Long-lasting antibiotics noninferior to vancomycin for skin infections

By Gene Emery

NEW YORK (Reuters Health) - Two research teams are reporting that a pair of long-acting IV antibiotics show promise against serious gram-positive skin infections, with results comparable to IV vancomycin.

The drugs are dalbavancin, from Durata Therapeutics, and oritavancin, from the Medicines Company. Both showed effectiveness in the tests, which were noninferiority studies, published in the June 5 New England Journal of Medicine. The companies paid for their respective studies.

Dalbavancin was approved by the U.S. Food and Drug Administration last week.

The key attraction for the new drugs is their ability to treat stubborn skin infections with a once-a-week infusion, which could dramatically reduce the need for hospitalization.

"Both can be real game changers," said Dr. Helen Boucher of Tufts Medical Center, the lead author of the dalbavancin study. "The value of this drug in keeping people out of the hospital can't be overstated, if it works the way we hope it will."

Not only is it exciting to have two new antibiotics coming out," said Dr. Adam Friedman, director of dermatologic research at Montefiore Medical Center, who was not connected with the research. "You can give one dose and it's equivalent to a standard dosing regimen of vancomycin."

"To me, that's the most exciting part," he told Reuters Health by phone. After one treatment, he added, "you could send them home. You're preventing these patients from being admitted and developing complications."

"It will be relative to the cost," said Dr. G. Ralph Corey of Duke University Medical Center, chief author of the oritavancin study. "If you sell it for $10 an infusion, everyone will use it. If you sell it for a thousand dollars an infusion, nobody will use it."

"The key thing is, how are these going to work in bloodstream and bone infections, where you have to treat for six weeks?" Dr. Corey told Reuters Health by phone. "You could give one infusion a week versus two infusions a day."

But the newly-published tests look at skin infections.

In their dalbavancin studies, known as DISCOVER 1 and 2, Dr. Boucher and her colleagues found early clinical responses of 79.7% for the 659 dalbavancin recipients and 79.8% for the 653 who got vancomycin, or linezolid in cases where vancomycin wasn't offering a benefit.

Among patients infected with Staphylococcus aureus, including the methicillin-resistant strain, the clinical success rate was 90.6% versus for 93.8% with the conventional therapy.

One gram of the drug was given over 30 minutes. A second dose, half the size, was given a week later.

"The patients in our studies were extremely ill, much more ill than in other recent studies of skin infections," Dr. Boucher told Reuters Health. "Eighty-five percent of our patients had fever. They had very large infections -- over 300 square centimeters -- and a very large group had systemic inflammatory response syndrome. So our results really show us this drug was effective in seriously-ill patients with skin infection. That, to me as a clinician, is very important information."

In the oritavancin test, known as SOLO I, a single 1,200 mg IV dose of the drug was used. The patients there were not as sick as in the dalbavancin study -- less likely to have fever or an elevated white-cell count.

The Corey team found that 82.3% of 475 oritavancin patients met the primary end point, which was no further spreading or a reduction in lesion size, with an absence of fever and no use of a rescue antibiotic within 72 hours. The rate was 78.9% for the 479 with vancomycin.

In addition, 79.6% of the oritavancin recipients had a clinical cure after seven to 14 days, compared to 80.0% for conventional therapy, and a reduction of lesion size of at least 20% within 72 hours was seen in 86.9% of the patients with the test drug versus 82.9% with vancomycin therapy.

For both of the new drugs, nausea was the most common side effect, but not significantly more common than with vancomycin therapy. Pruritus was significantly less common with both test drugs. The diarrhea risk was comparable to vancomycin with oritavancin but significantly lower with dalbavancin.

In the dalbavancin study, "treatment-related serious adverse events were cellulitis and anaphylactoid reaction in one patient each in the dalbavancin group and cellulitis, gastrointestinal disorder, toxic nephropathy, and acute renal failure in one patient each in the vancomycin-linezolid group," the researchers reported.

"In the oritavancin group, the only adverse event that developed during treatment and led to discontinuation in more than one patient was cellulitis (in two patients). In the vancomycin group, adverse events that developed during treatment and led to discontinuation of the study drug were hypersensitivity (in five patients), cellulitis (in three patients), and sepsis, bacterial skin infection, drug hypersensitivity, pruritus, and rash (in two patients for each condition)," the researchers said.

Dr. Corey said both he and Dr. Boucher were concerned that the long-acting nature of the drug might compound any side effects problem.

"You say, 'What if they get an allergic reaction? Will they just carry on and carry on, and it will be awful? But we just haven't seen that with either drug," he said. "We haven't seen prolonged nausea and vomiting, and we haven't seen prolonged allergic reactions. And so far there haven't been big heart and liver issues. But we need to follow up on this as it goes in the market to make sure there isn't something we've missed or is hidden."

"Although neither antibiotic agent is new (both date to the 1990s), they could transform the treatment of acute bacterial skin and skin-structure infection," said Dr. Henry Chambers of San Francisco General Hospital, in a Journal editorial.

SOURCES: http://bit.ly/1kqfQ23 and http://bit.ly/1iLY2dl

N Engl J Med 2014.

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