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a sulfonamide (trade name Gantanol) used to treat infections (especially infections of the urinary tract) (同)Gantanol

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/10/10 01:41:23」(JST)

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Sulfamethoxazole (SMZ or SMX) is an antibiotic. It is used for bacterial infections such as urinary tract infections, bronchitis, and prostatitis and is effective against both gram negative and positive bacteria such as Listeria monocytogenes and E. coli.^[1]

Common side effects include nausea, vomiting, loss of appetite, and skin rashes. It is a sulfonamide and bacteriostatic. It resembles a component of folic acid. It prevents folic acid synthesis in the bacteria that must synthesize their own folic acid. Mammalian cells, and some bacteria, do not synthesize but require preformed folic acid (vitamin B9), they are therefore insensitive to sulfamethoxazole.^[2]

It was introduced to the United States in 1961.^[3] It is now mostly used in combination with trimethoprim (abbreviated SMX-TMP).^[4] Other names include: sulfamethalazole, sulfisomezole,^[5]^[6] and sulfamethazole.^[7]

Side effects

The most common side effects of sulfamethoxazole are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria).^[8] There have been rare instances where severe adverse reactions have resulted in fatalities. These include Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.^[8]

Allergic reactions to Sulfonamides have been shown to include the entire Gel-Coombs spectrum of hyperactivity reactions.^[9] Type 1 reactions include immunoglobulin E (IgE)-mediated reactions such as urticaria, angioedema, and anaphylaxis. In contrast, non-type 1 hypersensitivities are believed to be caused by metabolites of sulfonamides.^[10] Therefore, the liver and kidney are the determining factors of these other hypersensitivity reactions;^[10] alterations in kidney or liver functions may increase or decrease the frequencies of these reactions. One study has shown the allergic reaction rate to be about 3.0% over 359 courses of therapy.^[11] Of the allergic reactions, skin rashes, eosinophilia and drug fever were the most common, while serious reactions were less common.

Sulfamethoxazole is contraindicated in people with a known hypersensitivity to trimethoprim or sulfonamides.^[9]

Mechanism of action

Sulfamethoxazole, a sulfanilamide, is a structural analog of para-aminobenzoic acid (PABA). They compete with PABA to bind to dihydropteroate synthetase and inhibit conversion of PABA and dihydropteroate diphosphate to dihydrofolic acid, or dihydrofolate. Inhibiting the production of dihydrofolate intermediate interferes with the normal bacterial synthesis of folic acid (folate). Folate is an essential metabolite for bacterial growth and replication because it is used in DNA synthesis, primarily at thymidylate and purine biosynthesis, and amino acids synthesis, including serine, glycine and methionine.^[12] Hence, blockage of folate production inhibits the folate-dependent metabolic processes for bacterial growth. Since it inhibits bacterial growth, sulfamethoxazole is considered a bacteriostatic antibiotic.^[1]

Tetrahydrofolate synthesis pathway

Sulfonamides are selective against bacteria because they interfere with the synthesis of folate, a process which does not occur in humans. Human do not synthesize folate, and must acquire it through diet.^[13]

Pharmacokinetics

Absorption

Sulfamethoxazole is well-absorbed when administered topically. It is rapidly absorbed when it is orally administered.^[1]

Distribution

Sulfamethoxazole distributes into most body tissues as well as into sputum, vaginal fluid, and middle ear fluid.^[8]^[11] It also crosses the placenta. About 70% of the drug is bound to plasma proteins. Its Tmax (or time to reach maximum drug concentration in plasma) occurs 1 to 4 hours after oral administration. The mean serum half-life of sulfamethoxazole is 10 hours.^[8] However, the half-life of the drug noticeably increases in people with creatinine clearance rates equal to or less than 30 mL/minute. A half-life of 22–50 hours has been reported for people with creatinine clearances of less than 10 mL/minute.^[11]

Metabolism

Sulfamethoxazole is metabolized in the human liver to at least 5 metabolites. These metabolites are the N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxy-sulfamethoxazole metabolites, and an N-glucuronide conjugate. The CYP2C9 enzyme is responsible for the formation of the N4-hydroxy metabolite. In vitro studies suggest sulfamethoxazole is not a substrate of the P-glycoprotein transporter.^[8]

Excretion

Sulfamethoxazole is primarily renally excreted via glomerular filtration and tubular secretion.^[8] About 20% of the sulfamethoxazole in urine is the unchanged drug, about 15–20% is the N-glucuronide conjugate, and about 50–70 % is the acetylated metabolite.^[11] Sulfamethoxazole is also excreted in human milk.^[8]

Notes

^ ^a ^b ^c "Sulfamethoxazole". DrugBank. Retrieved 5 November 2015.
^ Brunton; et al. (2011). Goodman and Gilman’s The pharmacological Basis of Therapeautics. The McGraw-Hill Companies, Inc. pp. 1463–1469. ISBN 9780071624428.
^ Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. William Andrew Publishing.
^ SMZ-TMP in Abstract of "Cutaneous hypersensitivity to sulfamethoxazole-trimethoprim (SMZ TMP) in HIV infected patients" at nlm.nih.gov
^ PubChem. "Sulfamethoxazole - Substance Summary", PubChem, National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM), National Institutes of Health (NIH)
^ ChemDB. "Sulfamethoxazole", ChemDB, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)
^ Sulfamethazole in "Clinical Diabetes: Case Study: A 90-Year-Old Man With Confusion and Night Sweats", and "Chronic Granulomatous Disease"
^ ^a ^b ^c ^d ^e ^f ^g "Bactrim USPI" (PDF). FDA.
^ ^a ^b Wulf, Matuszewski (2013). "Sulfonamide cross-reactivity: Is there evidence to support broad cross-allergenicity?". Clinical Consultations. 70.
^ ^a ^b Choquet-Kastylevsky, Vial, Descotes (2002). "Allergic Adverse Reactions to Sulfonamides". Allergy and Asthma Reports.
^ ^a ^b ^c ^d "Toxnet: Sulfamethoxazole".
^ "Sulfonamides and Sulfonamide Combinations: Antibacterial Agents: Merck Veterinary Manual". www.merckvetmanual.com. Retrieved 2015-11-05.
^ "Sulfonamides - Infectious Diseases". Merck Manuals Professional Edition. Retrieved 2015-11-05.

External links

Sulfamethoxazole in the ChemIDplus database

UpToDate Contents

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Related Pictures

★リンクテーブル★

リンク元	「100Cases 33」「スルホンアミド系抗菌薬」「スルファメトキサゾール」
拡張検索	「trimethoprim-sulfamethoxazole combination」「trimethoprim-sulfamethoxazole」

「100Cases 33」

Sulfamethoxazole
Clinical data
Trade names	Gantanol
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy; category	AU: C; US: C (Risk not ruled out); ;
Routes of; administration	Oral, IV
ATC code	J01EC01 (WHO) QJ01EQ11 (WHO);
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only;
Pharmacokinetic data
Protein binding	70%
Metabolism	Hepatic acetylation and glucuronidation
Biological half-life	10 hours
Excretion	Renal
Identifiers
	IUPAC name 4-Amino-N-(5-methylisoxazol-3-yl)-benzenesulfonamide;
CAS Number	723-46-6 ;
PubChem CID	5329;
DrugBank	DB01015 ;
ChemSpider	5138 ;
UNII	JE42381TNV;
KEGG	D00447 ;
ChEBI	CHEBI:9332 ;
ChEMBL	CHEMBL443 ;
NIAID ChemDB	006897;
ECHA InfoCard	100.010.877
Chemical and physical data
Formula	C10H11N3O3S
Molar mass	253.279 g/mol
3D model (JSmol)	Interactive image;
Melting point	169 °C (336 °F)
	SMILES Nc1ccc(cc1)S(=O)(=O)Nc2cc(c)on2 ;
	InChI InChI=1S/C10H11N3O3S/c1-7-6-10(12-16-7)13-17(14,15)9-4-2-8(11)3-5-9/h2-6H,11H2,1H3,(H,12,13) ; Key:JLKIGFTWXXRPMT-UHFFFAOYSA-N ;
(verify)

　　[★]

☆case33　頭痛と混乱

■glossary

accompany

vt.

(人)と同行する、(人)に随行する。(もの)に付随する。～と同時に起こる。～に加える(添える、同封する)(with)

slurred n. 不明瞭

強直間代痙攣 tonic-clonic convulsion

　意識消失とともに全身の随意筋に強直痙攣が生じ(強直痙攣期tonic convulsion)、次いで全身の筋の強直と弛緩とが律動的に繰り返される時期(間代痙攣期clonic convulsion)を経て、発作後もうろう状態を呈する一連の発作。

■症例

28歳、女性　黒人　南アフリカ　手術室看護師　ロンドン住在

主訴：頭痛と混乱

現病歴：過去3週間で頭痛が続いており、ひどくなってきた。現在も頭痛が持続しており、頭全体が痛い。友人曰く「過去六ヶ月で体重が10kg減っていて、最近、混乱してきたようだ」。発話は不明瞭。救急室にいる間に強直間代痙攣を起こした。

・診察 examination

やせている。55kg。38.5℃。口腔カンジダ症(oral candidiasis)。リンパ節腫脹無し。心血管、呼吸器系、消化器系正常。痙攣前における神経検査では時間、場所、人の見当識無し。神経局所症状無し(no focal neurological sign)。眼底両側に乳頭浮腫有り。

・検査 investigation

血算：白血球増多

血液生化学：ナトリウム低下

CT：供覧

■キーワード＆着目するポイント

・口腔カンジダ症(oral candidiasis)

・頭痛、精神症状、強直間代痙攣

・眼底両側に乳頭浮腫

・CT 所見

・低ナトリウム血症は二次的なもの

■アプローチ

・口腔カンジダ症(oral candidiasis)　→　細胞免疫低下状態(DM、免疫抑制、AIDSなど) or 常在細菌叢の攪乱(長期の抗菌薬の使用)

　・The occurrence of thrush in a young, otherwise healthy-appearing person should prompt an investigation for underlying HIV infection.(HIM.1254)

　・More commonly, thrush is seen as a nonspecific manifestation of severe debilitating illness.(HIM.1254)

・精神症状、強直間代痙攣　→　一次的、あるいは二次的な脳の疾患がありそう

・頭痛　→　漠然としていて絞れないが、他の症状からして機能性頭痛ではなく症候性頭痛っぽい。

・眼底両側に乳頭浮腫　→　脳圧亢進の徴候　→　原因は・・・脳腫瘍、ことにテント下腫瘍と側頭葉の腫瘍、クモ膜下出血、脳水腫など、そのほか、眼窩内病変、低眼圧などの局所的要因、悪性高血圧、血液疾患、大量出血、肺気腫などの全身的要因 (vindicate本のp342も参考になる)

　・頭痛と脳圧亢進　→　頭蓋内圧占拠性病変、脳炎(IMD.274)

・CT 所見　→　ringformの病変、脳浮腫、脳圧亢進

・低ナトリウム血症　→　脳ヘルニアに続発して起こることがあるらしい。実際には下垂体にトキソプラズマによる病変が形成されることにより起こりうる。

・そのほか出身地、体重減少もHIVを疑わせる点

パターン認識でHIV + 精神症状 + てんかん発作(強直間代痙攣) + 脳圧亢進 + CT 所見 = 一番ありそうなのはToxoplasma gondiiによるトキソプラズマ脳症 cerebral toxoplasosis (トキソプラズマ脳炎 toxoplasmic encephalitis)

■Toxoplasma gondii

　原虫　胞子原虫類

(感染予防学 080521のプリント、CASES p,92、HIM p.1305-)

・疫学：西洋では30-80%の成人がトキソプラズマの感染の既往がある・・・うぇ(CASES)。日本では10%前後(Wikipedia)。

・生活環

　・終宿主：ネコ：ネコの小腸上皮細胞で有性・無性生殖　糞便にオーシストの排泄

　・中間宿主：ヒト.ブタを含むほ乳類と鳥類：無性生殖で増殖、シストの形成

　　　急性期の増殖盛んな急増虫体 tachyzoiteとシスト内の緩増虫体 bradyzoite

・病原、病因 phathogenesis

　・緩増虫体(bradyzoite)、接合子嚢(oocyst)

・感染経路

　1. オーシストの経口摂取

　2. 中間宿主の生肉中のシストの経口摂取

　3. 初感染妊婦からの経胎盤感染。既感染なら胎盤感染しないらしい(HIM.1306)

　(4)移植臓器、輸血。確率は低い(at low rate)(HIM.1306)

・病態

　1. 先天性トキソプラズマ症　congenital toxoplasmosis

　　　①網脈絡膜炎、 ②水頭症、 ③脳内石灰化、 ④精神・運動障害

　2. 後天性トキソプラズマ症　acquired toxoplasmosis

　　(1) 健常者

　　　・多くは不顕性感染。発熱、リンパ節腫脹、皮疹(rash)

　　　・(少数例)筋肉痛、暈疼痛、腹痛、斑状丘疹状皮疹(maculopapular rash)、脳脊髄炎、混乱(HIM.1308)

　　　・(まれ)肺炎、心筋炎、脳症、心膜炎、多発筋炎

　　　・網膜、脈絡叢に瘢痕や、脳に小さい炎症性の病変を残すことあり(CASES)。

　　　・急性感染の症状は数週間で消失　筋肉や中枢神経系に緩増虫体が残存

　　(2)HIV 感染者、臓器移植例、がん化学療法例

　　　シスト内緩増虫体→急増虫体→播種性の多臓器感染

　　　AIDSでは、トキソプラズマ性脳炎が指標疾患 AIDS-defineing illness(CASES)

・治療

　(日本)アセチルスピラマイシン、ファンシダール(感染予防学 080521)

■トキソプラズマ脳炎 toxoplasmic encephalitis、トキソプラズマ脳症 cerebral toxoplasosis

・症状

　発熱、頭痛、混乱ｍ、痙攣、認知の障害、局所神経徴候(不全片麻痺、歯垢、脳神経損傷、視野欠損、感覚喪失)(CASES)

・画像検査

　(CT,MRI)多発性、両側性、ring-enhancing lesion、特に灰白質-白質境界、大脳基底核、脳幹、小脳が冒されやすい(CASES)

・鑑別診断(臨床症状・画像診断の所見で)

　リンパ腫、結核、転移性脳腫瘍(CASES)

・病歴と画像所見からの鑑別診断

　リンパ腫、結核、転移性腫瘍

？

このCTがcerebral toxoplasmosisに特徴的かは不明

□最後に残る疑問

　AIDSでWBC(leukocyte)の数はどうなるんだろう？？？AIDSの初診患者ではWBCが低い人が多いらしいし()、HIVはCD4+ T cellとmacrophageに感染して殺すから、これによってB cellは減るだろうし、CD8+ T cellも若干減少するだろうからWBCは減るんじゃないか？！好中球はAIDSとは関係ない？好中球は他の感染症に反応性に増加している？ちなみに、好酸球は寄生虫(原虫)の感染のために増える傾向にあるらしい(HIMのどこか)。

葉酸拮抗剤である。

サルファ剤と併用され、抗トキソプラズマ薬、抗ニューモシチス・カリニ薬として相乗的に働く。

ST 合剤

SMX-TMP

スルファメトキサゾール・トリメトプリム合剤 sulfamethoxazole and trimethoprim mixture

□AIDSの定義(http://en.wikipedia.org/wiki/CDC_Classification_System_for_HIV_Infection_in_Adults_and_Adolescents)