中文摘要
背景：氟化奎林酮類抗生素是臨床上普遍使用的廣效型抗生素，近年來，許多使用氟化奎林酮類抗生素引起肌腱病變的病例陸續報告出來，然而目前相關文獻十分貧瘠，仍無足夠的證據去釐清兩者的關聯。
目的：觀察國內氟化奎林酮類抗生素的使用情形，以及肌腱病變的流行狀況，並進一步釐清氟化奎林酮類抗生素與肌腱斷裂的相關性。
方法：本研究為回溯性、觀察性研究，利用次級資料進行研究分析，資料來源為國家衛生研究院提供的全民健康保險資料檔一2005年百萬人承保抽樣歸人檔。為觀察國內氟化奎林酮類抗生素的使用情形，以及肌腱病變的流行狀況，研究設計有兩部分，首先挑選出「2000年至2005年間在保者」為研究世代（共950,663位個案），回溯2000年至2005年期間所有就醫資料；另一部分，採用配對病例對照研究法，由「2005年在保者」抽樣母群（共1.000,000位個案）中，挑選就醫年齡大於18歲，且於2005年至2007年間曾經被診斷為肌腱斷裂的個案，排除一年前有癌症和後天免疫缺乏症候群的個案，視為病例組，依據病例組的性別、年齡、就醫類型（門診/住院）和指標日期（index date）進行配對，共有1032位病例組和5160位對照組，本研究將分析肌腱斷裂的可能危險因子，並比較兩組人口自指標日期前一年內氟化奎林酮類抗生素的使用情形。統計軟體為SAS套裝軟體9.2版，採用條件式邏輯斯迴歸模型（conditional logistic regression model）進行統計分析。
結果：於研究期間每年平均有2％的國人曾經使用氟化奎林酮類抗生素。女性的使用率相較於男性更高，且60歲以上老年人口的使用率也相較於其他年齡層更高。肌腱炎與骨周圍附著組織病變的發生率較為接近，平均為3.07％ 和2.85％；相較之下，肌腱斷裂十分少見，發生率（0.03％）為肌腱炎的百分之一；又以阿基里斯腱斷裂更為罕見，發生率（0.001％）僅為肌腱炎的三千分之一。肌腱炎和骨周圍附著組織病變以女性發生率較高；肌腱斷裂和阿基里斯腱斷裂以男性發生率較高。肌腱病變大多以60歲以上老年人口的發生率最高；除了阿基里斯腱斷裂的病人，以18～59歲成年人口的發生率最高。罹患肌腱斷裂的可能危險因子有下述幾項：一年內的門診就醫次數、缺血性心臟病、高血壓、糖尿病、甲狀腺疾病、痛風、支氣管炎、氣喘、胃/十二指腸潰瘍、慢性肝病/肝硬化、中毒、肌肉骨骼系統疾病、損傷，以及過去一年內曾經使用類固醇。研究結果指出過去一年內曾經使用氟化奎林酮類抗生素的病人，罹患肌腱斷裂的風險顯著較低（ORadj=0.59，95％ CI =0.41-0.85）。若以不同的藥品使用特性切入，僅在過去三個月內使用藥品（ORadj =0.50，95％ CI=0.28-0.89）以及過去一年內曾經使用口服劑型（ORadj =0.61，95％ CI=0.42-0.88）的病人，罹患肌腱斷裂的風險亦顯著較低。
討論：單純從國內氟化奎林酮類抗生素的使用率以及肌腱病變的發生率來看，並沒有一致的趨勢，國內氟化奎林酮類抗生素的使用率和肌腱病變的發生率仍是相對較低，受限於研究樣本數十分稀少，以不同的藥品使用特性切入分析，大多無法觀察到統計上的顯著性，氟化奎林酮類抗生素與肌腱病變的相關性仍須未來進一步釐清與驗證。

英文摘要（Abstract）
Background:
Fluoroquinolones (FQs) have been widely used for antibacterial therapy. This class of antibiotics used to be regarded as safe and effective; however, FQs induced tendon disorders have been reported more frequently during the past years. Currently available literature is insufficient to explain the association between FQs and tendon disorders.
Objectives:
This study was intended to observe the potential health effects between FQs use and tendon disorders by describing the trend of FQs use and tendon disorders during the period 2000-2005 in Taiwan, and further, to explore the association between FQs and tendon rupture.
Methods:
This is a retrospective observational study. Data sources were derived from claims data of the National Health Insurance Research Database (NHIRD). To demonstrate the trend of FQs use and tendon disorders during the period 2000-2005 in Taiwan, a healthy insurer cohort (950,663 beneficiaries) in the period 2000-2005 was identified. Furthermore, matched case-controls were randomly sampled from the original dataset of one million beneficiaries in 2005. Cases were patients aged ≥18 years and had a diagnosis of non-traumatic tendon ruptures in 2005-2007. Controls were randomly selected by 1:5 sampling rate and matched by gender, age, type of medical visit (outpatient/inpatient), and index date. There are 1032 cases and 5160 controls to observe the potential risk factors of tendon disorders and to compare the use of FQs between the two groups for one year from the index date. SAS 9.2 Edition statistical package was used to analysis. A conditional logistic regression model was performed to estimate the odds ratio.
Results:
An average of 2% of the population had used FQs during the period 2000-2005 in Taiwan. Patients who were females or age ≧60 years were more often prescribed with FQs than other subgroups. The incidence rates of tendinitis, peripheral enthesopathies and allied syndromes were 3.07% and 2.85%, while the incidence rates of tendon rupture and Achilles tendon rupture were 0.03% and 0.001%. Tendinitis and peripheral enthesopathies were more often in females than males; on the contrary, tendon rupture and Achilles tendon rupture occurred more often in males than females. Incidence rates of tendon disorders were the highest among people aged ≧60 years except for Achilles tendon rupture which was among people aged 18~59 years. The potential risk factors for tendon rupture were inpatient visits, ischemic heart disease, hypertension, diabetes, thyroid disease, gout, bronchitis, asthma, stomach/duodenal ulcer, chronic liver disease/liver sclerosis, poisoning, musculoskeletal and connective tissue diseases, injuries, and corticosteroids use. FQs use within the past one year significantly decreased the risk of tendon rupture(OR adj = 0.59, 95% CI=0.41-0 .85), decreased risk was also observed for those who used FQs over the past three months(OR adj =0.50，95％ CI=0.28-0.89), and for those who used oral dosage form FQs over the past year (OR adj =0.61，95％ CI=0.42-0.88).
Discussion:
We did not observe a consistent trend of FQs use and tendon disorders. The sample size of FQs users was relatively small and the low incidence rate of tendon disorder in together limited the significance of statistical analysis. To demonstrate the association between FQs and tendon disorders would need further research for clarification and verification.
Discussion:
We did not observe a consistent trend of FQS use and tendon disorders. The sample size of FQs users was relatively small and the low incidence rate of tendon disorder in together limited the significance of statistical analysis. To demonstrate the association between FQs and tendon disorders would need further research for clarification and verification.

第一章 緒論 1
第一節 研究背景與動機…………………………………………… 1
第二節 研究目的與問題…………………………………………… 3
第三節 研究重要性………………………………………………… 4
第二章 文獻探討 5
第一節 氟化奎林酮類抗生素…………………………………..…… 5
一、起源與發展現況………………………………………… 5
二、藥品簡介………………………………………………… 6
三、藥品不良反應…………………………………………… 12
第二節 肌腱病變…………………………………………………… 15
第三節 氟化奎林酮類抗生素與肌腱病變的相關性……………… 17
一、相關實證研究…………………………………………… 17
二、研究現況………………………………………………… 21
三、探討相關因素…………………………………………… 24
第三章 研究材料與方法 28
第一節 研究設計…………………………………………………… 28
一、氟化奎林酮類抗生素與肌腱病變之現況分析……..… 28
二、氟化奎林酮類抗生素與肌腱斷裂之相關性研究……. 29
第二節 研究架構…………………………………………………… 31
第三節 資料來源與樣本選取……………………………………… 33
一、資料來源……………………………………….……… 33
二、樣本選取……………………………………….……… 34

第四節 研究變項定義及測量……………………………………… 39
一、病人特質………………………………………….……. 39
二、研究疾病………………………………………….…… 39
三、疾病史……………………………………………….… 40
四、醫療利用情形…………………………………………. 47
第五節 資料處理與統計分析……………………………………..… 62
一、資料處理流程……………………………………….… 62
二、統計分析………………………………………….…… 66
第四章 研究結果 69
第一節 國內氟化奎林酮類抗生素的使用情形……………..……… 69
一、藥品使用者形態……………………….……………… 69
二、處方箋形態……………………………….…………… 74
第二節 國內肌腱病變的流行狀況………………………..………… 78
一、各年度肌腱病變盛行率與發生率…………….……… 78
二、不同類型肌腱病變病人的人口學特性………….…… 81
三、肌腱斷裂的發生情形…………………………………. 85
第三節 氟化奎林酮類抗生素與肌腱病變的關聯………………..… 89
一、疾病史……………………………………………….… 89
二、醫療服務利用情形………………………………….… 94
三、氟化奎林酮類抗生素的使用情形……………………. 97
四、氟化奎林酮類抗生素與類固醇同時併用……………. 101
第五章 研究討論與討論 103
第一節 研究討論…………………………………………………… 103
一、氟化奎林酮類抗生素……….………………………… 103
二、肌腱病變……………………………………………… 104
三、氟化奎林酮類抗生素與肌腱斷裂之相關性研究……. 104
四、探討研究設計與方法….……………………………… 106
五、研究限制……………………………………………… 108
第二節 結論與建議…………………………………………….…… 109
一、結論…………………………………………………… 109
二、建議…………………………………………………… 110
參考文獻 112
附錄 115
一、 氟化奎林酮類抗生素之所有健保核准藥品………..….……… 115
二、 類固醇之所有健保核准藥品……..……………….…………… 118

1. Wolfson JS, Hooper DC. Overview of fluoroquinolone safety. Am J Med. 1991, 91, pp. 153S-161S.
2. Bailey RR, Kirk JA, Peddie BA. Norfloxacin-induced rheumatic disease. N Z Med J.1983, 96, p. 590.
3. Casparian JM, Luchi M, Moffat RE, et al. Quinolones and tendon ruptures. South Med J. 2000, 93, pp. 488-491.
4. Gold L, Igra H. Levofloxacin-induced tendon rupture: a case report and review of the literature. J Am Board Fam Pract. 2003, 16, pp. 458-460.
5. van der Linden PD, van Puijenbroek EP, Feenstra J, et al. Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998. Arthritis Rheum. 2001, 45, pp. 235-239.
6. Zabraniecki L, Negrier I, Vergne P, et al. Fluoroquinolone induced tendinopathy: report of 6 cases. J Rheumatol.1996, 23, pp. 516-520.
7. Harrell RM. Fluoroquinolone-induced tendinopathy: what do we know? South Med J. 1999;92, pp. 622-625.
8. Davey PG BR, Newey J, Reeves D, et al. Wilson J Growth in the use of antibiotics in the community in England and Scotland in 1980-93,. BMJ. 1996, 312, p. 613.
9. van der Linden PD, Nab HW, Simonian S, et al. Fluoroquinolone use and the change in incidence of tendon ruptures in the Netherlands. Pharm World Sci. 2001;23, pp. 89-92.
10. Melhus A. Fluoroquinolones and tendon disorders. Expert Opin Drug Saf. 2005, 4, pp. 299-309.
11. Food and Drug Administration. FDA Requests Boxed Warnings Fluoroquinolone Antimicrobial Drugs Seeks to Strengthen Warnings Concerning Increased Risk of Tendinitis and Tendon Rupture [Announcement]. Retrieved July 8 2008,from the World Wide Web: http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/2008/ucm116919.htm.
12. Appelbaum PC, Hunter PA. The fluoroquinolone antibacterials: past, present and future perspectives. Int J Antimicrob Agents. 2000, 16, pp. 5-15.
13. Emmerson AM, Jones AM. The quinolones: decades of development and use. J Antimicrob Chemother. 2003, 51, pp.13-20.
14. Andersson MI, MacGowan AP. Development of the quinolones. J Antimicrob Chemothe. 2003, 51, pp. 1-11.
15. Ambrose PG, Owens RC, Jr. New antibiotics in pulmonary and critical care medicine: focus on advanced generation quinolones and cephalosporins. Semin Respir Crit Care Med. 2000, 21, pp.19-32.
16. Hooper DC, Wolfson JS. Fluoroquinolone antimicrobial agents. N Engl J Med. 1991, 324, pp.384-394.
17. Rodvold KA, Piscitelli SC. New oral macrolide and fluoroquinolone antibiotics: an overview of pharmacokinetics, interactions, and safety. Clin Infect Dis. 1993, 7, pp. 192-199.
18. Mather R, Karenchak LM, Romanowski EG, et al. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002, 133, pp. 463-466.
19. Takayama S, Hirohashi M, Kato M, et al. Toxicity of quinolone antimicrobial agents. J Toxicol Environ Health. 1995, 45, pp. 1-45.
20. Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: a review focusing on newer agents. Clin Infect Dis. 1999 , 28, pp.352-364.
21. Grady R. Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J. 2003, 22, pp. 1128-1132.
22. Stahlmann R, Lode H. Fluoroquinolones in the elderly: safety considerations. Drugs Aging. 2003, 20, pp. 289-302.
23. J Leppilahti SO. Total Achilles Tendon Rupture: A Review. Sports Med. 1998, 25, pp.79-100.
24. Nyyssönen T LP. Achilles tendon ruptures in South-East Finland between 1986-1996, with special reference to epidemiology, complications of surgery and hospital costs. Ann Chir Gynaecol. 2000, 89, pp. 53-57.
25. Maffulli N WS, Squair J, Reaper J, et al. Changing incidence of Achilles tendon rupture in Scotland: a 15-year study. Clin J Sport Med. 1999, 9, pp. 157-160.
26. Houshian S TT, Riegels-Nielsen P. The epidemiology of Achilles tendon rupture in a Danish county. Injury 1998, 29, pp. 651-654.
27. Gregory M Sterne, Michael L Richardson, Bill H Warren. Imaging Findings in Two Cases of Fluoroquinolone-Induced Achilles Tendinopathy. Radiology Case Reports. 2006, 1, pp. 87-91.
28. Pierfitte C, Royer RJ. Tendon disorders with fluoroquinolones. Therapie. 1996, 51, pp. 419-420.
29. Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clin Infect Dis. 2003, 36, pp. 1404-1410.
30. Simonin MA, Gegout-Pottie P, Minn A, et al. Pefloxacin-induced achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen. Antimicrob Agents Chemother. 2000, 44, pp. 867-872.
31. Perrot S, Kaplan G, Ziza JM. 3 cases of Achilles tendinitis caused by pefloxacin, 2 of them with tendon rupture. Rev Rhum Mal Osteoartic. 1992, 9, p. 162.
32. Jorgensen C, Anaya JM, Didry C, et al. Arthropathy with achilles tendon involvement induced by pefloxacin. Apropos of a case. Rev Rhum Mal Osteoartic. 1991, 58, pp. 623-625.
33. Franck JL, Bouteiller G, Chagnaud P, et al. Achilles tendon rupture in 2 adults treated with pefloxacin, one of the cases with bilateral involvement. Rev Rhum Mal Osteoartic. 1991, 58, p. 904.
34. Braun D, Petitpain N, Cosserat F, et al. Rupture of multiple tendons after levofloxacin therapy. Joint Bone Spine. 2004, 71, pp. 586-587.
35. Lee WT, Collins JF. Ciprofloxacin associated bilateral achilles tendon rupture. Aust N Z J Med. 1992, 22, p. 500.
36. West MB, Gow P. Ciprofloxacin, bilateral Achilles tendonitis and unilateral tendon rupture--a case report. N Z Med J. 1998, 111, pp. 18-19.
37. Jagose JT, McGregor DR, Nind GR, et al. Achilles tendon rupture due to ciprofloxacin. N Z Med J. 1996, 109, pp. 471-472.
38. Shinohara YT, Tasker SA, Wallace MR, et al.What is the risk of Achilles tendon rupture with ciprofloxacin? J Rheumatol. 1997, 24, p. 238-239.
39. van der Linden PD, Sturkenboom MC, Herings RM, et al. Fluoroquinolones and risk of Achilles tendon disorders: case-control study. BMJ. 2002, 324, pp. 1306-1307.
40. Riley G FS, Hazleman B. The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism. Am J Sports Med. 2000, 28, pp. 364-369.
41. Williams RJ, 3rd, Attia E, Wickiewicz TL, et al. The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism. Am J Sports Med. 2000, 28, pp. 364-369.
42. Kashida Y, Kato M. Characterization of fluoroquinolone-induced Achilles tendon toxicity in rats: comparison of toxicities of 10 fluoroquinolones and effects of anti-inflammatory compounds. Antimicrob Agents Chemother. 1997, 41, pp.2389-2393.
43. van der Linden PD, van de Lei J, Nab HW, et al. Achilles tendinitis associated with fluoroquinolones. Br J Clin Pharmacol. 1999, 48, pp. 433-437.
44. Corrao G, Zambon A, Bertu L, et al. Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study. Drug Saf. 2006, 29, pp. 889-896.
45. Seeger JD, West WA, Fife D, et al. Johnson LN, Walker AM. Achilles tendon rupture and its association with fluoroquinolone antibiotics and other potential risk factors in a managed care population. Pharmacoepidemiol Drug Saf. 2006, 15, pp. 784-792.
46. Sode J, Obel N, Hallas J, et al. Use of fluroquinolone and risk of Achilles tendon rupture: a population-based cohort study. Eur J Clin Pharmacol. 2007, 63, pp.499-503.
47. Chhajed PN, Plit ML, Hopkins PM, et al. Achilles tendon disease in lung transplant recipients: association with ciprofloxacin. Eur Respir J. 2002, 19, pp. 469-471.
48. Muzi F, Gravante G, Tati E, et al. Fluoroquinolones-induced tendinitis and tendon rupture in kidney transplant recipients: 2 cases and a review of the literature. Transplant Proc. 2007, 39, pp. 1673-1675.
49. van der Linden PD, Sturkenboom MC, Herings RM, et al. Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids. Arch Intern Med. 2003, 163, pp. 1801-1818.
50. Anon. Nordic statistics on medicine 1993-95. Nordic Statistics on Medicines. 1996.