2014-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656832摘要：Trimethoprim-sulfamethoxazole 是一廣效抗菌藥品，對於多種革蘭氏陽性及陰性菌均有殺菌效果，也被廣泛地用於治療一些分枝桿菌、寄生蟲（例如弓蟲）、黴菌（例如肺囊蟲）等感染。過去有不少關於此藥物引起的肝毒性及紅疹等等的副作用的報告;同時也有一些中樞神經系統方面副作用的案例報告，但是仍然相當罕見。不過近來臨床醫師觀察到，在使用靜脈注射 trimethoprim-sulfamethoxazole 治療肺囊蟲肺炎的感染時，有不少免疫缺損的病人，特別是愛滋病毒感染者，會發生精神性異常的副作用，包括幻視、幻聽等等，根據一個近期發表台灣多家醫學中心的回溯性研究，發生率大約在 11%，統計學上發現發生率和使用的劑量相關，劑量越大，發生率越高。這些副作用大多會在停藥後緩解。目前引起此副作用的原因並不清楚，可能和病患個體差異性，包括個體特異性及藥物代謝速率的不同，或是使用藥物劑量多寡有關。大部分 trimethoprim 經由腎臟排除，sulfamethoxazole 則主要是經由 CYP2C9 及乙醯基轉移酶（N-acetyltransferase）代謝，基因的多型性可能改變藥品代謝的速率，因而影響藥物及其代謝物血中濃度與副作用。 因為 trimethoprim-sulfamethoxazol是臨床上治療免疫系統缺損病患發生肺囊蟲肺炎的感染治療藥物，因此，本試驗擬建立監測 trimethoprim-sulfamethoxazole 的血中濃度的分析方法，並利用此方法進行療劑監測。我們預計在 2014 年 7 月 1 日至 2017 年 8 月31 日止，為期 36 個月間，在臺大醫院收案進行單中心的觀察性試驗。所有依醫師處方，並遵守醫生指示，正在接受 trimethoprim-sulfamethoxazole 治療劑量(至少 10 mg/kgtrimethoprim)的患者，排除 20 歲以下的病人。待開始治療後的第 3 天，在服用（或注射）早晨的藥品前抽取 7 c.c.的血液檢測病人藥品血中濃度（最低血中濃度，trough concentration）及服藥後（若為口服，為服藥後 3+1 小時，若是注射劑型則為輸注完畢後 5 分鐘）抽取 7 c.c.的血液檢測病人藥品血中濃度（最高血中濃度，peak concentration），並且在副作用發生後檢測病人血中最低及最高濃度。若無副作用發生，在使用藥品第 10 天後仍使用相同劑量、頻次、途徑者，也將測量血中最低及最高濃度。若病人有急性精神病的副作用出現，在醫師的判斷臨床需要及同意下，也將實施腰椎穿刺，留取 7 c.c 之腦脊髓液，以測定病人腦脊髓液中藥物及其代謝物的濃度。另外鑑定其相關代謝酵素的基因型，如血液檢體不適合分析基因型時（例如進行過異體骨髓移植者），將改為收集病人的口水 5~10 c.c.。 本計畫預定追蹤服用 trimethoprim-sulfamethoxazole 病人的藥物及其代謝物的血中濃度與基因多型性、療效、副作用等關係，另外也進一步了解trimethoprim-sulfamethoxazole 引起急性精神病副作用的相關因素。 <br> Abstract: Trimethoprim-sulfamethoxazole (TMP/SMX) is a broad-spectrum antibiotic that has bactericidal effect against many Gram-positive and Gram-negative bacteria. TMP/SMX is also used widely in treatment of nocardiosis, toxoplasmosis and Pneumocystis jirovecii pneumonia (PJP). There are many adverse effects related to treatment with TMP/SMX, such as skin rash, hepatotoxicity, acute kidney injury, and hyperkalemia. Recently, we observed in a multicenter retrospective study a high incidence of acute psychosis (11.9%; 95% CI, 6.3-17.4%), mainly visual or auditory hallucination, which increased with the increasing doses administered in HIV-infected patients receiving TMP/SMX for pneumocystosis. These symptoms has also been reported in other immunocompromised patients receiving TMP/SMX for pneumocystosis or other diseases. These symptoms would resolve soon after TMP/SMX was stopped or reduced in dose. This adverse effect may be caused by idiosyncratic reaction, or related to the dosage of the medication. Whether the parent drugs and their metabolites contribute to the symptoms observed remain unclear. TMP/SMX is metabolized by CYP2C9 and N-acetyltransferase (NAT). Genetic polymorphism may alter the metabolic rate, which may influence the amount of the parent drug and their metabolites, and further cause the adverse effects. In this study, we aim to investigate the incidence of the adverse reactions, the treatment outcomes, and the gene polymorphism associated with the plasma level of TMP/SMX and their metabolites (including N4-acetyl-sulfamethoxazole, sulfamethoxazole hydroxylamine and sulfamethoxazole-nitroso). We also aim to investigate the factors associated with the TMP/SMX-induced acute psychosis at the National Taiwan University Hospital (NTUH) from 1 August 2014 to 31 July 2017. Eligible subjects will be patients aged 20 years or older who are receiving oral or intravenous form of TMP/SMX at a daily dose of ≧12 mg/k TMP dose. On the day 3 of the treatment, steady-state plasma peak TMP/SMX concentrations will be measured (PO: 3+1 hours after taking TMP/SMX, IV: 5 minutes after complete infusion) and trough plasma concentrations (PO/IV: right before next dose) using an in-house validated HPLC assay with UV detection. The measurements will be repeated when the adverse reaction occurs. Lumbar puncture will be performed to obtain cerebrospinal fluid for measurement of the concentrations of TMP/SMX. If the patients do not develop adverse reactions, repeat measurement of peak and trough concentrations will be performed on day 10. Genetic polymorphism for the metabolism of TMP/SMX will be determined.不良反應抗微生物製劑血漿藥物濃度監測精神病antimicrobialtrimethoprim-sulfamethoxazoleadverse effecttherapeutic drug monitoringacute psychosis