Details of omadacycline tests show efficacy against skin infections, pneumonia

02/06/2019

By Gene Emery

(Reuters Health) - Two global double-blind tests of the new broad-spectrum antibiotic omadacycline show it is effective when given once a day for treating acquired bacterial pneumonia or acute bacterial skin and skin structure infections, although its role in treating drug-resistant pathogens remains unproven.

In the pneumonia study, it proved to be non-inferior to moxifloxacin, with comparable cure levels and levels of side effects.

Similarly, in the test on people with acute bacterial skin and skin-structure infections, omadacycline reduced the size of the lesion by at least 20% in 84.8% of the cases versus a rate of 85.5% with twice-daily linezolid, making it non-inferior for that use as well.

Derived from the tetracycline class, the drug is designed to avoid the mechanisms that have allowed a host of bacteria to become resistant to tetracycline itself.

The results, published online February 6 by The New England Journal of Medicine, served as the basis for the U.S. Food and Drug Administration's approval of drug for both indications on October 2. It became commercially available in the U.S. Tuesday.

But Dr. Henry Chambers, an infectious disease expert at Zuckerberg San Francisco General Hospital, notes in a Journal editorial that patients who were suspected to have a drug-resistant pathogen were excluded from the pneumonia trial, as were people with septic shock, immunologic deficiency and hemodynamic instability.

Thus, the role of omadacycline in treating pathogens that are resistant to established drugs "is a question desperately in need of an answer," he said.

"Well designed clinical trials of omadacycline for the treatment of infections caused by multiple-drug-resistant gram-negative pathogens are needed to determine its real value as an antibacterial agent," Dr. Chambers said.

At Boston-based Paratek Pharmaceuticals, which conducted and financed both studies, Chief Medical Officer Dr. Evan Loh, a co-author on both Journal papers, told Reuters Health by phone that the drug could be important in the fight against drug resistance.

"Now there is a once-daily, broad-spectrum, well-tolerated, IV and oral drug that's approved for both skin infections and pneumonia. It's the first one of these drugs with those indications to be approved and put on the market in the last 20 years," he said. "Now maybe doctors can change the selection pressure for resistance, which is good for patients in the long term."

"We went after the two known mechanisms of resistance for tetracyclines," said Dr. Loh. "Bugs will eventually find a way to go around it but based on our work in the lab, we tried to induce resistance and we've been unable to do that. So at least we think (development of resistance) will be a little slower."

It is being sold under the name Nuzyra and is expected to cost $300 to $350 per day, the company said.

According to the U.S. Centers for Disease Control and Prevention, drug-resistant bacteria cause about 2 million illnesses and 23,000 deaths each year.

In the pneumonia study, known as OPTIC, omadacycline was compared to Bayer's Avelox (moxifloxacin), with rates of early clinical response of 81.1% for the new drug and 82.7% with moxifloxacin.

Rates of clinical response in the post-treatment evaluation also showed omadacycline to be noninferior. All patients had a Pneumonia Severity Index risk class score of 2 to 4 on a 5-point scale, where 5 posed the highest risk of death.

The overall rates of adverse events were 41.1% with omadacycline and 48.5% with moxifloxacin.

Omadacycline seemed to produce fewer gastrointestinal side effects, notably with less diarrhea, but the death rate with the newer drug was twice as high, with 8 deaths among the 386 omadacycline patients versus 4 deaths in the 388 taking moxifloxacin.

"The cause of the mortality imbalance was not established," the researchers said. "The causes of the deaths were consistent with the population, and the mortality rates are consistent with the expected range of 1% to 3% in other phase 3 community-acquired bacterial pneumonia trials."

A higher death rate was not seen in the skin infection study, known as OASIS-1, where the target lesion resolved or didn't require further antibacterial therapy seven to 14 days after the final dose in 86.1% of the 316 patients getting omadacycline and 83.6% of the 311 volunteers treated with linezolid, which Pfizer markets as Zyvox.

"In both treatment groups, the median lesion size was reduced by approximately 50% on day 3. It was reduced by approximately 99% in both groups at the end of treatment," the researchers reported.

All of the lesions covered at least 75 square cm at the start of the test. Volunteers with infections that were expected to require more than 14 days of therapy were excluded from the test. People who had carried their lesions for more than three months were also excluded, as were patients whose lesions only contained gram-negative pathogens.

"In both groups, the efficacy of the trial drug was similar for methicillin-susceptible and methicillin-resistant Staphylococcus aureus infections," the team reported.

Again, the most common side effects were gastrointestinal, seen in 18.0% receiving omadacycline and in 15.8% treated with linezolid. Most of those cases included nausea and vomiting.

There were three deaths in that study, none of which were considered related to the antibiotic used.

SOURCE: https://bit.ly/2G72MkA and https://bit.ly/2WGZA43

N Engl J Med 2019

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