Antimicrobial Resistance in the Planning of the Empirical Therapy of Upper Respiratory Tract Infections: Current Situation and Treatment Strategies in Turkey and in the World

Abstract

Antimicrobial resistance (AMR) is a very important problem with increasing prevalence worldwide and poor clinical outcomes due to recurrent infections and risk of death. In spite of the increased development of antibiotic resistance due to excessive and irrational antibacterial use in recent years, a new antibacterial drug has not been developed despite the developing new technologies. This situation causes rapidly growing AMR problem. As a country among all ESAC-net European countries, Turkey has the highest rate of antibacterial drug use. Respiratory tract infections are a common problem in terms of high prevalence and high rates of antibiotic use, as well as an ongoing problem for the treatment of community-acquired and hospital-acquired infections and represent a challenge for AMR prevention strategies. Approaches to prevent excessive and irrational use of antibiotics at both the primary and hospital levels have a significant role in combating AMR. In this review, AMR which is generally ignored in the planning of empirical treatment of upper respiratory tract infections will be evaluated in terms of the current situation and strategies to combat, in Turkey and in the world.

Keywords

• antimicrobial resistance
• antibiotic use
• respiratory tract infections

ÜST SOLUNUM YOLU İNFEKSİYONLARININ AMPİRİK TEDAVİSİNİN PLANLAMASINDA ANTİMİKROBİYAL DİRENÇ: TÜRKİYE VE DÜNYADAKİ MEVCUT DURUM VE MÜCADELE STRATEJİLERİ

Abstract

Antimikrobiyal direnç (AMD) kötü klinik sonuçlar, artmış rekürren infeksiyon ve ölüm riski nedeniyle çok önemli, dünya genelinde prevalansı hızla artan bir sorundur. Son yıllarda aşırı ve akılcı olmayan antibakteriyel kullanımına bağlı artan direnç gelişimi sorununa karşın gelişen teknolojiye rağmen yeni bir antibakteriyel ilaç kullanıma alınamamıştır. Bu durum AMD probleminin hızla büyümesine neden olmaktadır. Türkiye ESAC-Net kapsamındaki tüm Avrupa ülkeleri arasında en yüksek oranda antibakteriyel ilaç kullanımına sahip ülke konumundadır. Solunum yolu infeksiyonları oldukça yaygın ve yüksek antibiyotik kullanım oranları açısından hastane kaynaklı infeksiyonlarda olduğu kadar, toplum kaynaklı infeksiyonların tedavisi için de süregiden bir sorun ve AMD önleme stratejileri için zorlu bir alandır. Gerek birinci basamak gerekse hastane düzeyinde aşırı ve akılcı olmayan antibiyotik kullanımının önüne geçilmesi için alınacak tedbirlerin AMD ile mücadelede rolü büyüktür. Bu derlemede, üst solunum yolu infeksiyonlarının ampirik tedavisinin planlamasında genelde göz ardı edilen AMD, Türkiye ve dünyadaki mevcut durum ve mücadele stratejileri açısından ele alınacaktadır.

Keywords

• antimikrobiyal direnç
• antibiyotik kullanımı
• solunum yolu infeksiyonları

References

1. Amsdemn GW. Pneumococcal resistance in perspective:how well are we combating it? Pediatr Infect Dis J. 2004;23(Suppl 2):S125-8. https://doi.org/10.1097/01.inf.0000112526.55182.e0
2. Antibiotic Resistance Threats in the United States. Centers for Disease Control and Prevention. 2013. Downloaded from http://www.cdc.gov/drugresistance/threat-report-2013/index.html (erişim tarihi 20.1.2018).
3. Antimicrobial resistance: global report on surveillance 2014. World Health Organization; 2014. Downloaded from http://www.who.int/drugresistance/documents/surveillancereport/en/ (erişim tarihi 12.03.2018).
4. Appaneal HJ, Caffrey AR, Jiang L, Dosa D, Mermel LA, LaPlante KL. Antibiotic resistance rates for Pseudomonas aeruginosa clinical respiratory and bloodstream isolates among the Veterans Affairs Healthcare System from 2009 to 2013. Diagn Microbiol Infect Dis. 2018;90(4):311-5. https://doi.org/10.1016/j.diagmicrobio.2017.11.022
5. Bae S, Lee J, Lee J, et al. Antimicrobial resistance in Haemophilus influenzae respiratory tract isolates in Korea: results of a nationwide acute respiratory infections surveillance. Antimicrob Agents Chemother. 2010;54(1):65-71. https://doi.org/10.1128/AAC.00966-09
6. Ball P, Baquero F, Cars O, et al. Antibiotic therapy of community respiratory tract infections: strategies for optimal outcomes and minimized resistance emergence. The consensus group on resistance and prescribing in respiratory tract infection. J Antimicrob Chemother. 2002;49(1):31-40. https://doi.org/10.1093/jac/49.1.31
7. Baysallar M, Küçükkaraaslan A, Özyurt M. Haemophilus influenzae’de in vitro makrolit direncinin araştırılması ve yorumlama kriterlerinin değerlendirilmesi. Infeksiyon Derg. 2002;16:43-7.
8. Baquero F. Antibiotic resistance in Spain. What can be done? Task force of the general direction for health planning of the Spanish Ministry of Health. Clin Infect Dis. 1996;23(4):819-23. https://doi.org/10.1093/clinids/23.4.819

9. Berkiten R. Beta-lactamase activity and ampicillin resistance in Haemophilus influenzae strains isolated in Turkey (1987-2002). ANKEM Derg. 2004;18(1):53-60.
10. Bodur H. Akılcı antibiyotik Kullanımı. Akılcı antibiyotik kullanımı ve farkındalık sempozyumu, Kasım 2015. http://www.anh.gov.tr (erişim tarihi 01.2.2018).
11. Boonyasiri A, Thamlikitkul V. Effectiveness of multifaceted interventions on rational use of antibiotics for patients with upper respiratory tract infections and acute diarrhea. J Med Assoc Thai. 2014;97(Suppl 3):S13-9.
12. Braman SS. Chronic cough due to acute bronchitis: ACCP evidence based clinical practice guidelines. Chest. 2006;129(Suppl 1):95-103. https://doi.org/10.1378/chest.129.1_suppl.95S
13. CDC. Antibiotic resistance threats in the United States, 2013. 2013. Available from: http://www. cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. (erişim tarihi 01.03.2018).
14. Chow AW, Benninger MS, Brook I, et al. Infectious Diseases Society of America. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis. 2012;54(8):72-112. https://doi.org/10.1093/cid/cis370
15. Cilloniz C, Gabarrus A, Ferrer M, et al. Communityacquired pneumonia due to multidrug- and nonmultidrug-resistant Pseudomonas aeruginosa. Chest. 2016;150(2):415-25. https://doi.org/10.1016/j.chest.2016.03.042
16. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin Infect Dis. 2006;42(Suppl 2):S82-9. https://doi.org/10.1086/499406
17. Croxatto A, Prod’hom G, Greub G. Applications of MALDI-TOF mass spectrometry in clinical diagnostic microbiology, FEMS. Microbiol Rev. 2012;36(2):380-407. https://doi.org/10.1111/j.1574-6976.2011.00298.x
18. Dagan R, Klugman KP, Craig WA et al. Evidence to support the rationale that bacterial eradication in respiratory tract infection is an important aim of antimicrobial therapy. J Antimicrob Chemother. 2001;47(2):129-40. https://doi.org/10.1093/jac/47.2.129
19. Darabi A, Hocquet D, Dowzicky MJ. Antimicrobial activity against Streptococcus pneumoniae and Haemophilus influenzae collected globally between 2004 and 2008 as part of the Tigecycline Evaluation and Surveillance Trial. Diagn Microbiol Infect Dis. 2010;67(1):78-86. https://doi.org/10.1016/j.diagmicrobio.2009.12.009
20. Erdoğan H, İnan N, Nazik H, Öngen B, Gürler N. Çocuklarda alt solunum yollarından izole edilen bakterilerde antibiyotik direnci. ANKEM Derg. 2004;18(1):12-8.
21. European Antimicrobial Resistance Surveillance System, (EARSS) Annual Report 2005 Bilthoven, The Netherlands (2005). https://ecdc.europa.eu (erişim tarihi 10.10 2017).
22. European Antimicrobial Resistance Surveillance System, (EARSS) Annual Report 2008 Bilthoven, The Netherlands (2008). https://ecdc.europa.eu(erişim tarihi 10.10 2017).
23. European Centre for Disease Prevention and Control, European Food Safety Authority, European Medicines Agency. ECDC/EFSA/EMA first joint report on the integrated analysis of the consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from humans and food-producing animals. EFSA J. 2015;13(1):4006-114. https://doi.org/10.2903/j.efsa.2015.4006
24. European Centre for Disease Prevention and Control. Antimicrobial Resistance Surveillance in Europe 2012. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2013. http://ecdc.europa.eu/en/publications/Publications/antimicrobialresistance-surveillance-europe-2012.pdf (erişim tarihi 01.01.2018).
25. Feikin DR, Klugman KP. Historical changes in pneumococcal serogrup distribution: Implications for the era of pneumococcal conjugate vaccines. Clin Infect Dis. 2002;35(5):547-55. https://doi.org/10.1086/341896
26. Fırat M, Ersoy Y, Eşel D, Bayraktar M, Çaylan R, Durmaz R. Meninjitli hastalardan izole edilen pnömokokların serotip dağılımı ve antibiyotiklere duyarlılıkları. Mikrobiyol Bul. 2006;40(3):169-77.
27. Fraser D, Givon-Lavi N, Bilenko N, Dagan R. A decade (1989-1998) of pediatric invasive pneumococcal disease in 2 populations residing in 1 geographic location: Implications for vaccine choice. Clin Infect Dis. 2001;33(4):421-7. https://doi.org/10.1086/321874
28. Gren K, Porter Pong S, Low DE. Pneumococcal resistance surveillance in Canada. Clin Microbiol Infect. 2005;11(2):314.
29. Gür D, Özalp M, Sümerkan B et al. Prevalence of antimicrobial resistance in Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and Streptococcus pyogenes: results of a multicentre study in Turkey. Int J Antimicrob Agents. 2002;19(3):207-11. https://doi.org/10.1016/S0924-8579(02)00003-1
30. Harbarth S, Albdirch W, Braun-Buisson C. Outpatient antibiotic use and prevalence of antibiotic-resistant pneumococci in France and Germany: A sociocultural perspective. Emerg Infect Dis. 2002;8(12):1460-7. https://doi.org/10.3201/eid0812.010533
31. Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: Implications for conjugate vaccine formulation and use, part I. Clin Infect Dis. 2000;30(1):100-21. https://doi.org/10.1086/313608
32. Hoban D, Baquero F, Reed V et al. Demographic analysis of antimicrobial resistance among Streptococcus pneumoniae: worldwide results from PROTEKT 1999-2000. Int J Infect Dis. 2005;9(5):262-73. https://doi.org/10.1016/j.ijid.2004.07.008
33. Hwang AY, Gums JG. The emergence and evolution of antimicrobial resistance: Impact on a global scale. Bioorg Med Chem. 2016;24(24):6440-5. https://doi.org/10.1016/j.bmc.2016.04.027
34. İlki A, Sagiroglu P, Ergormus N, Soyletir G. Trends in antibiotic susceptibility patterns of Streptococcus pneumoniae and Haemophilus influenzae isolates: four years follow up. Mikrobiyol Bul. 2010;44(2):169-75.
35. Kaleli İ, Aksit F. Penicillin resistance in Streptococcus pneumoniae strains. FLORA. 1999;4(4):287-92.
36. Kenealy T, Arroll B. Antibiotics for the common cold and acute purulent rhinitis. Cochrane Database Syst Rev. 2013;6:CD000247. https://doi.org/10.1002/14651858.CD000247.pub3
37. Laxminarayan R, Duse A, Wattal C et al. Antibiotic resistance-the need for global solutions. Lancet Infect Dis. 2013;13(12):1057-98. https://doi.org/10.1016/S1473-3099(13)70318-9
38. Liapikou A, Cilloniz C, Mensa J, Torres A. New antimicrobial approaches to gram positive respiratory infections. Pulm Pharmacol Ther. 2015;32:137-43. Review. https://doi.org/10.1016/j.pupt.2014.05.003 Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131(3):e964-99. https://doi.org/10.1542/peds.2012-3488
39. Liu B, Pop M. ARDB-Antibiotic Resistance Genes Database. Nucleic Acids Res. 2009;37(Database issue):D443-7. https://doi.org/10.1093/nar/gkn656
40. Lonks JR, Garau J, Medeiros AA. Implications of antimicrobial resistance in the empirical treatment of community-acquired respiratory tract infections: The case of macrolides. J Antimicrob Chemother. 2002;50(Suppl 2):87-92. https://doi.org/10.1093/jac/dkf512
41. Lynch III JP, Zhanel GG. Streptococcus pneumoniae: epidemiology and risk factors, evolution of antimicrobial resistance, and impact of vaccines. Curr Opin Pulm Med. 2010;16(3):217-25. https://doi.org/10.1097/MCP.0b013e3283385653
42. MacGowan A, Macnaughton E. Antibiotic resistance. Medicine. 2017;45(10):622-8. https://doi.org/10.1016/j.mpmed.2017.07.006
43. Malhan S, Oksuz E, Unal S. The economic burden of acute bacterial rhinosinusitis and acute otitis media in Turkey: an epidemiology based cost of illness study with respect to clinical practice and available guidelines. Value in Health. 2017;20: A785.https://doi.org/10.1016/j.jval.2017.08.2294
44. Mamal-Torun M, Alkan E, Altınkum SM, Aksın E, Kulaksız B, Yüksel P: Haemophilus influenzae’de antimikrobiklere direnç sıklığı. Türk Mikrobiyol Cem Derg. 1998;28:49.
45. McCaig LF, Besser RE, Hughes JM. Trends in antimicrobial prescribing rates for children and adolescents. JAMA. 2002;287(23):3096-102. https://doi.org/10.1001/jama.287.23.3096
46. Metlay JP, Singer DE. Outcomes in lower respiratory tract infections and the impact of antimicrobial drug resistance. Clin Microbiol Infect. 2002;8(Suppl 2):1-11. https://doi.org/10.1046/j.1469-0691.8.s.2.4.x
47. Munita JM, Arias CA. Mechanisms of Antibiotic Resistance. Microbiol Spectr. 2016;4(2):1-37.
48. Naguchi N, Tano J, Nasu Y, et al. Antimicrobial susceptibilities and distribution of resistance genes for beta-lactams and macrolides in Streptococcus pneumoniae isolated between 2002 and 2004 in Tokyo. Int J Antimicrob Agents. 2007;29(1):26-33. https://doi.org/10.1016/j.ijantimicag.2006.09.004
49. O’Neill J. Review on antimicrobial resistance. Tackling a global health crisis: initial steps. Tacking drug-resistant infections globally. London, UK: HM Government (2015).
50. O’Neill J. Review on antimicrobial resistance. Tackling drug-resistant infections globally. Final raport and recommendations. London, UK: HM Government (2016)
51. Özalp M, Anadol D, Kiper N, Gür D. Haemophilus influenzae ve Streptococcus pneumoniae suşlarında antibiyotik direnci, 8. Türk Klinik Mikrobiyoloji ve İnfeksiyon Hastalıkları Kongresi, Program ve Özet kitabı s.723, Antalya (1997).
52. Ozkurt Z, Erol S, Kadanali A, Ertek M, Ozden K, Tasyaran MA. Changes in antibiotic use, cost and consumption after an antibiotic restriction policy applied by infectious disease specialists. Jpn J Infect Dis. 2005;58(6):338-43.
53. Ozyilmaz E, Akan OA, Gulhan M, et al. Major bacteria of communityacquired respiratory tract infections in Turkey. Jpn J Infect Dis. 2005;58(1):50-2.
54. Öztürk R. Akilci antibiyotik kullanimi ve ülkemizde antimikrobik maddelere direnç sorunu I.Ü. Cerrahpasa Tıp Fakültesi Sürekli Tıp Egitimi etkinlikleri, Toplumdan edinilmis infeksiyonlara pratik yaklasimlar Sempozyum Dizisi 2008;61:1-16.
55. Pelgrift RY, Friedman AJ. Nanotechnology as a therapeutic tool to combat microbial resistance. Adv Drug Deliv Rev. 2013;65(13-14):1803-15. https://doi.org/10.1016/j.addr.2013.07.011
56. Pfaller MA, Farrell DJ, Sader HS, Jones RN. AWARE Ceftaroline Surveillance Program (2008e2010): trends in resistance patterns amongm Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States. Clin Infect Dis. 2012;55(Suppl. 3):S187-93. https://doi.org/10.1093/cid/cis561
57. Prat C, Lacoma A. Bacteria in the respiratory tracthow to treat? Or do not treat? Int J Infect Dis. 2016;51:113-22. https://doi.org/10.1016/j.ijid.2016.09.005
58. Prina E, Ranzani OT, Polverino E, et al. Risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia. Ann Am Thorac Soc. 2015;12(2):153-60. https://doi.org/10.1513/AnnalsATS.201407-305OC
59. Queenan K, Häsler B, Rushton J. A one health approach to antimicrobial resistance surveillance: is there a business case for it? Int J Antimicrob Agents. 2016;48(4):422-7. https://doi.org/10.1016/j.ijantimicag.2016.06.014
60. Reinert RR. The antimicrobial resistance profile of Streptococcus pneumoniae. Clin Microbiol Infect. 2009;15(Suppl 3):7-11. https://doi.org/10.1111/j.1469-0691.2009.02724.x
61. Restrepo MI, Mortensen EM, Velez JA, Frei C, Anzueto A. A comparative study of communityacquired pneumonia patients admitted to the ward and the ICU. Chest. 2008;133(3):610-7. https://doi.org/10.1378/chest.07-1456
62. Roca I, Akova M, Baquero F, et al. The global threat of antimicrobial resistance: science for intervention. New Microbes New Infect. 2015;6(6):22-9. https://doi.org/10.1016/j.nmni.2015.02.007
63. Ruggeberg JU, Ketteler K, MacKenzie CR, Von Kries R, Reinert RR, Schroten RH. Blood culture sampling rates at a German pediatric university hospital and incidence of invasive pneumococcal disease. Infection. 2004;32(7):78-81. https://doi.org/10.1007/s15010-004-3104-2
64. Sener B, Tunckanat F, Ulusoy S, et al. A survey of antibiotic resistance in Streptococcus pneumoniae and Haemophilus influenzae in Turkey, 2004-2005. J Antimicrob Chemother. 2007;60(3):587-93. https://doi.org/10.1093/jac/dkm232
65. Shaikh N, Leonard E, Martin JM. Prevalence of streptococcal pharyngitis and streptococcal carriage in children: a meta-analysis. Pediatrics. 2010;126(3):e557-564. https://doi.org/10.1542/peds.2009-2648
66. Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):e86-102. https://doi.org/10.1093/cid/cis629
67. Soyletir G, Altinkanat G, Gur D, et al. Results from the Survey of Antibiotic Resistance (SOAR) 2011-13 in Turkey. J Antimicrob Chemother. 2016;71(Suppl 1):i71-83. https://doi.org/10.1093/jac/dkw075
68. Sümerkan B, Gökahmetoğlu S, Aygen B, Karagöz S. Klinik örneklerden izole edilen Streptococcus pneumoniae suşlarının çeşitli antibiyotiklere duyarlılıkları. Mikrobiyol Bul. 1997;31:331-8.
69. Şener B, Tunçkanat F, Ulusoy S, et al. A survey of antibiotic resistance in Streptococcus pneumoniae and Haemophilus influenzae in Turkey 2004-2005. J Antimicrob Chemother. 2007;60(3):583-93. https://doi.org/10.1093/jac/dkm232
70. Tacconelli E, Cataldo MA, Dancer SJ, et al. ESCMID guidelines for the management of the infection control measures to reduce transmission of multidrug-resistant Gram negative bacteria in hospitalized patients. Clin Microbiol Infect. 2014;20(Suppl 1):1-55. https://doi.org/10.1111/1469-0691.12427
71. Tiryakioğlu N, Aksu B, Hasdemir UÖ. The relationship between macrolide resistance mechanisms and serotypes of Streptococcus pneumoniae. MÜSBED. 2012;2(3):124-9.
72. Torumkuney D, Gur D, Soyletir G, et al. Results from the Survey of Antibiotic Resistance (SOAR) 2002-09 in Turkey. J Antimicrob Chemother. 2016;71(Suppl 1):i85-91. https://doi.org/10.1093/jac/dkw067
73. Tosun E, Oya Topaloglu O, Yalçın A. Respiratory tract infections: antibiotic usage rates and cost of treatment. Türk Aile Hek Derg. 2008;12(1):25-30. https://doi.org/10.2399/tahd.08.025
74. Transatlantic Taskforce on Antimicrobial Resistance (TATFAR). Progress report: recommendations for future collaboration between the US and EU. Atlanta, GA: US Centers for Disease Control and Prevention (CDC); 2014.
75. Tristram S, Jacobs MR, Appelbaum PC. Antimicrobial resistance in Haemophilus influenza. Clin Microbiol Rev. 2007;20(2):368-89. https://doi.org/10.1128/CMR.00040-06
76. Tuncer İ, Arslan U, Fındık D, Ural O. Klinik örneklerden izole edilen Streptococcus pneumoniae suşlarında artan penisilin direnci ve bazı antibiyotiklere karşı direnç durumu. ANKEM Derg. 2005;19(1):35-8.
77. Tunçkanat F, Akan Ö, Gür D, Akalın HE. Streptococcus pneumoniae suşlarında penisilin direnci. Mikrobiyol Bul. 1992;26(4):307-13. Türk Eczacılar Birliği. 2016’da sağlık, ilaç ve eczacılık alanında neler oldu? Eczacılar gözünden kuşbakışı bir değerlendirme. 80. Türkiye İlaç ve Tıbbi Cihaz Kurumu. Ulusal Antibakteriyel İlaç Tüketim Sürveyansı – 2011. Ankara, 2015. http://www.akilciilac.gov.tr/?p=2280 (erişim tarihi 10.1.2018).
78. Versporten A, Bolokhovets G, Ghazaryan L, et al; WHO/Europe-ESAC Project Group. Antibiotic use in eastern Europe: a cross-national database study in coordination with the WHO Regional Office for Europe. Lancet Infect Dis. 2014;14(5):381-7. https://doi.org/10.1016/S1473-3099(14)70071-4
79. Viens AM, Littmann J. Is antimicrobial resistance a slowly emerging disaster? Public Health Ethics. 2015;8(3):255-65. https://doi.org/10.1093/phe/phv015
80. World Health Organization (WHO). Antimicrobial resistance: global report on surveillance-2014.
81. WHO updates Essential Medicines List. http://www.who.int/news-room/detail/06-06-2017- who-updates-essential-medicines-list-with-newadvice-on-use-of-antibiotics-and-adds-medicinesfor-hepatitis-c-hiv-tuberculosis-and-cancer (erişim tarihi 03.1.2018).
82. Yaman A, Kibar F, Büyükçelik Ö, Dündar İH. Klinik örneklerden izole edilen Streptococcus pneumoniae suşlarının çeşitli antibiyotiklere duyarlılıklarının araştırılması. ANKEM Derg. 2004;18(Ek 1):2.
83. Yildiz I, Varkal MA, Unuvar E. Günümüzde sefalosporinler ve antibiyotik direnci. Çocuk Derg. 2014;14(1):22-7.
84. Zarakolu P, Soyletir G, Gur D et al. Antimicrobial resistance patterns of respiratory pathogens: a local report from Turkey. Clin Microbiol Infect. 2003;9(12):1257-8. https://doi.org/10.1111/j.1469-0691.2003.00780.x