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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Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743–800.
The top 10 causes of death (fact sheet N°310) [Internet]: World Health Organization [updated May 2014; cited 2016 May 13]. http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed 10 May.
Van Bambeke F, Tulkens PM. The role of solithromycin in the management of bacterial community-acquired pneumonia. Expert Rev Anti Infect Ther. 2013;14(3):311–24.
Prina E, Ranzani OT, Torres A. Community-acquired pneumonia. Lancet. 2015;386(9998):1097–108.
Zhanel GG, Walters M, Noreddin A, Vercaigne LM, Wierzbowski A, Embil JM, et al. The ketolides: a critical review. Drugs. 2002;62(12):1771–804.
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;1(44 Suppl 2):S27–72.
Zhanel GG, Dueck M, Hoban DJ, Vercaigne LM, Embil JM, Gin AS, et al. Review of macrolides and ketolides: focus on respiratory tract infections. Drugs. 2001;61(4):443–98.
Brinker AD, Wassel RT, Lyndly J, Serrano J, Avigan M, Lee WM, et al. Telithromycin-associated hepatotoxicity: clinical spectrum and causality assessment of 42 cases. Hepatology. 2009;49(1):250–7.
Telithromycin (marketed as Ketek) Information [Internet].: U.S. Food and Drug Administration [updated 03/17/2016; cited 2016 May 25]. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm107824.htm. Accessed 15 May.
European Medicines Agency recommends restricted use and strengthened warnings for Ketek [Internet]. [updated 2007 Mar 30; cited 2016 May 25]. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2009/11/news_detail_000146.jsp&mid=WC0b01ac058004d5c1. Accessed 16 May.
Farrell DJ, Flamm RK, Sader HS, Jones RN. Results from the Solithromycin International Surveillance Program (2014). Antimicrob Agents Chemother. 2016;60(6):3662–8.
Bertrand D, Bertrand S, Neveu E, Fernandes P. Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors. Antimicrob Agents Chemother. 2010;54(12):5399–402.
Fernandes P, Martens E, Bertrand D, Pereira D. The solithromycin journey-it is all in the chemistry. Bioorg Med Chem. 2016. doi:10.1016/j.bmc.2016.08.035.
Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JH, et al. Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis. Antimicrob Agents Chemother. 2010;54(12):4961–70.
Van Bambeke F. Renaissance of antibiotics against difficult infections: focus on oritavancin and new ketolides and quinolones. Ann Med. 2014;46(7):512–29.
Sutcliffe JA. Antibiotics in development targeting protein synthesis. Ann N Y Acad Sci. 2011;1241:122–52.
Denis A, Bretin F, Fromentin C, Bonnet A, Piltan G, Bonnefoy A, et al. Beta-keto-ester chemistry and ketolides. Synthesis and antibacterial activity of 2-halogeno, 2-methyl and 2,3 enol-ether ketolides. Bioorg Med Chem Lett. 2000;10(17):2019–22.
Kannan K, Mankin AS. Macrolide antibiotics in the ribosome exit tunnel: species-specific binding and action. Ann N Y Acad Sci. 2011;1241:33–47.
Sothiselvam S, Liu B, Han W, Ramu H, Klepacki D, Atkinson GC, et al. Macrolide antibiotics allosterically predispose the ribosome for translation arrest. Proc Natl Acad Sci USA. 2014;111(27):9804–9.
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):1632–7.
Gupta P, Kannan K, Mankin AS, Vazquez-Laslop N. Regulation of gene expression by macrolide-induced ribosomal frameshifting. Mol Cell. 2013;52(5):629–42.
Lemaire S, Van Bambeke F, Tulkens PM. Cellular accumulation and pharmacodynamic evaluation of the intracellular activity of CEM-101, a novel fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in human THP-1 macrophages. Antimicrob Agents Chemother. 2009;53(9):3734–43.
Rodvold KA, Gotfried MH, Still JG, Clark K, Fernandes P. Comparison of plasma, epithelial lining fluid, and alveolar macrophage concentrations of solithromycin (CEM-101) in healthy adult subjects. Antimicrob Agents Chemother. 2012;56(10):5076–81.
Kobayashi Y, Wada H, Rossios C, Takagi D, Higaki M, Mikura S, et al. A novel macrolide solithromycin exerts superior anti-inflammatory effect via NF-kappaB inhibition. J Pharmacol Exp Ther. 2013;345(1):76–84.
Kobayashi Y, Wada H, Rossios C, Takagi D, Charron C, Barnes PJ, et al. A novel macrolide/fluoroketolide, solithromycin (CEM-101), reverses corticosteroid insensitivity via phosphoinositide 3-kinase pathway inhibition. Br J Pharmacol. 2013;169(5):1024–34.
Morrissey I, Fernandes P, Lemos B, Hawser S. Activity of solithromycin against azithromycin-resistant Streptococcus pneumoniae with characterized resistance mechanisms [abstract no. P1585 plus poster]. In: 24th European Congress of Clinical Microbiology and Infectious Diseases; 2014; Spain.
McGhee P, Clark C, Kosowska-Shick KM, Nagai K, Dewasse B, Beachel L, et al. In vitro activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with defined macrolide resistance mechanisms. Antimicrob Agents Chemother. 2010;54(1):230–8.
Magnet S, Morrissey I, Fernandes P, Keedy K, Hawser S. Assessment of the bactericidal activity of solithromycin (CEM-101) against Streptococcus pneumoniae with known macrolide resistance mechanism and serotype [abstract no. C-550 plus poster]. In: 55th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2015; San Diego.
Farrell DJ, Sader HS, Castanheira M, Biedenbach DJ, Rhomberg PR, Jones RN. Antimicrobial characterisation of CEM-101 activity against respiratory tract pathogens, including multidrug-resistant pneumococcal serogroup 19A isolates. Int J Antimicrob Agents. 2010;35(6):537–43.
Putnam SD, Sader HS, Farrell DJ, Biedenbach DJ, Castanheira M. Antimicrobial characterisation of solithromycin (CEM-101), a novel fluoroketolide: activity against staphylococci and enterococci. Int J Antimicrob Agents. 2011;37(1):39–45.
Tristram S, Jacobs MR, Appelbaum PC. Antimicrobial resistance in Haemophilus influenzae. Clin Microbiol Rev. 2007;20(2):368–89.
Woosley LN, Castanheira M, Jones RN. CEM-101 activity against Gram-positive organisms. Antimicrob Agents Chemother. 2010;54(5):2182–7.
Vandevelde NM, Tulkens PM, Diaz Iglesias Y, Verhaegen J, Rodriguez-Villalobos H, Philippart I, et al. Characterisation of a collection of Streptococcus pneumoniae isolates from patients suffering from acute exacerbations of chronic bronchitis: in vitro susceptibility to antibiotics and biofilm formation in relation to antibiotic efflux and serotypes/serogroups. Int J Antimicrob Agents. 2014;44(3):209–17.
Farrell DJ, Mendes RE, Jones RN. Antimicrobial activity of solithromycin against serotyped macrolide-resistant Streptococcus pneumoniae isolates collected from U.S. medical centers in 2012. Antimicrob Agents Chemother. 2015;59(4):2432–4.
Farrell DJ, Castanheira M, Sader HS, Jones RN. The in vitro evaluation of solithromycin (CEM-101) against pathogens isolated in the United States and Europe (2009). J Infect. 2010;61(6):476–83.
Piccinelli G, Fernandes P, Bonfanti C, Caccuri F, Caruso A, De Francesco MA. In vitro activity of solithromycin against erythromycin-resistant Streptococcus agalactiae. Antimicrob Agents Chemother. 2014;58(3):1693–8.
Putnam SD, Castanheira M, Moet GJ, Farrell DJ, Jones RN. 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.
Morrissey I, Fernandes P, Lemos B, Hawser S. Prevalence of SCCmec types and solithromycin susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) from respiratory samples colleted in 2012–2013 [abstract no. P1583 plus poster]. In: 24th European Congress of Clinical Microbiology and Infectious Diseases; 2014; Spain.
Keedy K, Jamieson B, Nitu M, Flores J, Rewerska B, Tanaseanu C, et al. Microbial characterization using multiple diagnostic methods in the first oral phase 3 community-acquired bacterial pneumonia (CABP) trial with solithromycin [abstract no. P1337 plus poster]. In: 26th European Congress of Clinical Microbiology and Infectious Diseases; 2016; Netherlands.
Tulkens PM, Van Bambeke F, Vandevelde NM, Vanhoof R, Van der Linden M. In vitro susceptibility of S. pneumoniae to solithromycin (SOL) in collections with an elevated proportion of isolates resistant to levofloxacin (LVX) and moxifloxacin (MXF) [abstract no. EV0153 plus poster]. In: 25th European Congress of Clinical Microbiology and Infectious Diseases; 2015; Denmark.
Morrissey I, Fernandes P, Keedy K, Lemos B, Hawser S. Activity of solithromycin and comparators against Streptococcus pneumoniae isolated from respiratory samples collected from pediatric, adult and elderly patients in 2012-2103 [abstract no. C1473 plus poster]. In: 54th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2014; Washington, D.C.
Biedenbach DJ, Castanheira M, Jones RN. Determination of CEM-101 activity tested against clinical isolates of Neisseria meningitidis from a worldwide collection. Antimicrob Agents Chemother. 2010;54(9):4009–11.
Hardy D, Pelton SI, Figueira M, Keedy K, Fernandes P, Vicino D. MICs and MBCs of solithromycin for non-typeable and typeable Haemophilus influenzae [abstract no. D-187 plus poster]. In: 55th Interscience Conference of Antimicrobial Agents and Chemotherapy; 2015; San Diego.
Soge O, Keedy K, Barbee LA, Kono CR, Fernandes P, Golden MR. In vitro activity of the combination of solithromycin and cephalosporins against Neisseria gonorrhoeae [abstract no. D-1123 plus poster]. In: 55th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2015; San Diego.
Weintraub A, Rashid M, Nord C. In-vitro activity of solithromycin against anaerobic bacteria in the normal intestinal microbiota [abstract no. P1335 plus poster]. In: 26th European Congress of Clinical Microbiology and Infectious Diseases; 2016; Netherlands.
Hardy D, Vicino D, Keedy K, Fernandes P. Susceptibility of Gardnerella vaginalis to solithromycin (CEM-101) [abstract no. F1616 plus poster]. In: 54th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2014; Washington, D.C.
Roblin PM, Kohlhoff SA, Parker C, Hammerschlag MR. In vitro activity of CEM-101, a new fluoroketolide antibiotic, against Chlamydia trachomatis and Chlamydia (Chlamydophila) pneumoniae. Antimicrob Agents Chemother. 2010;54(3):1358–9.
Waites KB, Crabb DM, Duffy LB. Comparative in vitro susceptibilities of human mycoplasmas and ureaplasmas to a new investigational ketolide, CEM-101. Antimicrob Agents Chemother. 2009;53(5):2139–41.
Mallegol J, Fernandes P, Melano RG, Guyard C. Antimicrobial activity of solithromycin against clinical isolates of Legionella pneumophila serogroup 1. Antimicrob Agents Chemother. 2014;58(2):909–15.
Zhanel GG, Adam HJ, Baxter MR, Fuller J, Nichol KA, Denisuik AJ, et al. Antimicrobial susceptibility of 22746 pathogens from Canadian hospitals: results of the CANWARD 2007-11 study. J Antimicrob Chemother. 2013;68(Suppl 1):i7–22.
File TM Jr, Rewerska B, Vucinic-Mihailovic V, Gonong JRV, Das AF, Keedy K, et al. SOLITAIRE-IV: a randomized, double-blind, multi-center study comparing the efficacy and safety of intravenous-to-oral solithromycin to intravenous-to-oral moxifloxacin for treatment of community-acquired bacterial pneumonia. Clin Infect Dis. 2016;63(8):1007–16.
Golparian D, Fernandes P, Ohnishi M, Jensen JS, Unemo M. In vitro activity of the new fluoroketolide solithromycin (CEM-101) against a large collection of clinical Neisseria gonorrhoeae isolates and international reference strains, including those with high-level antimicrobial resistance: potential treatment option for gonorrhea? Antimicrob Agents Chemother. 2012;56(5):2739–42.
Still JG, Schranz J, Degenhardt TP, Scott D, Fernandes P, Gutierrez MJ, et al. Pharmacokinetics of solithromycin (CEM-101) after single or multiple oral doses and effects of food on single-dose bioavailability in healthy adult subjects. Antimicrob Agents Chemother. 2011;55(5):1997–2003.
Schranz J, Clark K, Degenhardt T, Scott D, Fernandes P, Still JG, et al. Phase 1 pharmacokinetic and safety of multiple doses and effects of food on the bioavailability of oral solithromycin (CEM-101) in healthy adults [abstract no. A1-689 plus poster]. In: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2010; Boston.
Still JG, Clark K, Degenhardt TP, Scott D, Fernandes P, Gutierrez MJ. Single oral dose pharmacokinetics and safety of CEM-101 in healthy subjects [abstract no. F1-3972a plus poster]. In: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th annual meeting; 2008; Washington, DC.
Gonzalez D, Palazzi DL, Bhattacharya-Mithal L, Al-Uzri A, James LP, Bradley J, et al. Solithromycin pharmacokinetics in plasma and dried blood spots and safety in adolescents. Antimicrob Agents Chemother. 2016;60(4):2572–6.
Gonzalez D, Palazzi D, Bhattacharya-Mithal L, Al-Uzri A, James L, Bradley J, et al. Pharmacokinetics and safety of solithromycin in adolescents with suspected or confirmed bacterial infection [abstract and poster]. In: Pediatric Academic Societies annual meeting; 2015; San Diego.
Jamieson BD, Ciric S, Fernandes P. Safety and pharmacokinetics of solithromycin in subjects with hepatic impairment. Antimicrob Agents Chemother. 2015;59(8):4379–86.
Jamieson B, Ciric S, Rosiak C, Fernandes P. Safety and pharmacokinetics of solithromycin in subjects with hepatic impairment [abstract no. P-1686 plus poster]. In: 24th European Congress of Clinical Microbiology and Infectious Diseases; 2014; Spain.
Zithromax product monograph [Internet].: Pfizer [updated 2014 Jul 2; cited 2015 Jul 14]. http://www.pfizer.ca/sites/g/files/g10017036/f/201411/Zithromax.pdf. Accessed 30 June.
Lexicomp Online. Azithromycin (pharmacodynamics/kinetics) [Internet].: Wolters Kluwer; 2016 [cited 2016 Aug 3]. online.lexi.com. Accessed 10 July.
Amsden GW, Nafziger AN, Foulds G. Pharmacokinetics in serum and leukocyte exposures of oral azithromycin, 1,500 milligrams, given over a 3- or 5-day period in healthy subjects. Antimicrob Agents Chemother. 1999;43(1):163–5.
Biaxin product monograph [Internet].: Abbott [updated 2015 Apr 9; cited 2016 Jul 14]. http://www.abbott.ca/docs/BIAXIN-PM-E.pdf. Accessed 30 June.
Rodvold KA. Clinical pharmacokinetics of clarithromycin. Clin Pharmacokinet. 1999;37(5):385–98.
Lexicomp Online. Clarithromycin (pharmacodynamics/kinetics) [Internet].: Wolters Kluwer; 2016 [cited 2016 Aug 3]. online.lexi.com. Accessed 10 July.
Okusanya OO, Bhavnani SM, Forrest A, Bulik CC, Jamieson B, Oldach D, et al. Population pharmacokinetic and pharmacokinetic-pharmacodynamic target attainment analysis for solithromycin to support intravenous dose selection in patients [abstract no. A1269 plus poster]. In: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2012; San Francisco.
Ciric S, Dunnington K, Gartner MR, Hernandez R, Fernandes P. Assessment of a pharmacokinetic drug interaction between solithromycin and digoxin [abstract no. W5229 plus poster]. In: American Association of Pharmaceutical Scientists annual meeting and expo; 2015; Denver.
Pereira DE, Degenhardt T, Fernandes P. Comparison of CEM-101 metabolism in mice, rats, monkeys and humans [abstract no. A-687 plus poster]. In: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2010; Boston.
Andes DR, Okusanya OO, Forrest A, Bhavnani SM, Fernandes P, Ambrose PG. Pharmacokinetic-pharmacodynamic analysis of solithromycin (CEM-101) against Streptococcus pneumoniae using data from a murine-lung infection model [abstract no. A1-688 plus poster]. In: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2010; Boston.
Murphy TM, Gaffney M, Little S, Wu R, Slee AM, Ong C, et al. Efficacy and pharmacodynamic evaluation of CEM-101, a novel macrolide, in murine infection models [abstract no. P1098 plus poster]. In: 19th European Congress of Clinical Microbiology and Infectious Diseases; 2009; Helsinki.
Oldach D, Clark K, Schranz J, Das A, Craft JC, Scott D, et al. 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. Antimicrob Agents Chemother. 2013;57(6):2526–34.
Okusanya OO, Bhavnani SM, Forrest A, Fernandes P, Ambrose PG. Pharmacokinetic-pharmacodynamic target attainment analysis supporting solithromycin (CEM-101) Phase 2 dose selection [abstract no. A1-692 plus poster]. In: 50nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2010; Boston.
Barrera CM, Mykietiuk A, Metev H, Nitu MF, Karimjee N, Doreski PA, et al. Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of community-acquired bacterial pneumonia: a global, double-blind, multicentre, randomised, active-controlled, non-inferiority trial (SOLITAIRE-ORAL). Lancet Infect Dis. 2016;16(4):421–30.
Solithromycin for the treatment of community acquired bacterial pneumonia. Cempra briefing document. Advisory Drugs Advisory Committee, FDA, November 4, 2016.
Rashid M, Rosenberg S, Panagiotidis G, Holm J, Lofdal KS, et al. Ecological effect of solithromycin on normal human oropharyngeal and intestinal microbiota. Antimicrob Agents Chemother. 2016;60(7):4244–51.
Pai MP, Graci DM, Amsden GW. Macrolide drug interactions: an update. Ann Pharmacother. 2000;34(4):495–513.
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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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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