Antimicrobial Activity of Solithromycin against Clinical Isolates of Legionella pneumophila Serogroup 1

Abstract

The activity of solithromycin was evaluated against clinical Legionella pneumophila serogroup 1 (Lp1) isolates (n ‫؍‬ 196) collected in Ontario, Canada, from 1980 to 2011. Its in vitro activity was compared to that of azithromycin (AZM) using the broth microdilution method. Solithromycin had a MIC 50 of <0.015 g/ml and a MIC 90 of 0.031 g/ml, making its activity at least 8-fold to 32-fold higher than that of AZM (MIC 50 and MIC 90 , 0.125 g/ml and 1 g/ml, respectively). Ninety-nine percent of the isolates had MICs for solithromycin ranging from <0.015 g/ml to 0.031 g/ml, whereas 83.6% of the isolates showed MICs for AZM ranging from 0.062 g/ml to 0.25 g/ml. Interestingly, 96.7% (30 out of 31 clinical isolates) identified with higher AZM MICs (0.5 g/ml to 2 g/ml) belonged to the clinically prevalent sequence type 1. To investigate the intracellular activity of solithromycin, in vitro invasion assays were also performed against a subset of representative Lp1 isolates internalized within human lung epithelial cells. Solithromycin and AZM both inhibited growth of all intracellular Lp1 isolates at 1؋ or 8؋ MICs, displaying bacteriostatic effects, as would be expected with protein synthesis inhibitor rather than bactericidal activity. Solithromycin demonstrated the highest in vitro and intracellular potency against all Lp1 isolates compared to AZM. Given the rapid spread of resistance mechanisms among respiratory pathogens and the reported treatment failures in legionellosis, the development of this new fluoroketolide, already in phase 3 oral clinical studies, constitutes a promising alternative option for the treatment of legionellosis.

Current and Emerging Legionella Diagnostics for Laboratory and Outbreak Investigations

“…A follow-up study detailing the molecular basis for this resistance was not able to determine if mutations (in the gyrA gene) arose before or after the antibiotic was administered (224). Of particular interest, a next-generation macrolide (the first fluoroketolide), solithromycin, is currently in phase III clinical trials and, at least in vitro, appears to be highly active against Lp1 (225). In contrast, while timely processing is still important, epidemiological investigations that link one or more disease cases to common environmental exposures must employ more thorough approaches for identifying shared phylogenies between clinical and environmental strains.…”

Results from the Solithromycin International Surveillance Program (2014)

“…Solithromycin has also demonstrated activity comparable to that of azithromycin against H. influenzae; very potent activity against Moraxella catarrhalis, beta-hemolytic streptococci, Legionella pneumophila, Mycoplasma pneumoniae (including macrolide-resistant strains), and Chlamydophila pneumoniae; and variable activity against S. aureus (activity dependent upon the type of macrolide resistance mechanisms present) (2,(8)(9)(10)(11)(12). This documented wide spectrum of in vitro activity against the major CABP pathogens has provided the impetus for solithromycin to move forward into clinical investigations.…”

Solithromycin monotherapy for treatment of community‐acquired bacterial pneumonia: A meta‐analysis of randomised controlled trials

“…It also has activity against drug‐resistance bacteria, including macrolide‐ and penicillin‐resistant isolates of S pneumoniae , macrolide‐resistant M pneumoniae , and methicillin‐sensitive or community‐acquired methicillin‐resistant S aureus strains . Additionally, it was the most potent compound tested against Mycoplasma species and L pneumophila strains …”

“…25 Additionally, it was the most potent compound tested against Mycoplasma species and L pneumophila strains. 24,[26][27][28] A number of trials have been carried out in the past several years, comparing the efficacy and safety of solithromycin with other antibiotics for CABP. However, the exact role of solithromycin in the treatment of CABP remains unclear.…”