Septra, Bactrim Linked to 'Serious' Side Effects



By Michael Smith, North American Correspondent, MedPage Today
Published: October 11, 2011
Reviewed by 
Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner.
Trimethoprim-sulfamethoxazole -- a widely used antibiotic sold as Septra, Bactrim, and others -- has a set of adverse reactions that range from minor to potentially fatal, according to a literature review.
 Trimethoprim-sulfamethoxazole (TMP-SMX) 又稱 Septra, Bactrim 等 (譯按:或者在台灣常聽到的 - Baktar),是一種被廣泛使用的抗生素,而根據文獻回顧指出,此品可能與輕微甚至是潛在致死性的副作用有關。
The drug was introduced in 1968 and is popular because it's cheap, effective and familiar, according to Joanne Ho, MD, and David Juurlink, MD, PhD, both of the University of Toronto.
此品於 1968 年現世,並由於其價格便宜、有效與容易使用而廣受歡迎
 - Joanne Ho, MD, and David Juurlink, MD, PhD, both of the University of Toronto.
 Although the drug is usually well tolerated, it is "associated with several potentially serious adverse reactions," Ho and Juurlink reported online in CMAJ.
雖然病人對 TMP-SMX 通常具有良好的耐受性,但其可能與許多潛在性的嚴重藥物不良反應有關。
 - Ho and Juurlink reported online in CMAJ  [Canadian Medical Association Journal]
 "Clinicians should be cognizant of the potential consequences of prescribing trimethoprim-sulfamethoxazole, monitor patients for adverse events during therapy, or use an alternate antibiotic when appropriate," they concluded.
臨床醫師應該充分認知其潛在風險,並在投予 TMP-SMX 之治療期間監測病人之藥物不良反應發生情形,或在適當的狀況下改用其他替代抗生素進行治療。
On the other hand, trimethoprim-sulfamethoxazole "has been an incredibly useful workhorse antibiotic for decades" and its limitations are well known, according to Brad Spellberg, MD, an expert on antibiotic issues at the University of California Los Angeles.
縱然在這幾十年間, TMP-SMX 是如此不可思議的被廣泛使用著,但另一方面,它的缺陷同樣廣為週知。
- According to Brad Spellberg, MD, an expert on antibiotic issues at the UCLA.
The compound, "is inexpensive, gets into all body tissues well, and is very effective at treating many types of infections," Spellberg told MedPage Today in an email.
- Spellberg told MedPage Today in an email.
And the adverse events are relatively rare, he added. "I have treated many, many patients extremely safely and effectively with this drug, as have tens of thousands of physicians for many decades."
而其副作用發生率是較低的,Spellberg 表示:「我用它治療過好多好多病人啊~ 在這幾十年來,對很多醫師來說,它非常安全又有效的啊~ 」
To pin down the adverse reactions, Ho and Juurlink conducted a search of medical literature from 1950 to 2011, eventually winnowing more than 900 citations down to 70 articles, including case reports, volunteer studies, observational studies, and randomized trials, that shone light on possible safety issues.
爲探討 TMP-SMX 的副作用,Ho 與 Juurlink 搜索了 1950 - 2011 年間的醫藥文獻,從超過 900 篇的參考文獻中篩選至 70 篇,包括病例報告、自願受試者研究和隨機分配之試驗等,以探討其安全性議題。
The most common adverse effects, they found, are rashes and fixed drug eruptions, drug-drug interactions, and hyperkalemia.
他們發現,最常見的藥物不良反應為 rashes, fixed drug eruptions, drug-drug interactions (DDIs) & hyperkalemia
The rashes and fixed drug eruptions occur in about 3% of patients, the researchers reported, and are some of the most common adverse effects of the drug.
其中最常見的是 rashes & fixed drug eruptions (3%)。
Some drug-drug interactions occur because trimethoprim-sulfamethoxazole affects two isoforms of the cytochrome P450 enzyme system, and may reduce or enhance the effects of other drugs that are metabolized by the enzymes, including oral hypoglycemic agents and warfarin.
因為 TMP-SMX 會影響 cytochrome P-450 的兩個 isoforms ,可能會減少或增強其他經由相同路徑代謝之藥物的代謝,影響範圍包括了口服降血糖藥 (oral hypo- glycemic agents, OHAs)Warfarin,因此,藥物交互作用是 TMP-SMX 的一個大問題。
小風:TMP-SMX 會影響到 CYP3A4, 2C9/10 等 isoenzymes 
For instance, trimethoprim-sulfamethoxazole increases levels of sulfonylureas, leading to an increased release of insulin and hypoglycemia. As well, taking the drug with warfarin leads to increased risk of gastrointestinal hemorrhage compared with other antibiotics.
舉例來說,TMP-SMX 會增加 sulfonylureas (SUs) 的血中濃度,從而增加 insulin 的分泌而造成低血糖。此外,相較於其他抗生素,當 TMP-SMP 併服 warfarin 時,則可能會導致腸胃道出血機率增加。
Trimethoprim-sulfamethoxazole also affects renal clearance of several drugs, including methotrexate.
TMP-SMX 也會影響包含 methotrexate (MTX) 在內的許多藥物在腎臟之清除率。
Excess of potassium is a "predictable and potentially fatal adverse effect of treatment with trimethoprim-sulfamethoxazole," the researchers argued, noting that in a randomized trial, 6% of patients experienced hyperkalemia -- defined as serum potassium greater than 5.5 mmol/L -- and 81.5% had an increase in serum potassium.
在一篇隨機分派研究中,約有 6% 的病患接受 TMP-SMX 治療後出現高血鉀的症狀 ( 定義為血中鉀離子濃度高於 5.5 mmol/L ),此外有高達 81.5% 的病人出現血中鉀離子濃度增高的狀況,指出鉀離子濃度過高是 TMP-SMX 用於治療時可能預期的潛在性之致命藥物不良反應。
The hyperkalemia takes several days to build up, and risk factors include diabetes, renal insufficiency, older age, AIDS, and drugs that inhibit excretion of potassium, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, they reported.
報告指出這些病人的高血鉀大部分是在數天內發生,並合併有其他風險因子如糖尿病、腎功能不良、年齡較長者、AIDS 和併服某些會抑制鉀離子排除的藥物,如 ACEIs ARBs 等。

Uncommon and rare adverse reactions include:
Neurologic events, including aseptic meningitis, delirium, tremor, and gait

 ※ Decreased oxygen- carrying capacity and other hematologic abnormalities,
   including methemoglobinemia and blood dyscrasia

 ※ Drug hypersensitivity, with fever, rash and internal organ involvement.
   The fever can fool clinicians into thinking they are dealing with infection.

 ※ Reproductive toxicity, including such effects as hyperbilirubinemia, small-
   for-gestational-age babies, and structural malformations

 ※ Kidney effects, such as acute interstitial nephritis, obstructive tubulopathy,
   and hyponatremia

 ※ 神經學症狀:無菌性腦膜炎,幻覺,震顫和步態不穩
 ※ 降低氧氣的攜帶能力和其他血液學異常:血色素變性和惡質血液
 ※ 藥物過敏:發燒,皮疹並可能侵犯內臟器官等。而臨床人員很容易誤解此發燒是
 ※ 生殖毒性:高膽紅素血症,出生體重較低之嬰兒 (SGA) 以及畸胎。
 ※ 腎功能 :急性腎間質腎炎,阻塞性腎小管病變與低血鈉。
Primary source: CMAJ
Source reference:
Ho JMW, and Juurlink D "Considerations when prescribing trimethoprim–sulfamethoxazole" CMAJ 2011; DOI: 10.1503/cmaj.111152.

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Wind Chang

12 Oct 2011




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