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Prabhavathi Fernandes - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetic pharmacodynamic evaluation of Solithromycin against streptococcus pneumoniae using data from a neutropenic murine lung infection model
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: Olanrewaju O Okusanya, Prabhavathi Fernandes, Alan Forrest, Sujata M Bhavnani, Paul G Ambrose, David R Andes
    Abstract:

    Solithromycin (CEM-101) is a novel fluoroketolide antimicrobial agent with activity against typical and atypical pathogens associated with community-acquired bacterial pneumonia. Using a neutropenic murine lung infection model, the objectives of this study were to identify the pharmacokinetic/pharmacodynamic (PK/PD) index most closely associated with efficacy and the magnitude of such indices associated with Solithromycin efficacy against Streptococcus pneumoniae Plasma and epithelial lining fluid (ELF) samples for pharmacokinetics (PK) were collected serially over 24 hours from healthy mice administered single doses of Solithromycin (0.625 to 40 mg/kg). Neutropenic CD-1 mice infected with 108 CFUs of one of five S. pneumoniae isolates were administered Solithromycin (0.156 to 160 mg/kg/day) via oral gavage. Doses were administered in a fractionated manner for mice infected with one isolate, while mice infected with the remaining four isolates received Solithromycin as either a regimen every 6 hours or every 12 hours. A three-compartment model best described Solithromycin PK in the plasma and ELF (r2 = 0.935 and 0.831, respectively). The ratio of total-drug ELF to free-drug plasma area under the concentration-time curve (AUC) from time 0 to 24 hours was 2.7. Free-drug plasma and total-drug ELF AUC to minimum inhibitory concentration ratios (AUC/MIC ratios) were most predictive of efficacy (r2 = 0.851 and 0.850, respectively). The magnitude of free-drug plasma/total-drug ELF AUC/MIC ratios associated with net bacterial stasis and a 1- and 2-log10 CFU reduction from baseline was 1.65/1.26, 6.31/15.1, and 12.8/59.8, respectively. These data provided dose selection support for Solithromycin for clinical trials in patients with community-acquired bacterial pneumonia.

  • analyzing the mechanisms behind macrolide antibiotic induced liver injury using quantitative systems toxicology modeling
    Pharmaceutical Research, 2019
    Co-Authors: Jeffrey L Woodhead, Prabhavathi Fernandes, David Oldach, Kyunghee Yang, Chris Maclauchlin, Paul B Watkins, Scott Q Siler, Brett A Howell
    Abstract:

    Macrolide antibiotics are commonly prescribed treatments for drug-resistant bacterial infections; however, many macrolides have been shown to cause liver enzyme elevations and one macrolide, telithromycin, has been pulled from the market by its provider due to liver toxicity. This work seeks to assess the mechanisms responsible for the toxicity of macrolide antibiotics. Five macrolides were assessed in in vitro systems designed to test for bile acid transporter inhibition, mitochondrial dysfunction, and oxidative stress. The macrolides were then represented in DILIsym, a quantitative systems pharmacology (QST) model of drug-induced liver injury, placing the in vitro results in context with each compound’s predicted liver exposure and known biochemistry. DILIsym results suggest that Solithromycin and clarithromycin toxicity is primarily due to inhibition of the mitochondrial electron transport chain (ETC) while erythromycin toxicity is primarily due to bile acid transporter inhibition. Telithromycin and azithromycin toxicity was not predicted by DILIsym and may be caused by mechanisms not currently incorporated into DILIsym or by unknown metabolite effects. The mechanisms responsible for toxicity can be significantly different within a class of drugs, despite the structural similarity among the drugs. QST modeling can provide valuable insight into the nature of these mechanistic differences.

  • the effect of Solithromycin a cationic amphiphilic drug on the proliferation and differentiation of human meibomian gland epithelial cells
    Current Eye Research, 2018
    Co-Authors: Yang Liu, Prabhavathi Fernandes, Wendy R Kam, David A Sullivan
    Abstract:

    Purpose: We previously discovered that azithromycin (AZM) acts directly on immortalized human meibomian gland epithelial cells (IHMGECs) to stimulate their lipid and lysosome accumulation and overa...

  • the Solithromycin journey it is all in the chemistry
    Bioorganic & Medicinal Chemistry, 2016
    Co-Authors: Prabhavathi Fernandes, Evan Martens, Daniel Bertrand, David E Pereira
    Abstract:

    The macrolide class of antibiotics, including the early generation macrolides erythromycin, clarithromycin and azithromycin, have been used broadly for treatment of respiratory tract infections. An increase of treatment failures of early generation macrolides is due to the upturn in bacterial macrolide resistance to 48% in the US and over 80% in Asian countries and has led to the use of alternate therapies, such as fluoroquinolones. The safety of the fluoroquinolones is now in question and alternate antibiotics for the outpatient treatment of community acquired bacterial pneumonia are needed. Telithromycin, approved in 2003, is no longer used owing to serious adverse events, collectively called the 'Ketek effects'. Telithromycin has a side chain pyridine moiety that blocks nicotinic acetylcholine receptors. Blockade of these receptors is known experimentally to cause the side effects seen with telithromycin in patients use. Solithromycin is a new macrolide, the first fluoroketolide, which has been tested successfully in two Phase 3 trials and is undergoing regulatory review at the FDA. Solithromycin is differentiated from telithromycin chemically and biologically in that its side chain is chemically different and does not significantly block nicotinic acetylcholine receptors. Solithromycin was well tolerated and effective in clinical trials.

  • solitaire iv a randomized double blind multicenter study comparing the efficacy and safety of intravenous to oral Solithromycin to intravenous to oral moxifloxacin for treatment of community acquired bacterial pneumonia
    Clinical Infectious Diseases, 2016
    Co-Authors: Thomas M File, Prabhavathi Fernandes, Kara Keedy, Anita F Das, Barbara Rewerska, Violeta Vucinicmihailovic, Joven Gonong, David N Taylor, Amanda Sheets, David Oldach
    Abstract:

    BACKGROUND Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. METHODS A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team [PORT] class II-IV) were randomized 1:1 to receive either intravenous-to-oral Solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of Solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. RESULTS In the ITT population, 79.3% of Solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, -0.46; 95% confidence interval [CI], -6.1 to 5.2). In the micro-ITT population, 80.3% of Solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, -8.1 to 10.6). In the ITT population, 84.6% of Solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the Solithromycin group. Other adverse events were comparable between treatment groups. CONCLUSIONS Intravenous-to-oral Solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. CLINICAL TRIALS REGISTRATION NCT01968733.

Brian Jamieson - One of the best experts on this subject based on the ideXlab platform.

  • metabolism excretion and mass balance of Solithromycin in humans
    Antimicrobial Agents and Chemotherapy, 2018
    Co-Authors: Christopher Maclauchlin, Prabhavathi B Fernandes, Kara Keedy, Stephen E Schneider, Brian Jamieson
    Abstract:

    Solithromycin, a novel macrolide and the first fluoroketolide, is being developed as a therapy for community-acquired bacterial pneumonia, with a distinct mechanism that provides activity against macrolide-resistant bacteria. The pharmacokinetics, metabolism, and excretion of Solithromycin were studied in healthy male subjects after oral administration of a single 800-mg (∼100-μCi) dose of [14C]Solithromycin. Solithromycin was well tolerated, and absorption from the solution occurred with a median time to peak concentration of 4.0 h. Solithromycin and the total radioactivity had similar profiles with no long-lived metabolites. The whole-blood total radioactivity was approximately 75% of the plasma total radioactivity. Recovery was essentially complete (mean, 90.6%), with 76.5% and 14.1% of the dose recovered in feces and urine, respectively. Unchanged Solithromycin (CEM-101) was the predominant circulating radioactive component in plasma (77% of the total radioactivity area under the concentration-time curve [AUC]), with two minor plasma metabolites, CEM-214 and CEM-122 (N-acetyl-CEM-101), each accounting for approximately 5% of the total radioactivity. Urinary excretion was predominantly like that of the parent. Solithromycin was primarily eliminated in the feces after extensive metabolism via a complex metabolic pathway with CEM-262 as the major constituent (27.36% of the administered dose). Overall oxidative pathways, presumably carried out mostly by CYP3A4, represented the majority of the metabolism, with N-acetylation present to a lesser extent. No disproportionate human metabolites were observed.

  • Solithromycin a novel macrolide does not prolong cardiac repolarization a randomized three way crossover study in healthy subjects
    Journal of Antimicrobial Chemotherapy, 2017
    Co-Authors: Borje Darpo, Philip T Sager, Prabhavathi B Fernandes, Brian Jamieson, Kara Keedy, Meijian Zhou, David W Oldach
    Abstract:

    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) μg/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 (ΔQTcF) was similar after dosing with Solithromycin and placebo and the resulting placebo-corrected ΔQTcF (ΔΔQTcF) 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.

  • detection of pneumococcal pneumonia in a phase 3 trial comparing oral Solithromycin versus oral moxifloxacin for treatment of community acquired bacterial pneumonia in adults
    Open Forum Infectious Diseases, 2015
    Co-Authors: Sopio Chochua, Prabhavathi Fernandes, Brian Jamieson, Kara Keedy, David Oldach, Anita F Das, Amanda Sheets, Keith P Klugman, Jorge E Vidal
    Abstract:

    Cempra conducted a randomized, double-blinded Phase 3 trial which evaluated the efficacy and safety of oral Solithromycin (5 days) compared to the oral fluoroquinolone, moxifloxacin (7 days), for the treatment of adult patients with CABP. As pneumococcal vaccines are becoming widely used worldwide, including PCV13 (children) and PPSV23 (adults), this phase 3 trial presented a unique opportunity to further evaluate the overall prevalence of pneumococcal types causing CABP, the correlation between the pneumococcal type isolated from the nasopharynx and those strains isolated from blood or sputum and the use of pneumococcal density in nasopharyngeal specimens for detecting pneumococcal pneumonia.

  • characterization of mycoplasma pneumoniae infection and outcomes in the solitaire oral global phase 3 clinical trial for Solithromycin
    Open Forum Infectious Diseases, 2015
    Co-Authors: David W Oldach, Kay Clark, Brian Jamieson, Kara Keedy, Anita F Das, Amanda Sheets, Analia Mykietiuk, Hristo Metev, Cristina Mihaela Tanaseanu, Donna M Crabb
    Abstract:

    Background: Solithromycin is a 4th generation macrolide antibiotic with potent activity against typical and atypical pathogens that cause community acquired bacterial pneumonia (CABP), including ‘macrolide-resistant’ pneumococci and Mycoplasma pneumoniae (Mpn). In SOLITAIRE-Oral, a global Phase 3 clinical trial, a 5-day course of oral Solithromycin was demonstrated to be non-inferior to a 7-day course of oral moxifloxacin for treatment of community acquired bacterial pneumonia (CABP) among adult patients with PORT II-IV disease.

  • a phase 2 trial of oral Solithromycin 1200 mg or 1000 mg as single dose oral therapy for uncomplicated gonorrhea
    Clinical Infectious Diseases, 2015
    Co-Authors: Edward W Hook, Brian Jamieson, Matthew R Golden, Paula Dixon, Hanne S Harbison, Sylvan Lowens, Prabhavathi Fernandes
    Abstract:

    BACKGROUND: Progressive resistance to antimicrobial agents has reduced options for gonorrhea therapy worldwide. Solithromycin (CEM-101) is a novel oral fluoroketolide antimicrobial with substantial in vitro activity against Neisseria gonorrhoeae. METHODS: We conducted a phase 2 trial of 2 oral doses of Solithromycin (1200 and 1000 mg) for treatment of uncomplicated gonorrhea. RESULTS: A total of 59 participants were enrolled and treated in this trial; 28 participants received 1200 mg of Solithromycin and 31 received 1000 mg. Forty-six (78%) participants had positive cultures for N. gonorrhoeae at the time of enrollment: 24 of the 28 persons (86%) who received 1200 mg of oral Solithromycin, and 22 of 31 (71%) who received 1000 mg. In addition, 8 participants had positive pharyngeal gonococcal cultures, and 4 had positive rectal cultures. All patients with positive cultures for N. gonorrhoeae were cured at all sites of infection. Chlamydia trachomatis and Mycoplasma genitalium coinfections were evaluated using nucleic acid amplification tests and were negative at 1 week of follow-up in 9 of 11 (82%) participants positive for C. trachomatis and 7 of 10 (70%) participants positive for M. genitalium. Mild dose-related gastrointestinal side effects (nausea, loose stools, vomiting) were common but did not limit therapy. CONCLUSIONS: Oral single-dose Solithromycin, in doses of 1000 mg and 1200 mg, was 100% effective for treatment of culture-proven gonorrhea at genital, oral, and rectal sites of infection and is a promising new agent for gonorrhea treatment. CLINICAL TRIALS REGISTRATION: NCT01591447.

Zhiwei Lin - One of the best experts on this subject based on the ideXlab platform.

  • staphylococcus aureus with an erm mediated constitutive macrolide lincosamide streptogramin b resistance phenotype has reduced susceptibility to the new ketolide Solithromycin
    BMC Infectious Diseases, 2019
    Co-Authors: Weiming Yao, Bing Bai, Hongyan Wang, Hang Cheng, Jinxin Zheng, Xiang Sun, Zhiwei Lin, Qiwen Deng
    Abstract:

    Solithromycin, the fourth generation of ketolides, has been demonstrated potent antibacterial effect against commonly-isolated gram-positive strains. However, Staphylococcus aureus (S. aureus) strains with a higher Solithromycin MIC have already been emerged, the mechanism of which is unknown. Antimicrobial susceptibility test was performed on 266 strains of S. aureus. The antibiotic resistance phenotype of erm-positive strain was determined by D-zone test. Spontaneous mutation frequency analysis was performed to compare the risk levels for Solithromycin resistance among different strains. Efflux pumps and mutational analysis of ribosomal fragments as well as erm(B) gene domains were detected. Quantitative reverse transcription polymerase chain reaction was conducted to compare the transcriptional expression of the erm gene between the constitutive macrolide-lincosamide-streptogramin B (cMLSB)- and inducible MLSB (iMLSB)-phenotypes. In the erm-positive S. aureus strains, the minimum inhibitory concentration (MIC)50/90 of Solithromycin (2/> 16 mg/L) was significantly higher than that in the erm-negative strains (0.125/0.25 mg/L). Of note, the MIC50 value of the strains with iMLSB (0.25 mg/L) was significantly lower than that of the strains with cMLSB (4 mg/L). A comparison among strains demonstrated that the median mutational frequency in isolates with cMLSB (> 1.2 × 10− 4) was approximately > 57-fold and > 3333-fold higher than that in iMLSB strains (2.1 × 10− 6) and in erythromycin-sensitive strains (3.6 × 10− 8), respectively. The differential antibiotic in vitro activity against strains between cMLSB and iMLSB could not be explained by efflux pump carriers or genetic mutations in the test genes. The expression of the erm genes in strains with cMLSB did not differ from that in strains with iMLSB. The reduced susceptibility to Solithromycin by S. aureus was associated with the cMLSB resistance phenotype mediated by erm.

  • Additional file 1: of Staphylococcus aureus with an erm-mediated constitutive macrolide-lincosamide-streptogramin B resistance phenotype has reduced susceptibility to the new ketolide, Solithromycin
    2019
    Co-Authors: Weiming Yao, Bing Bai, Hongyan Wang, Hang Cheng, Jinxin Zheng, Xiang Sun, Zhiwei Lin, Qiwen Deng
    Abstract:

    Table S1. Primers used to amplify, sequence and quantify S. aureus efflux pumps, 23 s rRNA, ribosomal proteins and erm genes throughout the whole study. Table S2. Antibacterial activity of Solithromycin against S. aureus strains appeared on Solithromycin containing at 2 times the MIC plates. (DOC 61 kb

  • Staphylococcus aureus with an erm-mediated constitutive macrolide-lincosamide-streptogramin B resistance phenotype has reduced susceptibility to the new ketolide, Solithromycin
    'Springer Science and Business Media LLC', 2019
    Co-Authors: Weiming Yao, Bing Bai, Hongyan Wang, Hang Cheng, Jinxin Zheng, Xiang Sun, Zhiwei Lin, Qiwen Deng
    Abstract:

    Abstract Background Solithromycin, the fourth generation of ketolides, has been demonstrated potent antibacterial effect against commonly-isolated gram-positive strains. However, Staphylococcus aureus (S. aureus) strains with a higher Solithromycin MIC have already been emerged, the mechanism of which is unknown. Methods Antimicrobial susceptibility test was performed on 266 strains of S. aureus. The antibiotic resistance phenotype of erm-positive strain was determined by D-zone test. Spontaneous mutation frequency analysis was performed to compare the risk levels for Solithromycin resistance among different strains. Efflux pumps and mutational analysis of ribosomal fragments as well as erm(B) gene domains were detected. Quantitative reverse transcription polymerase chain reaction was conducted to compare the transcriptional expression of the erm gene between the constitutive macrolide-lincosamide-streptogramin B (cMLSB)- and inducible MLSB (iMLSB)-phenotypes. Results In the erm-positive S. aureus strains, the minimum inhibitory concentration (MIC)50/90 of Solithromycin (2/> 16 mg/L) was significantly higher than that in the erm-negative strains (0.125/0.25 mg/L). Of note, the MIC50 value of the strains with iMLSB (0.25 mg/L) was significantly lower than that of the strains with cMLSB (4 mg/L). A comparison among strains demonstrated that the median mutational frequency in isolates with cMLSB (> 1.2 × 10− 4) was approximately > 57-fold and > 3333-fold higher than that in iMLSB strains (2.1 × 10− 6) and in erythromycin-sensitive strains (3.6 × 10− 8), respectively. The differential antibiotic in vitro activity against strains between cMLSB and iMLSB could not be explained by efflux pump carriers or genetic mutations in the test genes. The expression of the erm genes in strains with cMLSB did not differ from that in strains with iMLSB. Conclusions The reduced susceptibility to Solithromycin by S. aureus was associated with the cMLSB resistance phenotype mediated by erm

  • in vitro induced erythromycin resistance facilitates cross resistance to the novel fluoroketolide Solithromycin in staphylococcus aureus
    Fems Microbiology Letters, 2018
    Co-Authors: Weiming Yao, Bing Bai, Hongyan Wang, Jinxin Zheng, Zhiwei Lin, Minggui Deng, Xiangbin Deng, Xiaojun Liu
    Abstract:

    The aim of this study was to determine whether in vitro induced erythromycin resistance facilitates the cross-resistance to the novel fluoroketolide, Solithromycin, in Staphylococcus aureus. Four strains of methicillin-susceptible S. aureus strains S2, S3, S5 and S7 were successfully induced to establish erythromycin-resistant strains by continuous in vitro culture with erythromycin. Mutations at drug binding sites were shown to increase the minimal inhibitory concentrations for ketolides, including telithromycin and the novel compound Solithromycin, but did not increase for lincosamides, chloramphenicols or oxazolidinones. In S2-, S5- and S7-derived strains, L22 protein mutations occurred first, resulting in a low level of cross-resistance to ketolides (≤4 μg/mL). The L4 protein mutations were dependent on the L22 protein, resulting in high-level cross-resistance to ketolides (≥8 μg/mL). In S3-derived strains, high levels of cross-resistance occurred concurrently in the 23S rRNA domains II/V and the L22 protein. Hence, long-term exposure of erythromycin results in resistance to ketolides in S. aureus through drug binding site mutations. These results demonstrate that since erythromycin has been used clinically for a long time, it is necessary to carefully evaluate the rewards and risks when prescribing Solithromycin for the treatment of infectious diseases.

David Oldach - One of the best experts on this subject based on the ideXlab platform.

  • analyzing the mechanisms behind macrolide antibiotic induced liver injury using quantitative systems toxicology modeling
    Pharmaceutical Research, 2019
    Co-Authors: Jeffrey L Woodhead, Prabhavathi Fernandes, David Oldach, Kyunghee Yang, Chris Maclauchlin, Paul B Watkins, Scott Q Siler, Brett A Howell
    Abstract:

    Macrolide antibiotics are commonly prescribed treatments for drug-resistant bacterial infections; however, many macrolides have been shown to cause liver enzyme elevations and one macrolide, telithromycin, has been pulled from the market by its provider due to liver toxicity. This work seeks to assess the mechanisms responsible for the toxicity of macrolide antibiotics. Five macrolides were assessed in in vitro systems designed to test for bile acid transporter inhibition, mitochondrial dysfunction, and oxidative stress. The macrolides were then represented in DILIsym, a quantitative systems pharmacology (QST) model of drug-induced liver injury, placing the in vitro results in context with each compound’s predicted liver exposure and known biochemistry. DILIsym results suggest that Solithromycin and clarithromycin toxicity is primarily due to inhibition of the mitochondrial electron transport chain (ETC) while erythromycin toxicity is primarily due to bile acid transporter inhibition. Telithromycin and azithromycin toxicity was not predicted by DILIsym and may be caused by mechanisms not currently incorporated into DILIsym or by unknown metabolite effects. The mechanisms responsible for toxicity can be significantly different within a class of drugs, despite the structural similarity among the drugs. QST modeling can provide valuable insight into the nature of these mechanistic differences.

  • solitaire iv a randomized double blind multicenter study comparing the efficacy and safety of intravenous to oral Solithromycin to intravenous to oral moxifloxacin for treatment of community acquired bacterial pneumonia
    Clinical Infectious Diseases, 2016
    Co-Authors: Thomas M File, Prabhavathi Fernandes, Kara Keedy, Anita F Das, Barbara Rewerska, Violeta Vucinicmihailovic, Joven Gonong, David N Taylor, Amanda Sheets, David Oldach
    Abstract:

    BACKGROUND Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. METHODS A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team [PORT] class II-IV) were randomized 1:1 to receive either intravenous-to-oral Solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of Solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. RESULTS In the ITT population, 79.3% of Solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, -0.46; 95% confidence interval [CI], -6.1 to 5.2). In the micro-ITT population, 80.3% of Solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, -8.1 to 10.6). In the ITT population, 84.6% of Solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the Solithromycin group. Other adverse events were comparable between treatment groups. CONCLUSIONS Intravenous-to-oral Solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. CLINICAL TRIALS REGISTRATION NCT01968733.

  • detection of pneumococcal pneumonia in a phase 3 trial comparing oral Solithromycin versus oral moxifloxacin for treatment of community acquired bacterial pneumonia in adults
    Open Forum Infectious Diseases, 2015
    Co-Authors: Sopio Chochua, Prabhavathi Fernandes, Brian Jamieson, Kara Keedy, David Oldach, Anita F Das, Amanda Sheets, Keith P Klugman, Jorge E Vidal
    Abstract:

    Cempra conducted a randomized, double-blinded Phase 3 trial which evaluated the efficacy and safety of oral Solithromycin (5 days) compared to the oral fluoroquinolone, moxifloxacin (7 days), for the treatment of adult patients with CABP. As pneumococcal vaccines are becoming widely used worldwide, including PCV13 (children) and PPSV23 (adults), this phase 3 trial presented a unique opportunity to further evaluate the overall prevalence of pneumococcal types causing CABP, the correlation between the pneumococcal type isolated from the nasopharynx and those strains isolated from blood or sputum and the use of pneumococcal density in nasopharyngeal specimens for detecting pneumococcal pneumonia.

  • late breaking abstract oral Solithromycin has a favorable profile versus oral moxifloxacin for treatment of adult community acquired pneumonia cabp in elderly patients and those with copd or asthma
    European Respiratory Journal, 2015
    Co-Authors: David Oldach, Kara Keedy, Anita F Das, Carlos Barrera, Ismail Mitha, Cristina Mihaela Tanaseanu, Carlos M Luna, Peter Szabo, Alexis Doreski, Brian Jamieson
    Abstract:

    Rationale & Methods: Advanced age and underlying lung disease are risk factors for CABP morbidity. We evaluated a 4 th generation macrolide antibiotic, Solithromycin (S), vs Moxifloxacin (M) in a global, P3, DB-RCT for CABP of PORT II-IV severity. Outcomes included clinical improvement at 72 hours (early clinical response or ECR) and success at short term follow up visit (SFU), 5-10 days after last dose of study drug. Results: 860 CABP patients from 16 countries were randomized 1:1 to receive oral S or M. Mean age was 58.5 years (S) versus 56.7 years (M). 50.7% of S patients had PORT III/IV CABP (11.3%, PORT IV) vs. 48.6% of M patients (8.8% PORT IV). S was non-inferior to M in ECR and SFU success rates (%) in the ITT population (78.2 vs 77.9 and 84.5 vs 86.6, respectively). Among patients ≥ age 75, ECR and SFU success rates (%) (83.9 vs 69.8 and 85.5 vs 84.1, respectively) favored S. Among patients with history of COPD or asthma, ECR (71.0 vs 67.2) and SFU (91.9 vs 85.9) success rates (%) also favored S. S demonstrated comparable safety to M in the occurrence of adverse events (AEs) (36.6% vs 35.6%), study drug related AEs (10.1% vs 12.5%), Serious Adverse Events (6.6% vs 6.3%) (none attributed to study drug) and deaths (1.4% vs 1.4%). Two episodes of C. difficile diarrhea were detected, both among M recipients. Conclusions: Oral S was non-inferior to oral M for treatment of CABP. Strikingly, S demonstrated greatest efficacy relative to M in the elderly and among patients with history of COPD or asthma. A global P3 CABP trial evaluating IV-to-Oral Solithromycin versus moxifloxacin is ongoing.

  • randomized double blind multicenter phase 2 study comparing the efficacy and safety of oral Solithromycin cem 101 to those of oral levofloxacin in the treatment of patients with community acquired bacterial pneumonia
    Antimicrobial Agents and Chemotherapy, 2013
    Co-Authors: David Oldach, Kay Clark, Brian Jamieson, Jennifer Schranz, Anita F Das, Carl J Craft, Drusilla Scott, Prabhavathi Fernandes
    Abstract:

    Solithromycin, a new macrolide, and the first fluoroketolide in clinical development, with activity against macrolide-resistant bacteria, was tested in 132 patients with moderate to moderately severe community-acquired bacterial pneumonia (CABP) in a multicenter, double-blind, randomized phase 2 study. Patients were enrolled and randomized (1:1) to either 800 mg Solithromycin orally (PO) on day 1, followed by 400 mg PO daily on days 2 to 5, or 750 mg levofloxacin PO daily on days 1 to 5. Efficacy outcome rates of clinical success at the test-of-cure visit 4 to 11 days after the last dose of study drug were comparable in the intent-to-treat (ITT) (84.6% for Solithromycin versus 86.6% for levofloxacin) and microbiological-intent-to-treat (micro-ITT) (77.8% for Solithromycin versus 71.4% for levofloxacin) populations. Early response success rates at day 3, defined as improvement in at least two cardinal symptoms of pneumonia, were also comparable (72.3% for Solithromycin versus 71.6% for levofloxacin). More patients treated with levofloxacin than with Solithromycin experienced treatment-emergent adverse events (TEAEs) during the study (45.6% versus 29.7%). The majority of TEAEs were mild or moderate gastrointestinal symptoms and included nausea (1.6% for Solithromycin; 10.3% for levofloxacin), diarrhea (7.8% for Solithromycin; 5.9% for levofloxacin), and vomiting (0% for Solithromycin; 4.4% for levofloxacin). Six patients, all of whom received levofloxacin, discontinued the study drug due to an adverse event. Solithromycin demonstrated comparable efficacy and favorable safety relative to levofloxacin. These findings support a phase 3 study of Solithromycin for the treatment of CABP. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168713.).

Kara Keedy - One of the best experts on this subject based on the ideXlab platform.

  • metabolism excretion and mass balance of Solithromycin in humans
    Antimicrobial Agents and Chemotherapy, 2018
    Co-Authors: Christopher Maclauchlin, Prabhavathi B Fernandes, Kara Keedy, Stephen E Schneider, Brian Jamieson
    Abstract:

    Solithromycin, a novel macrolide and the first fluoroketolide, is being developed as a therapy for community-acquired bacterial pneumonia, with a distinct mechanism that provides activity against macrolide-resistant bacteria. The pharmacokinetics, metabolism, and excretion of Solithromycin were studied in healthy male subjects after oral administration of a single 800-mg (∼100-μCi) dose of [14C]Solithromycin. Solithromycin was well tolerated, and absorption from the solution occurred with a median time to peak concentration of 4.0 h. Solithromycin and the total radioactivity had similar profiles with no long-lived metabolites. The whole-blood total radioactivity was approximately 75% of the plasma total radioactivity. Recovery was essentially complete (mean, 90.6%), with 76.5% and 14.1% of the dose recovered in feces and urine, respectively. Unchanged Solithromycin (CEM-101) was the predominant circulating radioactive component in plasma (77% of the total radioactivity area under the concentration-time curve [AUC]), with two minor plasma metabolites, CEM-214 and CEM-122 (N-acetyl-CEM-101), each accounting for approximately 5% of the total radioactivity. Urinary excretion was predominantly like that of the parent. Solithromycin was primarily eliminated in the feces after extensive metabolism via a complex metabolic pathway with CEM-262 as the major constituent (27.36% of the administered dose). Overall oxidative pathways, presumably carried out mostly by CYP3A4, represented the majority of the metabolism, with N-acetylation present to a lesser extent. No disproportionate human metabolites were observed.

  • surveillance of the activity of Solithromycin cem 101 against bacteria from respiratory tract infections
    International Journal of Antimicrobial Agents, 2017
    Co-Authors: Stephen Hawser, Kara Keedy, Ian Morrissey, Barbara Lemos, Prabhavathi B Fernandes
    Abstract:

    Abstract The activity of Solithromycin, a fourth-generation macrolide and novel fluoroketolide, was evaluated by determining its minimum inhibitory concentration (MIC) (via Clinical and Laboratory Standards Institute broth microdilution) against 2797 contemporary clinical respiratory tract isolates collected from North America, Europe, Asia-Pacific and other regions of the world in 2012–13. Solithromycin was very active against Streptococcus pneumoniae and Streptococcus pyogenes , with MIC 90 of 0.25 and 0.12 µg/mL, respectively. Isolates with combined macrolide resistance genes ermB and mefE had a higher Solithromycin MIC distribution, but the highest MIC recorded was 1 µg/mL for one S. pneumoniae isolate from Japan and one S. pyogenes isolate from China. Solithromycin was active against methicillin-susceptible Staphylococcus aureus (MIC 90 0.12 µg/mL) but not against methicillin-resistant S. aureus (MRSA) (MIC 90 >32 µg/mL). However, MRSA strains most commonly observed with community-associated infections (i.e. SCC mec IV) were more susceptible than other MRSA SCC mec types. Gram-negative pathogens that cause community-acquired respiratory tract infections ( Haemophilus influenzae and Moraxella catarrhalis ) were inhibited by Solithromycin isolated from worldwide locations (MIC 90 2 and 0.25 µg/mL, respectively). These data support the continued development of Solithromycin for the treatment of community-acquired pneumonia globally.

  • Solithromycin a novel macrolide does not prolong cardiac repolarization a randomized three way crossover study in healthy subjects
    Journal of Antimicrobial Chemotherapy, 2017
    Co-Authors: Borje Darpo, Philip T Sager, Prabhavathi B Fernandes, Brian Jamieson, Kara Keedy, Meijian Zhou, David W Oldach
    Abstract:

    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) μg/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 (ΔQTcF) was similar after dosing with Solithromycin and placebo and the resulting placebo-corrected ΔQTcF (ΔΔQTcF) 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.

  • solitaire iv a randomized double blind multicenter study comparing the efficacy and safety of intravenous to oral Solithromycin to intravenous to oral moxifloxacin for treatment of community acquired bacterial pneumonia
    Clinical Infectious Diseases, 2016
    Co-Authors: Thomas M File, Prabhavathi Fernandes, Kara Keedy, Anita F Das, Barbara Rewerska, Violeta Vucinicmihailovic, Joven Gonong, David N Taylor, Amanda Sheets, David Oldach
    Abstract:

    BACKGROUND Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. METHODS A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team [PORT] class II-IV) were randomized 1:1 to receive either intravenous-to-oral Solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of Solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. RESULTS In the ITT population, 79.3% of Solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, -0.46; 95% confidence interval [CI], -6.1 to 5.2). In the micro-ITT population, 80.3% of Solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, -8.1 to 10.6). In the ITT population, 84.6% of Solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the Solithromycin group. Other adverse events were comparable between treatment groups. CONCLUSIONS Intravenous-to-oral Solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. CLINICAL TRIALS REGISTRATION NCT01968733.

  • detection of pneumococcal pneumonia in a phase 3 trial comparing oral Solithromycin versus oral moxifloxacin for treatment of community acquired bacterial pneumonia in adults
    Open Forum Infectious Diseases, 2015
    Co-Authors: Sopio Chochua, Prabhavathi Fernandes, Brian Jamieson, Kara Keedy, David Oldach, Anita F Das, Amanda Sheets, Keith P Klugman, Jorge E Vidal
    Abstract:

    Cempra conducted a randomized, double-blinded Phase 3 trial which evaluated the efficacy and safety of oral Solithromycin (5 days) compared to the oral fluoroquinolone, moxifloxacin (7 days), for the treatment of adult patients with CABP. As pneumococcal vaccines are becoming widely used worldwide, including PCV13 (children) and PPSV23 (adults), this phase 3 trial presented a unique opportunity to further evaluate the overall prevalence of pneumococcal types causing CABP, the correlation between the pneumococcal type isolated from the nasopharynx and those strains isolated from blood or sputum and the use of pneumococcal density in nasopharyngeal specimens for detecting pneumococcal pneumonia.