergan, Cempra, Science37, Theravance, and Thermo Fisher Scientific, and is on the speaker’s bureau for Allergan.

References

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