#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Multidrug-resistant gonorrhea: A research and development roadmap to discover new medicines


Emilie Alirol and colleagues discuss the development of new treatments for gonorrhea.


Vyšlo v časopise: Multidrug-resistant gonorrhea: A research and development roadmap to discover new medicines. PLoS Med 14(7): e32767. doi:10.1371/journal.pmed.1002366
Kategorie: Essay
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1002366

Souhrn

Emilie Alirol and colleagues discuss the development of new treatments for gonorrhea.


Zdroje

1. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global Estimates of the Prevalence and Incidence of Four Curable Sexually Transmitted Infections in 2012 Based on Systematic Review and Global Reporting. PLoS ONE. 2015;10:12:e0143304. doi: 10.1371/journal.pone.0143304 26646541; PubMed Central PMCID: PMC4672879.

2. Public Health England. Sexually transmitted infections and chlamydia screening in England, 2015. Health Protection Report. 2016;10(22) Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/559993/hpr2216_stis_CRRCTD4.pdf.

3. Santé Publique France. Bacterial sexually transmitted infections in France: recent trends and characteristics in 2015 [French]. Bulletin épidémiologique hebdomadaire. 2016;41-42(29 Nov) Available from: http://invs.santepubliquefrance.fr/beh/2016/41-42/_41-42_1.html.

4. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance. Available from: https://wwwcdcgov/std/stats15/std-surveillance-2015-printpdf. 2015.

5. The Kirby Institute for infection and immunity in society. HIV, viral hepatitis and sexually transmissible infections in Australia. Available from: http://kirbyunsweduau/sites/default/files/hiv/resources/SERP_2016-Annual-Surveillance-Report_UPD170116pdf. 2016;Annual Surveillance Report 2016.

6. Paz-Bailey G, Mendoza MC, Finlayson T, Wejnert C, Le B, Rose C, et al. Trends in condom use among MSM in the United States: the role of antiretroviral therapy and seroadaptive strategies. AIDS (London, England). 2016;30(12):1985–90. doi: 10.1097/QAD.0000000000001139 27149088.

7. Fifer H, Natarajan U, Jones L, Alexander S, Hughes G, Golparian D, et al. Failure of Dual Antimicrobial Therapy in Treatment of Gonorrhea. N Engl J Med. 2016;374(25):2504–6. doi: 10.1056/NEJMc1512757 27332921.

8. World Health Organization. Report on global sexually transmitted infection surveillance 2013. Sexual and reproductive health. 2014; Available from: http://apps.who.int/iris/bitstream/10665/112922/1/9789241507400_eng.pdf?ua=1.

9. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545–602. Epub 2016/10/14. doi: 10.1016/S0140-6736(16)31678-6 27733282.

10. Handsfield HH, Lipman TO, Harnisch JP, Tronca E, Holmes KK. Asymptomatic gonorrhea in men. Diagnosis, natural course, prevalence and significance. N Engl J Med. 1974;290(3):117–23. doi: 10.1056/NEJM197401172900301 4202519.

11. Harrison WO, Hooper RR, Wiesner PJ, Campbell AF, Karney WW, Reynolds GH, et al. A trial of minocycline given after exposure to prevent gonorrhea. N Engl J Med. 1979;300(19):1074–8. doi: 10.1056/NEJM197905103001903 107450.

12. Van Der Pol B. Sexually transmitted infections in women. Scand J Clin Lab Invest Suppl. 2014;244:68–74; discussion 3. doi: 10.3109/00365513.2014.936691 25083897.

13. Maxwell GL, Watson WJ. Preterm premature rupture of membranes: results of expectant management in patients with cervical cultures positive for group B streptococcus or Neisseria gonorrhoeae. Am J Obstet Gynecol. 1992;166(3):945–9. 1550170.

14. Tsevat DG, Wiesenfeld HC, Parks C, Peipert JF. Sexually transmitted diseases and infertility. Am J Obstet Gynecol. 2017;216(1):1–9. doi: 10.1016/j.ajog.2016.08.008 28007229; PubMed Central PMCID: PMC5193130.

15. Liu B, Roberts CL, Clarke M, Jorm L, Hunt J, Ward J. Chlamydia and gonorrhoea infections and the risk of adverse obstetric outcomes: a retrospective cohort study. Sex Transm Infect. 2013;89(8):672–8. doi: 10.1136/sextrans-2013-051118 24005255.

16. Donders GG, Desmyter J, De Wet DH, Van Assche FA. The association of gonorrhoea and syphilis with premature birth and low birthweight. Genitourin Med. 1993;69(2):98–101. 8509101; PubMed Central PMCID: PMC1195038.

17. Koedijk FD, van Bergen JE, Dukers-Muijrers NH, van Leeuwen AP, Hoebe CJ, van der Sande MA, et al. The value of testing multiple anatomic sites for gonorrhoea and chlamydia in sexually transmitted infection centres in the Netherlands, 2006–2010. Int J STD AIDS. 2012;23(9):626–31. doi: 10.1258/ijsa.2012.011378 23033514.

18. van Liere GA, Hoebe CJ, Dukers-Muijrers NH. Evaluation of the anatomical site distribution of chlamydia and gonorrhoea in men who have sex with men and in high-risk women by routine testing: cross-sectional study revealing missed opportunities for treatment strategies. Sex Transm Infect. 2014;90(1):58–60. doi: 10.1136/sextrans-2013-051248 24106338.

19. Unemo M, Nicholas RA. Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea. Future Microbiol. 2012;7(12):1401–22. doi: 10.2217/fmb.12.117 23231489; PubMed Central PMCID: PMC3629839.

20. Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev. 2014;27(3):587–613. doi: 10.1128/CMR.00010-14 24982323; PubMed Central PMCID: PMCPMC4135894.

21. Camara J, Serra J, Ayats J, Bastida T, Carnicer-Pont D, Andreu A, et al. Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain. J Antimicrob Chemother. 2012;67(8):1858–60. doi: 10.1093/jac/dks162 22566592.

22. Ohnishi M, Golparian D, Shimuta K, Saika T, Hoshina S, Iwasaku K, et al. 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. 2011;55(7):3538–45. doi: 10.1128/AAC.00325-11 21576437; PubMed Central PMCID: PMC3122416.

23. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother. 2012;56(3):1273–80. doi: 10.1128/AAC.05760-11 22155830; PubMed Central PMCID: PMC3294892.

24. Lahra MM, Enriquez RP. Australian Gonococcal Surveillance Programme, 1 April to 30 June 2016. Commun Dis Intell Q Rep. 2016;40(4):E557–E9. 28043233.

25. World Health Organization. Report on global sexually transmitted infection surveillance 2015. Available from: http://appswhoint/iris/bitstream/10665/249553/1/9789241565301-engpdf. 2016.

26. Lewis DA, Sriruttan C, Muller EE, Golparian D, Gumede L, Fick D, et al. Phenotypic and genetic characterization of the first two cases of extended-spectrum-cephalosporin-resistant Neisseria gonorrhoeae infection in South Africa and association with cefixime treatment failure. J Antimicrob Chemother. 2013;68(6):1267–70. doi: 10.1093/jac/dkt034 23416957.

27. Lewis D, Sriruttan C, Coetzee JD. Detection of multidrug-resistant gonorrhoea in the Gauteng province. S Afr J Infect Dis. 2012;27(4):199–200.

28. Golparian D, Ohlsson A, Janson H, Lidbrink P, Richtner T, Ekelund O, et al. Four treatment failures of pharyngeal gonorrhoea with ceftriaxone (500 mg) or cefotaxime (500 mg), Sweden, 2013 and 2014. Euro Surveill. 2014;19(30):20862. 25108533.

29. Allen VG, Mitterni L, Seah C, Rebbapragada A, Martin IE, Lee C, et al. Neisseria gonorrhoeae treatment failure and susceptibility to cefixime in Toronto, Canada. JAMA. 2013;309(2):163–70. doi: 10.1001/jama.2012.176575 23299608.

30. Unemo M, Golparian D, Syversen G, Vestrheim DF, Moi H. Two cases of verified clinical failures using internationally recommended first-line cefixime for gonorrhoea treatment, Norway, 2010. Euro Surveill. 2010;15(47):19721. 21144442.

31. Ison CA, Hussey J, Sankar KN, Evans J, Alexander S. Gonorrhoea treatment failures to cefixime and azithromycin in England, 2010. Euro Surveill. 2011;16(14):19833. 21492528.

32. Unemo M, Golparian D, Stary A, Eigentler A. First Neisseria gonorrhoeae strain with resistance to cefixime causing gonorrhoea treatment failure in Austria, 2011. Euro Surveill. 2011;16(43):19998. 22085601.

33. Singh AE, Gratrix J, Martin I, Friedman DS, Hoang L, Lester R, et al. Gonorrhea Treatment Failures With Oral and Injectable Expanded Spectrum Cephalosporin Monotherapy vs Dual Therapy at 4 Canadian Sexually Transmitted Infection Clinics, 2010–2013. Sex Transm Dis. 2015;42(6):331–6. doi: 10.1097/OLQ.0000000000000280 25970311.

34. Tapsall J, Read P, Carmody C, Bourne C, Ray S, Limnios A, et al. Two cases of failed ceftriaxone treatment in pharyngeal gonorrhoea verified by molecular microbiological methods. J Med Microbiol. 2009;58(Pt 5):683–7. doi: 10.1099/jmm.0.007641-0 19369534.

35. Chen MY, Stevens K, Tideman R, Zaia A, Tomita T, Fairley CK, et al. Failure of 500 mg of ceftriaxone to eradicate pharyngeal gonorrhoea, Australia. J Antimicrob Chemother. 2013;68(6):1445–7. doi: 10.1093/jac/dkt017 23390207.

36. Read PJ, Limnios EA, McNulty A, Whiley D, Lahra MM. One confirmed and one suspected case of pharyngeal gonorrhoea treatment failure following 500mg ceftriaxone in Sydney, Australia. Sexual health. 2013;10(5):460–2. doi: 10.1071/SH13077 24028864.

37. Unemo M, Golparian D, Potocnik M, Jeverica S. Treatment failure of pharyngeal gonorrhoea with internationally recommended first-line ceftriaxone verified in Slovenia, September 2011. Euro Surveill. 2012;17(25):20200. 22748003.

38. Unemo M, Golparian D, Hestner A. Ceftriaxone treatment failure of pharyngeal gonorrhoea verified by international recommendations, Sweden, July 2010. Euro Surveill. 2011;16(6):19792. 21329645.

39. Grad YH, Harris SR, Kirkcaldy RD, Green AG, Marks DS, Bentley SD, et al. Genomic Epidemiology of Gonococcal Resistance to Extended-Spectrum Cephalosporins, Macrolides, and Fluoroquinolones in the United States, 2000–2013. J Infect Dis. 2016;214(10):1579–87. doi: 10.1093/infdis/jiw420 27638945; PubMed Central PMCID: PMC5091375.

40. Vidovic S, Caron C, Taheri A, Thakur SD, Read TD, Kusalik A, et al. Using crude whole-genome assemblies of Neisseria gonorrhoeae as a platform for strain analysis: clonal spread of gonorrhea infection in Saskatchewan, Canada. J Clin Microbiol. 2014;52(10):3772–6. doi: 10.1128/JCM.01502-14 25056324; PubMed Central PMCID: PMC4187769.

41. Uehara AA, Amorin EL, Ferreira Mde F, Andrade CF, Clementino MB, de Filippis I, et al. Molecular characterization of quinolone-resistant Neisseria gonorrhoeae isolates from Brazil. J Clin Microbiol. 2011;49(12):4208–12. doi: 10.1128/JCM.01175-11 21976763; PubMed Central PMCID: PMC3232978.

42. Ito M, Deguchi T, Mizutani KS, Yasuda M, Yokoi S, Ito S, et al. Emergence and spread of Neisseria gonorrhoeae clinical isolates harboring mosaic-like structure of penicillin-binding protein 2 in Central Japan. Antimicrob Agents Chemother. 2005;49(1):137–43. doi: 10.1128/AAC.49.1.137-143.2005 15616287; PubMed Central PMCID: PMC538884.

43. Ameyama S, Onodera S, Takahata M, Minami S, Maki N, Endo K, et al. Mosaic-like structure of penicillin-binding protein 2 Gene (penA) in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime. Antimicrob Agents Chemother. 2002;46(12):3744–9. PubMed Central PMCID: PMC132769. doi: 10.1128/AAC.46.12.3744-3749.2002 12435671

44. Osaka K, Takakura T, Narukawa K, Takahata M, Endo K, Kiyota H, et al. Analysis of amino acid sequences of penicillin-binding protein 2 in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime and ceftriaxone. J Infect Chemother. 2008;14(3):195–203. doi: 10.1007/s10156-008-0610-7 18574654.

45. Kunz AN, Begum AA, Wu H, D'Ambrozio JA, Robinson JM, Shafer WM, et al. Impact of fluoroquinolone resistance mutations on gonococcal fitness and in vivo selection for compensatory mutations. J Infect Dis. 2012;205(12):1821–9. doi: 10.1093/infdis/jis277 22492860; PubMed Central PMCID: PMC3415892.

46. Warner DM, Shafer WM, Jerse AE. Clinically relevant mutations that cause derepression of the Neisseria gonorrhoeae MtrC-MtrD-MtrE Efflux pump system confer different levels of antimicrobial resistance and in vivo fitness. Mol Microbiol. 2008;70(2):462–78. doi: 10.1111/j.1365-2958.2008.06424.x 18761689; PubMed Central PMCID: PMC2602950.

47. Warner DM, Folster JP, Shafer WM, Jerse AE. Regulation of the MtrC-MtrD-MtrE efflux-pump system modulates the in vivo fitness of Neisseria gonorrhoeae. J Infect Dis. 2007;196(12):1804–12. doi: 10.1086/522964 18190261.

48. Tapsall JW, Ndowa F, Lewis DA, Unemo M. Meeting the public health challenge of multidrug- and extensively drug-resistant Neisseria gonorrhoeae. Expert Rev Anti Infect Ther. 2009;7(7):821–34. doi: 10.1586/eri.09.63 19735224.

49. Tapsall J. Multidrug-resistant Neisseria gonorrhoeae. CMAJ. 2009;180(3):268–9. doi: 10.1503/cmaj.081721 19188616; PubMed Central PMCID: PMC2630337.

50. World Health Organization. Global strategy for the prevention and control of sexually transmitted infections: 2006–2015. Available from: http://appswhoint/iris/bitstream/10665/43853/1/9789241563475_engpdf. 2007.

51. Maldonado NG, Takhar SS. Update on Emerging Infections: news from the Centers for Disease Control and Prevention. Update to the CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral cephalosporins no longer a recommended treatment for gonococcal infections. Ann Emerg Med. 2013;61(1):91–5. doi: 10.1016/j.annemergmed.2012.10.015 23260686.

52. Bignell C, Unemo M, European STIGEB. 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS. 2013;24(2):85–92. doi: 10.1177/0956462412472837 24400344.

53. Rice LB. Will use of combination cephalosporin/azithromycin therapy forestall resistance to cephalosporins in Neisseria gonorrhoeae? Sex Transm Infect. 2015;91(4):238–40. doi: 10.1136/sextrans-2014-051730 25926405.

54. Lagace-Wiens PR, Duncan S, Kimani J, Thiong'o A, Shafi J, McClelland S, et al. Emergence of fluoroquinolone resistance in Neisseria gonorrhoeae isolates from four clinics in three regions of Kenya. Sex Transm Dis. 2012;39(5):332–4. doi: 10.1097/OLQ.0b013e318248a85f 22504591; PubMed Central PMCID: PMC3328140.

55. Deguchi T, Saito I, Tanaka M, Sato K, Deguchi K, Yasuda M, et al. Fluoroquinolone treatment failure in gonorrhea. Emergence of a Neisseria gonorrhoeae strain with enhanced resistance to fluoroquinolones. Sex Transm Dis. 1997;24(5):247–50. 9153731.

56. Dillon JA, Trecker MA, Thakur SD, Gonococcal Antimicrobial Surveillance Program Network in Latin A, Caribbean. Two decades of the gonococcal antimicrobial surveillance program in South America and the Caribbean: challenges and opportunities. Sex Transm Infect. 2013;89 Suppl 4:iv36–41. doi: 10.1136/sextrans-2012-050905 24243878.

57. Starnino S, Group G-LW, Galarza P, Carvallo ME, Benzaken AS, Ballesteros AM, et al. Retrospective analysis of antimicrobial susceptibility trends (2000–2009) in Neisseria gonorrhoeae isolates from countries in Latin America and the Caribbean shows evolving resistance to ciprofloxacin, azithromycin and decreased susceptibility to ceftriaxone. Sex Transm Dis. 2012;39(10):813–21. doi: 10.1097/OLQ.0b013e3182631c9f 23001269.

58. Weinstock H, Workowski KA. Pharyngeal gonorrhea: an important reservoir of infection? Clin Infect Dis. 2009;49(12):1798–800. doi: 10.1086/648428 19911969.

59. Moran JS. Treating uncomplicated Neisseria gonorrhoeae infections: is the anatomic site of infection important? Sex Transm Dis. 1995;22(1):39–47. 7709324.

60. World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Available from: http://wwwwhoint/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHOpdf?ua=1. 2017.

61. Centers for Disease Control and Prevention. Antibiotic resistance trends in the United States, 2013. Available from: https://wwwcdcgov/drugresistance/pdf/ar-threats-2013-508pdf. 2013.

62. 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. doi: 10.1128/AAC.01343-09 20038627; PubMed Central PMCID: PMC2825974.

63. 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. doi: 10.1128/AAC.00090-09 19258276; PubMed Central PMCID: PMC2681567.

64. 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. doi: 10.1128/AAC.00036-12 22354296; PubMed Central PMCID: PMCPMC3346660.

65. Hook EW 3rd, Golden M, Jamieson BD, Dixon PB, Harbison HS, Lowens S, et al. A Phase 2 Trial of Oral Solithromycin 1200 mg or 1000 mg as Single-Dose Oral Therapy for Uncomplicated Gonorrhea. Clin Infect Dis. 2015;61(7):1043–8. doi: 10.1093/cid/civ478 26089222.

66. Huband MD, Bradford PA, Otterson LG, Basarab GS, Kutschke AC, Giacobbe RA, et al. In vitro antibacterial activity of AZD0914, a new spiropyrimidinetrione DNA gyrase/topoisomerase inhibitor with potent activity against Gram-positive, fastidious Gram-Negative, and atypical bacteria. Antimicrob Agents Chemother. 2015;59(1):467–74. doi: 10.1128/AAC.04124-14 25385112; PubMed Central PMCID: PMC4291388.

67. Kohlhoff SA, Huband MD, Hammerschlag MR. In vitro activity of AZD0914, a novel DNA gyrase inhibitor, against Chlamydia trachomatis and Chlamydia pneumoniae. Antimicrob Agents Chemother. 2014;58(12):7595–6. doi: 10.1128/AAC.03920-14 25288086; PubMed Central PMCID: PMC4249501.

68. Unemo M, Ringlander J, Wiggins C, Fredlund H, Jacobsson S, Cole M. High in vitro susceptibility to the novel spiropyrimidinetrione ETX0914 (AZD0914) among 873 contemporary clinical Neisseria gonorrhoeae isolates from 21 European countries from 2012 to 2014. Antimicrob Agents Chemother. 2015;59(9):5220–5. doi: 10.1128/AAC.00786-15 26077246; PubMed Central PMCID: PMC4538562.

69. Biedenbach DJ, Bouchillon SK, Hackel M, Miller LA, Scangarella-Oman NE, Jakielaszek C, et al. In Vitro Activity of Gepotidacin, a Novel Triazaacenaphthylene Bacterial Topoisomerase Inhibitor, against a Broad Spectrum of Bacterial Pathogens. Antimicrob Agents Chemother. 2016;60(3):1918–23. doi: 10.1128/AAC.02820-15 26729499; PubMed Central PMCID: PMC4776004.

70. Wi T, Lahra MM, Ndowa F, Bala M, Dillon JR, Ramon-Pardo P, et al. Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action. PLoS Med. 2017;14:7:e1002344. doi: 10.1371/journal.pmed.1002344 28686231.

71. Unemo M, Jensen JS. Antimicrobial-resistant sexually transmitted infections: gonorrhoea and Mycoplasma genitalium. Nat Rev Urol. 2017;14(3):139–52. doi: 10.1038/nrurol.2016.268 28072403.

72. Bolan GA, Sparling PF, Wasserheit JN. The emerging threat of untreatable gonococcal infection. N Engl J Med. 2012;366(6):485–7. doi: 10.1056/NEJMp1112456 22316442.

73. The Global Antibiotic Research and Development Partnership (GARDP) www.gardp.org. 2016.

74. Boslego JW, Tramont EC, Takafuji ET, Diniega BM, Mitchell BS, Small JW, et al. Effect of spectinomycin use on the prevalence of spectinomycin-resistant and of penicillinase-producing Neisseria gonorrhoeae. N Engl J Med. 1987;317(5):272–8. doi: 10.1056/NEJM198707303170504 2955222.

75. Ashford WA, Potts DW, Adams HJ, English JC, Johnson SR, Biddle JW, et al. Spectinomycin-resistant penicillinase-producing Neisseria gonorrhoeae. Lancet. 1981;2(8254):1035–7. 6118488.

76. Stolz E, Zwart HG, Michel MF. Activity of eight antimicrobial agents in vitro against N. Gonorrhoeae. Brit J Vener Dis. 1975;51(4):257–64. 125618; PubMed Central PMCID: PMC1046560.

Štítky
Interné lekárstvo

Článok vyšiel v časopise

PLOS Medicine


2017 Číslo 7
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#