Journal of Literature Pharmacy Sciences

Mikrobiyal Biyofilm Kontrolünde Lipozom Bazlı İlaç Taşıyıcı Sistemler
Liposome Based Drug Delivery Systems for Control of Microbial Biofilms
Aslınur ALBAYRAKa, Füsun ACARTÜRKb
aGazi Üniversitesi Eczacılık Fakültesi, Klinik Eczacılık ABD, Ankara, TÜRKİYE
bGazi Üniversitesi Eczacılık Fakültesi, Farmasötik Teknoloji ABD, Ankara, TÜRKİYE
J Lit Pharm Sci. 2020;9(1):77-89
doi: 10.5336/pharmsci.2019-71168
Article Language: TR
Full Text
ÖZET
Biyofilmler, bir yüzeye yapışarak kendi ürettikleri jelsi bir tabaka içinde yaşayan mikroorganizmaların oluşturduğu topluluk olarak tanımlanmaktadır. Biyofilm varlığı geleneksel antimikrobiyallerin kullanımı için büyük zorluklar doğurmaktadır. Biyofilmle ilgili klinik enfeksiyonlara kronik otitis media, tekrarlayan tonsilit, kronik yaralar, kistik fibrozis akciğer enfeksiyonları, üriner sistem enfeksiyonları, kronik rinosinüzitler, diş çürükleri ve alet kaynaklı enfeksiyonlar örnek verilebilir. Bakteri türleri tüm mikroorganizmalar arasında diğerlerinden daha fazla biyofilm üretme kapasitesine sahiptir. Çoğu tür, hücre dışı yapılarıyla mikropları yaşam ortamlarında korumaktadır ve olumsuz koşullarda bile mükemmel kolonizasyon yeteneğine sahiptir. Geniş spektrumlu antibiyotiklerin kullanımı, nötropeni, parenteral nütrisyon, kalıcı kateterler, immünsupresyon, cerrahi, kemoterapi ve radyoterapi mantar enfeksiyonları için en önemli faktörler arasındadır. Biyofilmlerin ortadan kaldırılmasındaki ana problem, şu anda klinikte kullanılan ilaçlara karşı oluşan dirençtir. Antibiyotiğin biyofilm içine yavaş ve düşük penetrasyonu, biyofilm içinde değişen kimyasal mikroçevre ve efluks pompalarının ekspresyonu direnç nedenleri arasındadır. Bu sebeple antibiyofilm aktivitesi olan yeni bileşiklerin ve ilaçların araştırılması zorunlu hâle gelmiştir. Lipozomlar, birçok alanda kullanılan önemli ilaç taşıyıcı sistemlerden biridir. Lipozomlar enkapsüllenmiş ilacın biyoyararlılığını, biyouyumluluğunu ve güvenlik profilini artırmaktadır. Bu bağlamda, lipozomlar biyofilmlerin neden olduğu çok sayıda mikrobiyal enfeksiyonu tedavi etmede ve ilaçların hedefe ulaştırılmasında güvenli platformlar sağlamaktadır. Bu derlemede, mikrobiyal biyofilmlerin enfeksiyon hastalıklarına olan etkisi ve lipozom bazlı ilaç taşıyıcı sistemlerle biyofilmlerin kontrolü ve tedavisi özetlenmiştir.

Anahtar Kelimeler: Lipozom; biyofilmler
ABSTRACT
Biofilms are defined as a group of microorganisms that live in a gelled layer that they produce by adhering to a surface. The presence of biofilm poses great challenges for the use of conventional antimicrobials. Biofilm-related clinical infections include chronic otitis media, recurrent tonsillitis, chronic wounds, cystic fibrosis lung infections, urinary tract infections, chronic rhinosinusitis, dental caries and instrument-borne infections. Bacterial species are capable of producing more biofilm among all microorganisms than others. Most species, with their extracellular structures, protect microbes in their habitats and have excellent colonization ability even in adverse conditions. Use of broad spectrum antibiotics, neutropenia, parenteral nutrition, permanent catheters, immunosuppression, surgery, chemotherapy and radiotherapy are among the most important factors for fungal infections. The main problem in eliminating biofilms is the resistance to drugs currently used in the clinic. The slow and low penetration of the antibiotic into the biofilm, the chemical microenvironment changing in the biofilm and the expression of efflux pumps are among the causes of resistance. Therefore, it has become necessary to search for novel compounds and drugs with anti-biofilm activity. Liposomes are one of the important drug delivery systems used in many areas. Liposomes increase the bioavailability, biocompatibility and safety profile of the encapsulated drug. In this regard, liposomes are safe in treating a large number of microbial infections caused by biofilms and delivering drugs to the target. In this review, the effect of microbial biofilms on infectious diseases and the control and treatment of biofilms with liposome based drug delivery systems are summarized.

Keywords: Liposom; biofilms
REFERENCES:
  1. Davies D. Understanding biofilm resistance to antibacterial agents. Nat Rev Drug Discov. 2003;2(2):114-22. [Crossref]  [PubMed] 
  2. Hall-Stoodley L, Stoodley P, Kathju S, Høiby N, Moser C, Costerton JW, et al. Towards diagnostic guidelines for biofilm-associated infections. FEMS Immunol Med Microbiol. 2012;65(2):127-45. [Crossref]  [PubMed] 
  3. D'Acunto B, Frunzo L, Klapper I, Mattei M. Modeling multispecies biofilms including new bacterial species invasion. Math Biosci. 2015;259:20-6. [Crossref]  [PubMed] 
  4. Liu Y, Tay JH. Detachment forces and their influence on the structure and metabolic behaviour of biofilms. World J Microbiol Biotechnol. 2001;17(2):111-7. [Crossref] 
  5. Vinh DC, Embil JM. Device-related infections: a review. J Long Term Effects Med Implants. 2005;15(5):467-88. [Crossref]  [PubMed] 
  6. Götz F. Staphylococcus and biofilms. Mol Microbiol. 2002;43(6):1367-78. [Crossref]  [PubMed] 
  7. Karchmer AW, Longworth DL. Infections of intracardiac devices. Infect Dis Clin North Am. 2002;16(2):477-505. [Crossref] 
  8. Lyczak JB, Cannon CL, Pier GB. Lung infections associated with cystic fibrosis. Clin Microbiol Rev. 2002;15(2):194-222. [Crossref]  [PubMed]  [PMC] 
  9. Gjødsbøl K, Christensen JJ, Karlsmark T, Jørgensen B, Klein BM, Krogfelt KA. Multiple bacterial species reside in chronic wounds: a longitudinal study. Int Wound J. 2006;3(3):225-31. [Crossref]  [PubMed] 
  10. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med. 2002;113(Suppl 1A):5S-13S. [Crossref] 
  11. Nicolle LE. Urinary tract infection in long-term-care facility residents. Clin Infect Dis. 2000;31(3):757-61. [Crossref]  [PubMed] 
  12. Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science. 1999;284(5418):1318-22. [Crossref]  [PubMed] 
  13. Tabibian JH, Gornbein J, Heidari A, Dien SL, Lau VH, Chahal P, et al. Uropathogens and host characteristics. J Clin Microbiol. 2008;46(12):3980-6. [Crossref]  [PubMed]  [PMC] 
  14. Warren JW. Catheter-associated urinary tract infections. Infect Dis Clin North Am. 1997;11(3):609-22. [Crossref] 
  15. Warren JW. Catheter-associated urinary tract infections Int J Antimicrob Agents. 2001;17(4):299-303. [Crossref] 
  16. Carron MA, Tran VR, Sugawa C, Coticchia JM. Identification of Helicobacter pylori biofilms in human gastric mucosa. J Gastrointest Surg. 2006;10(5):712-7. [Crossref]  [PubMed] 
  17. Yonezawa H, Osaki T, Kamiya S. Biofilm formation by Helicobacter pylori and its involvement for antibiotic resistance. Biomed Res Int. 2015;2015:914791. [Crossref]  [PubMed]  [PMC] 
  18. Krzyściak W, Jurczak A, Kościelniak D, Bystrowska B, Skalniak A. The virulence of Streptococcus mutans and the ability to form biofilms. Eur J Clin Microbiol Infect Dis. 2014;33(4):499-515. [Crossref]  [PubMed]  [PMC] 
  19. Acuin J, World Health Organization. Chronic Suppurative Otitis Media: Burden of Illness and Management Options. Geneva, Switzerland: World Health Organization; 2004. p.71.
  20. Verhoeff M, van der Veen EL, Rovers MM, Sanders EA, Schilder AG. Chronic suppurative otitis media: a review. Int J Pediatr Otorhinolaryngol. 2006;70(1):1-12. [Crossref]  [PubMed] 
  21. Hall-Stoodley L, Hu FZ, Gieseke A, Nistico L, Nguyen D, Hayes J, et al. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA. 2006;296(2):202-11. [Crossref]  [PubMed]  [PMC] 
  22. Swidsinski A, Mendling W, Loening-Baucke V, Ladhoff A, Swidsinski S, Hale LP, et al. Adherent biofilms in bacterial vaginosis. Obstet Gynecol. 2005;106(5 Pt 1):1013-23. [Crossref]  [PubMed] 
  23. Antas PR, Brito MM, Peixoto É, Ponte CG, Borba CM. Neglected and emerging fungal infections: review of hyalohyphomycosis by Paecilomyces lilacinus focusing in disease burden, in vitro antifungal susceptibility and management. Microbes Infect. 2012;14(1):1-8. [Crossref]  [PubMed] 
  24. Kumamoto CA, Vinces MD. Alternative Candida albicans lifestyles: growth on surfaces. Annu Rev Microbiol. 2005;59:113-33. [Crossref]  [PubMed] 
  25. Ramage G, Jose A, Coco B, Rajendran R, Rautemaa R, Murray C, et al. Commercial mouthwashes are more effective than azole antifungals against Candida albicans biofilms in vitro. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111(4):456-60. [Crossref]  [PubMed] 
  26. Coco B, Bagg J, Cross L, Jose A, Cross J, Ramage G. Mixed Candida albicans and Candida glabrata populations associated with the pathogenesis of denture stomatitis. Oral Microbiol Immunol. 2008;23(5):377-83. [Crossref]  [PubMed] 
  27. Ariani N, Vissink A, van Oort RP, Kusdhany L, Djais A, Rahardjo TB, et al. Microbial biofilms on facial prostheses. Biofouling. 2012;28(6):583-91. [Crossref]  [PubMed] 
  28. Martin-Garrido I, Carmona EM, Specks U, Limper AH. Pneumocystis pneumonia in patients treated with rituximab. Chest. 2013;144(1):258-65. [Crossref]  [PubMed]  [PMC] 
  29. Lanjewar DN. The spectrum of clinical and pathological manifestations of AIDS in a consecutive series of 236 autopsied cases in Mumbai, India. Patholog Res Int. 2011;2011:547618. [Crossref]  [PubMed]  [PMC] 
  30. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(3):291-322. [Crossref]  [PubMed]  [PMC] 
  31. Martinez LR, Fries BC. Fungal biofilms: relevance in the setting of human disease. Curr Fungal Infect Rep. 2010;4(4):266-75. [Crossref]  [PubMed]  [PMC] 
  32. Damman CJ, Miller SI, Surawicz CM, Zisman TL. The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation? Am J Gastroenterol. 2012;107(10):1452-9. [Crossref]  [PubMed] 
  33. Kumamoto CA. Inflammation and gastrointestinal Candida colonization. Curr Opin Microbiol. 2011;14(4):386-91. [Crossref]  [PubMed]  [PMC] 
  34. Wolcott R, Rumbaugh K, James G, Schultz G, Phillips P, Yang Q, et al. Biofilm maturity studies indicate sharp debridement opens a time-dependent therapeutic window. J Wound Care. 2010;19(8):320-8. [Crossref]  [PubMed] 
  35. de la Fuente-Nú-ez C, Reffuveille F, Fernández L, Hancock RE. Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies. Curr Opin Microbiol. 2013;16(5):580-9. [Crossref]  [PubMed] 
  36. Stewart PS. Theoretical aspects of antibiotic diffusion into microbial biofilms. Antimicrob Agents Chemother.1996;40(11):2517-22. [Crossref]  [PubMed]  [PMC] 
  37. Shigeta M, Tanaka G, Komatsuzawa H, Sugai M, Suginaka H, Usui T. Permeation of antimicrobial agents through Pseudomonas aeruginosa biofilms: a simple method. Chemotherapy. 1997;43(5):340-5. [Crossref]  [PubMed] 
  38. Nichols WW, Dorrington S, Slack M, Walmsley H. Inhibition of tobramycin diffusion by binding to alginate. Antimicrob Agents Chemother. 1988;32(4):518-23. [Crossref]  [PubMed]  [PMC] 
  39. Lebeaux D, Ghigo JM, Beloin C. Biofilm-related infections: bridging the gap between clinical management and fundamental aspects of recalcitrance toward antibiotics. Microbiol Mol Biol Rev. 2014;78(3):510-43. [Crossref]  [PubMed]  [PMC] 
  40. Zhang TC, Bishop PL. Evaluation of substrate and pH effects in a nitrifying biofilm. Water Environ Res. 1996;68(7):1107-15. [Crossref] 
  41. Tack KJ, Sabath LD. Increased minimum inhibitory concentrations with anaerobiasis for tobramycin, gentamicin, and amikacin, compared to latamoxef, piperacillin, chloramphenicol, and clindamycin. Chemotherapy. 1985;31(3):204-10. [Crossref]  [PubMed] 
  42. Tuomanen E, Cozens R, Tosch W, Zak O, Tomasz A. The rate of killing of Escherichia coli by beta-lactam antibiotics is strictly proportional to the rate of bacterial growth. J Gen Microbiol. 1986;132(5):1297-304. [Crossref]  [PubMed] 
  43. Mah TF. Biofilm-specific antibiotic resistance. Future Microbiol. 2012;7(9):1061-72. [Crossref]  [PubMed] 
  44. Podnecky NL, Rhodes KA, Schweizer HP. Efflux pump-mediated drug resistance in Burkholderia. Front Microbiol. 2015;6:305. [Crossref]  [PubMed]  [PMC] 
  45. Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms . Clin Microbiol Rev. 2009;22(4):582-610. [Crossref]  [PubMed]  [PMC] 
  46. Livermore DM. Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1992;36(9):2046-8. [Crossref]  [PubMed]  [PMC] 
  47. Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev. 2015;28(2):337-418. [Crossref]  [PubMed]  [PMC] 
  48. Schlisselberg DB, Kler E, Kisluk G, Shachar D, Yaron S. Biofilm formation ability of Salmonella enterica serovar Typhimurium acrAB mutants. Int J Antimicrob Agents. 2015;46(4):456-9. [Crossref]  [PubMed] 
  49. Ramage G, Bachmann S, Patterson TF, Wickes BL, López-Ribot JL. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J Antimicrob Chemother. 2002;49(6):973-80. [Crossref]  [PubMed] 
  50. Fenske DB, Cullis PR. Liposomal nanomedicines. Expert Opin Drug Deliv. 2008;5(1):25-44. [Crossref]  [PubMed] 
  51. Vanic Z, Holaeter AM, Skalko-Basnet N. (Phospho)lipid-based nanosystems for skin administration. Curr Pharm Des. 2015;21(29):4174-92. [Crossref]  [PubMed] 
  52. Rukavina Z, Vanić Ž. Current trends in development of liposomes for targeting bacterial biofilms. Pharmaceutics. 2016;8(2). pii: E18. [Crossref]  [PubMed]  [PMC] 
  53. Riaz MK, Riaz MA, Zhang X, Lin C, Wong KH, Chen X, et al. Surface functionalization and targeting strategies of liposomes in solid tumor therapy: a review. Int J Mol Sci. 2018;19(1). pii: E195. [Crossref]  [PubMed]  [PMC] 
  54. Torchilin V, Klibanov A, Huang L, O'Donnell S, Nossiff N, Khaw B. Targeted accumulation of polyethylene glycol-coated immunoliposomes in infarcted rabbit myocardium. FASEB J. 1992;6(9):2716-9. [Crossref]  [PubMed] 
  55. Northfelt DW, Martin FJ, Working P, Volberding PA, Russell J, Newman M, et al. Doxorubicin encapsulated in liposomes containing surface‐bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS‐related Kaposi's sarcoma. J Clin Pharmacol. 1996;36(1):55-63. [Crossref]  [PubMed] 
  56. Willis M, Forssen E. Ligand-targeted liposomes. Adv Drug Deliv Rev. 1998;29(3):249-71. [Crossref] 
  57. Catuogno C, Jones MN. The antibacterial properties of solid supported liposomes on Streptococcus oralis biofilms. Int J Pharm. 2003;257(1-2):125-40. [Crossref] 
  58. Mugabe C, Azghani AO, Omri A. Liposome-mediated gentamicin delivery: development and activity against resistant strains of Pseudomonas aeruginosa isolated from cystic fibrosis patients. J Antimicrob Chemother. 2005;55(2):269-71. [Crossref]  [PubMed] 
  59. Drulis-Kawa Z, Gubernator J, Dorotkiewicz-Jach A, Doroszkiewicz W, Kozubek A. In vitro antimicrobial activity of liposomal meropenem against Pseudomonas aeruginosa strains. Int J Pharm. 2006;315(1-2):59-66. [Crossref]  [PubMed] 
  60. Meers P, Neville M, Malinin V, Scotto A, Sardaryan G, Kurumunda R, et al. Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections. J Antimicrob Chemother. 2008;61(4):859-68. [Crossref]  [PubMed] 
  61. Halwani M, Yebio B, Suntres Z, Alipour M, Azghani A, Omri A. Co-encapsulation of gallium with gentamicin in liposomes enhances antimicrobial activity of gentamicin against Pseudomonas aeruginosa. J Antimicrob Chemother. 2008;62(6):1291-7. [Crossref]  [PubMed] 
  62. Alipour M, Suntres ZE, Omri A. Importance of DNase and alginate lyase for enhancing free and liposome encapsulated aminoglycoside activity against Pseudomonas aeruginosa. J Antimicrob Chemother. 2009;64(2):317-25. [Crossref]  [PubMed] 
  63. Zhou TH, Su M, Shang BC, Ma T, Xu GL, Li HL, et al. Nano-hydroxyapatite/β-tricalcium phosphate ceramics scaffolds loaded with cationic liposomal ceftazidime: preparation, release characteristics in vitro and inhibition to Staphylococcus aureus biofilms. Drug Dev Ind Pharm. 2012;38(11):1298-304. [Crossref]  [PubMed] 
  64. Alhajlan M, Alhariri M, Omri A. Efficacy and safety of liposomal clarithromycin and its effect on Pseudomonas aeruginosa virulence factors. Antimicrob Agents Chemother. 2013;57(6):2694-704. [Crossref]  [PubMed]  [PMC] 
  65. Kawai A, Yamagishi Y, Mikamo H. In vitro efficacy of liposomal amphotericin B, micafungin and fluconazole against non-albicans Candida species biofilms. J Infect Chemother. 2015;21(9):647-53. [Crossref]  [PubMed] 
  66. Dong D, Thomas N, Thierry B, Vreugde S, Prestidge CA, Wormald PJ. Distribution and inhibition of liposomes on Staphylococcus aureus and Pseudomonas aeruginosa biofilm. PLoS One. 2015;10(6):e0131806. [Crossref]  [PubMed]  [PMC] 
  67. Meng Y, Hou X, Lei J, Chen M, Cong S, Zhang Y, et al. Multi-functional liposomes enhancing target and antibacterial immunity for antimicrobial and anti-biofilm against methicillin-resistant Staphylococcus aureus. Pharm Res. 2016;33(3):763-75. [Crossref]  [PubMed] 
  68. Sugano M, Morisaki H, Negishi Y, Endo-Takahashi Y, Kuwata H, Miyazaki T, et al. Potential effect of cationic liposomes on interactions with oral bacterial cells and biofilms. J Liposome Res. 2016;26(2):156-62.
  69. Rivero Berti I, Dell'Arciprete ML, Dittler ML, Mi-an A, Fernández Lorenzo de Mele M, Gonzalez M. Delivery of fluorophores by calcium phosphate-coated nanoliposomes and interaction with Staphylococcus aureus biofilms. Colloids Surf B Biointerfaces. 2016;142:214-22. [Crossref]  [PubMed] 
  70. Zahra MJ, Hamed H, Mohammad RY, Nosratollah Z, Akbarzadeh A, Morteza M. Evaluation and study of antimicrobial activity of nanoliposomal meropenem against Pseudomonas aeruginosa isolates. Artif Cells Nanomed Biotechnol. 2017;45(5):975-80. [Crossref]  [PubMed] 
  71. Dias-Souza MV, Soares DL, Dos Santos VL. Comparative study of free and liposome-entrapped chloramphenicol against biofilms of potentially pathogenic bacteria isolated from cooling towers. Saudi Pharm J. 2017;25(7):999-1004. [Crossref]  [PubMed]  [PMC] 
  72. Alhariri M, Majrashi MA, Bahkali AH, Almajed FS, Azghani AO, Khiyami MA, et al. Efficacy of neutral and negatively charged liposome-loaded gentamicin on planktonic bacteria and biofilm communities. Int J Nanomedicine. 2017;12:6949-61. [Crossref]  [PubMed]  [PMC] 
  73. Ye T, Sun S, Sugianto TD, Tang P, Parumasivam T, Chang YK, et al. Novel combination proliposomes containing tobramycin and clarithromycin effective against Pseudomonas aeruginosa biofilms. Int J Pharm. 2018;552(1-2):130-8. [Crossref]  [PubMed] 
  74. Vanić Ž, Rukavina Z, Manner S, Fallarero A, Uzelac L, Kralj M, et al. Azithromycin-liposomes as a novel approach for localized therapy of cervicovaginal bacterial infections. Int J Nanomedicine. 2019;14:5957-76. [Crossref]  [PubMed]  [PMC] 
  75. Li D, Chen S, Dou H, Wu W, Liu Q, Zhang L, et al. Preparation of cefquinome sulfate cationic proliposome and evaluation of its efficacy on Staphylococcus aureus biofilm. Colloids Surf B Biointerfaces. 2019;182:110323. [Crossref]  [PubMed] 

.: Up To Date

.: Process List

Login



Contact


Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com