住院病人之sulfamethoxazole-trimethoprim血中濃度測定

Abstract

背景 Sulfamethoxazole (SMX)-trimethoprim (TMP)為一廣效型抗生素，在肺囊蟲肺炎（Pneumocystis jirovecii pneumonia, PJP）及多種多重抗藥性細菌所致感染的治療都扮演重要的角色。過去研究觀察到，血中SMX-TMP濃度有很大的個體間（inter-individual）差異性，且因過去文獻建議之最佳療效均以血中最高濃度為參考，但是監測血中最低濃度不需如監測血中最高濃度需算好時間點，而在給藥前抽血即可，臨床實用性較高。本研究的目的，希望找出血中最高濃度與血中最低濃度之關聯性，以血中最低濃度預測血中最高濃度。目前臺灣臨床上尚未有SMX-TMP濃度的測量，再者，一些本土的臨床觀察顯示，高劑量的SMX-TMP發生副作用的機率似乎也較高，因此本研究以前瞻性收案接受高劑量SMX-TMP治療的病人，藉由量測SMX-TMP的血中濃度，分析濃度之分布情形，及評估病人不良反應、臨床療效與血中SMX-TMP濃度之關聯性。 研究目的 本研究主要目的為：分析SMX-TMP血中濃度的分布情形。探討使用劑量和血中濃度的關係、影響血中濃度的相關因素，並評估血中最低濃度和最高濃度的關係性，及SMX-TMP血中濃度和副作用的關係。次要目的為：分析SMX-TMP血中濃度和治療肺囊蟲肺炎療效的關係。

研究方法 本研究於2014年1月19日至2014年6月30日間，於國立臺灣大學醫學院附設醫院前瞻性收案，收案對象是接受SMX-TMP治療並且年紀大於20歲之住院病人。在病人簽署受試者同意書後，待開始用SMX-TMP的第3-4天達到穩定血中濃度之後，於服藥（或注射）前量測血中最低濃度（trough concentration）；等到服用口服劑型後3小時（或靜脈注射輸注完畢後1小時）檢測血中最高濃度（peak concentration）。測量儀器為高效能液相層析儀以UV偵測吸收波長，以檢測病人血中藥物濃度。 收案期間，記錄病人的基本資料、使用SMX-TMP的劑量、頻次、途徑、用藥開始及結束日期、實驗室檢查值等，同時也觀察用藥期間不良反應的發生，以Naranjo scale評估這些不良反應與SMX-TMP之相關性。 統計方法採用χ2 test、Student’s t test、Mann-Whitney U Test比較兩組樣本間之差異，以ANOVA test檢定三組以上之差異。同時以簡單線性迴歸（simple linear regression）及多重線性迴歸（multiple linear regression）分析影響濃度的因素，並以羅吉斯迴歸（logistic regression）分析SMX-TMP不良反應及治療反應之相關預後因子。使用複廣義相加模式（generalized additive model，GAM）找出不良反應與血中濃度分界點。所有檢定皆為雙尾檢定（two-sided），以p-value小於0.05視為統計上顯著。 研究結果 在研究期間，本研究共收案43位病人，其中41位病人被納入研究結果分析，共有52組抽血事件。這些病人中，共有34位為治療肺囊蟲肺炎的案例。檢測血中最高濃度共有43次，而檢測血中最低濃度共52次。SMX最高濃度和最低濃度的中位數，分別為121.7 μg/mL (range, 54.6-279.1 μg/mL)和103.3 μg/mL (range, 23.5-245.8 μg/mL)，TMP最高濃度和最低濃度的中位數分別為4.9 μg/mL (range, 0.6-10.1 μg/mL)和3.5 μg/mL (range, 0.2-9.4 μg/mL)。病人所接受的藥物劑量之中位數為12.6 mg/kg/day (range, 4.2-20.3 mg/kg/day)，雖然低於治療指引建議的15-20 mg/kg/day，但無論是口服或靜脈注射，合計有70%落在過去各文獻之建議肺囊蟲肺炎治療之TMP最高濃度為3-8 μg/mL的範圍內，顯示參加研究的本國的住院病人不需使用如文獻所建議之劑量即可達有效血中濃度。 不論是SMX或者TMP，血中最高濃度及最低濃度均有良好的線性關係(r>0.9)。治療期間，AST及ALT grade1-3上升者分別佔總人數之17.3%，這些病人相較於沒有發生AST、ALT上升者有較高的SMX血中最高及最低濃度（p<0.05）；發生高血鉀（發生率26.9%）及低血鈉（發生率5.8%）不良反應的病人有較高的TMP血中濃度。另外，發生高血鉀不良反應之病人使用較高的劑量（14.1 vs. 12.3 mg/kg/day, p=0.0302）。 結論 本研究雖發現住院的成人使用SMX-TMP的劑量低於仿單建議劑量，但大多數病人可達文獻建議之TMP治療濃度，因此推測成人可能不需依照仿單建議的使用劑量即可達到理想濃度。肝毒性和SMX濃度有顯著關係；電解質不平衡和藥物濃度與使用劑量之間也有顯著關係。病人血中濃度個體間變異性大，因此，監測藥物血中濃度將有助於避免副作用。由於兩藥之血中最高濃度及最低濃度有良好的線性關係，本研究建議，可利用臨床上較易取得之血中最低濃度去預測最高濃度。

Background Sulfamethoxazole-trimethoprim (SMX-TMP), a broad-spectrum antibiotic combination, has been the drug of choice in the treatment of Pneumocystis jirovecii pneumonia (PJP) and several multidrug-resistant bacterial infections. SMX-TMP has large inter-individual variation. Limited studies suggested measuring peak concentrations when targeting the optimized therapeutic range. However, measuring peak concentrations is less clinically practical than measuring trough concentrations. There were no such previous studies as measurements of SMX-TMP plasma concentrations in Taiwan. We aimed to evaluate the correlation between the plasma trough and the peak concentrations of SMX-TMP, to describe the distribution of plasma concentrations, and to investigate the association between adverse events and clinical response and plasma SMX-TMP concentrations. Objectives The primary purpose of the study is to describe the distribution of SMX-TMP concentrations, evaluate the relationship between SMX-TMP concentration and dosage, and evaluate the correlation between the plasma trough and the peak concentrations of SMX-TMP. Also, to identify the factors associated with SMX-TMP concentration and the association between adverse events and SMX-TMP concentration. The secondary purpose is to evaluate the association between PJP treatment effectiveness and SMX-TMP concentrations. Method This prospective, observational study was conducted at the National Taiwan University Hospital (NTUH) from 19 January 2014 to 30 June 2014. Eligible patients were 20 years old or older who were receiving SMX-TMP, the indications and doses administered were at the discretion of the treating physician. Patients were enrolled after they gave written informed consents. Steady-state plasma concentrations were drawn 3-4 days after initiating SMX-TMP. Blood samples for determination of peak concentrations were collected 3 hours after oral SMX-TMP or 1 hour after completion of infusion, while blood samples for trough concentration were collected right before the next dose. Plasma concentrations of SMX and TMP were analyzed using a validated HPLC-UV method. Patient’s demographic characters, dosage, dosing frequency, administration route, the duration of SMX-TMP treatment, laboratory results and adverse events (ADRs) were recorded. The causality of ADRs were evaluated with Naranjo scale. χ2 test, Student’s t test, Mann-Whitney U Test were used to compare the differences between two groups, and ANOVA test is used to compare the differences between three or more groups, when appropriate. Simple linear regression and multiple linear regression were used to evaluate the factors contributing to plasma concentrations. Logistic regression was used to evaluate the factors associated with ADRs. GAM (generalized additive model) was used to find out concentration cutoff points for adverse events of SMX-TMP. All statistics were two-sided, and a p-value of <0.05 was considered significant.

Results During the study period, a total of 43 patients were enrolled, but only 41 patients were included in the analysis. 34 patients received the diagnosis of Pneumocystis jirovecii pneumonia (PJP), for which SMX-TMP was given. There were 43 episodes of measuring plasma peak concentration, and 52 episodes of measuring plasma trough concentration. The median peak and trough level of SMX was 121.7 μg/mL (range, 54.6-279.1 μg/mL) and 103.3 μg/mL (range: 23.5-245.8 μg/mL), respectively, and the median peak and trough level of TMP was 4.9 μg/mL (range, 0.6-10.1 μg/mL) and 3.5 μg/mL (range, 0.2-9.4 μg/mL), respectively. The median dose of SMX-TMP administered was 12.6 mg/kg/day (range, 4.2-20.3 μg/mL) based on TMP component. Although the dose was lower than the recommended dose of 15-20 mg/kg/day in the treatment guidelines, 70% of the peak TMP levels were in the range of 3-8 μg/mL, which is the recommended concentration in treatment of PJP in previous studies. Our findings suggest that using the lower dose in the hospitalized patients can also attain the recommended target levels. We found a good correlation between the peak and trough concentrations for both SMX and TMP in hospitalized adult patients (r>0.9). There were 17.3% of patients who developed AST and ALT elevation, respectively, which tended to occur in the paitents with higher peak and trough SMX concentrations (p<0.05). Higher peak and trough TMP concentrations were found in 26.9% of the patients who developed hyperkalemia and 5.8% of the patients who developed hyponatremia. Patients who developed hyperkalemia adverse drug reaction used a higher dosage (14.1 vs. 12.3 mg/kg/day, p=0.0302).

Conclusions Although patients received a lower dosage than that recommended in the package insert, TMP plasma concentrations were achieved in the target range in most of patients studied, which suggests that the optimized plasma concentrations could be attained by using a lower dose in the adults. Liver function elevation was significantly associated with plasma SMX concentration, and electrolyte imbalance was significantly associated with plasma concentration and dosage of TMP. There were large inter-individual plasma concentration variations, so monitoring plasma levels might assist in avoiding the adverse events. Good correlation was shown between peak and trough concentrations for both SMX and TMP in hospitalized adult patients. Measurements of the trough concentrations of SMX and TMP, which is more practical, can be considered to replace measurements of peak concentrations as has been recommended by previous studies.