筆記摘要
1. 輕度至中度: 二擇一. 通常選 doxycycline, 因為使用經驗及研究報告最多. 但azithromycin 的臨床研究也逐漸增加, 治療效果或副作用或住院天數與 doxycycline 相似
doxycycline 100mg po or IV BID
azithromycin 500mg po or IV qd
2. 重度: 建議選擇 doxycycline, 總共療程是 7 天
第一天劑量加倍 200 mg po bid
第二天起劑量改為 100mg po bid
不建議 doxycycline 與 azithromycin 常規合併使用(死亡率可能上升). 在選擇性個案可考慮合併藥物治療.
重度患者使用單方 doxycycline 治療這項建議來自於下面這篇研究(於2023年發表於NEJM) Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.
研究共收入794位患者, 平均年齡 48歲. 出現呼吸道併發症佔62%, 肝臟併發症佔 54%., 心血管併發症佔 42%, 腎臟併發症佔 30%, 神經併發症佔20%
合併兩種抗生素治療與單一藥物治療, 相較之下有較低的 primary efficacy outcome.
primary efficacy outcome 包括: 28天全因死亡率. 第七天持續出現併發症, 第五天持續發燒
第七天持續出現併發症定義: 任何器官系統異常, 包括心血管, 呼吸, 中樞神經, 肝臟, 腎臟
secondary outcomes: 28天全因死亡率, 恢復期, 包括持續24小時不發燒時間, 使用呼吸器時間, ICU住院天數. 恢復正常神智時間, 安全性.
Outcomes
The primary efficacy outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever (oral temperature, ≥37.5°C [99.5°F]) on day 5. Persistent complications at day 7 were defined as the presence of dysfunction in any organ system, including cardiovascular, respiratory, central nervous system, hepatic, or renal, as outlined in the criteria described in Section S1D. Secondary outcomes were death from any cause at 28 days; measures of recovery, including time to fever defervescence (oral temperature, <99.5°F) sustained for 24 hours, duration of ventilation, duration of ICU stay, duration of hospitalization, and the time until recovery to normal sensorium (a score of 15 on the Glasgow Coma Scale, which ranges from 3 to 15, with higher scores indicating greater awareness); and safety.
The Common Terminology Criteria for Adverse Events, version 5, was used to grade adverse events.
Results: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%).
The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of -13.3 percentage points (95% confidence interval [CI], -21.6 to -5.1; P = 0.002).
The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P<0.001).
No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, -7.0 to 10.0; P = 0.73).
The results in the per-protocol analysis were similar to those in the primary analysis.
Adverse events and 28-day mortality were similar in the three groups.
下面內容來自 uptodate, 中文部分使用google翻譯
首選處方 — 取決於疾病的嚴重程度以及患者是否懷孕。
輕度至中度疾病患者 —
對於推定為輕度至中度恙蟲病的患者，我們建議使用多西環素或阿奇黴素單藥治療。
對於大多數患者，我們傾向於使用多西環素(每次100 mg，口服或靜脈內，每日2次)，因為我們對該藥物有豐富的經驗，包括在已發表的研究中使用[ 59,60 ]。此外，它對可能引起類似臨床綜合徵的其他病原體(例如，其他立克次體病)具有廣泛的活性；這一點很重要，因為在初始治療時通常無法確診恙蟲病。 (參見上文『鑑別診斷』 )
然而，當強烈懷疑恙蟲病診斷或有血清學證據支持恙蟲病診斷時，阿奇黴素(每次500 mg，口服或靜脈內，每日1次)也是一個合理的選擇。越來越多的臨床試驗表明，阿奇黴素在一系列相關結局指標(例如，退燒時間、併發症風險、住院時長)上的療效與多西環素相似[ 42,57,61,62 ]。
重症患者 —
對於大多數重症患者，我們建議使用多西環素單一藥物治療。在這種情況下，我們在第1天給予多西環素，每次200mg，每日2次；之後給予多西環素，每次100mg，每日2次，共治療7天。多西環素一直是重症恙蟲病患者的標準治療方案。此外，近期一項隨機試驗納入了794例恙蟲病患者，這些患者出現併發症，需要靜脈注射治療。結果顯示，接受多西環素單一藥物治療的患者，其絕對死亡率低於接受多西環素和阿奇黴素合併治療的患者（分別為11% vs 13%），但差異不顯著[ 62 ]。在該試驗中，兩組患者的機械通氣需求、通氣時長、ICU住院時長、總住院時長也相似。然而，多西環素和阿奇黴素 聯合治療可依具體情況考慮。在上述隨機試驗中，合併治療組的複合主要結局（第28日全因死亡、第7日持續性併發症和第5日持續性發燒）發生率低於多西環素單藥治療組（33% vs 47%；風險差異為-13.3%，95% CI -21.6至5.1）或阿奇黴素 13.3%，95% CI -21.6至5.1）或阿奇黴素第8%， -23.1至-6.5）[ 62 ]。這種差異主要是因為第7日某些併發症的持續性減少（例如，需要輔助供氧、高膽紅素血症[膽紅素血症>2]消退以及肌酸酐升高消退）。因此，聯合治療可更快地緩解某些次要結局和實驗室檢查異常，如果患者認為這是當務之急，聯合治療可能是合理的。
療程 — 最佳治療療程仍不確定。使用多西環素時，我們通常傾向於7日療程，儘管已發表的試驗採用了多種方案。對於阿奇黴素，我們對大多數患者實施5-7日的療程，對較輕微病例則採用較短療程。在上述隨機研究中，7日的多西環素、阿奇黴素或合併療法與重症患者的治癒率較高相關[ 62 ]。開始靜脈治療的患者一旦臨床狀況穩定，就可以改用口服療法。
雖然有人提倡使用短至1日的多西環素(400mg，分2次服用)的方案來治療恙蟲病[ 63 ]，但短期多西環素療程與復發風險增加有關。在一項評估3日療程的研究中，7名接受氯黴素治療的患者中有3名復發，6名接受多西環素治療的患者中有3名復發；相比之下，接受任一方案治療 5 天或更長時間的 37 名患者均未出現復發[ 59 ]。鑑於治療通常是在診斷未確診時進行的，標準 7 天多西環素療程的另一個好處是它與用於類似感染綜合徵的治療方案有重疊。
對於阿奇黴素單一治療，已研究了各種療程（從 1 到 7 天不等），儘管沒有進行比較。鑑於已發表研究中治療時長差異較大，且部分研究認為較短的療程可能與發燒持續時間延長有關，我們傾向於 5 至 7 天的療程[ 42,57,61,62 ]。
替代抗菌方案—
鑑於多西環素和在阿奇黴素之後，雖然現有數據顯示其他替代藥物可能有效，但一般不建議使用它們治療恙蟲病。但是，有時患者可能有強力黴素和阿奇黴素的禁忌症，在這種情況下，可以考慮使用以下藥物之一：
●利福平– 當患者對強力黴素和阿奇黴素（首選藥物）有禁忌症時，利福平是治療恙蟲病的一種選擇。雖然利福平通常是一種有效的選擇，但它存在許多藥物交互作用，因此存在挑戰。再加上目前已發表的支持強力黴素和阿奇黴素的證據較多，在大多數情況下，利福平只能作為三線治療藥物。 (參見上文『首選抗菌方案』 )與多西環素
相比，利福平(600 mg，每日1次，連用5日)療法治癒了所有接受該療法的患者(n = 119)，且發燒、肌痛、頭痛或皮疹的消退時間無差異[ 64 ]。多西環素合併利福平療法也已被研究，但鑑於其他方案的有效性和安全性，很少適用這種聯合療法。在泰國北部地區進行的一項隨機試驗，在86例輕度恙蟲病感染患者中，比較了多西環素單藥治療與多西環素聯合利福平治療的療效[ 65 ]。 24位每日服用900毫克和600毫克利福平的患者（平均退燒時間分別為22.5毫克和27.5小時），其發燒時間中位數顯著短於52例僅接受多西環素治療的患者（平均退燒時間52小時）。 ●氟喹諾酮類藥物– 氟喹諾酮類藥物(FQ)已被證明可有效治療恙蟲病，尤其對於輕度/中度患者。然而，與多西環素或米諾環素相比，使用FQ治療恙蟲病也已被證明與緩解時間延遲和死亡率更高相關[ 66 ]。●氯黴素－氯黴素（每6小時口服或靜脈注射250至500毫克）是第一種被證實對治療恙蟲病有效的藥物，一項包含3項治療試驗的分析發現，在接受多西環素或氯黴素治療的患者中，退燒時間和復發率沒有顯著差異[ 67]
然而，鑑於該藥物的毒性且在大多數國家難以獲得，應僅在沒有其他選擇的情況下才使用氯黴素。
妊娠注意事項 —
恙蟲病可能導致懷孕婦女自然流產或死產[ 4,68-70 ]。例如，一篇文獻回顧納入了 55 例恙蟲病孕婦（其中 3 例同時患有恙蟲病和瘧疾）的信息，發現 55 例患者中有 24 例（44%）新生兒結局不良，定義為死產、早產或低出生體重[ 69 ]。
對於此類患者，我們通常給予阿奇黴素（每日 500 mg），連續 7 天，因為這種方案有最多已發表的數據支持其在妊娠期使用[ 68,71 ]。
文獻中表明，較短療程(1-5天)的阿奇黴素治療方案在妊娠期也可能有效，但支持該人群採用任何特定方案的數據仍然很少，並且有報導稱，較短療程的阿奇黴素治療會導致發熱和其他臨床體徵緩解較慢，這也提示在選擇較短療程的方案時應謹慎[ 62,72 ]。
Preferred antimicrobial regimens — The choice of regimen depends on the severity of disease and if the patient is pregnant.
Persons with mild to moderate disease — For patients with presumed mild to moderate scrub typhus, we suggest monotherapy with doxycycline or azithromycin.
For most patients, we favor doxycycline (100 mg orally or intravenously twice daily) due to extensive experience with this agent, including its use in published studies [59,60]. In addition, it has broad activity against other organisms that may cause similar clinical syndromes (eg, other rickettsial diseases); this is important since the diagnosis is often not confirmed at the time of initial treatment. (See 'Differential diagnosis' above.)
However, azithromycin (500 mg orally or intravenously daily) is also a reasonable choice when the diagnosis of scrub typhus is strongly suspected or supported by serologic evidence. An increasing number of clinical trials have shown that azithromycin offers similar efficacy to doxycycline across a wide array of relevant outcomes (eg, time to defervescence, risk of complications, length of hospitalization) [42,57,61,62].
Specific considerations for regimen selection in persons who are pregnant are discussed below. (See 'Considerations during pregnancy' below.)
Persons with severe disease — For most patients with severe disease, we suggest monotherapy with doxycycline. In this setting, we administer 200 mg of doxycycline twice daily on day one, followed by 100 mg twice daily for a total duration of seven days. Doxycycline has been the historical standard of care for patients with severe scrub typhus. In addition, in a recent randomized trial of 794 patients with scrub typhus who had complications requiring intravenous therapy, those who received monotherapy with doxycycline had a nonsignificant but lower absolute mortality than those who received combination therapy with doxycycline and azithromycin (11 versus 13 percent, respectively) [62]. In this trial, the need for mechanical ventilation, the duration of ventilation, the length of stay in the ICU, and the overall hospital length of stay were also similar between the groups.
However, combination therapy with doxycycline and azithromycin may be considered on a case-by-case basis. In the randomized trial above, those who received combination therapy had a lower incidence of a composite primary outcome (death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5) than those who received monotherapy with doxycycline (33 versus 47 percent; risk difference of -13.3 percent, 95% CI -21.6 to -5.1) or azithromycin (33 versus 48 percent; risk difference -14.8 percent, 95% CI -23.1 to -6.5) [62]. This difference was due primarily to a reduction in persistence of certain complications at day 7 (eg, the need for supplemental oxygen, resolution of hyperbilirubinemia [T. bili >2], and resolution of elevated creatinine). Thus, combination therapy may offer more rapid resolution of some secondary outcomes and laboratory abnormalities and may be reasonable in patients if this is deemed to be a priority.
Duration — The optimal duration of treatment remains uncertain. When doxycycline is used, we typically favor seven days of therapy, although published trials have utilized a variety of regimens. For azithromycin we administer therapy for five to seven days for most patients, reserving shorter durations for milder cases. In the randomized study discussed above, seven days of doxycycline, azithromycin, or combination therapy was associated with high rates of cure in those with severe disease [62]. Patients who initiate intravenous therapy can switch to oral therapy as soon as they are clinically stable.
Although regimens as short as one day of doxycycline (400 mg given in two divided doses) have been advocated for the therapy of scrub typhus [63], short courses of doxycycline have been associated with an increased risk of relapse. In one study evaluating a three-day course of therapy, relapse occurred in three of seven patients treated with chloramphenicol and three of six treated with doxycycline; in comparison, no relapses were noted in 37 patients treated with either regimen for five days or longer [59]. Given that treatment is often given while the diagnosis remains unconfirmed, another benefit of a standard seven-day course of doxycycline is its overlap with regimens used for similar infectious syndromes.
For azithromycin monotherapy, a variety of durations (ranging from one to seven days) have been studied, although not comparatively. We favor the five to seven day duration given the heterogeneity of lengths of therapy in published studies and the suggestion from some that shorter courses may be associated with prolonged duration of fever [42,57,61,62].
Alternate antimicrobial regimens — Given the efficacy and safety of doxycycline and azithromycin, the use of alternative agents for treatment of scrub typhus is generally not warranted, even though available data suggest they may be effective. However, on occasion, a patient may have contraindications to doxycycline and azithromycin, and in this setting, one of the following agents can be considered:
●Rifampin – Rifampin is an option for treatment of scrub typhus when there are contraindications to doxycycline and azithromycin (the preferred agents). While a generally effective option, rifampin creates challenges with its many drug-drug interactions. This, combined with the overall greater body of published evidence supporting doxycycline and azithromycin, relegates rifampin to third-line therapy in most situations. (See 'Preferred antimicrobial regimens' above.)
When compared with doxycycline, rifampin (600 mg once daily for five days) therapy cured all patients who received it (n = 119) and showed no difference in time to resolution of fever, myalgias, headache, or rash [64].
Combination therapy with doxycycline plus rifampin has also been studied, but given the efficacy and safety of other regimens, this combination is rarely indicated. A randomized trial performed in an area of northern Thailand compared the efficacy of doxycycline alone with the combination of doxycycline and rifampin in 86 patients with mild scrub typhus infection [65]. The median duration of fever was significantly shorter in the 24 patients treated with daily doses of 900 and 600 mg of rifampin (mean fever clearance times 22.5 and 27.5 hours, respectively) than in 52 patients treated with doxycycline therapy alone (mean fever clearance time 52 hours).
●Fluoroquinolones – Fluoroquinolones (FQ) have shown efficacy for the treatment of scrub typhus, particularly in mild/moderate disease. However, use of FQ for scrub typhus has also been shown to be associated with delayed time to resolution and higher mortality compared with doxycycline or minocycline [66].
●Chloramphenicol – Chloramphenicol (250 to 500 mg orally or intravenously every six hours) was the first drug shown to be effective for the treatment of scrub typhus, and an analysis that included three treatment trials found no significant differences in time to resolution of fever and incidence of relapse in patients treated with doxycycline or chloramphenicol [67]. However, given the toxicity of this drug and difficulty obtaining it in most countries, chloramphenicol should be reserved for situations when other options are not available.
Considerations during pregnancy — Scrub typhus may cause spontaneous abortions or stillbirths in pregnant persons [4,68-70]. As an example, a literature review that included information on 55 pregnant persons with scrub typhus (including three who had both scrub typhus and malaria) found that 24 out of 55 patients (44 percent) had a poor neonatal outcome, defined as stillbirths, preterm birth, or low birth weight [69].
For such patients we typically administer azithromycin (500 mg daily) for seven days, as this regimen has the greatest amount of published data supporting its use in pregnancy [68,71].
There is suggestion in the literature that shorter regimens (ranging one to five days) of azithromycin may also be effective in pregnancy, but the data supporting any specific regimen in this population remain sparse, and reports of slower resolution of fever and other clinical signs with shorter courses of azithromycin also suggest caution when selecting regimens of shorter duration [62,72]. (See 'Duration' above.)
