• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of aacPermissionsJournals.ASM.orgJournalAAC ArticleJournal InfoAuthorsReviewers
Antimicrob Agents Chemother. May 2012; 56(5): 2739–2742.
PMCID: PMC3346660

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?

Abstract

Gonorrhea may become untreatable, and new treatment options are essential. We investigated the in vitro activity of the first fluoroketolide, solithromycin. Clinical Neisseria gonorrhoeae isolates and reference strains (n = 246), including the two extensively drug-resistant strains H041 and F89 and additional isolates with clinical cephalosporin resistance and multidrug resistance, were examined. The activity of solithromycin was mainly superior to that of other antimicrobials (n = 10) currently or previously recommended for gonorrhea treatment. Solithromycin might be an effective treatment option for gonorrhea.

TEXT

Neisseria gonorrhoeae resistance to antimicrobials previously recommended for treatment of gonorrhea is common worldwide. Currently, first-line treatment is the extended-spectrum cephalosporins (ESCs) cefixime and ceftriaxone. ESC susceptibility has, however, decreased rapidly during the last decade (1, 4, 8, 12, 15, 16, 18, 19, 28, 29, 36). Treatment failures with cefixime have been verified in Japan (9, 40) and Europe (13, 3335). With ceftriaxone, three cases of failure treating pharyngeal gonorrhea were confirmed in Australia (30) and Sweden (32); however, the ceftriaxone MICs of these isolates were only slightly elevated. It is of grave concern that in the past year the two first extensively drug-resistant (XDR) gonococcal strains, H041 (21) and F89 (33), which are highly resistant to all ESCs and related to ESC treatment failure, were described from Japan and France, respectively. If these strains spread internationally, gonorrhea may become untreatable (21, 29, 33), and it is imperative to promptly develop new treatment options. Recently, the first fluoroketolide, solithromycin (CEM-101) (Fig. 1), entered clinical development. Solithromycin has shown advantages over other macrolides in activity against many bacterial pathogens (2, 10, 17, 20, 23, 24, 37, 38). The chemical alterations of solithromycin appear to account for more-potent antimicrobial activity but also greater metabolic stability and tolerability. In a previous study (23), solithromycin was more potent than azithromycin against a small collection of gonococcal isolates. However, only 34 gonococcal isolates were tested, none of which displayed high-level azithromycin resistance.

Fig 1
Chemical structure of solithromycin (also known as CEM-101). The molecule possesses an 11,12-carbamate-butyl-[1,2,3]-triazolyl-aminophenyl side chain (circled) and a fluorine atom (circled) substituting for a hydrogen atom in position 2 of the lactone ...

We investigated the in vitro activity of solithromycin (CEM-101) against clinical gonococcal isolates and international reference strains (n = 246), including strains with high-level resistance to various antimicrobials, relative to the activities of other antimicrobials (n = 10) currently or previously recommended for gonorrhea treatment and the activity of telithromycin (the first developed ketolide).

In total, 100 consecutive clinical Swedish gonococcal isolates obtained in 2011 and clinical isolates (n = 118) and reference strains (n = 28) selected for their resistance phenotype (cultured from 1991 to 2011) were examined. The collection contained geographically (mainly global representativeness), temporally, and genetically diverse isolates, including the XDR gonococcal strains H041 (21) and F89 (33), with clinical high-level resistance to all ESCs, additional isolates that showed ESC resistance and that were related to ESC treatment failure (n = 4) (32, 34, 35), and isolates with other types of multidrug resistance (MDR) (Table 1). The WHO 2008 N. gonorrhoeae reference strains (n = 8) (31) were used for quality control. The MICs of solithromycin, azithromycin, erythromycin, and telithromycin were determined by the agar dilution technique recommended by the Clinical and Laboratory Standards Institute (CLSI) (7). The MICs of cefixime, ceftriaxone, ampicillin, ciprofloxacin, spectinomycin, and tetracycline were determined using the Etest (AB bioMérieux, Solna, Sweden) (Table 1).

Table 1
MICs of solithromycin, relative to MICs of antimicrobials previously or currently used for treatment of gonorrhea and MICs of telithromycin (first developed ketolide), against 246 clinical N. gonorrhoeae isolates and international reference strains

The MIC50, MIC90, and MIC range of solithromycin were 0.125 μg/ml, 0.25 μg/ml, and 0.001 to 32 μg/ml, respectively. The MIC50 and MIC90 of the other macrolides (azithromycin, telithromycin, and erythromycin) were substantially higher (Table 1). Only 2.4% (n = 6) of the isolates had an MIC of >0.5 μg/ml for solithromycin (1, 4, 4, 4, 16, and 32 μg/ml) (Fig. 2), and the corresponding MICs of azithromycin (telithromycin) for these isolates were 2 (0.5), 4 (4), 8 (4), >256 (>256), >256 (>256), and >256 (>256) μg/ml, respectively. For comparison, 11.0% (n = 27), 37.8% (n = 93), and 94.3% (n = 232) of all isolates had an MIC of >0.5 μg/ml for telithromycin, azithromycin, and erythromycin, respectively. For all isolates with in vitro and clinical resistance to cefixime (n = 16; 6.5%) and ceftriaxone (n = 3; 1.2%), the MIC50, MIC90, and MIC range of solithromycin were 0.125 μg/ml, 0.25 μg/ml, and 0.064 to 0.25 μg/ml, respectively. None of the isolates resistant to ampicillin, gentamicin (n = 2; MIC = 96 μg/ml), or spectinomycin had an MIC of >0.5 μg/ml for solithromycin. Only two (0.8%) isolates and three (1.2%) isolates resistant to ciprofloxacin and tetracycline, respectively, displayed an MIC of >0.5 μg/ml for solithromycin.

Fig 2
MIC (μg/ml) distribution of solithromycin, azithromycin, and telithromycin for 246 clinical N. gonorrhoeae isolates and international reference strains.

Herein, we report the first comprehensive evaluation of the activity of the new fluoroketolide solithromycin (CEM-101), relative to the activities of other antimicrobials currently or previously recommended for gonorrhea treatment, against a large collection of N. gonorrhoeae clinical isolates and international reference strains with various clinical XDR and MDR. The activity of solithromycin was superior to that of azithromycin, other macrolides, and many other antimicrobials currently or previously recommended for gonorrhea treatment. Importantly, solithromycin was highly active against gonococcal strains with resistance to ESCs. Consequently, solithromycin may be an effective option for treatment of gonorrhea and especially ESC-resistant cases and for use in antimicrobial combination therapy, particularly because solithromycin also appears to be effective against Chlamydia trachomatis (24) and Mycoplasma genitalium (37), which are commonly present as concomitant sexually transmitted infections. Combination therapy has been introduced in the United States (39) and the United Kingdom (3), where administration of ESC (ceftriaxone or cefixime [in the United States, if ceftriaxone is not an option]) plus azithromycin (in the United States, azithromycin or doxycycline) is recommended for treatment of uncomplicated anogenital gonorrhea cases. The superior activity of solithromycin combined with the identification of gonococcal isolates with very high-level resistance (>256 μg/ml) to azithromycin in many countries (5, 6, 11, 14, 22, 26) and the gastrointestinal side effects of azithromycin indicates that solithromycin might be a more appropriate choice than azithromycin for treatment of gonorrhea. Solithromycin also has very high activity against intracellular bacteria (17), due to high intracellular accumulation, and is well distributed in extracellular tissues. Finally, solithromycin is well absorbed orally, with high plasma levels and tissue distribution, has a long postantimicrobial effect and anti-inflammatory properties, and appears safe and well tolerated at high doses (1.6-g single dose) (27).

In conclusion, solithromycin had superior activity against gonococcal isolates compared to activities of azithromycin, other macrolides, and many other classes of antimicrobials. Solithromycin might be an effective option for gonorrhea treatment, as single-antimicrobial treatment especially for ESC-resistant cases and in antimicrobial combination therapy. However, it will be crucial to perform additional in vitro studies investigating solithromycin susceptibility and also the selection and mechanisms of solithromycin resistance in N. gonorrhoeae (and other pathogens and commensals exposed to the drug during gonorrhea treatment). Furthermore, additional studies regarding pharmacokinetics/pharmacodynamics of solithromycin (for single-drug treatment and combination therapy, including measurement of concentration and activity of drug in urethral secretions) and clinical trials (measuring parameters such as efficacy, cost, and toxicity) are crucial.

ACKNOWLEDGMENTS

The present work was funded by the Örebro County Council Research Committee, the Foundation for Medical Research at Örebro University Hospital, Sweden, and Cempra Pharmaceuticals, Inc., Chapel Hill, NC.

The work was performed at the WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.

Footnotes

Published ahead of print 21 February 2012

REFERENCES

1. Barry PM, Klausner JD. 2009. The use of cephalosporins for gonorrhea: the impending problem of resistance. Expert Opin. Pharmacother. 10:555–577 [PMC free article] [PubMed]
2. Biedenbach DJ, Castanheira M, Jones RN. 2010. Determination of CEM-101 activity tested against clinical isolates of Neisseria meningitidis from a worldwide collection. Antimicrob. Agents Chemother. 54:4009–4011 [PMC free article] [PubMed]
3. Bignell C, Fitzgerald M., Guideline Development Group 2011. UK national guideline for the management of gonorrhoea in adults, 2011. Int. J. STD AIDS 22:541–547 [PubMed]
4. Centers for Disease Control and Prevention (CDC) 2011. Cephalosporin susceptibility among Neisseria gonorrhoeae isolates—United States, 2000–2010. MMWR Morb. Mortal. Wkly. Rep. 60:873–877 [PubMed]
5. Chisholm SA, Dave J, Ison CA. 2010. High-level azithromycin resistance occurs in Neisseria gonorrhoeae as a result of a single point mutation in the 23S rRNA genes. Antimicrob. Agents Chemother. 54:3812–3816 [PMC free article] [PubMed]
6. Chisholm SA, et al. 2009. Emergence of high-level azithromycin resistance in Neisseria gonorrhoeae in England and Wales. J. Antimicrob. Chemother. 64:353–358 [PubMed]
7. Clinical and Laboratory Standards Institute 2011. Performance standards for antimicrobial susceptibility testing, 21st informational supplement, CLSI document M100-S21. CLSI, Wayne, PA
8. Cole MJ, et al. 2011. The European gonococcal antimicrobial surveillance programme, 2009. Euro Surveill. 16(42):pii=19995 [PubMed]
9. Deguchi T, et al. 2003. Treatment of uncomplicated gonococcal urethritis by double-dosing of 200 mg cefixime at a 6-h interval. J. Infect. Chemother. 9:35–39 [PubMed]
10. Farrell DJ, Castanheira M, Sader HS, Jones RN. 2010. The in vitro evaluation of solithromycin (CEM-101) against pathogens isolated in the United States and Europe (2009). J. Infect. 61:476–483 [PubMed]
11. Galarza PG, et al. 2010. New mutation in 23S rRNA gene associated with high level of azithromycin resistance in Neisseria gonorrhoeae. Antimicrob. Agents Chemother. 54:1652–1653 [PMC free article] [PubMed]
12. Golparian D, Hellmark B, Fredlund H, Unemo M. 2010. Emergence, spread and characteristics of Neisseria gonorrhoeae isolates with in vitro decreased susceptibility and resistance to extended-spectrum cephalosporins in Sweden. Sex. Transm. Infect. 86:454–460 [PubMed]
13. Ison CA, Hussey J, Sankar KN, Evans J, Alexander S. 2011. Gonorrhoea treatment failures to cefixime and azithromycin in England, 2010. Euro Surveill. 16(14):pii=19833 [PubMed]
14. Katz AR, et al. 2012. Neisseria gonorrhoeae with high-level resistance to azithromycin: case report of the first isolate identified in the United States. Clin. Infect. Dis. 54:841–843 [PubMed]
15. Kirkcaldy RD, Ballard RC, Dowell D. 2011. Gonococcal resistance: are cephalosporins next? Curr. Infect. Dis. Rep. 13:196–204 [PubMed]
16. Kubanova A, et al. 2010. The Russian gonococcal antimicrobial susceptibility programme (RU-GASP)—national resistance prevalence in 2007 and 2008, and trends during 2005-2008. Euro Surveill. 15(14):pii=19533 [PubMed]
17. Lemaire S, Van Bambeke F, Tulkens PM. 2009. 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. 53:3734–3743 [PMC free article] [PubMed]
18. Lewis DA. 2010. The gonococcus fights back: is this time a knock out? Sex. Transm. Infect. 86:415–421 [PubMed]
19. Martin I, et al. 2011. Trends in antimicrobial resistance in Neisseria gonorrhoeae isolated in Canada: 2000-2009. Sex. Transm. Dis. 38:892–898 [PubMed]
20. McGhee P, et al. 2010. In vitro activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with defined macrolide resistance mechanisms. Antimicrob. Agents Chemother. 54:230–238 [PMC free article] [PubMed]
21. Ohnishi M, et al. 2011. Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob. Agents Chemother. 55:3538–3545 [PMC free article] [PubMed]
22. Palmer HM, Young H, Winter A, Dave J. 2008. Emergence and spread of azithromycin-resistant Neisseria gonorrhoeae in Scotland. J. Antimicrob. Chemother. 62:490–494 [PubMed]
23. Putnam SD, Castanheira M, Moet GJ, Farrell DJ, Jones RN. 2010. CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria. Diagn. Microbiol. Infect. Dis. 66:393–401 [PubMed]
24. Roblin PM, Kohlhoff SA, Parker C, Hammerschlag MR. 2010. In vitro activity of CEM-101, a new fluoroketolide antibiotic, against Chlamydia trachomatis and Chlamydia (Chlamydophila) pneumoniae. Antimicrob. Agents Chemother. 54:1358–1359 [PMC free article] [PubMed]
25. Ross DB. 2007. The FDA and the case of Ketek. N. Engl. J. Med. 356:1601–1604 [PubMed]
26. Starnino S, Stefanelli P., Neisseria gonorrhoeae Italian Study Group 2009. Azithromycin-resistant Neisseria gonorrhoeae strains recently isolated in Italy. J. Antimicrob. Chemother. 63:1200–1204 [PubMed]
27. Still JG, et al. 2011. 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. 55:1997–2003 [PMC free article] [PubMed]
28. Tanaka M, et al. 2011. Antibiotic-resistant phenotypes and genotypes of Neisseria gonorrhoeae isolates in Japan: identification of strain clusters with multidrug-resistant phenotypes. Sex. Transm. Dis. 38:871–875 [PubMed]
29. Tapsall JW, Ndowa F, Lewis DA, Unemo M. 2009. Meeting the public health challenge of multidrug- and extensively drug-resistant Neisseria gonorrhoeae. Expert Rev. Anti Infect. Ther. 7:821–834 [PubMed]
30. Tapsall J, et al. 2009. Two cases of failed ceftriaxone treatment in pharyngeal gonorrhoea verified by molecular microbiological methods. J. Med. Microbiol. 58:683–687 [PubMed]
31. Unemo M, Fasth O, Fredlund H, Limnios A, Tapsall J. 2009. Phenotypic and genetic characterization of the 2008 WHO Neisseria gonorrhoeae reference strain panel intended for global quality assurance and quality control of gonococcal antimicrobial resistance surveillance for public health purposes. J. Antimicrob. Chemother. 63:1142–1151 [PubMed]
32. Unemo M, Golparian D, Hestner A. 2011. Ceftriaxone treatment failure of pharyngeal gonorrhoea verified by international recommendations, Sweden, July 2010. Euro Surveill. 16(6):pii=19792 [PubMed]
33. Unemo M, et al. 2012. High-level cefixime- and ceftriaxone-resistant N. gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob. Agents Chemother. 56:1273–1280 [PMC free article] [PubMed]
34. Unemo M, Golparian D, Stary A, Eigentler A. 2011. First Neisseria gonorrhoeae strain with resistance to cefixime causing gonorrhoea treatment failure in Austria, 2011. Euro Surveill. 16(43):pii=19998 [PubMed]
35. Unemo M, Golparian D, Syversen G, Vestrheim DF, Moi H. 2010. Two cases of verified clinical failures using internationally recommended first-line cefixime for gonorrhoea treatment, Norway, 2010. Euro Surveill. 15(47):pii=19721 [PubMed]
36. Unemo M, Shafer WM. 2011. Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future. Ann. N. Y. Acad. Sci. 1230:E19–E28 [PubMed]
37. Waites KB, Crabb DM, Duffy LB. 2009. Comparative in vitro susceptibilities of human mycoplasmas and ureaplasmas to a new investigational ketolide, CEM-101. Antimicrob. Agents Chemother. 53:2139–2141 [PMC free article] [PubMed]
38. Woosley LN, Castanheira M, Jones RN. 2010. CEM-101 activity against Gram-positive organisms. Antimicrob. Agents Chemother. 54:2182–2187 [PMC free article] [PubMed]
39. Workowski KA, Berman S., Centers for Disease Control and Prevention (CDC) 2010. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recommend. Rep. 59(RR-12):1–110 [PubMed]
40. Yokoi S, et al. 2007. Threat to cefixime treatment of gonorrhea. Emerg. Infect. Dis. 13:1275–1277 [PMC free article] [PubMed]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

  • In Vitro Activity of the New Fluoroketolide Solithromycin (CEM-101) against a La...
    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?
    Antimicrobial Agents and Chemotherapy. May 2012; 56(5)2739
    PMC

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...