VIENNA – Two infusions of the long-acting lipoglycopeptide antibiotic dalbavancin showed a favorable clinical benefit for treatment of adult osteomyelitis in a phase II study.
Dalbavancin (Dalvance) showed positive results while avoiding the complexities of standard therapies that require longer, more frequent dosing, Urania Rappo, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.
Dalbavancin already is approved for acute bacterial skin and skin structure infections, and its long terminal half-life of 14 days and high bone penetration made it a natural candidate for evaluation in the treatment of osteomyelitis, said Dr. Rappo, director of clinical development (anti-infectives) at Allergan, which markets the drug and sponsored.
Dalbavancin is a glycopeptide antibiotic with a lipid tail that prolongs its half-life, compared with other drugs in this category, such as vancomycin and teicoplanin, to which it is structurally related. It is highly potent against gram-positive bacterial infections, including methicillin-resistant Staphylococcus aureus.
The drug’s MIC90 for S. aureus is 0.06 mcg/mL; vancomycin’s, in comparison, is 1 mcg/mL. A 2015 bone penetration study found that the bone level 12 hours after a 1,000-mg infusion was 6.3 mcg/g. This remained elevated for 14 days; the concentration at 2 weeks was 4 mcg/g ().
“The mean bone-to-plasma penetration ratio was 13%, and drug levels in bone were very similar to free drug levels in serum, so we expect that much of this is free drug in the bone, available for antimicrobial activity,” Dr. Rappo noted. “It’s not only long lasting, but highly potent, meaning we need less drug to kill the infecting organism.”
Dalbavancin was administered as two 1,500-mg IV infusions, 1 week apart in Dr. Rappo’s randomized, open-label, phase II study – the first clinical trial to examine the drug’s effect in osteomyelitis in adults. The study is ongoing; she presented interim results on 68 patients, 59 of whom took dalbavancin. The nine patients in the standard-of-care arm were treated according to the investigator’s clinical judgment. Vancomycin was the most commonly employed therapy. Three patients received vancomycin infusions for 4 weeks. Four received a regimen of 4-16 days of intravenous vancomycin followed by intravenous linezolid or levofloxacin to complete a 4- to 6-week course of therapy. Adjunctive aztreonam was permitted for presumed coinfection with a gram-negative pathogen and a switch to oral antibiotic for gram-negative coverage was allowed after clinical improvement.
The primary endpoint was clinical cure at 42 days in the clinically evaluable population, defined as recovery without need for further antibiotic therapy. Failure was defined as the need for additional antibiotics; more than 6 weeks of treatment in the comparator arm; new purulence; amputation due to infection progression; or death. Indeterminate response was defined as loss to follow-up or amputation due to vascular insufficiency.
There were several secondary endpoints: clinical improvement at day 21, including changes in C-reactive protein level and clinical response in patients who had follow-up at days 42, 180, and 365.
In the dalbavancin arm, patients had a mean age of 51 years. All had undergone surgical debridement and bone culture. The most common site of infection was the foot or leg (about 83%). The baseline mean CRP level was 41.8 mg/L. About half of the patients had methicillin-susceptible S. aureus on bone culture. Coagulase-negative staphylococci were present in 20%. About 22% had gram-negative pathogens, mostly present in a mixed infection along with gram-positive pathogens. Five patients (three on dalbavancin, two on standard of care) discontinued the study drug early because they were solely infected with gram-negative pathogens.
At day 42, clinical cure was seen in all the dalbavancin patients and six of the standard treatment patients. In the group with treatment data out to 180 days (54 on dalbavancin and 5 on standard therapy), clinical cure rates were similar.
At 180 days, clinical cure continued in 93% of the dalbavancin patients (50 of 54). Two patients were defined as failures, and two patients were indeterminate because of loss to follow-up. In the standard therapy group at 180 days, four of five standard therapy patients maintained clinical cure; none of these patients has reached the 365-day outcome.
There were no treatment-emergent adverse events (TEAEs) in the standard therapy group. In the dalbavancin group, 10 patients experienced TEAEs, only one of whom had TEAEs related to the study drug, which were not serious, Dr. Rappo said.
This study was performed at a single center in the Ukraine, and an additionalin the United States has begun, she added.