Solithromycin noninferior to moxifloxacin for CABP, circumvents macrolide resistance

Issue: July 2016

BOSTON — Converting from IV to oral solithromycin regimens appeared noninferior to similar courses of moxifloxacin for treatment of community-acquired bacterial pneumonia, regardless of macrolide resistance, according to trial data presented at ASM Microbe 2016.

These results build on previous phase 3 data published in February, which reported similar findings in an all-oral trial of the experimental, next-generation macrolide.

“For [community-acquired pneumonia (CAP)], there really haven’t been any new oral drugs for use in the community — telithromycin and moxifloxacin were really the only two in the last 15 years, but neither of these were useful in pediatric populations,” Brian D. Jamieson, MD, senior director of clinical research at Cempra, told Infectious Disease News. “[Solithromycin would] be the first new antibiotic for CAP in about 25 years that will have pediatric suspension, IV and oral formulations.”

Brian D. Jamieson

Solithromycin efficacious against numerous pathogens

From January 2014 to July 2015, Amanda Sheets, PhD, manager of drug development at Cempra, Jamieson and colleagues randomly assigned IV solithromycin (CEM-101, Cempra) or moxifloxacin to 863 patients with community-acquired bacterial pneumonia (CABP). They permitted patients to switch to an oral formulation after initial treatment, and reported the proportion of those treated demonstrating early clinical response at 72 hours after their first dose. The researchers detected and described the infecting pathogens by employing several different microbiological techniques, including blood and sputum culture, urinary antigen test, quantitative PCR and serology.

Amanda Sheets

According to Jamieson, approximately 75% of the participants switched to an oral formulation during the study period. Early clinical response rates were similar between solithromycin and moxifloxacin within the intent-to-treat (ITT) population (79.3% vs. 79.7%; difference, –0.46 [95% CI, –6.1 to 5.2]), and the novel treatment was noninferior when examining clinical responses at 12 to 17 days.

Among the 38% of the ITT population for whom microbiological data was available, Streptococcus pneumoniae (n = 155), Mycoplasma pneumoniae (n = 69), Haemophilus influenza (n = 38) and Staphylococcus aureus (n = 37) were the most prevalent. Among S. pneumoniae cases, 27% contained macrolide-resistant genes.

“This rate of macrolide resistance is why you can’t use, say, azithromycin monotherapy for pneumonia,” Sheets told Infectious Disease News. “However, we still have a good distribution of [minimum inhibitory concentrations (MICs)] of solithromycin against these isolates, regardless of the presence of [erythromycin ribosome methylation (erm)] and [macrolide efflux (mef)] genes that confer macrolide resistance.”

The reason solithromycin is able to overcome these resistances, Jamieson said, is “because it binds to three different parts of the bacterial ribosome, compared to just one spot on the bacterial ribosome-like older macrolides. That gives it the advantage to overcome the growing resistance, which is now about 49% in the United States.”

Solithromycin MICs were often lower than moxifloxacin for gram-positive and atypical pathogens but not for gram-negative pathogens; however, these were not related to clinical outcomes.

Taken together, these data would support solithromycin therapy for both inpatient and outpatient treatment of CABP, Sheets and Jamieson said.

New macrolide with no resistance ‘a very important finding’

Solithromycin noninferiority previously has been reported in a phase 3 trial comparing oral formulations of these two macrolides.

Carlos M. Barrera, MD, pulmonologist and endocrinologist at South Miami Hospital of Baptist Health Miami, and colleagues recruited 860 adult patients with clinically and radiographically confirmed pneumonia from 114 health care centers worldwide. They randomly assigned participants to receive either a once-daily oral moxifloxacin regimen for 7 days, or once-daily oral solithromycin for 5 days and placebo for 2 days. The primary outcome was early clinical response based on symptoms, with others including clinical success and the incidence of adverse events.

Carlos M. Barrera

Within the ITT population, 78.2% of patients in the solithromycin group and 77.9% of patients in the moxifloxacin group had an early clinical response (absolute difference, 0.29%; 95% CI, –5.5 to 6.1), the researchers wrote. No significant differences were observed in clinical success rates or the proportion of participants who were clinically evaluable for analysis. Safety profiles were similar between groups. As in the study conducted by Sheets and Jamieson, solithromycin remained efficacious against a variety of different pathogens regardless of macrolide resistance.

“You now have available to you a monotherapy drug with a 5-day treatment that you can treat mild to severe pneumonia,” Barrera told Infectious Disease News. “A drug that has no resistance, and has such wide coverage is a very important finding.”

Cempra completed submission of New Drug Applications for both the oral and IV formulations of solithromycin in April. The FDA has granted solithromycin fast track designation and priority review, and Jamieson said trials examining safety and efficacy among a pediatric population with CAP are underway. – by Dave Muoio

Reference:

Sheets A, et al. Abstract Saturday-467. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Disclosures: Jamieson and Sheets report employment with Cempra. Barrera reports no relevant financial disclosures. Please see the full studies for lists of all other authors’ relevant financial disclosures.