Intravenous Fosfomycin In Development for United States

Originally discovered in the 1960s, fosfomycin is an epoxide antibiotic with activity against drug-resistant organisms such as carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum β-lactamases (ESBLs), and Pseudomonas aeruginosa. Similar to β-lactams, fosfomycin inhibits cell wall synthesis, but is unique in that it inactivates the enzyme responsible for the first step of peptidoglycan synthesis acting earlier than the mechanism of other cell wall active agents. Because of the recent concern in the United States around the rise of resistant pathogens, intravenous (IV) fosfomycin has gained renewed interest because of its activity and demonstrated synergy with other classes of antibiotics.

Currently, only the oral formulation of fosfomycin is available in the United States and approved for uncomplicated urinary tract infections. Because of poor oral absorption, its use in more invasive infections is limited and therefore an IV form is being developed in the United States as an 18-gram dose. Although it is available in many countries outside of the United States, IV fosfomycin is currently not US Food and Drug Administration (FDA)-approved. Zavante Therapeutics (a subsidiary of Nabriva Therapeutics) is currently planning to submit a New Drug Application for IV fosfomycin with an indication for complicated urinary tract infections, based on the results of a recent clinical trial.

The ZEUS clinical trial was a phase 3 noninferiority study that evaluated 6 g IV fosfomycin every 8 hours versus piperacillin-tazobactam 4.5 g every 8 hours for complicated urinary tract infections or acute pyelonephritis in hospitalized patients. The results indicated similar clinical cure rates between both treatment groups. Both regimens were administered over a 1-hour infusion and given for a duration of 7 days, with the exception of bacteremic patients who could receive treatment for up to 14 days. Unlike other studies of similar design, no oral step-down therapy was permitted.

Although the primary endpoint of overall success, defined as the combination of clinical cure and microbiologic eradication in the microbiologic modified intent to treat (m-MITT) population at the test-of-cure visit, was found to be similar between both treatment groups, there were some notable differences in certain infection types. The overall success in the complicated urinary tract infections group was 61% in the fosfomycin arm compared with 42% in the piperacillin-tazobactam arm, resulting in a 19.5% difference, compared with only a 1.7% difference between the treatment arms for patients with acute pyelonephritis. In addition to positive efficacy findings, fosfomycin was found to be well tolerated with most adverse events being reversible laboratory abnormalities or gastrointestinal-related. Because the clinical utility of IV fosfomycin is likely to be in high acuity patients with resistant gram-negative pathogens, toxicity of antimicrobials can play an integral role in the overall outcome. The findings of this study were most recently presented at the annual ID Week 2018 meeting, held in San Francisco, California, October 3-7, 2018.

Although new agents for multidrug-resistant gram-negative infections such as ceftazidime-avibactam, and meropenem-vaborbactam are often first approved for use in the United States, IV fosfomycin is unique in that it has been available in European and Asian countries for many years. This allows for some insight on the clinical utility of the drug outside of regimented clinical trials that often do not capture a pragmatic use of the drug. For example, Hinduja Hospital in Mumbai India presented their experience at ID Week 2018 in 21 patients treated with IV fosfomycin for mostly CRE. Despite having a significant country-wide issue with gram-negative resistance, the most recently FDA-approved β-lactam—β-lactamase inhibitor combinations are not approved for use in India, therefore fosfomycin has the potential to have a significant role in the treatment of these infections. Of the 21 patients that were treated, 10 patients were deemed clinical cures or improvements. Three patients died, and 8 patients were categorized as clinically worsened. One patient received a 14-day course of IV fosfomycin for a bacteremic urinary tract infection for which they relapsed and presented with the same organism that had developed resistance to fosfomycin. Combination therapy is often preferred for more deep-seated infections to help mitigate the emergence of resistance.

In addition to the clinical trial data being generated by Zavante Therapeutics for the NDA submission, another study by the Spanish Network for Research in Infectious Diseases is being carried out on the evaluation of the use of IV fosfomycin compared with either meropenem or ceftriaxone for patients with bacteremic urinary tract infections caused by ESBL-producing Escherichia coli. The intention to study the drug in a “real practice” randomized, multicenter study will provide insight on a more practical clinical application of the antibiotic, according to the investigators.

Despite recent advances in new drug development, combating drug resistance will likely continue to be a challenge. In the era of unmet medical need due to growing concerns of multidrug-resistant bacteria, IV fosfomycin offers a novel therapeutic option. Data to help define the clinical utility of these new agents, such as intravenous fosfomycin, is fundamental to ensure appropriate use and successfully treat patients with resistant infections.

Disclosures: Dr. Bhalodi is the director, ID Studies, and an employee of the Scientific Affairs group at Accelerate Diagnostics, Inc.