Solithromycin

Solithromycin (CEM-101) is a new, potent and broad-spectrum fluoroketolide antibiotic [1][2].

Antibiotic is an antimicrobial used in the treatment and prevention of bacterial infection.

Solithromycin (CEM-101) is a broad-spectrum fluoroketolide antibiotic. CEM-101 exhibited high potency against diverse groups of Gram-positive and Gram-negative bacteria, including mycoplasma and ureaplasma, as well as bacteria associated with respiratory tract infections and skin infections, with MIC50 values of 0.015 μg/mL and 4 μg/mL, respectively [1]. Solithromycin (CEM-101) bound to the large 50S subunit of the ribosome and inhibited protein biosynthesis. In Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, solithromycin inhibited cell viability, protein synthesis, and growth rate with IC50 values of 7.5, 40, and 125 ng/ml. Solithromycin also inhibition the formation of the 50S subunit [3]. In monocytic U937 cells, solithromycin inhibited TNFα/CXCL8 production and MMP9 activity. In PBMC isolated from chronic obstructive pulmonary disease (COPD) patients, solithromycin (10 μM) inhibited TNFα release and MMP9 activity. In monocytic U937 cells, solithromycin (10 μM) significantly inhibited NF-κB activity activated by oxidative stress [4].

In C57BL/6J mice, solithromycin also inhibited cigarette smoke-induced neutrophilia and pro-MMP9 production [4]. CEM-101 was also an effective antimicrobial for the prevention and treatment of intrauterine infection [2].

References:
[1].  Putnam SD, Castanheira M, Moet GJ, et al. CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria. Diagn Microbiol Infect Dis, 2010, 66(4): 393-401.
[2].  Keelan JA, Kemp MW, Payne MS, et al. Maternal administration of solithromycin, a new, potent, broad-spectrum fluoroketolide antibiotic, achieves fetal and intra-amniotic antimicrobial protection in a pregnant sheep model. Antimicrob Agents Chemother, 2014, 58(1): 447-454.
[3].  Rodgers W, Frazier AD, Champney WS. Solithromycin inhibition of protein synthesis and ribosome biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Antimicrob Agents Chemother, 2013, 57(4): 1632-1637.
[4].  Kobayashi Y, Wada H, Rossios C, et al. A novel macrolide solithromycin exerts superior anti-inflammatory effect via NF-κB inhibition. J Pharmacol Exp Ther, 2013, 345(1): 76-84.

Solithromycin: A Novel Fluoroketolide for the Treatment of Community-Acquired Bacterial Pneumonia.[Pubmed:27909995]

Drugs. 2016 Dec;76(18):1737-1757.

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.

In-vitro activity of solithromycin against anaerobic bacteria from the normal intestinal microbiota.[Pubmed:27725229]

Anaerobe. 2016 Dec;42:119-122.

Solithromycin is a novel fluoroketolide with high activity against bacteria associated with community-acquired respiratory tract infections as well as gonorrhea. However, data on the activity of Solithromycin against anaerobic bacteria from the normal intestinal microbiota are scarce. In this study, 1024 Gram-positive and Gram-negative anaerobic isolates from the normal intestinal microbiota were analyzed for in-vitro susceptibility against Solithromycin and compared to azithromycin, amoxicillin/clavulanic acid, ceftriaxone, metronidazole and levofloxacin by determining the minimum inhibitory concentration (MIC). Solithromycin was active against Bifidobacteria (MIC50, 0.008 mg/L) and Lactobacilli (MIC50, 0.008 mg/L). The MIC50 for Clostridia, Bacteroides, Prevotella and Veillonella were 0.5, 0.5, 0.125 and 0.016 mg/L, respectively. Gram-positive anaerobes were more susceptible to Solithromycin as compared to the other antimicrobials tested. The activity of Solithromycin against Gram-negative anaerobes was equal or higher as compared to other tested agents.

Solithromycin, a novel macrolide, does not prolong cardiac repolarization: a randomized, three-way crossover study in healthy subjects.[Pubmed:27798210]

J Antimicrob Chemother. 2017 Feb;72(2):515-521.

BACKGROUND: Macrolide antibiotics may cause QT prolongation. OBJECTIVES: To study the QT effect of a novel macrolide, Solithromycin. METHODS: This was a thorough QT study with a three-way crossover design performed in healthy male and female subjects to evaluate the ECG effects of a novel macrolide, Solithromycin. Forty-eight subjects were randomized to receive 800 mg of intravenous (iv) Solithromycin, 400 mg of oral moxifloxacin and placebo in three separate treatment periods. Continuous 12 lead ECGs were recorded at a pre-dose baseline and serially after drug administration for 24 h. RESULTS: After the 40 min infusion of 800 mg of Solithromycin, the geometric mean Solithromycin peak plasma concentration (Cmax) reached 5.9 (SD: 1.30) mug/mL. Solithromycin infusion caused a heart rate increase with a peak effect of 15 bpm immediately after the end of the infusion. The change-from-baseline QTcF (DeltaQTcF) was similar after dosing with Solithromycin and placebo and the resulting placebo-corrected DeltaQTcF (DeltaDeltaQTcF) for Solithromycin was therefore small at all timepoints with a peak effect at 4 h of only 2.8 ms (upper bound of the 90% CI: 4.9 ms). Using a linear exposure-response model, a statistically significant, slightly negative slope of -0.86 ms per ng/mL (90% CI: -1.19 to -0.53; P = 0.0001) was observed with Solithromycin. The study's ability to detect small QT changes was confirmed by the moxifloxacin response. Solithromycin did not have a clinically meaningful effect on the PR or QRS interval. CONCLUSIONS: The study demonstrated that Solithromycin, unlike other macrolide antibiotics, does not cause QT prolongation.

Solithromycin (CEM-101) is an orally bioavailable, effective antimicrobial agent, with IC50s for inhibition of cell viability, protein synthesis, and growth rate are 7.5 ng/mL, 40 ng/mL, and 125 ng/mL for Streptococcus pneumonia, Staphylococcus aureus, and Haemophilus influenzae, respectively. Solithromycin binds to the large 50S subunit of the ribosome and inhibits protein biosynthesis.

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