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.
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.
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.
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.
- WHO publishes list of bacteria for which new antibiotics are urgently needed [news release]. Geneva: World Health Organization. Published February 27, 2017. Accessed November 8, 2017.
- Golan Y, Cloutier DJ, Komirenko AS, et al. Improved outcomes at late follow-up with plazomicin compared with meropenem in patients with complicated urinary tract infections, including acute pyelonephritis, in the EPIC study. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1859.
- Bhavnani SM, Trang M, Griffith DC, et al. Meropenem-vaborbactam pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses as support for dose selection in patients with normal renal function and varying degrees of renal impairment. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1852.
- Cloutier DJ, Komirenko AS, Cebrik DS, et al. Plazomicin versus meropenem for complicated urinary tract infection (cUTI) and acute pyelonephritis (AP): diagnosis-specific results from the phase 3 EPIC study. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1855.
- Plazomicin granted FDA breakthrough therapy designation [press release]. South San Francisco, CA: Achaogen, Inc. Published May 23, 2017. Accessed January 16, 2018.
- Achaogen submits plazomicin New Drug Application (NDA) to the U.S. FDA for treatment of complicated urinary tract infections and bloodstream infections [press release]. South San Francisco, CA: Achaogen, Inc. Published October 26, 2017. Accessed January 16, 2018.
- McKinnell JA, Connolly LEe, Pushkin R, et al. Improved outcomes with plazomicin (PLZ) compared with colistin (CST) in patients with bloodstream infections (BSI) caused by carbapenem-resistant Enterobacteriaceae (CRE): results from the CARE study. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1853.
- Kaye Ks, Vazquez J, Mathers A, et al. Clinical outcomes of serious infections due to carbapenem-resistant Enterobacteriaceae (CRE) in TANGO II, a phase 3, randomized, multi-national, open-label trial of meropenem-vaborbactam (M-V) versus best available therapy (BAT). Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1862.
- Wunderink R, Giamarellos-Bourboulis E, Rahav G, et al. Meropenem-vaborbactam vs. best available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO II: primary outcomes by site of infection. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1867.
- Paterson DL, Kwak EJ, Bhowmick T, et al. Meropenem-vaborbactam vs. best available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO II: outcomes in immunocompromised patients. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1868.
- Lomovskaya O, Castanheira M, Vazquez J, et al. Assessment of MIC increases with meropenem-vaborbactam and ceftazidime-avibactam in TANGO II (a phase 3 study of the treatment of CRE infections). Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1874.
- Mathers A, Hope W, Kaye KS, et al. Meropenem-vaborbactam: outcomes in subjects with renal impairment in phase 3 studies TANGO I and II. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1879.
- Castanheira M, Huband MD, Mendes RE, Flamm RK. Meropenem-vaborbactam tested against contemporary Gram-negative isolates collected worldwide during 2014, including carbapenem-resistant, KPC-producing, multidrug-resistant, and extensively drug-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2017;61:e00567-00617.
- Portsmouth S, Van Veenhuyzen D, Echols R, et al. Clinical response of cefiderocol compared with imipenem/cilastatin in the treatment of adults with complicated urinary tract infections with or without pyelonephritis or acute uncomplicated pyelonephritis: Results from a multicenter, double-blind, randomized study (APEKS-cUTI). Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1869.
- Leuthner KD, Kullar R, Jayakumar B, Hewlett DA, Nguyen T, Puzniak L. Real world evaluation of ceftolozane/tazobactam (C/T) use and clinical outcomes at an academic medical center in Las Vegas. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 828.
- Munita JM, Aitken SL, Miller WR, et al. Multicenter evaluation of ceftolozane/tazobactam for serious infections caused by carbapenem-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2017;65:158-161.
- Torres A, Rank D, Rekeda L, et al. Phase 3, randomized, double-blind noninferiority (NI) study of ceftazidime-avibactam (CAZ-AVI) versus meropenem (MER) in the treatment of patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP): analyses of the REPROVE study per US FDA endpoints. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1864.
- Stets R, Popescu M, Gonong J, et al. A phase 3, randomized, double-blind, multi-center study to compare the safety and efficacy of IV to oral omadacycline to moxifloxacin for the treatment of adult patients with CABP (the OPTIC study). Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1883.
- Solomkin J, Evans D, Slepavicius A, et al. Assessing the efficacy and safety of eravacycline vs ertapenem in complicated intra-abdominal infections in the investigating Gram-negative infections treated with eravacycline (IGNITE 1) trial: a randomized clinical trial. JAMA Surg. 2017;152:224-232.
- Tetraphase pharmaceuticals announces positive oral dosing data from lead-in of IGNITE 2 phase 3 trial of eravacycline in cUTI support advancement to pivotal portion [press release]. Watertown, MA: Tetraphase Pharmaceuticals, Inc. Published September 2, 2017. Accessed January 16, 2018.
- Horn P, Redican S, Tsai L. Impact of meal timing on eravacycline exposure during the oral portion of an IV to oral transition dosing regimen. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1832.
- Tetraphase announces positive top-line results from phase 3 IGNITE4 clinical trial in complicated intro-abdominal infections [press release]. Watertown, MA: Tetraphase Pharmaceuticals, Inc. Published July 25, 2017. Accessed November 10, 2017.
- Kaye KS, Rice LB, Dane A, et al. Intravenous fosfomycin (ZTI-01) for the treatment of complicated urinary tract infections (cUTI) including acute pyelonephritis (AP): Results from a multi-center, randomized, double-blind phase 2/3 study in hospitalized adults (ZEUS). Presented at: IDWeek 2017; October 4-8, 2017; San Diego, California. Poster 1845.
- Nabriva therapeutics announces positive topline results from global, phase 3 clinical trial evaluating IV and oral lefamulin for the treatment of community-acquired bacterial pneumonia [press release]. Dublin: Nabriva Therapeutics. Published September 18, 2017. Accessed November 10, 2017.
- Paschke A. New antibiotics: what’s in the pipeline: imipenem-relebactam. Presented at: IDWeek 2017; October 4-8, 2017; San Diego, CA. Symposium 865.