Solithromycin: A Novel Fluoroketolide for the Treatment of Community-Acquired Bacterial Pneumonia

Abstract

Solithromycin is a novel fluoroketolide developed in both oral and intravenous formulations to address increasing macrolide resistance in pathogens causing community-acquired bacterial pneumonia (CABP). When compared with its macrolide and ketolide predecessors, solithromycin has several structural modifications which increase its ribosomal binding and reduce its propensity to known macrolide resistance mechanisms. Solithromycin, like telithromycin, affects 50S ribosomal subunit formation and function, as well as causing frame-shift errors during translation. However, unlike telithromycin, which binds to two sites on the ribosome, solithromycin has three distinct ribosomal binding sites. Its desosamine sugar interacts at the A2058/A2059 cleft in domain V (as all macrolides do), an extended alkyl-aryl side chain interacts with base pair A752-U2609 in domain II (similar to telithromycin), and a fluorine at C-2 of solithromycin provides additional binding to the ribosome. Studies describing solithromycin activity against Streptococcus pneumoniae have reported that it does not induce erm-mediated resistance because it lacks a cladinose moiety, and that it is less susceptible than other macrolides to mef-mediated efflux due to its increased ribosomal binding and greater intrinsic activity. Solithromycin has demonstrated potent in vitro activity against the most common CABP pathogens, including macrolide-, penicillin-, and fluoroquinolone-resistant isolates of S. pneumoniae, as well as Haemophilus influenzae and atypical bacterial pathogens. Solithromycin displays multi-compartment pharmacokinetics, a large volume of distribution (>500 L), approximately 67% bioavailability when given orally, and serum protein binding of 81%. Its major metabolic pathway appears to follow cytochrome P450 (CYP) 3A4, with metabolites of solithromycin undergoing biliary excretion. Its serum half-life is approximately 6–9 h, which is sufficient for once-daily administration. Pharmacodynamic activity is best described as fAUC0–24/MIC (the ratio of the area under the free drug concentration–time curve from 0 to 24 h to the minimum inhibitory concentration of the isolate). Solithromycin has completed one phase II and two phase III clinical trials in patients with CABP. In the phase II trial, oral solithromycin was compared with oral levofloxacin and demonstrated similar clinical success rates in the intention-to-treat (ITT) population (84.6 vs 86.6%). Clinical success in the clinically evaluable patients group was 83.6% of patients receiving solithromycin compared with 93.1% for patients receiving levofloxacin. In SOLITAIRE-ORAL, a phase III trial which assessed patients receiving oral solithromycin or oral moxifloxacin for CABP, an equivalent (non-inferior) early clinical response in the ITT population was demonstrated for patients receiving either solithromycin (78.2%) or moxifloxacin (77.9%). In a separate phase III trial, SOLITAIRE-IV, patients receiving intravenous-to-oral solithromycin (79.3%) demonstrated non-inferiority as the primary outcome of early clinical response in the ITT population compared with patients receiving intravenous-to-oral moxifloxacin (79.7%). Overall, solithromycin has been well tolerated in clinical trials, with gastrointestinal adverse events being most common, occurring in approximately 10% of patients. Transaminase elevation occurred in 5–10% of patients and generally resolved following cessation of therapy. None of the rare serious adverse events that occurred with telithromycin (i.e., hepatotoxicity) have been noted with solithromycin, possibly due to the fact that solithromycin (unlike telithromycin) does not possess a pyridine moiety in its chemical structure, which has been implicated in inhibiting nicotinic acetylcholine receptors. Because solithromycin is a possible substrate and inhibitor of both CYP3A4 and P-glycoprotein (P-gp), it may display drug interactions similar to macrolides such as clarithromycin. Overall, the in vitro activity, clinical efficacy, tolerability, and safety profile of solithromycin demonstrated to date suggest that it continues to be a promising treatment for CABP.

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Acknowledgements

The authors are grateful to Cempra Pharmaceuticals Inc. (Dr. Glenn Tillotson) for their assistance with literature retrieval and review of the manuscript.

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Correspondence to George G. Zhanel.

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Zhanel, G.G., Hartel, E., Adam, H. et al. Solithromycin: A Novel Fluoroketolide for the Treatment of Community-Acquired Bacterial Pneumonia. Drugs 76, 1737–1757 (2016). https://doi.org/10.1007/s40265-016-0667-z

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Keywords

  • Chronic Obstructive Pulmonary Disease
  • Azithromycin
  • Levofloxacin
  • Macrolides
  • Moxifloxacin